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To describe multiple faces of necrobiotic granulomas of skin
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NON-INFECTIOUSampNECROBIOTIC GRANULOMATOUS DISEASES OF THE SKIN
MYABDEL-MAWLA
Granulomatous reactions in the skin develop as an immune system response to an antigen in which epithelioid macrophages and various inflammatory and immune cells congregate often surrounded by fibrosis or a lymphocyte cuff
They are classified as infectious or non-infectious
There is a poor understanding of the inciting antigen which may range from infectious (including live or dead microorganisms) to drugs (andor their metabolites) or result from innate host pathology (eg connective tissue disease vasculitis or cancerous antigens)
it is important to acknowledge the proposed role for infection in the etiology of several of these conditions that are regarded as non-infectious granulomatous disorders such as a slow-growing infection a post-infectious immunologic response or presentation of granulomatous disease in the setting of infection
ldquo
rdquo
NON-INFECTIOUS GRANULOMATOUS DISORDERS ENCOMPASS A CHALLENGING GROUP OF DISEASES BOTH IN TERMS OF THEIR DIAGNOSIS AND IN COUNSELING PATIENTS REGARDING THEIR PROGNOSIS IN ADDITION TO THE POSSIBLE SYSTEMIC CO-MORBIDITIES THEY MAY SUBSEQUENTLY ENCOUNTER AN IMPORTANT SOURCE OF THIS CHALLENGE IS THE CLINICAL AND HISTOLOGIC OVERLAP AMONG THESE CONDITIONS (ALONG WITH THE POTENTIAL FOR MISDIAGNOSIS DUE TO THIS OVERLAP)
NECROBIOSIS IS DEFINED AS THE PHYSIOLOGICAL DEATH OF A CELL IT IS ASSOCIATED WITH ALTERATION OF COLLAGEN AND OR ELASTIC FIBRESIT IS IDENTIFIED BOTH WITH AND WITHOUT NECROSIS (PATHOLOGIC DEATH)IT IS ASSOCIATED WITH NECROBIOSIS LIPOIDICA AND GRANULOMA ANNULARE
NECROBIOSIS
Necrobiosis refers to the degeneration of collagen fibres
Although this is easily noted in most necrobiotic dermatitides it can be very subtle at times or even absent depending on the necrobiotic entity and the timing of the biopsy
STAINS HELPHUL IN NECROBIOSIS
It is advisable to obtain three HampE levels and colloidal iron (Halersquos stain for mucin) Elastochrome (elastic trichrome) could also be helpful in
examining the vascular component of the lesion Special stains in granulomatous skin diseases including
necrobiotic dermatitides to try to visualize any possible infectious agent
These stains include periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) for fungal organisms Zeil-Neilson (ZN) stain for acid-fast bacilli and Warthin-Starry silver stain for spirochetes
ACCUMULATION OF BASOPHILIC FIBERS IN DERMIS REFERRED TO AS BASOPHILIC DEGENERATION
BASOPHILIC DEGENERATION
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Granulomatous reactions in the skin develop as an immune system response to an antigen in which epithelioid macrophages and various inflammatory and immune cells congregate often surrounded by fibrosis or a lymphocyte cuff
They are classified as infectious or non-infectious
There is a poor understanding of the inciting antigen which may range from infectious (including live or dead microorganisms) to drugs (andor their metabolites) or result from innate host pathology (eg connective tissue disease vasculitis or cancerous antigens)
it is important to acknowledge the proposed role for infection in the etiology of several of these conditions that are regarded as non-infectious granulomatous disorders such as a slow-growing infection a post-infectious immunologic response or presentation of granulomatous disease in the setting of infection
ldquo
rdquo
NON-INFECTIOUS GRANULOMATOUS DISORDERS ENCOMPASS A CHALLENGING GROUP OF DISEASES BOTH IN TERMS OF THEIR DIAGNOSIS AND IN COUNSELING PATIENTS REGARDING THEIR PROGNOSIS IN ADDITION TO THE POSSIBLE SYSTEMIC CO-MORBIDITIES THEY MAY SUBSEQUENTLY ENCOUNTER AN IMPORTANT SOURCE OF THIS CHALLENGE IS THE CLINICAL AND HISTOLOGIC OVERLAP AMONG THESE CONDITIONS (ALONG WITH THE POTENTIAL FOR MISDIAGNOSIS DUE TO THIS OVERLAP)
NECROBIOSIS IS DEFINED AS THE PHYSIOLOGICAL DEATH OF A CELL IT IS ASSOCIATED WITH ALTERATION OF COLLAGEN AND OR ELASTIC FIBRESIT IS IDENTIFIED BOTH WITH AND WITHOUT NECROSIS (PATHOLOGIC DEATH)IT IS ASSOCIATED WITH NECROBIOSIS LIPOIDICA AND GRANULOMA ANNULARE
NECROBIOSIS
Necrobiosis refers to the degeneration of collagen fibres
Although this is easily noted in most necrobiotic dermatitides it can be very subtle at times or even absent depending on the necrobiotic entity and the timing of the biopsy
STAINS HELPHUL IN NECROBIOSIS
It is advisable to obtain three HampE levels and colloidal iron (Halersquos stain for mucin) Elastochrome (elastic trichrome) could also be helpful in
examining the vascular component of the lesion Special stains in granulomatous skin diseases including
necrobiotic dermatitides to try to visualize any possible infectious agent
These stains include periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) for fungal organisms Zeil-Neilson (ZN) stain for acid-fast bacilli and Warthin-Starry silver stain for spirochetes
ACCUMULATION OF BASOPHILIC FIBERS IN DERMIS REFERRED TO AS BASOPHILIC DEGENERATION
BASOPHILIC DEGENERATION
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
ldquo
rdquo
NON-INFECTIOUS GRANULOMATOUS DISORDERS ENCOMPASS A CHALLENGING GROUP OF DISEASES BOTH IN TERMS OF THEIR DIAGNOSIS AND IN COUNSELING PATIENTS REGARDING THEIR PROGNOSIS IN ADDITION TO THE POSSIBLE SYSTEMIC CO-MORBIDITIES THEY MAY SUBSEQUENTLY ENCOUNTER AN IMPORTANT SOURCE OF THIS CHALLENGE IS THE CLINICAL AND HISTOLOGIC OVERLAP AMONG THESE CONDITIONS (ALONG WITH THE POTENTIAL FOR MISDIAGNOSIS DUE TO THIS OVERLAP)
NECROBIOSIS IS DEFINED AS THE PHYSIOLOGICAL DEATH OF A CELL IT IS ASSOCIATED WITH ALTERATION OF COLLAGEN AND OR ELASTIC FIBRESIT IS IDENTIFIED BOTH WITH AND WITHOUT NECROSIS (PATHOLOGIC DEATH)IT IS ASSOCIATED WITH NECROBIOSIS LIPOIDICA AND GRANULOMA ANNULARE
NECROBIOSIS
Necrobiosis refers to the degeneration of collagen fibres
Although this is easily noted in most necrobiotic dermatitides it can be very subtle at times or even absent depending on the necrobiotic entity and the timing of the biopsy
STAINS HELPHUL IN NECROBIOSIS
It is advisable to obtain three HampE levels and colloidal iron (Halersquos stain for mucin) Elastochrome (elastic trichrome) could also be helpful in
examining the vascular component of the lesion Special stains in granulomatous skin diseases including
necrobiotic dermatitides to try to visualize any possible infectious agent
These stains include periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) for fungal organisms Zeil-Neilson (ZN) stain for acid-fast bacilli and Warthin-Starry silver stain for spirochetes
ACCUMULATION OF BASOPHILIC FIBERS IN DERMIS REFERRED TO AS BASOPHILIC DEGENERATION
BASOPHILIC DEGENERATION
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
NECROBIOSIS IS DEFINED AS THE PHYSIOLOGICAL DEATH OF A CELL IT IS ASSOCIATED WITH ALTERATION OF COLLAGEN AND OR ELASTIC FIBRESIT IS IDENTIFIED BOTH WITH AND WITHOUT NECROSIS (PATHOLOGIC DEATH)IT IS ASSOCIATED WITH NECROBIOSIS LIPOIDICA AND GRANULOMA ANNULARE
NECROBIOSIS
Necrobiosis refers to the degeneration of collagen fibres
Although this is easily noted in most necrobiotic dermatitides it can be very subtle at times or even absent depending on the necrobiotic entity and the timing of the biopsy
STAINS HELPHUL IN NECROBIOSIS
It is advisable to obtain three HampE levels and colloidal iron (Halersquos stain for mucin) Elastochrome (elastic trichrome) could also be helpful in
examining the vascular component of the lesion Special stains in granulomatous skin diseases including
necrobiotic dermatitides to try to visualize any possible infectious agent
These stains include periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) for fungal organisms Zeil-Neilson (ZN) stain for acid-fast bacilli and Warthin-Starry silver stain for spirochetes
ACCUMULATION OF BASOPHILIC FIBERS IN DERMIS REFERRED TO AS BASOPHILIC DEGENERATION
BASOPHILIC DEGENERATION
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
NECROBIOSIS
Necrobiosis refers to the degeneration of collagen fibres
Although this is easily noted in most necrobiotic dermatitides it can be very subtle at times or even absent depending on the necrobiotic entity and the timing of the biopsy
STAINS HELPHUL IN NECROBIOSIS
It is advisable to obtain three HampE levels and colloidal iron (Halersquos stain for mucin) Elastochrome (elastic trichrome) could also be helpful in
examining the vascular component of the lesion Special stains in granulomatous skin diseases including
necrobiotic dermatitides to try to visualize any possible infectious agent
These stains include periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) for fungal organisms Zeil-Neilson (ZN) stain for acid-fast bacilli and Warthin-Starry silver stain for spirochetes
ACCUMULATION OF BASOPHILIC FIBERS IN DERMIS REFERRED TO AS BASOPHILIC DEGENERATION
BASOPHILIC DEGENERATION
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
STAINS HELPHUL IN NECROBIOSIS
It is advisable to obtain three HampE levels and colloidal iron (Halersquos stain for mucin) Elastochrome (elastic trichrome) could also be helpful in
examining the vascular component of the lesion Special stains in granulomatous skin diseases including
necrobiotic dermatitides to try to visualize any possible infectious agent
These stains include periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) for fungal organisms Zeil-Neilson (ZN) stain for acid-fast bacilli and Warthin-Starry silver stain for spirochetes
ACCUMULATION OF BASOPHILIC FIBERS IN DERMIS REFERRED TO AS BASOPHILIC DEGENERATION
BASOPHILIC DEGENERATION
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
ACCUMULATION OF BASOPHILIC FIBERS IN DERMIS REFERRED TO AS BASOPHILIC DEGENERATION
BASOPHILIC DEGENERATION
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
1 DEGENERATIVE CHANGE IN ELASTIC TISSUE2 DEGENERATION OF COLLAGEN FIBERS WITH ALTERED STAINING PROPERTIES RESEMBLING ELASTIC TISSUE3-FORMATION BY FIBROBLAST-ACTIVATED ULTRAVIOLET OR MAST CELL MEDIATORS OF ABNORMAL FIBRES
ELASTOTIC DEGENERATIONelastoid degeneration
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
ELASTOTIC DEGENERATION(SYNONYM ELASTOID DEGENERATION
First of all either collagen fibres split into microfibrils and granular material with subsequent appearance of the amorphous mass
Amorphous mass is formed directly through the gradual loss of the matrix and membrane with subsequent confluence into future elastotic fibres At the amorphous stage optically denser material appearsThese are acquiring elastic stain properties
The elastic fibres were also often altered When amorphous their smaller size was helpful in distinguishing them from similarly altered collagen bundles
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities
Many of these disorders have significant associations with systemic diseases that impact the patients overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease
1 granuloma annulare
2 annular elastolytic giant cell granuloma
3 necrobiosis lipoidica
4 methotrexate induced accelerated rheumatoid nodulosis
5 necrobiotic xanthogranuloma
6 interstitial granulomatous dermatitis
7 interstitial granulomatous drug reaction
8 palisaded neutrophilic granulomatous dermatitis
9 sarcoidosis
10 metastatic Crohn disease
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
BLUE VS RED COLLAGENOLYTIC NECROBIOTIC GRANULOMAS
A collagenolytic or necrobiotic non-infectious granuloma is one in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers
The altered fibers lose their distinct boundaries and exhibit new staining patterns becoming either more basophilic or eosinophilic
Within the area of altered collagen there may be deposition of acellular substances such as mucin (blue) or fibrin (red) or there may be neutrophils with nuclear dust (blue) eosinophils (red) or flame figures (red)
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
BLUE CPLLAGENOLYTIC NECROBIOTIC GRANULOMAS
These are the lesions of granuloma annulare Wegenerrsquos granulomatosis and rheumatoid vasculitis
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
ETIOLOGY
Human macrophage metalloelastases have been found in these lesions and may aid in the macrophage migration to these lesions
The activated histiocytes can surround the altered dermis in a palisading manner potentially cordoning off harmful products of the inflammatory process such as immune complexes
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
WHY ARE THEY BLUE
A non-infectious granuloma can be centrally basophilic either due to mucin deposition or due to the presence of neutrophilsnuclear dust
If increased interstitial mucin is responsible for the blue color as confirmed by either an Alcian blue or colloidal iron stain one should consider the diagnosis of granuloma annulare (GA)
If the basophilia of the central zone is due to the presence of neutrophilsnuclear dusteitherWegenerrsquos granulomatosis (WG) or rheumatoid vasculitis enters the differential
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
THE lsquoREDrsquo COLLAGENOLYTIC GRANULOMAS
The lesions of necrobiosis lipoidica necrobiotic xanthogranuloma rheumatoid nodules ChurgndashStrauss syndrome and eosinophilic cellulitis (Wellrsquos syndrome)
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
REDrsquo COLLAGENOLYTIC GRANULOMASWHY ARE THEY RED
Eosinophilic staining of the necrobiotic area within a non-infectious granuloma can be due to hyalinized collagen fibrin deposition or degranulated eosinophils
If the collagen is hyalinized the differential diagnosis of necrobiosis lipoidica (NL) vs necrobiotic xanthogranuloma (NXG) exists
If the red color is due to fibrin deposition then a rheumatoid nodule (RN) should be considered
If degranulated eosinophils are responsible for the color then the lesions of Churgndash Strauss syndrome (CSS) vs eosinophilic cellulitis (EC) (Wellrsquos syndrome) should be considered
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
FEATURES OF NECROBIOTIC GRANULOMAS IN THE DERMIS
- Located in the superficial and mid dermis- Areas of necrobiosis surrounded by peripheral rim of histiocytes and lymphocytes- Multinucleated giant cells (+-) - Intervening areas of dermis between the necrobiotic granulomas is normal- Central necrobiotic area contains abundant connective tissue mucins which is lightly basophilic in apperance Mucin stains (Colloidal iron and alcian blue) are useful- Small amounts of fibrin may be present as fibrillary eosinophilic material- Perivascular infiltrate of lymphocytes in superficial amp mid dermis- Neutrophils and nuclear dusts are present in some cases- Vasculitis may be present near foci of necrobiosis
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Click icon to add picture
Granulomas
A) Tuberculoid granuloma
(B) Sarcoidal granuloma
(C) Palisaded granuloma
(D) Caseation necrosis within a granuloma
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
GRANULOMA ANNULARE
1 GA is a benign inflammatory condition that often presents with a ring of multiple small erythematous or flesh-colored firm papules on the dorsal surface of the hands andor feet
2 Classified according to lesion morphology into subgroups
bull localized macular or patch and atypical (consisting of perforating subcutaneous disseminated palmar photodistributed or generalized forms)
bull Lesions are generally non-pruritic and self-limited often resolving without treatment within 2 years though a variety of treatments have been attempted
bull A clinically similar non-infectious granulomatous disease is annular elastolytic giant cell granuloma (AEGCG) which is often regarded as GA in sun-exposed areas
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Granuloma annulare is a common form of dermatosis in children and young adults Lesions are typically found on the hands the feet and the extensor surfaces of the limbs and occasionally on the trunk We report a case original in terms of its palpebral localization
CASE-REPORT A 5 year-old girl consulted for papular lesions on the eyelids The clinical examination revealed papules on the right lower eyelid measuring 8 mm on the left lower eyelid measuring 5 mm and on the right upper eyelid measuring 3 mm Laboratory tests including serum glucose lipids and calcium as well as a complete blood count proved normal Biopsy showed granulomatous lesions a region of central necrosis surrounded by a palisade of inflammatory cells confirmed the diagnosis of granuloma annulare The lesions disappeared in a few weeks without treatment
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Histopathologic features OF GRANULOMA ANNULARE1 ldquoInterstitial GArdquo -May be early changes in other types of GA -Lymphocytes around small vessels histiocytes between collagen bundles -Interstitial mucin (Alcian blue colloidal iron positive pH 25) in areas of
histiocytes
`Differential diagnoses Morphea reticular erythematous mucinosis (REM) interstitial pattern of mycosis fungoides
1 bull Palisaded GA -Superficial and deep perivascular lymphocytic infiltrates -Interstitial histiocytes -Rings of histiocytes surrounding degenerating (and regenerating collagen)
and mucin -A few neutrophils and some dust around necrotic venules in the centers of
granulomas (rare)
-Elastic tissue absent from centers of granulomatous foci
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Differential diagnosis Necrobiosis lipoidica rheumatoid nodule palisaded neutrophilic and granulomatous dermatitis others
3-bull Deep GA -Large oval mass of histiocytes surrounding less cellular area -Degenerating collagen and mucin in the center but more
brightly eosinophlic than in conventional palisaded granuloma annulare
Differential diagnosis Rheumatoid nodule phaeohyphomycotic cyst
4-bull Actinic GA -Palisaded histiocytes around fibrosis -Giant cells commonly present -Elastotic material in cytoplasm of giant cells
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Granuloma annulare
(A) Pink papules annularly arranged
B) and (C) Palisaded granulomas with mucin in the center
D) colloidal iron stain highlighting increased mucin
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
ANNULAR ELASTOLYTIC GIANT CELL GRANULOMA (AEGCG)
A GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to actinic injury
While the clinical features of AEGCG and GA are similar and these conditions are often treated with the same approach they are histologically distinct
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic tissue
Additionally AEGCG lesions do not show necrobiosis and palisading granuloma
An association of AEGCG with malignancy (eg T-cell leukemia)
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Click icon to add picture
PATCHY GRANULOMATOUS INFILTRATE IN RETICULAR DRMIS
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Gimesa statin showing consumption of elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Hematoxylin-eosin stain (original magnification
times550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis Note made of
the multinucleated giant cells
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Hematoxylin-eosin stain (original magnification times550) showing degenerated elastin and multinucleated giant cells
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Well-defined infiltrated plaque over forearm Atrophic scarring can be appreciated at places
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition but one that is important to recognize as it can maim patients and some patients have died of its complications
Its name refers to its infiltrates of foamy histiocytes zones of necrobiosis (degenerating and regenerating collagen) and frequent paraproteinemia Despite the paraprotein and the rare eventuation of myeloma in patients with NXG it seems to be an inflammatory and not a neoplastic condition
Age Middle-aged or elderly patients Clinical presentation Lesion presents as reddish partly xanthomatous nodules or
plaques These are usually located around the periorbital area Other sites include extremities amp trunk
Frequently associated with paraproteinemia and lymphoproliferative diseases
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
NECROBIOTIC XANTHOGRANULOMA Clinical features
bull Yellow plaques on limbs with perioccularperiorbital lesions in most patients
bull Progression of lesions in some patients
bull Hyperlipidemiahypercholesterolemia
bull Many patients diabetic
bull Serum paraprotein (usually IgG κ)
bull Loss of limbs or eye possible
Paraprotein levels play an important role in the pathogenesis of NXG because they might be autoantibodies that stimulate fibroblast proliferation and dermal macrophage deposition
The paraproteins cause a giant-cell inflammatory response after being complexed with lipids and deposited in skin
Activated monocytes accumulate lipids and are deposited in the skin thereby eliciting a giant-cell foreignbody response
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
HISTOPATHOLOGICAL FEATURES
Extensive areas of hyaline necrobiosis surrounded by a palisade of histiocytes amp multinucleated giant cells Large numbers of necrotic inflammatory cells in the reticular dermis Superficial and deep perivascular lymphoplasmacytic infiltrate Presence of foam cells multinucleated giant cells (Touton amp foreign body types) cholesterol clefts amp extracellular lipid Lymphoid follicles may be present Extensive areas of fat necrosis in the subcutaneous tissue
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
HISTOPATHOLOGIC FEATURES
bull Infiltrate mid- and deep dermis and both subcutaneous lobules and septa
bull Superficial and deep perivascular infiltrates of lymphocytes and plasma cells sometimes very dense
bull Lymphoid follicles
bull Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
bull Foamy histiocytes and Touton giant cells in subcutis (ldquoTouton cell panniculitisrdquo)
bull Giant cells with scalloped margins
bull Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
NECROBIOTIC XANTHOGRANULOMA
Histopathologymultiple giant cells including Tuton cells
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Successful IVIg treatment of paraproteinemiaassociated dermatoses such as scleromyxedema has been
IVIg showed a striking therapeutic effect on NXG Given the association of NXG with IgG-monoclonal gammopathy (more often IgG- than IgG-) and with multiple myeloma
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
NECROBIOTIC XANTHOGRANULOMA VS NECROBIOSIS LIPODICA
NXG is often mistaken for NLD as both can present as yellow plaques on the limbs of diabetic patients
Cholesterol clefts surrounded by foamy histiocytes are practically pathognomomonic of the condition(NXG)
Cholesterol clefts were present in specimens of NLD in one study but not surrounded by foamy macrophages and Touton giant cells
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
NECROBIOSIS LIPODICA
Necrobiosis lipoidica (NL) originally known as necrobiosis lipoidica diabeticorum is a disorder of collagen degeneration with a granulomatous response and thickening of blood vesselsDiabetes mellitus is present in more than half the patients with necrobiosis lipoidica
Age amp sex Average age of onset is 30 years (may occur at any age) and females are commonly affected
Site Most cases are located on the leg specially above the tibiae but may also occur on the face scalp forearm and trunk
Clinical presentation Lesions may be single but multiple lesions are more common NL may present as red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and slightly depressed centerThe lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate Clinical features-
bull Most lesions bilaterally on shins
bull Early lesions are red papules with sharp borders
bull Later yellow hard atrophic plaques
bull 60 have frank diabetes another 20 abnormal glucose tolerance o
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
HISTOPATHOLOGICAL FEATURES Necrobiotic granuloma and inflammatory infiltrate Full thickness of the dermis is involved with extension into the subcutis The inflammatory cells are composed of histiocytes lymphocytes plasma cells and occasional eosinophils are arranged in two or three
tiers These are aligned parallel to the skin surface There are several layers of necrobiosis within the reticular dermis Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans
or foreign body giant cells The necrobiosis is irregular and less complete than in granuloma annulare ( Note Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration Late lesions show crowded and
thickened collagen bundles ) The intervening areas of the dermis are also abnormal
Lymphoid cell aggregates with germinal centers may be present Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with
granulomatous inflammation) Vascular changes Vascular changes are more prominent in diabetic patients Superficial and deep perivascular inflammatory infiltrate Plasma cells are conspicuous Superficiall vessels are telangiectatic amp increased in number Deeper vessels may show endothelial swelling Lymphocytic vasculitis may be present Epithelioid granulomas within or adjacent to the vessel wall Other features
Intradermal nerves are reduced in number Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain Stains for mucin (colloidal iron or alcian blue) are usually negative
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS (PNGD
A disease spectrum described in patients with systemic diseases of various kinds
Terms such as rheumatoid papules Churg-Strauss granuloma extravascular necrotizing granuloma and Winkelmann granuloma also refer to this condition
The main clinical presentation is of small umbilicated papules on the dorsal aspects of joints esp those of the fingers elbows and knees
The range of systemic diseases in patients with PNGD includes patients with
1048707 Systemic lupus erythematosus
1048707 Rheumatoid arthritis (incl seronegative cases)
1048707 Wegenerrsquos granulomatosis
1048707 Lymphomaleukemia
1048707 Inflammatory bowel disease
1048707 Systemic
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
PALISADED NEUTROPHILIC AND GRANULOMATOUS DERMATITIS
The salient histopathologic features differ for each stage of PNGD
Early
1048707 Fibrin around vessel walls
1048707 Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed
1048707 Palisaded histiocytes around neutrophils and their debris
1048707 Thick but discolored collagen bundles
1048707 Evidence of vasculitis sometimes
Late
1048707 Palisaded histiocytes around zones of fibrosis with few neutrophils
1048707 No vasculitis
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
HISTOPATHOLOGICAL FEATURES
Early lesions have increased dermal spindle cells
Increased mucin with thin elastic fibres
Later lesions have more epithelioid or stellate cells that may extend into septa in subcutaneous fat
Thick collagen bundles
The spindle cells are fibrocytes that are positive immunohistochemically with both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUSDERMATITIS THERE IS A PALISADE OF HISTIOCYTES AROUND CENTRAL FOCUS OF NECROTIC COLLAGEN
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
Late palisaded neutrophilic and granulomatous dermatitisinterstitial granulomatous dermatitis wit arthritis The central necrosis has disappeared to leave a diffuse granulomatous dermatitis In contrast to granuloma annulare there are neutrophils no collections of mucin and the process is diffuse
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
ldquoINTERSTITIAL GRANULOMATOUS DRUG ERUPTION
large interstitial histiocytes and a more subtle palisaded pattern It presents with dusky erythema in flexural areas There are small foci in which degenerated neutrophils andor eosinophils are present
Palisaded foci surrounding degenerated neutrophils and eosinophils are not yet reported but histiocytes form rosettes that surround and adhere to thick collagen bundles demarcated from the rest of the dermis by clefts
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
PALISADED GRANULOMATOUS REACTIONS TO FOREIGN MATERIAL
Histiocytes can be radially arranged around a variety of foreign substances including suture material beryllium and injectable (bovine) collagen
The mechanism by which the dermis is altered in some of these reactions is unclear
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
RHEUMATOID NODULE(RN)
Clinical features
bull Symmetrical papules and nodules
bull Usually subcutaneous sometimes fixed to tendons
bull Skin color unchanged sometimes yellow (simulating xanthomas)
bull Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
bull Large oval mass in deep dermissubcutis
bull Palisaded histiocytes surrounding degenerated collagen large amounts of fibrin neutrophils and nuclear dust
bull Mucin scant or absent
bull Vasculitis in adjacent vessels rarely
The vast majority of diagnoses of RN in well children are misdiagnoses of deep GA
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
WEGENERrsquoS GRANULOMATOSIS(WG)
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis nasal crusting and bleeding
Gingivitis called lsquostrawberry gumsrsquo
Accompanied by a slow loss of nasal cartilage leading to the lsquosaddle nosersquo deformity
A fulminant process with acute respiratory symptoms often with alveolar hemorrhage
Cardiac involvement with necrotizing coronary vasculitis and pancarditis
Constitutional symptoms including fever weight loss anorexia and arthralgia as well as cough
The most common cutaneousWGlesions are clinically
1 papulonecrotic lesions or palpable purpura
2 usually on the extremities
3 Less common lesions include vesicles petechiae subcutaneous nodules and frank ulcerations with thrombosis and necrosis
An acneiform presentation has been reported in childrenchest and pain
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
HISTOPATHOLOGIC PATTERNS OF WEGNER GRANULOMATOSIS
The most common histologic pattern seen within WG lesions of the skin is that of a necrotizing vasculitis
Palisading necrotizing granuloma Focal necrobiosis with peripheral palisading
Granulomatous vasculitis No mucinfibrin Lymphomatoid granulomatosis-like
patternvasculitis infiltrated with atypical lymphocytes but not true lymphoma
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
RHEUMATOID NODULE
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
RHEUMATOID NODULE
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
RHEUMATOID VASCULITIS
Palisading granuloma due to
leukocytoclastic
vasculitis
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
CHURGndashSTRAUSS SYNDROME It has three distinct phases The first clinical phase of CSS is the prodromal
or allergic
phaseasthma which may or not be preceded by allergic rhinitis Nasal obstruction recurrent sinusitis and nasal polyposis frequently develop
The second clinical phase of CSS features marked peripheral eosinophilia and eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic gastroenteritis)Abdominal pain is common and may reflect bowel perforation peritonitis intestinal obstruction mesenteric vasculitis or cholecystitis
The third phase of CSS development can include a neuropathy
skin lesion(ChurgndashStrauss granuloma)a papule or subcutaneous noduleerythematous orviolacious and are often symmetrically distributed
They are persistent and tender often become crusted or ulcerated and resolve with scarring within 2ndash3months These lesions usually occur on the extremitiesand scalp and less commonly on the trunk with the most common sites located over pressure points especially the elbows fingers and thumbs
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
CHURGndashSTRAUSS GRANULOMA
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
HISTOPATHOLOGY
The palisading ChurgndashStrauss granuloma consists of leukocytoclastic vasculitis and degeneration of the surrounding collagen with an extravascular palisading granulomatous reaction consisting of mononuclear cells macrophages and eosinophils around the necrobiotic collagen
The degenerated collagen becomes admixed with polymorphonuclear leukocytes and leukocytoclastic debris
The palisading granulomatous infiltrate probably develops due to an influx of eosinophils which degranulate and develop pyknotic fragmented nuclei
fibrinoid swelling and increased degeneration of the collagen fibers with the eventual destruction of the fibers
Macrophages infiltrate the area palisading around the central necrotic core and Langhans or foreign body-type giant cells appear
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
CHURGndashSTRAUSS GRANULOMA
Palisading granulomatous infiltrate surrounding degenerated collagen
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
EOSINOPHILIC CELLULITIS (WELLrsquoS SYNDROME)
Patients can become febrile and develop peripheral eosinophilia
typically erupts suddenly as single or multiple edematous erythematous well-defined annular plaques on a limb that often initially appear urticarial
lesions include papules vesicles poorly demarcated erythematous plaques or nodules
The subsequent edema may become so severe as to generate bullae Although the affected area clinically resembles a bacterial cellulitis the skin is cool to the touch
As the acute edema and erythema subsides the affected area becomes indurated and acquires a bluish or greenish gray color clinically resembling morphea
The cause a hypersensitivity reaction to some triggering event including insect bites fungal infections herpes simplex virus flaresunderlying hematologic disorders oxocara canis infections or drug hypersensitivities
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
HISTOPATHOLOGY The biopsy of a newly developing EC lesion shows a
papillary dermis that is markedly edematous with overlying spongiosis and intraepidermal spongiotic vesicles
The dermis is heavily infiltrated with eosinophils As the lesion develops eosinophils degranulate and then
degenerate Fragments of the degenerated eosinophils and their expelled granules are deposited onto the surrounding collagen fibers producing lsquoflame figuresrsquo
Older lesions show a granulomatous infiltrate comprised of large histiocytes and giant cells that surround the flame figures
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
EARLY PHASES OF WELLS DISEASE
Eosinophilic cellulitis early edema and eosinophilic infiltrate
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
LATE PHASE OF WELLS DISEASE
Eosinophilic cellulitis late granulomatous infiltrate around degenerated collagen and eosinophilic granules
THANK YOU
THANK YOU
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