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Nonneoplastic Skin Diseases

1. Anatomical hints:- Functions: Skin is not only a passive protective barrier, but a complex organ with many functions:

● Protects deeper tissues from injury, drying and invasion of microorganisms (through production of protective keratin layer and presence of immune cells like Langerhans cells and T lymphocytes).

● Keratinocytes are sites for the biosynthesis of soluble molecules (cytokines) that regulate adjacent epidermal cells as well as cells in the dermis.● Has important role in thermoregulation (through sweat glands).● Absorbs ultraviolet light (by melanin pigments).● Has cosmetic function● Metabolizes vitamin D● Contains peripheral endings of sensory nerves (warn of potentially damaging physical factors in the environment).

- Histology: Skin is composed of three main components (epidermis & skin adnexa, melanocytic system, and dermis & subcutis).

E p i d e r m i s

● Epidermis is outer layer of skin● Epidermis forms outer layer of keratin that is protective and waterproof.● Epidermis is composed of stratified squamous epithelium (keratinocytes) in 4 layers: inner basal, squamous, granular and outer cornified.● Other cells present include melanocytes, Langerhans’ cells and Merkel cells.● Skin is thicker in palms and soles, which contain epidermal ridges that prevent slipping and form fingerprints and footprints.● Keratinization takes 30-45 days; alterations in pattern and speed cause dermatoses, hyperkeratosis or parakeratosis.● Dermoepidermal junction: thrown into undulating folds of interlocking ridges of epidermis (rete ridges) and dermal papillae.

Basal layeror Stratum basale

Squamous layeror Prickle layer

or Stratum spinosum

Granular layeror Stratum granulosum

Stratum lucidumCornified layeror Horny layer

or Stratum corneum

- Mitotically active, produces other keratinocytes. - Separated from dermis by continuous basal membrane (keratinocytes are attached to this membrane by hemi-desmosomes). - Also contains melanocytes.

- Has several layers of cells, larger than basal layer, which become flat and eosinophilic as they approach the surface (due to an increase in keratin and reduction in ribosomes). - May have clear vacuolated cytoplasm. - Cells are attached to each other by fine spiny bridges with central dot-like desmosomes (Bizzozero’s nodule).- Loss of these spiny bridges causes acantholysis.

- 1 to 3 layers of flattened cells with intensely basophilic keratohyaline granules.- These granules contain precursors of filaggrin protein, which causes aggregation of keratin filaments.

- Present only in soles and palms.- Located between granular and cornified layer. - Consist of several layers of dead cells, appear as homogenous eosinophilic zone.

- Basket weave pattern of multiple layers of polyhedral cells without nuclei. - Thicker and more compact in acral region (peripheral body-limbs, fingers, ears).

Langerhans cells Merkel cells Melanocytes

- Bone marrow derived dendritic cells that present antigens to T cells.- Scattered in upper squamous layer and in the dermis, but difficult to see on H&E.

- Mechanoreceptors concentrated in skin of digits, finger pads, palms, dorsum of feet, lips, hard palate.- Difficult to see with H&E or special stains.- contain neurosecretory granules in its cytoplasm (positive for NSE).

- Neural crest origin.- Seen in basal epidermis, hair follicles, most squamous mucous membranes, leptomeninges.- Produce melanin from tyrosine, transfer it (via cytoplasmic processes) to adjacent epithelial cells to protect against ultraviolet rays.- Racial skin color is due to amount of melanin in keratinocytes, not number of melanocytes.- Positive for: Fontana-Masson, tyrosinase, S100, MelanA, HMB45.- Negative for: GFAP, neurofilament.

Desmosomes (macula adherens) Hemidesmosomes

- Definition:They are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes. They are specialized for cell-to-cell adhesions and helpful to resist shearing forces.- Structure:(1) Desmosomes are molecular complexes of cell adhesion proteins (desmoglein and desmocollin), and linking proteins that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments.(2) Desmoglein and desmocollin (members of the cadherin family) are transmembrane proteins that bridge the space between adjacent epithelial cells by way of homophilic binding of their extracellular domains to other desmogleins and desmocollins on the adjacent cell.(3) On the cytoplasmic side of the plasma membrane, there are two dense structures (outer and inner dense Plaques), spanned by the Desmoplakin protein. The Outer Dense Plaque is where the cytoplasmic domains of the cadherins attach to desmoplakin (via plakoglobin and plakophillin). The Inner Dense Plaque is where desmoplakin attaches to intracellular keratin cytoskeletal filaments.

- Definition:Situated at the undersurface of basal keratinocytes, linking them to basement membrane.- Structure:(1) The hemidesmosome represent half desmosome.(2) The hemidesmosome might consist of two proteins: the BPAg1 protein (located at the intracellular side of the hemidesmosome, bind to keratin intermediate filaments), and the BPAg2 protein (transmembranous protein that contains an intracellular domain bonded to BPAg1, a transmembranous segment, and an extracellular domain that projects into the lamina lucida of basement membrane).(4) Other proteins that either form or stabilize hemidesmosomes are also present. For example intracellular plectin protein (that binds to keratin filaments) is bonded to a single-pass transmembrane adhesion molecule (α6β4 integrin). The integrin might then attach to one of many multi-adhesive proteins such as laminin & collageb VII (anchoring filaments & fibrils), that resident within the basement membrane.

S k i n A d n e x a e

Hair Sebaceous glands Sweat glands

- Most of the skin is haired although the hair in most areas is short, fine and only lightly pigmented. This type of hair is called vellus hair.- Truly hairless parts are: the palms and soles, the distal phalanges and sides of fingers and toes, and parts of the external genitalia.- The free part of each hair is called the shaft. The root of each hair is anchored in a tubular invagination of the epidermis (the hair follicle), which extends down into the dermis and, usually, a short distance into the hypodermis. - Hair follicles form hair via cyclic process of (a) anagen or growing phase, (b) catagen or involuting phase and (c) telogen or resting phase.- The deepest end of the hair follicle forms an enlargement, called the bulb. Matrix (regenerative) cells are cells of the bulb that line the dermal papillae, they are mitotically active, give rise to hair shaft and inner root sheath.- Inner root sheath is surrounded by layer of large clear cells called outer root sheath.- Outer root sheath cells undergo abrupt keratinization without a granular layer, at level of isthmus (mid hair follicle, extends from arrector pili insertion to sebaceous duct), this is called trichilemmal keratinization.- Outer root sheath cells undergo usual keratinization (as epidermis) at level of infundibulum (upper hair follicle).

- Lobulated structures which develop as a lateral protrusion from the outer root sheath of hair follicles.- Can also be found in some of the areas where no hair is present (e.g. lips, oral surfaces of the cheeks and external genitalia).- The secretory part (alveoli) have outer basal cells that are mitotically active, move inward and accumulate intracytoplasmic lipid droplets, causing multivacuolation and multiple indentations of nuclei- Excretory ducts of these glands empty into infundibulum of hair follicle.- The lipid secretion of the sebaceous glands has no softening effect on the skin, and it has only very limited antibacterial and antifungal activity. Its importance in humans is unclear. Clinically the sebaceous glands are important in that they are liable to infections (e.g. with the development of acne).

- Sweat glands are either eccrine (regulate body temperature), apocrine or mixed.

Eccrine Apocrine

- Tubular glands with secretory and excretory portions.- Secretory coil is in deep dermis or subcutis, has inner secretory and outer myoepithelial cells.- Excretory portion open directly onto skin surface, and has dermal (straight) and intraepidermal (spiral, also called acrosyringium) portions.

- Concentrated in axilla, groin and perineum; also in face, external auditory meatus, eyelid and areola. - Have secretory and excretory components- The secretory portion has an outer discontinuous layer of myoepithelial cells and an inner secretory cells.- The excretory duct of apocrine sweat glands does not open directly onto the skin surface, but into the upper part of the hair follicle.

- Pilosebaceous unit: complex of hair follicle, sebaceous gland, erector pili muscle, and if present, apocrine sweat glands.

D e r m i s & S u b c u t i s

● Contains collagen and elastic fibers within ground substance composed of mucopolysaccharides and mucoproteins.● Also contains adnexa, nerves, blood vessels, few fibroblasts, mast cells, macrophages, lymphocytes and dermal dendrocytes. ● Divided into superficial papillary dermis and deeper reticular dermis (papillary dermis has thin and delicate collagen fibers compared to thicker fibers in reticular dermis).

● Dermis has varying degrees of thickness - thicker on back● Acral skin has Sucquet-Hoyel canals – specialized arteriovenous anastomoses, surrounded by glomus cells● Glomus cells are modified smooth muscle cells that are round with clear cytoplasm and well defined cytoplasmic borders● Papillary dermis of palms and soles contains Wagner-Meissner corpuscles with a tactile function● Deep dermis and subcutis of weight bearing areas contain Pacinian corpuscles, sensitive to pressure● Subcutis also called subcutaneous; contains lobules of mature adipose tissue and thin connective tissue septa

2. Common Terms:Pathological terms Clinical terms

Acantholysis

loss of intercellular connections (desmosomes) between keratinocytes; occurs in pemphigus vulgaris and related disorders; causes change in cell shape from polygonalto round

Epidermolysis

alteration of granular layer with perinuclear clear spaces, swollen and irregular keratohyalin granules, increased thickness of granular layer; different from acantholysis

Acanthosis thickening of epidermis (squamous layer); rete ridges usually extend deeper into dermis

Papillomatosis outward overgrowth of epidermis with elongation of dermal papillae

Dyskeratosisabnormal, premature keratinization of keratinocytes below granular cell layer; often have brightly eosinophilic cytoplasm

Hyperkeratosis thickened cornified layer, often with prominent granular layer

Parakeratosiscells of cornified layer retain their nuclei, often less prominent or absent granular layer; normal for mucous membranes

Lentiginous linear pattern of melanocytic proliferation within epidermal basal cell layer

Lichenoid interface change

destruction of basal keratinocytes, causing remodeling of basement membrane zone; also bandlike lymphocytic infiltrate

Exocytosis Infiltration of the epidermis by inflammatory cells

Macule Circumscribed lesion, 5 mm or smaller in diameter, characterized by flatness and distinguished by coloration

Patch flat discoloration > 5 mm

Papule elevated and solid area, 5 mm or less

Plaque elevated flat topped area, usually > 5 mm

Nodule solid, deeply extending lesion > 5 mm

Pustule Discrete, pus-filled, raised lesion

Blister common term for vesicle or bullae

Vesicle fluid filed area, 5 mm or less

Bullae

fluid filled area > 5 mm; either intraepidermal or subepidermal; intraepidermal bullae are due to spongiosis or acantholysis; subepidermal bullae are due to extensive papillary dermal edema

Wheal itchy, transient, elevated area with variable blanching and erythema, due to dermal edema

Comedo hair follicle infundibulum is dilated and plugged with keratin and lipids

Horn conical mass of cornifed cells

Scale dry, horny, platelike excrescence usually due to imperfect cornification

Lichenification thick, rough skin with prominent skin markings usually due to repeated rubbing

Excoriation deep linear scratch, often self-induced

Onycholysis Separation of nail plate from nail bed

Leukocytoclasiskaryorrhexis and destruction of neutrophils; occurs with neutrophilic vasculitis (also called leukocytoclastic vasculitis)

Hydropic degeneration

Intracellular edema of keratinocytes, often seen in viral infections

Spongiosisintraepidermal edema, causing splaying apart of keratinocytes in stratum spinosum (resembling a sponge), vesicles due to shearing of desmosomes

Erosion discontinuity of skin causing partial loss of epidermis (compare to ulceration)

Ulceration discontinuity of skin causing complete loss of epidermis and possible loss of dermis

3. Infections: Many disorders (such as herpes simplex and herpes zoster, deep fungal infections, TB, Leprosy, Syphilis, and parasitic infestations) are discussed in General Pathology

Warts(Verrucae)

- Etiology:(1) Organism: human papilloma viruses (HPV), a type of papova virus.(2) Mode of transmission: direct contact (including sexual) or auto-inoculation.- Clinical:(1) Common in children and young adults, however any age may be affected.(2) Usually self-limited, regressing spontaneously within 6 months to 2 years.(3) Confirm diagnosis by PCR: detect HPV DNA.- M/P:(1) Epidermal acanthosis with hyperkeratosis, parakeratosis, and (not in verruca plana) papillomatosis. (2) Infected cells show cytoplasmic vacuolization (koilocytosis), with raisinoid nuclei.(3) These cells may also demonstrate prominent keratohyaline granules (eosinophilic intracytoplasmic keratin aggregates) as a result of viral cytopathic effects (these changes may be lost in old lesions).(4) Nuclear viral inclusion bodies may be seen.- Types:based largely on appearance, location and HPV subtype

Verruca vulgaris Verruca plana Verruca plantaris/palmaris

- Most common type of warts. - Usually due to HPV10. - Occur on the soles and palms, respectively.

- Usually due to HPV2.- Most frequently on the hands (particularly on the dorsal surfaces and periungual areas).- Appear as white to tan, elevated, small papules with a rough surface.- M/P: Striking papillomatosis & hyperkeratosis with pointed mounds resembling church spires.

- Most common on the face or the dorsal surfaces of the hands.- Appear as flat, smooth, tan papules.- M/P: Acanthosis but no papillomatosis.

- Appear as rough, scaly lesions may reach 1 to 2 cm in diameter.

Condyloma acuminatum(venereal warts)

Epidermodysplasia verruciformis

- Usually due to HPV6 and HPV11.- occurs on the penis, female genitalia, urethra, perianal areas, and rectum.- Appear as soft, tan, cauliflower-like masses that occasionally reach many centimeters in diameter.

- Usually HPV 5 or 8.- Often appears before age 10 years or after renal transplantation.- Appear as multiple flat warts on face or distal extremities, often disseminated throughout the body.- 30-50% progress to invasive squamous cell carcinoma, mean age 30 years.- M/P: mild to moderate acanthosis and hyperkeratosis. Epidermis shows large keratinocytes with blue-green cytoplasm and perinuclear pallor. Dysplasia & pleomorphism may be seen.

Note: HPV type 16 has also been associated with squamous cell carcinoma and carcinoma in situ of the genitalia (Bowen’s disease).

Molluscum Contagiosum

- Etiology:(1) Organism: Poxvirus.(2) Mode of transmission: Direct contact (including sexual).- Clinical:(1) Common in children and young adults.(2) Multiple lesions may occur on the skin and mucous membranes, especially the trunk and anogenital areas.(3) Lesions are firm, small, often pruritic, pink - tan papules, with central umbilication contains white curd-like material.(4) Confirm diagnosis: smearing this material onto a glass slide and staining with Giemsa reagent often shows diagnostic molluscum bodies.- M/P:(1) Lobulated endophytic epidermal hyperplasia (that produces a circumscribed intradermal pseudotumor).(2) The diagnostically specific structure is the molluscum bodies: large, ellipsoid, homogeneous, cytoplasmic inclusions in cells of the

stratum granulosum and the stratum corneum that displace nuclei and contain viral particles.

Impetigo

- Etiology:(1) Organism: due to Staphylococcus (mostly) or streptococcus infection.(2) Mode of transmission: The bacteria gain access into the skin at the site of an abrasion, such as might occur from a scratch or a cut or as a result of picking the face with dirty finger nails.(3) Pathogenesis:

Bacterial species in the epidermis evoke an innate immune response that tends to be destructive within the epidermis leading to local serous exudate with formation of a scale crust (scab).

Blister formation in impetigo is related to bacterial production of a toxin that specifically cleaves desmoglein 1, the protein responsible for cell-to-cell adhesion within the uppermost epidermal layers.

Because there is virtually no involvement of the dermis, once the bacteria are eliminated the lesions heal without scarring.- Types:

Impetigo contagiosa Impetigo bullosa

- Clinical:(1) Highly contagious and is frequently seen in otherwise healthy children as well as occasionally in adults in poor health.(2) Usually involves exposed skin (particularly that of the face, neck and hands).(3) It presents as an erythematous macule, but multiple small pustules rapidly supervene.(4) As pustules break, shallow erosions form, covered with drying serum, giving the characteristic clinical appearance of honey-colored crust.(5) May be associated with impetigo bullosa.

- Clinical:(1) Highly contagious, seen mainly in infants and children.(2) Usually seen on face, trunk, buttock, perineum or extremities.(3) Vesicles rapidly enlarge and become flaccid transparent bullae up to 5 cm, containing clear yellow to dark yellow / turbid fluid.(4) May be associated with impetigo contagiosa.

-M/P:(1) Accumulation of neutrophils beneath the stratum corneum, often producing a subcorneal pustule.(2) Rupture of pustules results in superficial layering of serum, neutrophils, and cellular debris to form the characteristic crust.(3) Stains: Gram-positive cocci are usually easily found in the surface crust.

- M/P:(1) Accumulation of fluid and neutrophils beneath the stratum corneum, with variable acantholysis.(2) Stains: bacterial clusters are evident with Gram stain.(3) Differential diagnosis: herpes simplex, burns, and other blistering disorders.

Tinea(Dermatophytoses)

- Etiology:(1) Organism: Dermatophytes (Trichophyton, Microsporum and Epidermophyton).(2) Mode of transmission: direct contact.

- M/P: (1) Fungal spores, hyphae and neutrophils usually are present in stratum corneum, nails or hair shafts (best stained with PAS).(2) Variable intercellular epidermal edema, dermal inflammation.- Types:

Tinea capitis Tinea barbae Tinea corporis

- Infection causing hairless patches of skin in scalp, with mild erythema, crust formation, and scaling.- Usually in children, rarely seen in infants and adults.- Kerion: superimposed bacterial folliculitis on tinea of scalp.

- Infection of beard area of adult men

- Infection of body, showing erythematous round plaques with an elevated scaling border (ringworm).- Affect any age.- Predisposing factors include excessive heat and humidity, and chronic dermatophytosis of the feet or nails.

Tinea cruris Tinea pedis Onychomycosis

- Infection of inguinal area (upper inner thigh) of obese men.- Predisposing factors include warm weather, friction, and maceration.

- Infection of the web spaces of feet (athlete’s foot), causing diffuse erythema and scaling.

- Infection of the nails, producing discoloration, thickening, and deformity of the nail plate.

Tinea Versicolor

- Etiology:(1) Organism: Malassezia furfur (yeast rather than a dermatophyte).(2) Mode of transmission: contact.- Clinical: Usually occurs on the upper trunk, appear as groups of macules of all sizes, lighter or darker than surrounding skin, with a fine peripheral scale.- M/P:Yeast spores and pseudohyphae within stratum corneum (spaghetti and meatballs on PAS).

4. Ichthyosis:- Definition:

Disorder of epidermal maturation, in which skin resembles fish scales.

- Pathogenesis:

Excessive keratin buildup due to a desquamation defect, leading to retention of abnormally formed scale - Types:

Ichthyosis Vulgaris Congenital Ichthyosiform Lamellar Ichthyosis X-Linked Ichthyosis

Erythroderma

(1) Most common type.(2) May be hereditary: autosomal dominant.(3) May be acquired: present at adult, usually associated with:* Malignancies (lymphoma, carcinoma of bronchus, breast and cervix).* Sarcoidosis.* Lupus.* Drugs.

Hereditary (autosomal recessive). (1) Hereditary (autosomal recessive).(2) Often called collodion baby as at birth the baby is covered by a thickened collodion-like membrane which is then shed.

(1) Deficiency in steroid sulfatase, which removes cholesterol sulfate from intracellular spaces.(2) Accumulation of cholesterol sulfate results in persistent cell-to-cell adhesion within the stratum corneum, hindering the desquamation process

- Clinical:

(1) Most ichthyoses become apparent either at or around the time of birth. Acquired ichthyosis appears in adult.

(2) Skin resembles fish scales; rough scaly patches and plaques.

- M/P:

(1) Compact, thickened stratum corneum with loss of normal basket weave pattern.

(2) Generally little or no inflammation.

5. Acute Inflammatory Dermatoses: Acute dermatoses last from days to weeks and are characterized by inflammatory infiltrates (usually composed of lymphocytes and macrophages rather than neutrophils), edema, and variable degrees of epidermal, vascular, or subcutaneous injury.

Urticaria(Hives)

- Definition:Common disorder of the skin characterized by localized mast cell degranulation and resultant dermal microvascular hyperpermeability. This gives rise to pruritic edematous plaques called wheals.

NB: Angioedema is closely related to urticaria and is characterized by deeper edema of both the dermis and the subcutaneous fat.

- Pathogenesis:

IgE-dependent urticaria IgE-independent urticaria Complement-mediated urticaria

- Most of cases.- Follow exposure to many different antigens (e.g. pollens, foods, drugs, insect venom).

- May also result from substances that in certain individuals directly incite the degranulation of mast cells (such as opiates, certain antibiotics, curare, and radiographic contrast media).

- Seen in hereditary angioneurotic edema, caused by an inherited deficiency of C1 inhibitor (results in uncontrolled activation of the early components of the complement system and production of vasoactive mediators).

- Antigens induce release of vasoactive mediators from mast cell granules through sensitization with specific IgE antibodies.

- Or may be due to exposure to chemicals (such as aspirin), that suppress prostaglandin synthesis from arachidonic acid.

- Clinical:(1) Urticaria most often occurs between ages 20 and 40, although all age groups are susceptible.(2) Individual lesions develop and fade within hours (usually <24 hours), and episodes may last for days or persist for months.(3) Lesions vary from small, pruritic papules to large edematous plaques (may coalesce to form annular, linear, or arciform configurations).(4) Most common sites for urticarial eruptions include any area exposed to pressure (such as the trunk, distal extremities, and ears).(5) Persistent episodes of urticaria may herald an underlying disease (e.g., collagen vascular disorders, Hodgkin lymphoma).- M/P:(1) Usually a sparse superficial perivascular mononuclear infiltrate, eosinophils may also be present.(2) Collagen bundles are more widely spaced than in normal skin, a result of superficial dermal edema.(3) Superficial lymphatic channels are dilated due to increased absorption of edema fluid.(4) Epidermal changes are typically absent.

Eczematous (spongiotic) Dermatitis

- Definition:The Greek word eczema, meaning “to boil over,” vividly describes the appearance of acute eczematous dermatitis.- Clinical:All forms of eczema are characterized by red, pruritic, papulovesicular, oozing, and crusted lesions that, if persistent, develop into raised, scaling plaques (due to reactive acanthosis and hyperkeratosis).- M/P:(1) During the earliest stages, there is a superficial, perivascular, lymphocytic infiltrate associated with papillary dermal edema and mast cell degranulation. (2) Then Epidermal spongiosis occurs. Edema seeps into the intercellular spaces of the epidermis, splaying apart keratinocytes (particularly in the stratum spinosum). Mechanical shearing of desmosomes and cell membranes by progressive accumulation of intercellular fluid may result in the formation of intraepidermal micro-vesicles.(3) Persistent lesions show epidermal acanthosis, hyperkeratosis, parakeratosis, and decreasing spongiosis. Dermis is fibrotic with variable perivascular lymphocytic infiltrate- Types:

Allergic contact dermatitis

- Etiology: contact reaction to topical antigens (such as poison ivy or nickel).- Pathogenesis: Delayed (Type IV) hypersensitivity reaction

Initially, antigens at the epidermal surface are taken up by dendritic Langerhans cells, which then migrate by way of dermal lymphatics to draining lymph nodes, and present antigen to naive CD4+ T cells, which are

activated and develop into effector and memory cells. On antigen re-exposure, these memory T cells migrate to affected skin sites of antigen localization, where

they adhere to post-capillary venules, extravasate into tissues, and release cytokines and chemokines that recruit the numerous inflammatory cells characteristic of eczema.

- Clinical: as before (but dermatitis occurs at site of contact).- M/P: as before (but extensive spongiosis, evident from the start).

Atopic dermatitis

- Etiology: atopy (associated with history of asthma and allergic rhinitis).- Pathogenesis: Type I hypersensitivity reaction.- Clinical: as before (but commonly on flexure areas, mainly seen in children).- M/P: as before.

drug-related eczematous dermatitis

- Etiology: usually systemic drugs (penicillin).- M/P: as before (but more prominent eosinophilic infiltrate in dermis).

Photo-eczematous dermatitis

- Due to UV light exposure.

Primary irritant dermatitis

- Due to repeated rubbing.

NB: Other forms of spongiotic dermatitis1 – Seborrheic dermatitis (see later).2 – Pityriasis rosea.3 – Stasis dermatitis.

Erythema Multiforme(interface

dermatitis)

- Etiology: seems to be a hypersensitivity reaction to

Infections Drugs Malignancy Collagen vascular diseases

Such as herpes simplex, mycoplasma, histoplasmosis, coccidioidomycosis, typhoid, and leprosy.

Such as penicillin, barbiturates, phenytoin, salicylates, sulfa.

Carcinomas and lymphomas.

Lupus erythematosus, dermatomyositis, and polyarteritis nodosa.

- Pathogenesis:(1) Epithelial cells are killed by skin-homing CD8+ cytotoxic T lymphocytes.(2) These cytotoxic cells are more prominent in the central portion of the lesions while CD4+ helper and Langerhans cells are more common in the raised, erythematous periphery.(3) The precise target antigens within the epidermis in erythema multiforme remain unknown, but there is growing evidence that the basal cells that reside at the very tips of epidermal rete ridges may preferentially undergo apoptosis.- Clinical:

(1) Usually self-limited, affect any age.(2) Affects skin (extensor surfaces of distal extremities, palms, and soles) and mucous membranes.(3) Lesions are variable (multiform) lesions: papules, macules, vesicles, bullae, and characteristic target lesion (red macule or papule with a pale, vesicular, or eroded center).(4) Variants:

Stevens-Johnson syndrome

- Severe adverse cutaneous drug reaction that predominantly involves the skin and mucous membranes (represent systemic variant of erythema multiforme).- Mainly affect children.- Mainly affect lips and oral mucosa (although the conjunctiva, urethra, and genital and perianal areas may also be affected).- Presented with fever, erosions and hemorrhagic crusts in affected areas.- Secondary infection of involved areas due to loss of skin integrity may result in life-threatening sepsis.

Toxic epidermal necrolysis

- Diffuse necrosis and sloughing of cutaneous and mucosal epithelial surfaces.- Producing a clinical situation analogous to an extensive burn when both infection and fluid loss are clinical concerns.

- M/P:(1) Early lesions show a pattern termed interface dermatitis, where a superficial perivascular lymphocytic infiltrate associated with dermal edema and accumulation of lymphocytes along the dermoepidermal junction, associated with vacuolization of the basal layer of epidermis (hydropic degeneration).(2) With time there is upward migration of lymphocytes into the epidermis. Discrete and confluent zones of epidermal necrosis occur with concomitant blister formation. Dyskeratotic cells are evidenced.(3) The clinical targetoid (target-like) lesion shows central necrosis surrounded by a rim of perivenular inflammation.- Differential diagnosis: from other dermatoses with interface dermatitis(1) Acute graft versus host disease: similar in M/P, differentiated by clinical history (present 2 – 4 weeks after bone marrow transplantation).(2) Steven Johnson syndrome or toxic epidermal necrolysis: full thickness epidermal necrosis with separation of epidermis from dermis.(3) Morbilliform drug eruptions: usually less epidermal damage in comparison to erythema multiform, increased eosinophilic infiltrate in dermis.(4) Dermatomyositis / Lupus erythematosis: Chronic disease associated with hyperkeratosis, parakeratosis. Also mucin deposition in dermis which not seen in erythema multiforme.

6. Chronic Inflammatory Dermatoses :

Chronic lesions persist for months to years and are often associated with changes in epidermal growth (atrophy or hyperplasia) or dermal fibrosis. The skin surface in some chronic inflammatory dermatoses is roughened as a result of excessive or abnormal scale formation and shedding. However, not all scaling lesions are inflammatory (as seen in ichthyoses).

Psoriasis Vulgaris(psoriasiform dermatitis)

- Etiology & pathogenesis:(1) Seems to be multifactorial, with contributions from genetic and environmental factors.(2) There is a strong association between psoriasis and HLA-C (particularly with the HLA-Cw*0602 allele, which present in 2/3 affected individuals).(3) Sensitized populations of CD4+ T helper cells and activated CD8+ effector T cells enter the skin and accumulate in the epidermis. The causative antigens for this reaction remain unclear. T cell homing to the skin may create an abnormal microenvironment by inducing the secretion of cytokines (e.g. interferon- γ and TNF) and growth factors that induce keratinocyte proliferation, resulting in the characteristic lesions.

NB: There is much evidence that, as with rheumatoid arthritis, TNF is a major mediator in the pathogenesis of psoriasis. Indeed, anti-TNF therapies provide benefit and are currently in use.

(4) Koebner phenomenon: Psoriatic lesions can be induced in susceptible individuals by local trauma, which may induce a local inflammatory response that promotes lesion development.- Clinical:(1) Most frequently affects the skin of the elbows, knees, scalp, lumbosacral areas, intergluteal cleft, and glans penis.(2) The typical lesion is a well-demarcated, pink to salmon-colored plaque covered by loosely adherent scale that is characteristically silver-white in color.(3) Auspitz sign: multiple, minute, bleeding points when the scale is lifted from the plaque.(4) Nail changes occur in 30% of cases, including yellow-brown discoloration, with pitting, dimpling, and separation of the nail plate from the underlying bed (onycholysis).(5) Also may be associated with arthritis (Psoriatic arthritis).- M/P:(1) Marked acanthosis, with regular downward elongation of the rete ridges (sometimes described as appearing like test tubes in a rack).(2) Extensive overlying parakeratotic scale is also seen.(3) The stratum granulosum is thinned or absent.(4) Typical of psoriatic plaques is thinning of the portion of the epidermal cell layer that overlies the tips of dermal papillae (suprapapillary plates) and dilated, tortuous blood vessels within these papillae (This is why Auspitz sign is seen in psoriasis).(5) Neutrophils form small aggregates within the superficial epidermis (spongiform pustules of Kogoj) and within the parakeratotic stratum corneum (Munro microabscesses).- Psoriasis variants:

Pustular psoriasis Guttate psoriasis

(1) Characterized by acute onset of sterile pustules rather than large erythematous plaques.(2) Either benign and localized (hands and feet) or generalized and life-threatening (with associated fever, leukocytosis, arthralgia, diffuse cutaneous and mucosal pustules, secondary infection, and electrolyte disturbances).- M/P: large pustules in stratum corneum/epidermis, intact or slightly diminished stratum granulosum with less prominent acanthosis (because of rapid onset of disease).

(1) Characterized by rapid onset of widespread small scaly plaques.(2) Frequently associated with antecedent streptococcal pharyngitis.- M/P: Focal mounts of parakeratosis with neutrophils, with minimal acanthosis.

- Differential diagnosis: from other lesions with Psoriasiform dermatitis(1) Pityriasis rubra pilaris: has diffuse hyperkeratosis with alternating parakeratosis and orthokeratosis (anuclear keratin) in both vertical and horizontal directions (giving what is called checkerboard pattern); stratum granulosum is intact, no suprapapillary thinning or neutrophils in stratum corneum (unless secondary infection).(2) Lichen simplex chronicus: scarring of dermal papillae due to persistent rubbing or itching; no thinning of suprapapillary plate; marked hyperkeratosis and prominent stratum granulosum (similar to acral skin).(3) Secondary syphilis: epidermis shows parakeratosis & psoriasiform hyperplasia, within dermis there is perivascular lymphocytes infiltrate that usually contains plasma cells, also visualization of organism (Warthin-Starry stain or better IHC stains).(4) Dermatophytes: parakeratosis, acanthosis, +/- spongiosis, and Hyphae are seen by PAS stain.

Seborrheic Dermatitis - Etiology & pathogenesis:(1) Therapeutic studies with ketoconazole suggest that Malassezia furfur (which is associated with tinea versicolor), may have a role in some cases.(2) Also observed in people with Parkinson disease (show increased sebum production secondary to dopamine deficiency) and once treated with levodopa, the oiliness of the skin decreases and the seborrheic dermatitis improves.

NB: it is important to note that seborrheic dermatitis is not a disease of the sebaceous glands. Other conditions associated with increased sebaceous activity (e.g. acne) do not show association between increased sebum and appearance of seborrheic dermatitis, so sebum production is unlikely to be the sole or primary factor in the pathogenesis of seborrheic dermatitis.

(3) Seborrheic dermatitis is also common in many HIV–infected individuals (and usually difficult to be treated).- Clinical:(1) Classically involves regions with a high density of sebaceous glands (e.g. the scalp, glabella, external auditory canal, retroauricular area, nasolabial folds, and the presternal area).(2) Lesions are erythematous scaling papules and macules, sometimes with a greasy yellow appearance.(3) Dandruff is the common clinical expression of seborrheic dermatitis of the scalp.(4) In infants, seborrheic dermatitis presents as cradle cap.- M/P:Seborrheic dermatitis share histologic features with both spongiotic dermatitis and psoriasis

Early (acute) seborrheic dermatitis Late (chronic) seborrheic dermatitis Subacute seborrheic dermatitis

(1) Being more spongiotic.(2) Typically, mounds of parakeratosis containing neutrophils and serum, often present at the ostia of hair follicles (so-called follicular lipping).(3) Papillary dermis show edema, dilated blood vessels and superficial perivascular infiltrate of lymphocytes, histiocytes and occasional neutrophils.

(1) More pronounced psoriasiform hyperplasia and only minimal spongiosis.(2) Sometimes the differentiation from psoriasis can be difficult but the presence of scale crusts in a folliculocentric distribution favors seborrheic dermatitis.

- Transition between acute and chronic.

Lichen Planus(interface dermatitis with

band-like infiltrate = lichenoid dermatitis)

- Etiology & Pathogenesis:(1) May represent an abnormal, delayed hypersensitivity reaction to altered epidermal antigens.(2) These antigens at the level of the basal cell layer and the dermoepidermal junction elicit a cell-mediated cytotoxic (CD8+) T cell immune response (In support of this notion, T lymphocyte infiltrates and hyperplasia of Langerhans cells are characteristic features of this disorder).(3) It shows Koebner phenomenon like psoriasis. - Clinical:(1) Usually flexor arms and legs, glans penis and mucous membranes (especially oral mucosa).(2) Usually self-limited (resolves spontaneously 1 to 2 years after onset), often leaving zones of postinflammatory hyperpigmentation.(3) Cutaneous lesions consist of itchy, purple, flat-topped papules that may coalesce focally to form plaques.(NB: Lichen planus is disease of 6 P’s = Pruritic, purple, polygonal, planar papules, and plaques).(4) Wickham straie: papules are often highlighted by white dots or lines, which are created by areas of hypergranulosis.(5) Oral mucosal lesions may last longer, appear as white, reticulated, or netlike areas involving the mucosa.- M/P:(1) Dense, bandlike chronic inflammatory infiltrate (T cells and macrophages) along the dermoepidermal junction.(2) Basal keratinocytes, which show degeneration, necrosis, and a resemblance in size and contour to more mature cells of the stratum spinosum (squamatization).(3) A consequence of this destructive infiltration of lymphocytes is a redefinition of the normal, smoothly undulating configuration of the dermoepidermal interface to a more angulated zigzag pattern with pointed rete ridges (sawtoothing).(4) Civatte’s (colloid) bodies: Anucleate, necrotic basal cells may become incorporated into the inflamed papillary dermis.(5) There are also hyperkeratosis and hypergranulosis.- Lichen planus variants:

Atrophic Lichen Planus Hypertrophic Lichen Planus Bullous Lichen Planus Lichen Planopilaris

- Thinned epidermis, subtle - Thickened epidermis - Subepidermal blister - Preferentially affecting

interface changes and subtle hypergranulosis.

(acanthosis) the epithelium of hair follicles (causing alopecia).

- Differential diagnosis: from other causes of lichenoid dermatitis(1) Lichenoid keratosis: Solitary lesion, identical to lichen planus, adjacent areas of solar lentigo may be the clue to diagnosis.(2) Lichenoid drug eruption: similar to lichen planus but with parakeratosis and eosinophils.(3) Lichenoid pigmented purpuric dermatosis: less epidermal changes and more prominent dermal hemorrhage.

7. Blistering (Bullous) Diseases:- Definition:

Heterogeneous group of disorders affecting the skin or mucous membranes and characterized by blister formation.

- Classification:

Intraepidermal BullaeSubepidermal Bullae

Suprabasal Spinous Subcorneal

1. Pemphigus vulgaris and variants.2. Paraneoplastic pemphigus.3. Darier’s disease.

1. Spongiotic Dermatitis (e.g. eczema, contact dermatitis). 2. Hailey-Hailey disease. 3. Herpes infections. 4. Fixed Drug eruptions (epidermal type). 5. Friction Blisters. 6. Erythema multiforme (epidermal type ).

1. Bullous Impetigo.2. Erythema toxicum neonatorum.3. Subcorneal Pustular dermatosis.4. Miliaria Crystallina.5. Pemphigus foliaceus and variants.

1. Bullous Pemphigoid.2. Cicatricial Pemphigoid.3. Linear IgA Dermatosis.4. Dermatitis Herpetiformis.5. Erythema Multiforme (dermal type).6. Fixed Drug Eruptions (dermal type).7. Epidermolysis Bullosa.8. Bullous Lupus Erythematosus:

Pemphigus - Definition:Inflammatory Blistering disorder caused by autoantibodies to desmosomes, result in the dissolution of intercellular attachments within the epidermis and mucosal epithelium.- Pathogenesis:All forms of pemphigus are caused by IgG autoantibodies against desmogleins.- M/P:(1) Intraepidermal blisters due to acantholysis (from IgG against desmosomes).(2) Acantholytic cells dissociate from one another, lose their polyhedral shape and become rounded.(3) Variable superficial dermal infiltration by lymphocytes, histiocytes, and eosinophils accompanies all forms of pemphigus.

- Immunofluorescence:Lesional sites show a characteristic net-like pattern of intercellular IgG deposits.- Differential diagnosis: other causes of intraepidermal bullae- Types:

Pemphigus Vulgaris

- Pathogenesis:IgG autoantibodies against Dsg1 and Dsg3 (cause blisters in the deep suprabasal epidermis).- Clinical:(1) The most common type (more than 80% of cases).(2) Involves the oral mucosa first, then may involve skin (especially on the scalp, face, axilla, groin, trunk, and points of pressure).(3) Primary lesions are superficial vesicles and bullae that rupture easily, leaving shallow erosions covered with dried serum and crust.(4) Positive Nikolsky sign: light rubbing of the skin results in exfoliation of the outermost layer, with blister formation in this area within minutes.(5) Healing is often accompanied by post–inflammatory hyperpigmentation but no scarring.- M/P:(1) Characteristic suprabasilar separation and acantholysis.(2) Single layer of intact basal cells that forms the blister base remains attached (tombstoning).(3) Prominent extension of acantholysis into hair follicles.

Pemphigus Vegetans

- Clinical:(1) Rare (1-2% of cases) variant of pemphigus vulgaris.(2) Usually presents not with blisters but with large, moist, verrucous (wart-like) plaques studded with pustules on the groin, axillae, and flexural surfaces.- M/P:(1) Supra basal acantholysis is subtle, masked by marked proliferation of squamous epithelium (acanthosis).(2) Large intraepidermal microabscesses filled with eosinophils and occasional acantholytic keratinocytes.

Pemphigus Foliaceus

- Pathogenesis:IgG autoantibodies are against Dsg1 alone (leading to superficial, subcorneal blisters).- Clinical:(1) Endemic in Brazil (where it is called fogo selvagem or “wild fire”).(2) Usually affects scalp, face, chest, and back. The mucous membranes are rarely affected.(3) Bullae are so superficial that may not appear on examination and replaced by superficial erosions and crusting.- M/P:

(1) Acantholysis occurs in subcorneal areas (only the granular cell layer is affected).(2) Stratum corneum may be denuded.

Pemphigus Erythematosus

- Clinical:(1) Combined features of pemphigus foliaceus and SLE.(2) Blisters selectively involve the malar area of the face in a lupus erythematosus–like fashion.(3) SLE manifestations usually not present, but if present usually are mild.- M/P:As pemphigus foliaceus.

Paraneoplastic Pemphigus

- Clinical:(1) Occurs in association with various malignancies, most commonly hematopoietic malignancies (e.g. non-Hodgkin lymphoma, CLL, Castleman tumor, Waldenstrom macroglobulinemia). May also associated with thymoma.(2) Present with oral and cutaneous erosions and bullae.- M/P: more than ½ of cases show combination of(1) Suprabasal acantholysis.(2) Lichenoid changes (band-like chronic inflammatory cell infiltrate).(3) Changes of interface dermatitis (vacuolar degeneration, dyskeratotic keratinocytes and lymphocyte exocytosis).

Bullous Pemphigoid

- Definition:Inflammatory blister disorder of skin causing subepidermal blistering due to IgG antibodies to hemidesmosomes.- Pathogenesis:(1) IgG antibodies against hemidesmosomal proteins, where most of the bullous pemphigoid antigen (BPAG) is located.(2) Two types of proteins/antigens: BPAG1 and BPAG2 (see histology). Only antibodies to BPAG2 are proven to cause blistering.- Clinical:(1) It may involve only the skin (including inner aspects of the thighs, flexor surfaces of the forearms, axillae, groin, and lower abdomen) or the skin and mucosal surfaces (mainly oral mucosa, usually appearing after the cutaneous lesions).(2) Lesions are pruritic tense bullae, filled with clear fluid, on normal or red patches of skin. Nikolsky sign is negative.(3) Prior to blistering, the red itchy patches may be thought to be a kind of urticaria.(4) The bullae do not rupture as easily as do the blisters seen in pemphigus and if they are not secondarily infected, they heal without scarring.- M/P:(1) Subepidermal nonacantholytic blisters, with inflammatory infiltrate including lymphocytes and eosinophils, no neutrophils.(2) Early or prodromal lesions may show: basal cell vacuolization (spongiosis) without frank blister formation, upper dermal edema, perivascular lymphohistiocytic infiltrate, accompanied by conspicuous eosinophils.

- Immunofluorescence:(1) Linear IgG and C3 antibodies to hemidesmosomes at lamina lucida of basement membrane.(2) Antibodies bind to epidermal side in NaCl split skin test.- Differential diagnosis: other causes of subepidermal bullae(1) Epidermolysis bullosa acquisita: subepidermal blister with mixed inflammatory cell dermal infiltrate, linear band of IgG along dermal-epidermal junction but on dermal side in NaCl split skin test.(2) Cicatricial pemphigoid: usually affects mucus membrane (especially conjunctiva – causing ocular scarring), subepidermal blister with mixed inflammatory cells, linear band of IgG along dermal-epidermal junction but on dermal side in NaCl split skin test.(3) Bullous lupus erythematosus: fulfills criteria for SLE (including positive lupus serology), linear or granular deposition of autoantibodies along basement membrane, reactivity on dermal side in NaCl split skin.(4) Dermatitis herpetiformis (see below).

Dermatitis Herpetiformis

- Definition:Very pruritic autoimmune blistering disorder associated with gluten-sensitive enteropathy (celiac disease).- Pathogenesis:(1) Genetically predisposed individuals develop lgA antibodies to dietary gluten (derived from the wheat protein gliadin).(2) The antibodies cross-react with reticulin (a component of the anchoring fibrils that anchor hemidesmosomes to the dermis).(3) The resultant injury and inflammation produce a subepidermal blister.- Clinical:(1) Mainly involves extensor surfaces of elbows, knees, buttocks and back.(2) “Herpetiform” because vesicles are small (pinhead sized) and grouped bilaterally and symmetrically (as with herpes).(3) Intense purities, which may lead to erosions due to intense scratching.(4) May show response to a gluten-free diet.- M/P:(1) Early event, fibrin and neutrophils accumulate selectively at the tips of dermal papillae, forming small microabscesses.(2) The basal cells overlying these microabscesses show vacuolization and focal dermoepidermal separation that ultimately coalesce to form a true subepidermal blister.- Immunofluorescence:Granular IgA pattern in dermal papillae.- Differential diagnosis: other causes of subepidermal bullae(1) Bullous pemphigoid: large tense blisters on flexor surfaces, axilla, groin and mucosa, subepidermal nonacantholytic blisters with inflammatory infiltrate including lymphocytes and eosinophils, no microabscesses, linear deposition of IgG and C3 at basememnt membrane.(2) Linear IgA dermatosis: Often occurs after administration of antibiotics (predominantly vancomycin or penicillin), subepidermal blisters with neutrophilic infiltration, homogenous band of IgA at the dermal-epidermal junction; no anti-endomysial or anti-tissue transglutaminase IgA antibodies; not gluten sensitive.

Epidermolysis Bullosa

- Definition:Group of noninflammatory blister disorders caused by inherited defects in structural proteins that lend mechanical stability to the skin.- Types & Pathogenesis:

EB Simplex Junctional EB Dystrophic EB

(1) Result from mutations in the genes encoding keratins 14 or 5 (these two proteins normally pair with one another to make a functional keratin fiber).(2) Causes intraepidermal tissue separation & degeneration of basal cell layer.

(1) Result from mutations in genes encoding laminin &/or a6b4 integrin.(2) Causes blisters within lamina lucida (skin appears normal).

(1) Result from mutations in gene encoding type VII collagen.(2) Causes blisters are sub-lamina densa.

- Clinical:(1) Family history of epidermolysis bullosa or an affected parent.(2) Blisters at sites of pressure, rubbing, or trauma, at or soon after birth.(3) Nail loss or deformed nails.(4) Blistering in or around the mouth and throat with feeding difficulty or swallowing difficulty.(5) Complications: severe malnutrition secondary to feeding difficulty, infections, loss of function of the hands and feet, squamous cell carcinoma (especially in dystrophic type).- M/P:(1) Noninflammatory subepidermal blister, with sparse perivascular lymphocytic infiltrate.(2) Superficial dermis is fibrotic in old lesions.- Immunofluorescence:Negative.

NB: Epidermolysis bullosa acquisita* Definition: Non-congenital, autoimmune, chronic blistering disease of skin and mucus membranes. * Pathogenesis: IgG Autoantibodies against NC1 (noncollagenous) domain of type VII collagen, or central triple-helical (collagenous) domain of type VII.* Clinical: Usually affects elderly with blisters at trauma-prone areas.* M/P: Subepidermal blister with mixed inflammatory cell dermal infiltrate (bullous pemphigoid-like).* Immunofluorescence: Linear band of IgG along dermal-epidermal junction but on dermal side in NaCl split skin test.

Porphyria - Definition:Non-inflammatory blistering disorder due to disturbance of porphyrin metabolism (porphyrin is present in hemoglobin, myoglobin and cytochromes.- Types & Pathogenesis:

Congenital Erythropoietic Porphyria

Erythrohepatic Protoporphyria Acute Intermittent Porphyria

Porphyria Cutanea Tarda Mixed Porphyria

Rare autosomal recessive disease with mutation in uroporphyrinogen-III synthase gene

Rare autosomal recessive form of porphyria cutanea tarda, with markedly deficient activity of uroporphyrinogen decarboxylase.

(1) Second most common type of porphyria (but still rare).(2) Autosomal dominant disorder with porphobilinogen deaminase enzyme (ALA dehydratase enzyme) deficiency.

(1) Most frequent type of porphyria.(2) Autosomal dominant disorder with deficiency of uroporphyrinogen decarboxylase enzyme.

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- Clinical:(1) Hemolytic anemia & splenomegaly.(2) Cutaneous manifestations: photosensitivity, urticaria, vesicles and pigmentary changes in sun-exposure areas.(3) Neurological manifestations (prominent in acute intermittent porphyria): peripheral neuropathy, seizures, psychotic symptoms.(4) Lab: Porphyrin level in urine, stool and RBCs is the golden diagnostic test.- M/P:(1) Noninflammatory subepidermal vesicle, with no/minimal inflammation(2) Marked thickening of superficial dermal vessels (may appear rigid).(3) Porphyria cutanea tarda: dermal papillae protrude into bulla with festooned pattern, Occasional eosinophilic PAS positive globules arranged in linear fashion are seen in blister roof (caterpillar bodies).- Immunofluorescence:(1) Deposition of IgG (and to lesser extent IgM, fibrinogen and C3) at blood vessels in the papillary dermis.(2) Weak linear deposition at the dermo-epidermal junction and within basement membrane is also seen.

8. Scleroderma:- Definition:

Multisystem connective tissue disease that is subdivided into two major groups:

(1) Limited scleroderma: disease is limited, involves hands, forearms and face, may be a part of CREST syndrome.

(2) Diffuse scleroderma: diffuse cutaneous sclerosis, frequent visceral involvement.

- Pathogenesis:

A marked increase in type 1 collagen gene expression occurs in scleroderma, leading to increased collagen synthesis.

- Clinical:

(1) Indurated skin plaques with irregular areas of hyper- or hypopigmentation.

(2) CREST syndrome (Calcinosis, Raynaud's syndrome, Esophageal dysmotility, Sclerodactyly = limited scleroderma, Telangiectasia).

(3) Laboratory tests: show anti-topoisomerase antibodies (diffuse systemic form), or anti-centromere antibodies (limited form, and the CREST syndrome).

- M/P:

(1) Thickening and hyalinization of connective tissue of deep dermis, subcutaneous fat and muscular fascia, may be mucin deposition between collagen bundles.

(2) Perivascular and focal interstitial lymphocytic and plasma cell infiltrate in subcutaneous fat.

(3) Often atrophy of epidermis, atrophy of adnexal structures, and thickening and narrowing of small vessels.

- Differential diagnosis: from other causes of sclerosing dermatosis

(1) Morphea: appear as localized indurated plaques on trunk, with similar M/P of scleroderma (also known as localized scleroderma).

(2) Lichen sclerosus: presented with atrophic hypopigmented patches or plaques, M/P shows hyperkeratosis, epidermal atrophy, loss of rete ridges, with papillary dermal collagen homogenization and edema, and lymphocytic infiltrate beneath altered papillary dermal collagen.

9. Panniculitis:- Definition:

Panniculitis is an inflammatory reaction in the subcutaneous adipose tissue.

NB: Inadequate biopsy specimens (particularly punch biopsies) may include no subcutaneous fat, so biopsy of a deep wedge of tissue to generously sample the subcutis is usually required for histologic diagnosis.

- Types: It may be septal or lobular.

Septal Lobular

Affect the connective tissue septa separating lobules of fat.e.g. erythema nodosum, alpha1 antitrypsin deficiency, or lipodermatosclerosis (sclerosing panniculitis).

Affect the lobules of fat themselves.e.g. nodular vasculitis (erythema induratum), pancreatic fat necrosis, physical and factitious panniculitis (due to blunt force, pinching, cold or injection of foreign substances for secondary gain), or lupus panniculitis (lupus profundus).

Erythema Nodosum Erythema Induratum

- Most common form, usually has an acute presentation.- Causes: often associated with(1) Infections (β-hemolytic streptococcal infection, tuberculosis and, less commonly, coccidioidomycosis, histoplasmosis, and leprosy).(2) Drug administration (sulfonamides, oral contraceptives).

- Uncommon type of panniculitis that affects primarily adolescents and menopausal women, usually has a chronic presentation.- Causes:(1) Originally considered a hypersensitivity response to tuberculosis, but today most commonly occurs without an associated underlying disease.(2) The exact etiology still unknown, may be primary vasculitis affecting deep

(3) Sarcoidosis. (4) Inflammatory bowel disease.(5) Certain malignant neoplasms. (6) Idiopathic.- Clinical:(1) Often involves the lower legs.(2) Presents as poorly defined, tender, erythematous plaques and nodules, usually not ulcerate.(3) Fever and malaise may accompany the cutaneous signs.(4) Over the course of weeks, lesions usually flatten and pigmented, leaving no residual clinical scars, while new lesions develop. - M/P:(1) Early lesions, widening of the connective tissue septa is due to edema, fibrin exudation, and neutrophilic infiltration.(2) Later, septal infiltration by lymphocytes, histiocytes, multinucleated giant cells, and occasional eosinophils is associated with septal fibrosis.(3) Vasculitis is not present.

vessels supplying lobules of the subcutis, with subsequent necrosis and inflammation within the fat.- Clinical:(1) Often involves the lower legs.(2) Presents as an erythematous, slightly tender nodule that usually goes on to ulcerate.- M/P:(1) Early lesions show necrotizing vasculitis affecting small- to medium-sized arteries and veins in the deep dermis and subcutis.(2) Later, granulomatous inflammation and zones of caseous necrosis involve the fat lobule.

Lipodermatosclerosis (sclerosing panniculitis) Lupus Panniculitis (lupus profundus)

- Associated with stasis secondary to venous insufficiency or obesity.- M/P:(1) Predominantly septal, with membranocyctic fat necrosis characterized by cystic cavitis lined by crenulated hayaline membrane.(2) There are variable mild perivascular lymphocytic infiltrate.(3) Epidermis and superficial dermis usually show features of stasis changes.

- May develop in normal skin or preexisting skin lesion of patient with systemic or discoid lupus erythematosus.- M/P:(1) Predominantly lobular, with hyaline fat necrosis characterized by dense eosinophilic sclerosis around remnants of adipocytes.(2) There are lymphoid nodules with germinal centers at periphery of fat lobules.

11. Disorders of Epidermal Appendages:Acne

Vulgaris- Incidences:(1) Age: most common in middle to late teenage years.(2) Sex: affects both males and females, although males tend to have more severe disease.(3) Race: seen in all races, but is usually milder in people of Asian descent.- Etiology & pathogenesis:(1) Four key components contribute to the development of acne:

changes in keratinization of the lower portion of the follicular

hypertrophy of sebaceous glands with puberty or increased

lipase-synthesizing bacteria (Propionibacterium acnes)

inflammation of the follicle associated with release of

infundibulum with the development of a keratin plug blocking outflow of sebum to the skin surface

activity (sebum secretion) due to hormonal stimulation

colonizing the upper and midportion of the hair follicle, converting lipids within sebum to pro-inflammatory fatty acids

cytotoxic and chemotactic factors

(2) Acne may be induced or exacerbated by:* Drugs (corticosteroids, adrenocorticotropic hormone, testosterone, gonadotropins, contraceptives, trimethadione, iodides, and bromides).* Occupational contactants (cutting oils, chlorinated hydrocarbons, and coal tars).* Occlusive conditions (heavy clothing, cosmetics, and tropical climates).- Clinical:(1) Acne is divided into noninflammatory and inflammatory types, although the types may coexist.(2) Noninflammatory types consists of open and closed comedones:

Open comedones (blackhead) Closed comedones (whitehead)

Small follicular papules containing a central black keratin plug.This color is the result of oxidation of melanin pigment (not dirt).

Follicular papules without a visible central plug.Because the keratin plug is trapped beneath the epidermal surface, these lesions are potential sources of follicular rupture and inflammation.

(3) Inflammatory acne is characterized by erythematous papules, nodules, and pustules.(4) Severe variants (e.g., acne conglobata) result in sinus tract formation and physical scarring.- M/P:(1) Comedones (open or closed): cyst-like cavities filled with compact mass of keratinous material, trapped hairs, and numerous bacteria. Sebaceous acini are atrophic or absent.(2) Variable lymphohistiocytic infiltrates are present in and around affected follicles, and extensive acute and chronic inflammation accompanies follicular rupture.(3) Then gradual resolution, often with scar.- Treatment:Antibiotics (for Propionibacterium acnes), isotretinoin (anti-sebaceous action).

Rosacea(acne

rosacea)

- Definition:Skin disorder leading to redness and pimples on the nose, forehead, cheekbones, and chin. The inflamed pimples and redness of rosacea can look a great deal like acne, but blackheads are almost never present.- Incidences:(1) Age: Rosacea is a common disease of middle age and beyond.(2) Sex: common in females.(3) Race: common in fair-skinned individuals.- Etiology and pathogenesis:

(1) It seems that inappropriate activation of the innate immune system may play a role in this disorder.(2) Individuals with rosacea have high cutaneous levels of the endogenous antimicrobial peptide cathelicidin (an important mediator of the innate immune response).- Clinical: Four stages are recognized(1) Flushing episodes (pre-rosacea).(2) Persistent erythema and telangiectasia.(3) Pustules and papules.(4) Rhinophyma: permanent thickening of the nasal skin by confluent erythemaous papules and follicular prominence.- M/P:(1) Rosacea is characterized by a nonspecific perifollicular infiltrate composed of lymphocytes surrounded by dermal edema and telangiectasia.(2) In the pustular phase neutrophils may colonize the follicles, and follicular rupture may cause a granulomatous dermal response.(3) The development of rhinophyma is associated with hypertrophy of sebaceous glands and follicular plugging by keratotic debris.