PATHOLOGY, By Kumar et al. BASICReference: ROBBINS 9th © 2013: Chapter 22. Skin (59 W + 34 Figures = 93 PPP) @ 19-11-2018, Lectures prepared by:

Dr Mohammad Kamel Alwiswasi, MBChB, PhD, FRCPath.

Skin

Cutaneous disorders are extremely common & range from irritating acne to life-threatening melanoma. Many are intrinsic to the skin, but some are manifestations of systemic disease, e.g., Kaposi sarcoma of AIDS, SLE, neurofibromatosis genetic syndromes.

for the recognition windowThus, skin provides a uniquely of numerous & varied disorders.

Skin, the largest organ of the body, is a complex organ, with regulated cellular & molecular events that govern interactions with the external environment. Skin is constantly bathed with microbial & non microbial antigens that are processed by bone-marrow-derived dendritic Langerhans cells, which in turn communicate with the immune system by migrating to regional LNs.

) help maintain skin keratinocytesThe squamous cells ( homeostasis by secreting many cytokines that not only regulate interactions among the epidermal cells but also diffuse into & influence the dermal microenvironment.

+ cytotoxic T 8+ helper & CD4contains both CD dermisThe lymphocytes; some of these T cells home selectively to the skin by virtue of homing receptors called the cutaneous lymphocyte antigen (CLA).

contains intraepithelial lymphocytes, including epidermisThe γ/δ T cells. All these cells are rich sources of cytokines.

The local tissue response, involving these T cells & cytokines, accounts for the microscopic patterns & clinical expressions of cutaneous inflammatory & infectious disease. These patterns can be recognized & interpreted through the microscope by the experienced pathologist.

This chapter focuses on common &/or illustrative diseases

of the skin only.

The practice of dermatopathology is unique in its close interaction with dermatologists. Clinical assessment of skin diseases involves:

Clinical presentation + history + gross skin examination, + correlated (sometimes) with Histopathological Ex to make a…

.iagnosisD

Glossary (Dermatologic terms) Gross or Macroscopic Terms

area of any size colored circumscribed (limited) Flat Macule:

Papule: Elevated solid area <5mm in Diameter=Ǿ)

Nodule: Elevated solid area >5mmǾ

Plaque: Elevated flat-topped area >5mmǾ

mm Ǿ 5<raised area filled-Fluid Vesicle:

mmǾ 5>raised area, filled-Fluid Bulla:

Blister: Common term used for both vesicle or bulla. raised discrete (isolated) area. filled-Pus Pustule:

Scale: Dry, horny, platelike excrescence (growth); usually the result of imperfect cornification.

Lichenification: Thickened rough skin characterized by prominent skin markings; usually the result of

ichen Lrepeated rubbing in susceptible persons (see "")hronicusCimplex S

Excoriation: A traumatic lesion characterized by breakage of the epidermis, causing a raw linear area usually due to scratching.

Microscopic Terms

Spongiosis: Intercellular edema of the epidermis

Acanthosis: hyperplasia of the stratum spinosum

Acantholysis: Loss of intercellular connections,

resulting in lack of cohesion between keratinocytes.

Hyperkeratosis: Hyperplasia with thickening of the

keratin layer.

Parakeratosis: keratinization characterized by in the keratin layer. retention of the nuclei

on mucosal membranes, parakeratosis is normal.

Dyskeratosis: Abnormal premature keratinization occurring in individual cells or groups of cells, below the stratum granulosum.

Papillomatosis: hyperplasia of papillary dermis,

with elongation &/or widening of the dermal papillae.

Litigious: linear melanocyte proliferation within the

epidermal basal cell layer; can occur as a reactive

change or as part of a tumor of melanocytes.

ACUTE INFLAMMATORY DERMATOSES

Are acute lesions, with limited course, lasting from days to (unlike other tissues, inflammation, characterized by weeks

rather than mononuclear cells marked by these are often , & sometimes epidermal vascular, or edemaneutrophils)

subcutaneous injury. Many are self-limited & never progress; but some acute lesions may persist, resulting in transition to a chronic phase.

Urticaria

Urticaria is a common disorder, mediated by localized mast cell deregulation, resulting in dermal vascular hyperpermeability This gives rise to erythematous, edematous, & pruritic (itchy) plaques termed wheals (F14 -10). Pathogenesis

In most cases, urticaria (typical example of Type I Hypersensitivity Reaction), results from exposure to a number of antigens {Ag}, including pollens, foods, drugs, & insect venom. The Ag-react with specific IgE Abs on the surface of mast cell, induce their sensitization, degranulation & release of their vasoactive mediators.

F14-10: Urticaria. The skin of the left buttock & upper thigh is

covered with a diffuse, semi-confluent pink maculo-papular

rash, slightly raised due to dermal edema. The lesions are

usually transient & subside in 2 to 3 days.

Ag-independent urticaria may result from substances that directly incite mast cell degranulation, such as opiates & certain antibiotics.

In the vast majority of cases, no clinical cause is discovered despite extensive searching.

Hereditary angioneurotic edema results from inherited deficiency of C1 esterase inhibitor, yielding uncontrolled activation of the early components of the complement system. The resulting urticaria affects the lips, throat, eyelids, genitals, & distal extremities. When the larynx is affected, it can result in dangerous airway obstruction. ◙ H, features of urticaria are often subtle with; (1) Superficial dermal edema; (2) very sparse superficial perivenular infiltrate of mononuclear cells & scattered eosinophils,

(3) Degranulation of mast cells that normally reside around superficial dermal venules (these cells are often not prominent in routine H & E stains, but can be highlighted using special Giemsa stain).

►Clinically, Urticaria generally occurs between the ages of 20 & 40 years. Lesions develop & fade within hours (usually <24 hours), but episodes may persist for days or even months.

redto large pruritic papulesLesions vary from small

edematous plaques resulting from superficial vascular dilation & ↑ vascular permeability, leading to dermal edema. Sites include any area exposed to pressure, such as the trunk, distal extremities, & ears. Urticaria is more irritating & embarrassing than life-threatening & is managed with antihistamines, or steroids in more severe cases.

Acute Eczematous Dermatitis Eczema is a clinical term that embraces a number of conditions with different underlying etiologies.

& oozing,papulovesicular, red, are characterized by All at an early stage. The degree of these crusted lesions

changes varies with clinical subtype. With persistence, these lesions develop into raised, scaling plaques.

Clinical differences permit classification of eczematous dermatitis into: (1) allergic contact, (2) atopic, (3) drug-related eczematous, (4) photoeczematous, & (5) primary

completely when resolveMost of these forms . irritant formsthe offending stimulus is removed or exposure to it is limited, thus stressing the importance of investigating the underlying cause. ☼ Only the most common form, contact dermatitis, will be discussed here.

Pathogenesis of contact dermatitis

After initial exposure to an environmental contact sensitizing agent, e.g., poison ivy, self-proteins modified by the agent are processed by epidermal Langerhans cells that then migrate to draining LNs & present the Ag to naive T cells. This sensitization event leads to acquisition of immunologic memory;

on re-exposure to the Ag, the now-educated CD4+ T lymphocytes migrate to the affected skin sites, where they release cytokines that recruit additional inflammatory cells & also mediate the epidermal damage as in any (DHR).

forms of acute eczematous allcharacterizes Spongiosis ► dermatitis. Spongiosis is intercellular edema of the epidermis with accumulation of edema fluid within it (hence the synonym "spongiotic dermatitis“). Edema seeps into the intercellular spaces, separating the keratinocytes. Intercellular bridges are stretched & become more prominent visually, giving a "spongy"

). A1-22F appearance (

►This is accompanied by a superficial perivascular lymphocytic infiltrate, papillary dermal edema, & mast cell degranulation. Eosinophils may be present & especially prominent in spongiotic eruptions provoked by drugs, but … In general, there are no specific features for differentiating the various causes of eczema & therefore, careful clinical correlation is needed. Clinically, acute eczematous dermatitis lesions are pruritic (itchy), edematous, oozing plaques, with vesicles & bullae. With persistent Ag stimulation, lesions become progressively scaly (hyperkeratotic) & acanthotic & can become chronic. Some of these changes also result from scratching or

").Lichen Simplex Chronicusrubbing of the lesion (see "

F 22-1: Eczematous

(contact) dermatitis.

A, Spongiosis = fluid

accumulation between

epidermal cells, results in

stretching of intercellular

connections until broken

(thus the term spongiotic

dermatitis).

B, Note the patterned

erythema & scale associated

nickel contactwith

dermatitis resulting from this

woman’s necklace.

The clinical causes of eczema are sometimes divided into "inside" & "outside" jobs-disease resulting from external application of antigen (such as poison ivy) or reaction to an internal circulating antigen (such as ingested food or drug).

Susceptibility to atopic dermatitis is often inherited & this form can be more chronic, although it sometimes improves with age. Atopic individuals often suffer from asthma.

Erythema Multiforme

Erythema multiforme is an uncommon, self-limited . infections & drugsresponse to certain hypersensitivity

are those caused by herpes infectionsAmong antecedent ● simplex, mycoplasmas, & fungi such as Histoplasma Capsulatum, & Coccidiodes imitis.

include sulfonamides, penicillin, drugsThe implicated ● salicylates, hydantoins, & antimalarials.

● Patients present with an array of "multiform" lesions, including macules (F14-19), papules, vesicles, & bullae, as well as the characteristic targetoid lesion consisting of a red

-22F ( macule or papule with a pale vesicular or eroded center).A2

F14-9: Erythema multiforme, macular type. Result of toxic

hypersensitivity response to drugs, which includes

sulfonamides, penicillin, salicylates, hydantoins antiepileptic,

& antimalarials, so-called drug rash.

F 22-2: Erythema

multiforme.

A, Characteristic target-like

appearance of erythema

multiforme minor, with

central zone of dusky pink-

gray discoloration that

correlates with epidermal

necrosis or early blister

formation, surrounded by a

pink-red rim.

B, Interface dermatitis,

with aligment of lymphocytes

along the dermoepidermal

junction causing destruction

of the basal epidermal cells.

Pathogenesis of erythema multiforme

The lesions of erythema multiforme result from the action of cutaneous lymphocyte antigen (CLA) positive, skin-homing cytotoxic T cells that are concentrated in the central portion of

are more + helper & Langerhan cells4CDthe lesions, while prominent in the raised, erythematous periphery. The cytotoxic cells directed against an inciting drug or microbe presumably respond to cross-reactive antigens of the basal cell layer of skin & mucosae, damaging these tissues (Cytotoxic, or Type II Hypersensitivity Reaction).

H, Early lesions show a (1) superficial perivascular, lymphocytic infiltrate associated with dermal edema & (2) margination of lymphocytes along the dermoepidermal junction in intimate association with degenerating keratinocytes

). With time, discrete, confluent B2-22F((interface dermatitis) zones of basal epidermal necrosis occur, with concomitant

. blister formation In the more rare & severe form of this disease, toxic epidermal bullosal necrosis, the necrosis extends through the full thickness of the epidermis.

Clinical Features of erythema multiforme

Range of severity: erythema multiforme forms associated with infection, most often herpesvirus, are sometimes termed

less severebecause of their minorerythema multiforme clinical presentation.

are termed erythema multiformeforms of More severe Johnson syndrome, -, Stevensmajorerythema multiforme

toxic epidermal necrolysis. These can be life-threatening because they can cause sloughing of large portions of the epidermis & loss of moisture & infectious barriers. They are most often seen as idiopathic reactions to drugs such as antibiotics or NSAID CHRONIC INFLAMMATORY DERMATOSES

These are persistent inflammatory dermatoses that exhibit their most characteristic features over many months to years, although they may begin with an acute stage. The skin surface in some chronic inflammatory dermatoses is roughened as a result of excessive or abnormal scale formation & shedding (desquamation).

Psoriasis

Psoriasis is a common chronic inflammatory dermatosis affecting 1% to 2% of US people (6 Millions). Rarely, it is associated with arthritis, myopathy, enteropathy, & spondylitic heart disease. Pathogenesis

Psoriasis is an immunologic disease with contributions from genetic susceptibility & environmental factors. It is not known if the inciting antigens are self or environmental.

Sensitized populations of T cells enter the skin, including dermal CD4+ TH1 cells & CD8+ T cells that accumulate in the epidermis. T cells homing to the skin secrete cytokines & GFs that induce acanthosis, resulting in the characteristic lesions.

Psoriatic lesions can be induced in susceptible individuals by local trauma, a process known as the Koebner phenomenon. The trauma may induce a local inflammatory response that promotes lesion development.

While reserved for use in severe psoriatic arthritis, recent therapeutics exploits advances in our understanding of T-cell biology. Various clinically useful agents block: (1) T-cell activation & proliferation; (2) T cell trafficking & keratinocyte interaction with T cells; (3) binding of TNF to its receptor, thus inhibiting T cell functions.

, with regular downward elongation acanthosisThere is H, )A3-22F ( "test tubes in a rack"of the rete ridges, likened to

due to the ↑ epidermal cell , Extensive parakeratosis turnover & lack of maturation resulting in loss of the stratum granulosum with extensive overlying parakeratotic scale.

, i.e., thinning of the suprapapillary platesThere is epidermal cell layer overlying the tips of dermal papillae & the blood vessels within the papillae are dilated & tortuous. These vessels bleed readily when the scale is removed, giving rise to multiple punctate bleeding points (Auspitz sign).

F 22-3: Psoriasis:

A, Typical plaques showing prominent parakeratotic scale

focally infiltrated by neutrophils + marked acanthosis with

uniform downward extension of the rete ridges.

B, Chronic plaques of psoriasis show silvery-white scale on

the surface of erythematous plaques.

Neutrophils form small aggregates within both the spongiotic superficial epidermis (pustules of Kogoj) & the parakeratotic

). Munro microabscessesstratum corneum (

Similar changes can be seen in superficial fungal infections, & it is important to exclude this possibility with special stains in newly diagnosed psoriasis.

Clinically, Psoriasis most frequently affects the skin of the elbows, knees, scalp, lumbosacral areas, intergluteal cleft, & glans penis.

Typical lesion is a well-demarcated, pink to salmon-colored plaque covered by loosely adherent silver-white

). B3-22F( scale

% of cases of psoriasis & consist of 30occur in Nail changes yellow-brown discoloration, pitting, thickening, crumbling & separation of the nail plate from the underlying bed (onycholysis). In most cases, psoriasis is limited in distribution, but it can be widespread & severe on occasion.

Lichen Planus

►Skin & mucosal “6p's“ lesions “, pruritic + purple + polygonal + planar + papules + plaques" (F 13-12). Lichen planus is self-limited & usually resolves spontaneously 1 to 2 years after onset. Oral lesions may persist for years.

The pathogenesis is not known. Expression of altered Ags (which could be due to viral infection or drug treatment) at the level of the basal cell layer & the dermoepidermal junction may elicit a CD8+ Tcell-mediated cytotoxic immune response.

◙ H, Lichen planus characterized by interface dermatitis; i.e., a dense, continuous inflammatory infiltrate of lymphocytes along the dermoepidermal junction, resulting in basal cell keratinocytes degeneration & necrosis, causes the dermoepidermal interface to assume an angulated, zigzag

nucleate, necrotic -). NonA4-22F ( ("sawtoothing").contour basal cells are seen in the inflamed papillary dermis & are

. Civatte bodiesreferred to as colloid bodies or

F14-12: Lichen planus. Polygonal, glistening , flat-topped

pinkish papules, the surface of which contain characteristic

Itchy chronic papules ►(Wickham‟s striae). whitish lines

(lasting months to years) typically distributed over flexor

aspects of the wrists, forearms & legs.

Wickham‟s

striae “whitish

lines”

F 22-4: Lichen planus.

A, There is interface dermatitis, with a thick & dens band of

lymphocytes along the dermoepidermal junction. The rete

ridges show pointed “saw- tooth,” architecture. There is also

acanthosis + hypergranulosis + & hyperkeratosis.

B, Multiple flat-topped papules with white, lacey or netlike

markings (Wickham striae) are characteristic.

Clinical Features

Cutaneous lesions consist of pruritic, violaceous, flat-topped papules, which may coalesce focally to form

may result from melanin Hyperpigmentation ).B4-22F( plaquesloss into the dermis from the damaged basal cell layer.

Multiple lesions are symmetrically distributed, particularly on the extremities, often about the wrists & elbows, & on the glans penis. In 70% of cases, oral lesions are present as white, reticulated, or netlike areas involving the mucosa.

Lichen Simplex Chronicus

Lichen simplex chronicus presents as roughening of the skin that takes on an appearance reminiscent of lichen on a tree.

local repetitive trauma such as It is a response to ► . When this condition is continual rubbing or scratching

localized to nodules, it is termed prurigo nodularis.

Pathogenesis:- it is probable that repetitive trauma induces epithelial hyperplasia with eventual dermal scarring.

◙ H, lesions are characterized by acanthosis (with elongation of the rete ridges) + hypergranulosis + hyperkeratosis + fibrosis of the papillary dermis with a chronic inflammatory

). 5-22F infiltrate (

volar normallesions are similar to Interestingly, these ☼ (palms & soles) skin, an area conditioned by constant "trauma," but at these sites the changes appear to represent an adaptive response to such stimuli.

Clinically, the lesions are often raised & erythematous, with ↑ scale & can be mistaken for keratinocytic neoplasms. Often lichen simplex chronicus is superimposed upon, & masks another (often pruritic) dermatomes; & it is therefore important to rule out an underlying cause, But…

inflicted!-entirely selflesion can be keep in mind that the

F 22-5: Lichen simplex chronics. Acanthosis (with

elongation of the rete ridges)+ hypergranulosis+

hyperkeratosis+ superficial dermal fibrosis & vascular ectasia.

There is no cytological atypia thus distinguishing it form

squamous cell carcinoma.

SUMMARY: Inflammatory Dermatoses.

There are many specific inflammatory dermatoses; ), (urticaria IgE antibodieswhich may be mediated by

eczema, erythema ( specific T cells-antigenlichen simplex ( trauma), & multiforme, & psoriasis

chronicus). The histologic features can be grouped into patterns of inflammation, such as interface dermatitis (e.g. lichen planus & erythema multiforme), superficial perivascular dermatitis, & panniculitis (inflammation in subcutaneous fat) that provide insight into the mechanism & the ability to organize the diseases into pathogenic categories. ☼ Careful clinical correlation is needed to diagnose specific skin diseases, since the features overlap within histologic pattern groups.

INFECTIOUS DERMATOSES

Bacterial Infection

These range from superficial infections caused by Staph. & ,…)6-22F ( impetigospp., known as Strept.

to deeper dermal abscesses caused by anaerobes like Pseudomonas aeruginosa, associated with puncture wounds.

◙ H, skin biopsy typically shows spongiotic epidermis with a neutrophilic infiltrate. Cocci can be demonstrated using Gram stain in the superficial epidermis. Culture & sensitivity ( C/S) to various antibiotics can be useful.

Clinically, commonest skin bacterial infections is

Impetigo primarily seen in children, but can affect adults. Impetigo transmitted by direct contact, usually caused by Staph. aureus, or less commonly Strept. pyogenes. Impetigo often begins as a single small macule that rapidly evolves into a larger lesion with a "honey-colored crust" (dried serum or scab).

Impetigo most often involved the extremities, nose, & ). 6-22F ( mouth

F 22-6: Microbial infections. This child’s arm is involved by

resulting from a superficial bacterial infection. impetigo

Fungal Infection

Fungal infections are varied & range from superficial infections with Candida species to life-threatening infections of immunosuppressed individuals with Aspergillus species. In general, a fungal infection can be:

(1) Very superficial (stratum corneum, hair, & nails), (2) Deep, involving the dermis or subcutis, or

(3) Systemic involving skin by hematogenous spread (often in an immunocompromised host).

Pathogenesis

Superficial infections are often associated with a neutrophilic infiltrate in the epidermis. While bacterial dermal infections induce neutrophil-rich abscesses, fungal dermal infections often elicit a granulomatous response. The deeper infections are usually more destructive; in particular, Aspergillus can be angio- (vascular) invasive.

H, Superficial Candida infections often induce a clinical response that can mimic psoriasis {this indicates that psoriasiform hyperplasia is a generalized response of skin to stimulation by the immune system}. therefore, it is… Essential to perform a fungal stain to exclude infection in a newly diagnose case of psoriasis.

Deeper fungal infections produce greater tissue damage, probably induced by both the microbes themselves & the vigorous host immune response to their presence.

Clinical Features

Superficial infections (eg Candida) usually show erythematous macules with superficial scale that can be pruritic,

while deeper infections such as those seen with Aspergillus species in immunocompromised hosts are erythematous, often nodular, & sometimes show evidence of local hemorrhage.

Verrucae (Warts)

Verrucae are common lesions of children & adolescents, although they may be encountered at any age. Verrucae are caused by human papillomavirus (HPV). Transmission is by direct contact between individuals or autoinoculation.

Verrucae are generally self-limited, most often regressing spontaneously within 6 months to 2 years Pathogenesis

Some members of the HPV family (16 & 18) are associated with preneoplastic & invasive cancers of the anogenital region.

However, in contrast to HPV-associated carcinomas, most warts are caused by distinct low-risk HPV types that lack potential for causing malignant transformation. The virus subverts cell cycle control to allow ↑ proliferation of epithelial cells & production of new virus.

Normal immune response usually limits the growth of these tumors, but immunodeficiency can be associated with ↑ numbers & size of verrucae.

◙ H, features common to verrucae include: ● Verrucous or papillomatous epidermal hyperplasia; often

, top) & A7-22F ( like)-crownundulant in character (● koilocytosis = cytoplasmic vacuolization that preferentially involves the more superficial epidermal layers, producing halos of pallor surrounding infected nuclei (perinuclear hallow). ● Infected cells may also demonstrate keratohyaline granules & jagged eosinophilic intracytoplasmic protein aggregates as a

, bottom). A7-22Fresult of impaired maturation (

Clinically, Warts can be classified into several types on the basis of their morphology & location. In addition, each type of wart is generally caused by a distinct HPV type.

Verruca vulgaris is the most common type of wart, occuring anywhere, but are found most frequent on the hands, particularly on the dorsal surfaces & periungual (near the nail) areas, where they appear as gray-white to tan, flat to convex,

).B7-22Flike surface (-mm papules with a rough, pebble10-1

F 22-7: Verruca vulgaris. A, LP symmetrical papillary

epidermal proliferation radiating like the points of a crown (top).

HP shows nuclear pallor, prominent keratohyalin granules of

HPV infection

B, Multiple papules with

rough, pebble-like

surfaces at infection

sites.

LP

HP

Verruca plana (flat wart) is common on the face or dorsal surfaces of the hands. These warts are flat, smooth, tan macules.

Verruca plantaris & verruca palmaris occur on the soles & palms, respectively. These rough, scaly lesions may reach 1-2 cm in coalesce, & be confused with ordinary calluses.

Condyloma acuminatum (venereal wart) occurs on the penis, female genitalia, urethra, & perianal areas.

BLISTERING (BULLOUS) DISORDERS

These are disorders in which blisters are the primary & most distinctive features; although vesicles & bullae (blisters) occur as a secondary phenomenon in several unrelated conditions {e.g., herpesvirus infection, acute eczematous (spongiotic) dermatitis}, Blisters can occur at multiple levels within the skin, & assessment of their location within the skin is essential for an

).8-22Faccurate histologic diagnosis (

Pemphigus (Vulgaris & Foliaceus)

Pemphigus is a rare autoimmune blistering disorder resulting from loss of integrity of normal intercellular attachments within the epidermis & mucosal epithelium.

Most individuals who develop pemphigus are middle-aged & older. There are 3 major variants of pemphigus; (1) vulgaris, (2) foliaceus, & (3) paraneoplastic pemphigus. The latter is associated with internal malignancy & will not be discussed here.

F 22-8: Levels of blister formation.

A, Subcorneal (as in pemphigus foliaceus).

B, Suprabasal (as in pemphigus vulgaris).

C, Subepidermal (as in bullous pemphigoid or dermatitis

herpetiformis).

Subcorneal Suprabasal Subepidermal

Pathogenesis

Both pemphigus vulgaris & pemphigus foliaceus are (Abs directed reaction type II hypersensitivity caused by a

against a fixed tissue Ag) & show linkage to specific HLA types.

to intercellular pathogenic IgG Abs Patient sera contain desmosomal proteins (desmoglein types 1 & 3) of skin & mucous membranes. The distribution of these proteins within the epidermis determines the location of the lesions.

By direct immunofluorescence, lesional sites show a characteristic netlike “fishnet” pattern of intercellular IgG

primarily The antibodies seem to function ). 9-22F deposits (by disrupting the intercellular adhesive function of the desmosomes & may activate intercellular proteases as well.

◙ H, Common histologic denominator in all forms of pemphigus (lysis of the intercellular adhesion sites) within acantholysisis

a squamous epithelial surface. Detached acantholytic cells become rounded.

F 22-9: A, Pemphigus

vulgaris.

There is uniform

deposition of

immunoglobulin &

complement (green) along

the cell membranes of

keratinocytes, producing a

characteristic “fishnet”

appearance.

B, The immunoglobulin

deposits are more

superficial in pemphigus

foliaceus.

In pemphigus vulgaris, acantholysis selectively involves the layer of cells immediately above the basal cell layer

). B10-22F( uprabasal blisterS= In pemphigus foliaceus, acantholysis selectively involves the superficial epidermis at the level of the stratum granulosum

). B11-22F( Subcorneal blister= Variable superficial dermal infiltration by lymphocytes, histiocytes, & eosinophils accompanies all forms of pemphigus.

Clinically, Pemphigus vulgaris, the most common type, involves mucosa & skin, especially on the scalp, face, axillae, groin, trunk, & points of pressure. Lesions are superficial vesicles &

, leaving erosions covered with rupture easilybullae that ). A10-22Fserum crust (

Pemphigus foliaceus, a rare & benign form of pemphigus, results in bullae confined to skin, with infrequent involvement of mucous membranes. The blisters are so superficial that only zones of erythema & crusting sites of previous blister rupture

). A11-22Fare detected (

F 22-10: Pemphigus

vulgaris. A, Leg eroded area

representing confluent blisters

with loss of their roofs.

B, Suprabasal acantholysis

results in a suprabasal

(intraepidermal) blister,

containing rounded

kertatinocytes that are

separated from their

neighbors.

▲Initially, a single row of

basal cells is present on the

floor of the blister, but these

cells can divide & repopulate

this area with keratinocytes,

as seen in this case (inset, at

lower left)

F 22-11: Pemphigus

foliaceus.

A, Blisters are much less

erosive than those seen in

pemphigus vulgaris, since

the level of the blisters

(subcorneal) is more

superficial.

B, Subcorneal

separation of the epithelium

is seen.

Bullous Pemphigoid

individuals, bullous pemphigoid shows a elderlyAffecting wide range of clinical presentations, typically with generalized skin lesions & involvement of mucosal surfaces

Pathogenesis

Bullous pemphigoid is an autoimmune disease in which the characteristic finding is linear deposition of IgG Abs &

). A12-22F ( complement in the basement membrane zone

Reactivity also occurs in the basal cell-basement membrane attachment plaques (hemidesmosomes; a protein involves normally in dermoepidermal bonding), where most of the bullous pemphigoid Ag is located.

IgG auto-Abs to hemidesmosome components fixes complement with subsequent tissue injury by means of locally recruited neutrophils & eosinophils.

F22-12 Bullous pemphigoid

A, Both IgG Ab &

complement can be detected

by direct immunofluorescence

as a liner band outlining the

subepidermal basement

membrane zone.

B, The subepidermal vesicle

has an inflammatory infiltrate

rich in eosinophils.

C, Tense, fluid-filled blisters

result from vacuolization of

the basal layer, producing

subepidermal blisters.

Epidermis

Dermis

F14-11: Bullous pemphigoid. Several swollen vesicles

(bullae) & their content of clear yellow fluid

subepidermal, H, Bullous pemphigoid is characterized by a ◙. Early lesions show a perivascular blister nonacantholytic

infiltrate of lymphocytes, eosinophils, & an occasional neutrophils; superficial dermal edema, & associated basal cell layer vacuolization. The vacuolated basal cell layer eventually

). B12-22Ffilled blister (-gives rise to a fluid

Because the blister roof involves full-thickness epidermis, it is more resistant to rupture than blisters in pemphigus, & if uncomplicated by infection, heal without scarring.

, filled with clear fluid, tense bullaelesions are Clinically, ►

).. 11-14& C12-22F( on normal or erythematous skin Sites of occurrence include the inner aspects of the thighs, flexor surfaces of the forearms, axillae, groin, & lower abdomen. Oral involvement is present in 1/3 of patients.

Gestational pemphigoid occurs late in the 2nd or 3rd trimester of pregnancy & resolves after childbirth.

Dermatitis Herpetiformis

Dermatitis herpetiformis is a rare disorder characterized by urticaria & grouped vesicles. The disease affects predominantly males, often in the 3rd & 4th decades..

Pathogenesis

In some cases, dermatitis herpetiformis occurs in association with intestinal celiac disease. This association provides a clue to its pathogenesis.

Genetically predisposed individuals develop IgA Abs to dietary gluten (derived from the wheat protein gliadin).

The Abs cross-react with reticulin, a component of the anchoring fibrils that tether the epidermal basement membrane to the superficial dermis. The resultant injury & inflammation produce a subepidermal blister. Some people with dermatitis herpetiformis & gluten-sensitive enteropathy respond to a gluten-free diet.

Morphology

As an early event, fibrin & neutrophils accumulate selectively at the tips of dermal papillae, forming small microabscesses

). A13-22F( The basal cells overlying these microabscesses show vacuolization & focal dermoepidermal separation that ultimately coalesce to form a true subepidermal blister. By direct immunofluorescence, dermatitis herpetiformis shows discontinuous, granular deposits of IgA selectively

).B13-22F localized in the tips of dermal papillae (

Clinical Features

of dermatitis herpetiformis urticarial plaques & vesicles The , pruriticextremely are

bilateral, symmetric, & grouped, involving preferentially the -22Fextensor surfaces, elbows, knees, upper back, & buttocks (

).C13

F 22-13: Dermatitis

herpetiformis.

A, The blisters are associated

with basal cell layer injury

initially caused by

accumulation of neutrophils

(microabscesses) at the tips of

dermal papillae.

B, Selective & characteristic

deposition of IgA auto-Ab at

the tips of dermal papillae.

C, Elbows & arms grouped

lesions, consist of intact &

eroded (usually scratched)

erythematous blisters.

SUMMARY: Blistering Disorders

Blistering disorders are classified according to the epidermal layer where the separation occurs. This group of diseases is often caused by autoreactive antibodies to constituents of the epithelium or basement membrane.

Pemphigus is associated with formation of IgG auto-Abs to intercellular (desmogleins) with resulting acantholysis in the

subcorneal epidermis; giving rise to bullae that are (superficial) in the rare pemphigus foliaceus & suprabasal

(deeper) in the more common pemphigus vulgaris.

Bullous pemphigoid shows deposition of IgG auto-antibodies to basement membrane proteins

. subepidermal blister(hemidesmosomes) & produces a Dermatitis herpetiformis is associated with deposition of IgA auto-Abs to (reticulin) fibrils that bind epidermal

subepidermal basement membrane to dermis, thus producing . celiac disease. This disease may be associated with blisters

TUMORS (T) Benign & Premalignant Epithelial Lesions

Benign epithelial T are common & are probably derived from stem cells that reside in the epidermis & hair follicles, that tend to differentiate toward cells & structures in the epidermis & adenexa. The majority of these tumors show limited growth & do not undergo malignant transformation. Seborrheic Keratosis = Basal cell papilloma Common epidermal T, occur most frequently in middle-aged or older individuals, arise spontaneously & may become particularly numerous on the trunk, although the extremities, head, & neck may also be involved. Pathogenesis

Significant fraction of these T harbor activating mutations in fibroblast (FGF) receptor 3. In rare cases, the explosive onset of hundreds of lesions may occur as a paraneoplastic syndrome (sign of Lesser-Trelat) & patients with this presentation may harbor internal malignancies that produce GFs that stimulate epidermal proliferation.

Clinically, Basal cell papillomas are exophytic, round, flat, coin-like plaques that vary in diameter from mms to cms, tan to dark brown & usually show a velvety to granular surface

). 19-14& B14-22F(

Occasionally, they become inflamed,

◙ H, they composed of sheets of small cells that resemble ). A14-22Fof the normal epidermis ( monotonous basal cells

Hyperkeratosis occurs at the surface & the presence of filled cysts (horn cysts) is characteristic -keratinsmall

.feature

Variable melanin pigmentation is present within these basaloid cells, accounting for the brown coloration seen;

warranting their removal. mimicking melanoma,sometimes

F 22-14: Seborrheic

keratosis (Basal cell

papilloma).

A, Tumor consists of

proliferating, benign

basaloid keratinocytes with

a tendency to form keratin

microcysts (horn cysts).

B, This roughen, brown,

waxy lesion almost appears

to be “stuck on the skin.

F14-19: Seborrheic keratosis (Basal cell papilloma)

A bisected, grey-brown pigmented & lobulated 1.5cm

in Ǿ, sharply- defined papillomatous growth.

Sebaceous Adenoma

Sebaceous adenomas are rare T that primarily occur in the head & neck region of older individuals. They usually present as flesh-colored papules & can be a marker for an internal

!can save a life. Knowledge of this association malignancy

Pathogenesis

Much has been learned about the pathogenesis of these T by their association with the Muir-Torre syndrome.

In this condition, the T may be multiple or be distributed outside of the head & neck region. In addition there may be internal malignancy, most often colon carcinoma. These cases are a subset of the hereditary nonpolyposis colorectal carcinoma syndrome (HNPCC) which is associated with microsatellite instability due to loss of a DNA mismatch

).A15-22F (2 or MSH1 repair protein, either MLH

F 22-15: Sebaceous adenoma.

A, Immunohistochemistry

reveals loss () of nuclear

expression of the DNA

mismatch repair protein MSH2;

but retention in normal

epidermis & lymphocytes,

indicating probable association

with the Muir-Torre syndrome

B, HP: lobular proliferation of

sebocytes with ↑ peripheral

basaloid cells & more mature

sebocytes in the central portion.

Characteristic of sebocytes is

vacuolated cytoplasm (inset)

Morphology

◙ H, Sebaceous adenomas show a lobular proliferation of sebocytes that maintain an organoid

). The basal cell layer is B15-22Fappearance (normally two cells thick, but this is variably expanded in adenomas with maturation to mature sebocytes in the center of the lesion. These cells have clear cytoplasm vacuolated by vesicles filled with sebum. Clinical Features

Sebaceous adenomas are benign & self-limited, tend to occur in the face.

Clinically these can be separated from the much more common sebaceous hyperplasia, which has (1) an umbilicated (dimpled) center & (2) consists of hypertrophic sebaceous glands surrounding a central hair follicle.

Actinic Keratosis

Before the development of overt malignancy of the epidermis, a series of progressively dysplastic changes occurs. Because such skin dysplasia is usually the result of chronic exposure to sunlight & is associated with hyperkeratosis, these lesions are called actinic (i.e., sun-related) keratoses.

Pathogenesis

Although some actinic keratosis regress or remain stable, however, many do become malignant to warrant their local eradication. Mutation of p53 is often an early event with molecular changes suggestive of ultraviolet light injury.

H, Lower portions of the epidermis show cytologic atypia, ) or with early A16-22F often with hyperplasia of basal cells (

atrophy that results in diffuse thinning of the epidermal surface of the lesion. The dermis contains thickened, blue-gray elastic fibers (solar elastosis), the result of chronic sun damage.

F 22-16: Actinic keratosis.

A, Basal cell layer atypia (dyskeratosis) associated with marked

hyperkeratosis, parakeratosis, & dermal solar elastosis ()

B, Lesions on the cheek, nose, & chin of this woman forming

zones of redness or sandpaper-like keratinization.

C, More advanced lesions show full-thickness atypia,

qualifying as carcinoma in situ.

There are hyperkeratosis & parakeratosis.

Some, but not all lesions, progress to full-thickness atypia ).C16-22F ( squamous cell ca in situamounting to

-SPAINUseful for remembering the histologic features is ☼☼ a sun-soaked country perfect for acquiring such lesions:- (S) Solar elastosis (dermal sun damage), (P) Parakeratosis, (A) Atypia (keratinocytic), (I) Inflammation (lymphocytes in the superficial dermis), & (N) Not full thickness atypia.

Clinically, actinic keratosis is very common in fair-skinned individuals, usually less than 1 cm in diameter; tan-brown or red & has a rough, sandpaper-like consistency

(face, exposed areas-sun), with predilection for B16-22F(arms, dorsum of the hands). Lesions accumulate with age & degree of sun exposure.

cryotherapywith local treatedThe lesions can be or topical chemotherapeutic. (superficial freezing)

Malignant Epidermal Tumors: Squamous Cell Carcinoma

SCCa is a common T, arising on sun-exposed sites in older people. with a higher incidence in men than in women. ▼Predisposing factors include → sunlight + ionizing radiation + industrial carcinogens (tars & oils) + chronic ulcers + old burn scars + ingestion of arsenicals. Pathogenesis

☼ ☼ The most common exogenous cause of skin SCCa is UV light exposure, with subsequent unrepaired DNA damage. Both ▼Xeroderma pigmentosum patients & ▼ Immunosuppressed patients from chemotherapy or organ transplantation, whom are likely to be associated with high-risk HPV types infections are at ↑ risk.

☼ ☼ UV light → (1) inducing mutations &

(2) may have a transient immunosuppressive effect on skin by impairing antigen presentation by Langerhans cells. This may contribute to tumorigenesis by weakening immunosurveillance. p53 mutations with associated UV mutation signatures are common, as are activating mutations in RAS.

As with SCCa at other sites, those in the skin may be preceded by in situ lesions.

C) characterized microscopically by 16 -22(F SCCa in situ full thickness epidermal squamous dyplasia, with atypical cells at all levels of the epidermis, with nuclear crowding &

, with intact basement membrane.BUTdisorganization,

When these cells break through the basement membrane, ). A17-22F (SCCa invasive become SCCa in situthe

Invasive SCCa (◙14-50) differentiation ranges from : ▲well-differentiated tumors, formed by atypical squamous cells arranged in orderly lobules showing central keratinization (epithelial pearls or cell nests ◙14-50) to… ▼poorly-differentiated (anaplastic) with rounded cells, foci of necrosis & single-cell keratinization (dyskeratosis).

☼ While morphologic variation is wide, all SCCa share the feature of keratinization.

F14-25: Squamous cell carcinoma: Skin.

Advanced SCCa of the inner canthus of the right eye.

The large papillary growth forms elevated mass, with areas of

ulceration covered with a thick creamy-white slough.

SCCa

◙ 14-50: Squamous cell carcinoma. Malignant squamous

epithelial cells forming long strands, containing

(1) foci of laminated sheets of deeply eosinophilic keratinized

epithelial cells (thick arrows, „cell nests‟ or „epithelial pearls’.

(2) At the periphery of the strands, there are larger squamous

cells with large hyperchromatic & pleomorphic nuclei &

numerous mitotic figures (thin arrows).

F 22-17: Invasive squamous

cell carcinoma.

A, The SCCa invades the

dermis as irregular

projections of atypical

squamous epithelium; this

particular case is acantholytic

(i.e., the squamous cells are

poorly cohesive).

B, A nodular hyperkeratotic

SCCa occurring on the ear,

to a metastasiswith

postauricular lymph node

(arrow).

SCCa

LN

Clinically, SCCa in situ appears as sharply defined, red, scaling plaques; many arise from prior actinic keratoses.

Invasive SCCa lesions are nodular, show variable ). B17-22F ( ulceratescale, & may

They usually discovered while small & resectable; less than 5% have metastases to regional LN at diagnosis.

The likelihood of metastasis is related to the tumor thickness & the degree of invasion into the subcutis.

SCCa arising in the context of actinic keratoses may behave in a less aggressive fashion, while SCCa arising in burn scars, ulcers, & skin not exposed to the sun tend to behave less predictably.

Mucosal SCCa (oral, pulmonary, esophageal, etc.) are generally a much more aggressive cancers.

Basal Cell Carcinoma (BCCa, F14-23 & 24)

.wide-world most common human cancerthe BCCa is ☼BCCa is a slow-growing invasive T that rarely metastasizes. BCCa tends to occur at sites subject to chronic sun exposure (especially the face) & in lightly pigmented people.

▼ As with SCCa, the incidence of BCCa ↑ with: (1) immunosuppression (though not as dramatically as that of SCCa)

(2) in individuals with inherited defects in DNA repair. Pathogenesis

BCCa has been associated with dysregulation of the sonic hedgehog, or PTCH, pathway. Inherited defects in the PTCH gene with subsequent loss of heterozygosity in the numerous individual T foci cause the familial basal cell carcinoma

functions as a PTCH. Thus, Gorlin syndrome”“ syndromeclassic tumor suppressor. Some component of the PTCH pathway is also mutated in the great majority of sporadic BCCa; mutations in p53 are also common.

BCCa Morphology

☼ Small BCCa cells resemble the normal epidermal basal cell layer from which they are derived Because they arise from the epidermis or, sometimes, follicular epithelium,….. they are not encountered on mucosal surfaces.

The two common patterns seen are either ►multifocal growths originating from the epidermis (superficial type), or ▼nodular lesions growing downward into the dermis as cords & islands of basophilic baseloid cells with hyperchromatic nuclei, embedded in a fibrotic to

).A18-22Fmucinous matrix (

☼ Peripheral T cell nuclei align in the outermost layer + with separation from the stroma, (palisading)

).B18-22For separation artifact ( cleftcreating a

F14-23: Basal cell carcinoma: Two BCCa of the left eye, in

the inner canthus & on the lower eyelid. Both are smooth

ulcerated nodules with characteristic “rolled” red border.

, is BCCa is the most common human cancer in the world ☼

a locally invasive, slowly growing cancer, occurs predominantly

in fair- skinned people (as in this patient), in the part of the

face bounded by the hairline, ears & upper lip.

F14-24: Basal cell carcinoma („Rodent ulcer‟)

Advance, large ulcerating BCCa of the left temporal region, with

bright red granular base & a smooth, white, rolled border.

☼This is the cicatricial type of BCCa which is characterized by:

(1) superficial peripheral spread (arrow) with ulceration &

(2) subsequent central scarring (so-called fire in the field).

F 22-18: Basal cell carcinoma, in A, formed by multiple

nodules of basaloid cells infiltrating a fibrotic stroma.

B, Tumor cells (similar to basal cell layer cells of normal

epithelium) with scant cytoplasm & small hyperchromatic nuclei&

from the stroma. clefting) 2&( peripheral palisading) 1typical (

C, Pearly smooth papule with associated telangiectatic vessels.

Clinically, BCCa present as pearly papules, often containing prominent, dilated subepidermal blood

). Some BCCa C18-22F ( vessels (telangiectasia)contain melanin pigment & thus appear similar to melanocytic nevi or melanomas. Although BCCa may ulcerate (Rodent ulcer) & may show extensive local invasion of bone or of facial sinuses after many years of neglect, the

BCCa metastasis is extremely rare (Exam Case!).

BCCa is usually treated by complete local excision.

Tumors & Tumor-Like Lesions of Melanocytes Melanocytic Nevi

any denotes nevusStrictly speaking, the term , nevus Melanocytic. congenital lesion of the skin

however, refers to any benign congenital or acquired neoplasm of melanocytes.

Common Nevus (Melanocytic nevus) Pathogenesis

Melanocytic nevi are derived from the transformation of highly dendritic melanocytes {that are normally interspersed among basal keratinocytes}.

Progressive growth of nevus cells from the dermoepidermal junction into the underlying dermis is accompanied by maturation.

Superficial nevus cells are larger & less mature, tend to produce melanin pigment, & grow in nests;

Deeper nevus cells are smaller & more mature, produce little or no pigment, & grow in cords.

This maturation is of diagnostic importance, since melanomas usually show little or no maturation.

The majority of benign nevi have been shown to harbor an activating mutation in BRAF (a protein downstream from RAS in the extracellular receptor kinase pathway) or, less commonly, in RAS itself. These two mutations are mutually exclusive; the growth of melanocytic nevi is self-limited.

Development: (Fig 22-22)

-to-melanocytic nevi are composed of round earlynitially, I oval cells that grow in "nests" along the dermoepidermal junction, with uniform & round nuclei, inconspicuous nucleoli &

junctional nevi.little or no mitotic activity. These are called

, junctional nevi grow into the underlying dermis as Later compound nevi.nests or cords of cells, forming

the epidermal nests may be lost entirely to In older lesions, ). A19-22F ( dermal nevi-intra pureleave

Compound &dermal nevi are more elevated than junctional nevi

Clinically, numerous types of melanocytic nevi are present, the commonest are tan-to-brown, uniformly pigmented, small (usually ≤5 mm Ǿ), papules, with well-defined, rounded borders

). B19-22F (

Although these lesions are of cosmetic interest only & even referred to as "beauty spots“, prominently displayed on some celebrated faces, they can become irritating or mimic melanoma & thus may be surgically removed.

F 22-22: Development of melanocytic nevi & melanoma.

Junctional

nevus Compound

Pure intra-

dermal Extreme

maturation

Normal

lentiginous

hyperplasia

Radial growth

Vertical growth

☻

F 22-19: Melanotyic (Nevocytic) nevous.

A, ◙ Pure dermal nevus, showing rounded melanocytes

& cells loss of pigmentationextending into the dermis with

sings of more separated with depth, & becoming smaller

maturation.

B, Grossly, melanocytic nevi are relatively small, symmetric,

& uniformly pigmented.

Dysplastic Nevus

Dysplastic nevi may occur sporadically (in which the risk of malignant transformation seems very low). or in a familial form (inherited as an autosomal dominant & is considered precursors of melanoma).

Pathogenesis

A subset of dysplastic nevi are precursors of melanoma. In individuals with a family history of melanoma, the melanomas occur only in individuals who first develop dysplastic nevi. In these cases, the lifetime risk of developing melanoma is 100%.

The number of dysplastic nevi correlates with the risk of developing melanoma & transition from dysplastic nevus to early melanoma has been documented both clinically & histologically.

Despite such documented evolution from dysplastic nevi to melanoma….

► Most melanomas arise de novo & not from a preexisting nevus.

particular anyThus, the likelihood that , dysplastic or otherwise, would individual nevus

exceedingly low.is into melanomadevelop Consequently, these lesions should be viewed as markers of melanoma risk.

are mutations BRAFor RASActivating

encountered in dysplastic as well as in melanocytic nevi; additional complementing mutations occur in melanoma.

Morphology

Dysplastic nevi consist mainly of compound nevi, with both architectural & cytologic evidence of abnormal growth. In this sense they have some histologic & clinical properties that are reminiscent of both benign nevi & melanoma.

Nevus cell nests within the epidermis may be enlarged & exhibit abnormal fusion or coalescence with adjacent nests; with single nevus cells beginning to replace the normal basal cell layer along the dermoepidermal junction, producing so-

).B22-22F ( lentiginous hyperplasia called

Cytologic atypia {irregular, angulated nuclear contours & ). A&B20 -22F hyperchromasia is frequently observed (

Host response to these lesions occur in the superficial dermis including: (1) sparse lymphocytic infiltrate, (2) loss of melanin pigment with phagocytosis by dermal macrophages (melanin pigment incontinence), & (3) linear fibrosis surrounding epidermal nests of melanocytes.

Clinical Features: Dysplastic nevi are:

mm in Ø) 5 (> than most acquired nevilarger usually

of lesions on the body hundredsmay occur as

), C20-22F (surface

unlike ordinary nevi, they have a tendency to occur as well as not exposed to the sunon body surfaces

on sun-exposed body surfaces,

to slightly raised plaques, with a "pebbly" flat are

surface, & usually show variable pigmentation &

, inset).C20-22F irregular borders (

in multiple documentedDysplastic nevi have been

members of families to be prone to the development

the "familial melanoma of malignant melanoma (

syndrome").

dermal= central Compound dysplastic neviA, : 20-22F

component, correlates (see C, inset) with the more pigmented

junctional& raised central zone + an asymmetric “shoulder” of

melanocytes (left) correlates with the less pigmented flat

peripheral rim. B, Atypical nevous cells with irregular &

hyperchromatic nuclei. C, Back of dysplastic nevous

syndrome individual with numerous irregular nevi {>5mm in Ǿ

with irregular borders & variable pigmentation (inset)}.

Melanoma

Melanoma is less common, but much more deadly than BCCa or SCCa. Today, as a result of ↑ public awareness of the earliest signs of skin melanomas, most melanomas are cured

incidence of melanoma has ↑ surgically. Nonetheless, the , at least in part a dramatically over the last several decades

, necessitating vigorous surveillance.sun exposureresult of ↑

Pathogenesis

As with other skin cancers, sunlight plays an important role in the development of melanoma. Intense intermittent exposure at an early age is particularly harmful.

The incidence is highest in sun-exposed skin & in geographic locales such as New Zealand & Australia where sun exposure is high & the protective mantle of melanin is sparse (fair skin). Sunlight, however, does not seem to be the only predisposing factor; the presence of preexisting nevi & hereditary predisposition also play a role.

Central to an understanding of the complicated histology of melanoma is the concept of progression from an intraepithelial (in situ) to invasive (dermal) growth, or from the radial to the vertical growth.

) indicates the initial tendency of a A21-22F (Radial growth within the epidermis as an horizontallymelanoma to grow

& in the superficial dermal layers, often for a ) in situ,1(prolonged period. In this stage, melanoma cells (2) do not have the capacity to metastasize, & there is (3) no evidence of angiogenesis, (4) vast majority of these lesions are surgically curable,

vertical) 1With time, the pattern of growth assumes a ( component, & the melanoma now grows downward into the deeper dermal layers as an expansile mass lacking cellular

is heralded growth erticalV). E22-22& B21-22F maturation (nodule in the relatively flat development of a clinically by the

) correlates with the emergence of a 2& (phase radial growth .potential metastatic clone of cells with

F 22-21

adial growth: spread of melanoma cells in epidermis (flat macular areas in D).A, R

downward growth into deeper dermal layers (nodular areas in D) B, Vertical:

F14-27: Malignant melanoma. Local spread.

Many small metastatic satellite nodules have formed in the

tissue around the ulcerated & pigmented primary melanoma

chest wall.(right) which was situated on the

Primary melanoma

Satellite

nodules

F14-26: Malignant melanoma. Deeply pigmented, black,

. skin of the backcm situated on the 1X2X2elevated tumor

Note that in the dermis, beneath & to the left of the tumor, there

is a diffuse flat spreading brownish-colored lesion, suggesting

.melanoma arose in a previously benign nevousthat the

Malignant melanoma

Previously Benign nevous

F14-28: Malignant melanoma of the back of the knee.

Lower large blue-black spherical mass is the primary cancer.

satellite. metastaticnodule above it is a ulceratedThe

Primary malignant melanoma

Malignant melanoma: metastatic satellite

Melanoma is a highly aggressive malignancy; tumor only a few millimeters in thickness can give rise to metastasis & ultimately the death of the patient.

The probability of metastasis is predicted by measuring the depth of invasion in mms of this vertical growth phase nodule below the top of the granular cell layer of the overlying

Other indicators of metastatic (Breslow thickness).epidermis potential are lymphatic density, mitotic rate, & overlying ulceration.

Metastases involve not only regional LNs, but also liver, virtually any other site that can be seeded lungs, brain, &

Sentinel LN biopsy (first by the hematogenous route!!!draining node (s) of a primary melanoma) at the time of surgery provides additional information on biological aggressiveness. In some cases, metastases may appear for the first time many years after complete surgical excision of the primary tumor (in one personal case, in Newcastle upon Tyne RVI (UK) 1978, after 20 years!), suggesting a long phase of dormancy.

Most melanomas occur sporadically, but a few are hereditary (<5% to 10 %). Molecular genetic analysis of such familial as well as sporadic cases has provided important insights into the pathogenesis of melanoma. Germ-line mutations in the CDKN2A gene (located on 9p21) are found in 40% of the rare individuals with familial melanoma.

This gene encodes p16INK4A, a cyclin-dependent kinase inhibitor that regulates the G1-S transition of the cell cycle in a retinoblastoma protein (pRB)-dependent fashion. The CDNK2A gene can also be silenced by methylation.

Sporadic activating mutations in either NRAS or BRAF are also seen in a high portion of melanomas but are generally mutually exclusive since BRAF functions downstream of RAS. Suppression of the PTEN gene on 10q23.3 is also seen in primary melanomas, allowing activation of the AKT pathway that promotes cell proliferation.

Morphology

than larger) usually much 1Individual melanoma cells are ( ◙ contours large nuclei with irregular) contain 2nevus cells, (

having chromatin characteristically clumped at the periphery of nucleoli) prominent eosinophilic 3the nuclear membrane, (

C). 21-22F often described as "cherry red" (

Malignant cells grow as poorly formed nests or individual epidermis & as dermal expansile, of the at all levelscells

like nodules; these constitute the radial & vertical -balloon).D&E22 -22& A&B21 -22F ( growth phases, respectively

It is important to observe & record the nature & extent of the vertical growth & mitotic rate of melanoma cells. By using these & other variables in aggregate, accurate predictive statements regarding prognosis are possible.

Clinically, Although most melanomas arise in the skin, other less common sites of origin include the oral & anogenital mucosa, the esophagus, the meninges, & notably the eye.

The following comments apply to skin melanomas:

, although itching may be an early asymptomaticAre usually manifestation. The most important clinical sign of melanoma is a

.change in the color or size of a pigmented lesion Unlike benign nevi, melanomas exhibit striking variations in

, )D21-22F black (pigmentation, appearing in shades of & gray. ),27-14 F(brown, red, dark blue

The borders of melanomas are irregular & often "notched."

Clinical warning signs of melanoma in a preexisting mole are: (1) Enlargement

(2) Itching or pain

(3) Irregularity of the borders

(4) Variegation of color within a pigmented lesion & (5) Development of a new pigmented lesion during adult life,

These principles are expressed in the ABCDE of melanoma: Asymmetry, Border, Color, Diameter, & Evolution (change of an existing nevus).

It is vitally important to recognize & intervene in melanoma as rapidly as possible. Vast majority of superficial melanoma are cured surgically,

have metastatic, melanomas that become currentlyBUT, uniformly poor prognosis, with no effective therapy.

End of Skin in 59 W + 34 Figures = 93 PPP @ 19-11-2018 MS&S: Lectures prepared by:

Dr. Mohammad Kamel Alwiswasi, MBChB, PhD, FRCPath.