DERMATOPATHOLOGY
DEFINITIONS OF MACROSCOPIC TERMSMacule: Circumscribed lesion of up to 5 mm in diameter characterized by flatness and usually distinguished from surrounding skin by its coloration. Patch: Circumscribed lesion of more than 5 mm in diameter characterized by flatness and usually distinguished from surrounding skin by its coloration. Papule: Elevated dome-shaped or flat-topped lesion 5 mm or less across. Nodule: Elevated lesion with spherical contour greater than 5 mm across. Plaque: Elevated flat-topped lesion, usually greater than 5 mm across (may be caused by coalescent papules). Vesicle: Fluid-filled raised lesion 5 mm or less across. Bulla: Fluid-filled raised lesion greater than 5 mm across. Blister: Common term used for vesicle or bulla.
Pustule: Discrete, pus-filled, raised lesion. Scale: Dry, horny, platelike excrescence; usually the result of imperfect cornification. Lichenification: Thickened and rough skin characterized by prominent skin markings; usually the result of repeated rubbing in susceptible persons. Excoriation: Traumatic lesion characterized by breakage of the epidermis, causing a raw linear area (i.e., a deep scratch); often self-induced.
DEFINITIONS OF MICROSCOPIC TERMS
Hyperkeratosis: Thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin. Parakeratosis: Modes of keratinization characterized by the retention of the nuclei in the stratum corneum Acanthosis: Diffuse epidermal hyperplasia. Papillomatosis: Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae. Dyskeratosis: Abnormal keratinization occurring prematurely within individual cells or groups of cells below the stratum granulosum. Acantholysis: Loss of intercellular connections resulting in loss of cohesion between keratinocytes. Spongiosis: Intercellular edema of the epidermis.Urticaria This is a common disorder mediated by localized mast cell degranulation resulting in dermal microvascular hyperpermeability. This gives rise to erythematous, edematous, and pruritic plaques termed wheals. In most cases, it is a reflection of type I hypersensitivity i.e. IgE-mediated degranulation of mast cells. This follows exposure to a number of antigens including pollens, foods, drugs, and insect venom. IgE-independent urticaria results from substances that directly provoke mast cell degranulation, such as opiates and certain antibiotics. In the vast majority of cases, no cause is discovered.
This extensive example of urticaria shows erythematous, edematous, and pruritic plaques termed wheals
Urticaria
Hives (urticaria) is a common skin condition with an itchy rash of pink to red bumps that appear and disappear anywhere on the body. An individual lesion typically lasts a few hours before fading away, and new lesions can appear as older areas disappear.
Urticaria
Hereditary angioneurotic edema results from inherited deficiency of C1 esterase inhibitor, leading to uncontrolled activation of the early components of the complement system. The resulting urticaria affects the lips, throat, eyelids, genitals, and distal extremities. Involvement of the larynx can cause suffocation.
Microscopically, there is mild perivenular infiltrate of mononuclear cells admixed neutrophils or eosinophils. Superficial dermal edema results in more widely spaced collagen bundles. Individual lesions in urticaria develop and fade within hours (usually <24 hours), but episodes may persist for days or even months.
2. Acute Eczematous Dermatitis Eczema is a clinical term that embraces a number of conditions with different etiologies. All are characterized by itchy, red, papulovesicular, oozing, and crusted lesions at an early stage. Eczematous dermatitis is classified into: 1. Allergic contact dermatitis 2. Atopic dermatitis 3. Drug-related dermatitis 4. Photoeczematous dermatitis 5. Primary irritant dermatitis i.e. the agents are capable of directly damaging the skin this form include occupational dermatitis. Most of the above forms resolve completely when the offending stimulus is removed.
Contact dermatitis is the most common form of eczyma. Clinical examples of this form include sensitivity to 1. Nickel 2. Constituents of synthetic rubber 3. Topical medicaments
Pathogenesis After initial exposure to the sensitizing agent, self-proteins modified by the agent are processed by epidermal Langerhans cells that then migrate to draining lymph nodes and present the antigen to naive T cells. This leads to the development of immunologic memory. On re-exposure to the same antigen, the now-educated CD4+ T lymphocytes migrate to the affected skin sites to release cytokines that recruit additional inflammatory cells and also mediate the epidermal damage.
Pathological features All forms of eczema are characterized by spongiosis i.e. the accumulation of edema fluid in-between epidermal cells. This causes stretching of the intercellular bridges. The latter thus become more prominent (spongy appearance). There is also superficial dermal perivascular lymphocytic infiltrate, edema, and mast cell degranulation. Eosinophils may be present and are especially prominent in drug-related dermatitis. With persistent antigen stimulation, lesions may become progressively scaly (hyperkeratotic) as the epidermis thickens (acanthosis) and can become chronic. Some of these changes also result from scratching or rubbing of the itchy lesion. Susceptibility to atopic dermatitis is often inherited. Atopic individuals often suffer from asthma as well, perhaps another expression of an irritable and overactive immune system.
Contact dermatitis (eczema)
CD (eczema): acute vesicular, crusted lesions on the face of a young girl. There is an intense conjunctival injection and edema of the eyelids.Contact dermatitis (eczema)
This was due to a reaction to rubber gloves.A. Note the patterned erythema and scale associated with nickel contact dermatitis resulting from this woman's necklace. B. Fluid accumulation between epidermal cells results in spongiosis that can proceed to small vesicles if intercellular connections are stretched until broken-thus the term spongiotic dermatitis.
Eczematous dermatitis
Acute eczematous dermatitis
Fluid-filled vesicle due to intense spongiosis. Note the separation of the epidermal cells adjacent vesicle.Chronic dermatitis (eczema)
Hyperkeratosis, acanthosis and only slight spongiosis.CHRONIC INFLAMMATORY DERMATOSIS Psoriasis
Common chronic dermatoses. Bilaterally symmetric, nonpruritic lesion. Erythematous plaques covered by fine silvery scales. Typically, it involves the extensor surfaces such as the elbows, the knees, the back, and the scalp. Generalized lesions also occur .Pathogenesis As an immunologic disease, the pathogenesis psoriasis also involves genetic susceptibility and 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 and CD8+ T cells that accumulate in the epidermis. T cells homing to the skin secrete cytokines and growth factors that induce keratinocyte hyper-proliferation. 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.
Microscopically
Parakeratosis.Acanthosis in which there is a regular elongation of the rete ridges, seen as pegs in two dimensions, is prominent. Above the tips of the dermal papillae, the layer of epidermal cells is distinctly attenuated, a feature known as "suprapapillary thinning.“Transmigration of polymorphonuclear leukocytes through the reactive epidermis into the parakeratotic scale results in the formation of Munro microabscesses .Typical plaque with an irregular, but sharply demarcated border showing the characteristic erythema and silvery white scaling
Note the symmetrical distribution
Psoriasis
Psoriasis
Typical appearance of psoriasis. Note the engorgement of papillae and Munro microabscesses.
Lichen Planus
Pruritic, purple, polygonal, plane-surfaced papules, and plaques" are the traditional "p's" of this disorder of skin and mucosa. Lichen planus is self-limited and usually resolves spontaneously 1 to 2 years after onset. The pathogenesis is not known. Expression of altered antigens at the level of the basal cell layer and the dermo-epidermal junction may elicit a CD8+ Tcell-mediated cytotoxic immune responsePathological features There is characteristically a dense, continuous infiltrate of lymphocytes along the dermoepidermal junction (interface dermatitis). The lymphocytes are intimately associated with basal keratinocytes that show degeneration and necrosis. This pattern of inflammation causes the dermoepidermal interface to assume an angulated, zigzag contour ("sawtoothing"). Changes of chronicity include: epidermal hyperplasia, hypergranulosis, and hyperkeratosis.
Cutaneous lesions consist of pruritic, violaceous, flat-topped papules, which may coalesce focally to form plaques. These papules are often highlighted by white dots or lines, called Wickham's striae. Multiple lesions are symmetrically distributed, particularly on the extremities, often about the wrists and elbows, and on the glans penis. In 70% of cases, oral lesions are present as mucosal, white, netlike areas.
Lichen planus
Clinical appearance of lichen planus affecting the dorsum of the hand. One of the lesions has been biopsied.There is hyperkeratosis, hypergranulosis, hydropic degeneration of the basal layer, and a band-like inflammatory infiltrate.
Multiple flat-topped papules with white, lacey or netlike markings (Wickham striae) are characteristic.
Lichen planus
There is a band of lymphocytes along the dermoepidermal junction (interface dermatitis). The rete ridges have acquired a pointed, or "sawtooth," architecture. The hyperkeratosis and hypergranulosis are definite signs of chronicity.
Interlacing white lines (Wickham's striae) of buccal mucosa.
Lichen planusINFECTIOUS DERMATOSIS Warts Cutaneous (and sometimes mucosal) lesions. Caused by one of the several human papilloma viruses (HPV). Verruca vulgaris (generally associated with HPV-2) usually occurs on the hands as an elevated, hard, rough, flesh-colored lesion. The top may be peeled off, leaving a pink granular surface. Verruca plantaris occurs on the sole of the foot, is covered by a callus, and is often painful. Verruca plana (usually associated with HPV-10) is a flatter lesion usually seen in crops or clusters on the face and hands. Condyloma acuminatum or "venereal wart" (usually caused by HPV-6) occurs around the anus and vulva, on the glans penis, and sometimes in other mucosal membranes such as the oral cavity.
Manifested by hyperkeratosis and parakeratosis, varying degrees of acanthosis, and (except for verruca plana) papillomatosis . Distinct vacuolization of the cells in the upper portion of the malphigian layer is a feature in early lesions; some of these abnormal cells have large cytoplasmic eosinophilic aggregates. Smaller vacuolated cells with pyknotic nuclei may also be seen in the lower portions of the thickened stratum corneum.
Multiple papules with rough, pebble-like surfaces at infection sites
Verruca vulgarisLesions are formed by symmetric zones of papillary epidermal proliferation that often radiate symmetrically like the points of a crown (top). Nuclear pallor, prominent keratohyalin granules, and related cytopathic changes of human papillomavirus are confirmed at higher magnification (bottom).
Verruca vulgaris
BLISTERING (BULLOUS) DISEASESThese refer to a group of disorders in which blisters are the primary and most distinctive features. Blisters refer to “accumulations of fluid within or below epidermis and mucous membranes”. They are divided into1. Vesicles (< 1.0 cm)2. Bullae (> 1.0 cm)Blisters can occur at multiple levels within the skin, and assessment of their location is essential for an accurate histological diagnosis.
A, Subcorneal (as in pemphigus foliaceus). B, Suprabasal (as in pemphigus vulgaris). C, Subepidermal (as in bullous pemphigoid & dermatitis herpetiformis). Assessment of the levels of epidermal separation forms the basis of the initial differential diagnosis of these lesions.
Levels of blister formation
1. Pemphigus is a rare autoimmune blistering disorder resulting from loss of integrity of normal intercellular bridges (desmosomes) within the epidermis and mucosal epithelium. Most individuals who develop pemphigus are middle-aged and older. The are 5 major variants: 1. Pemphigus vulgaris 2. Pemphigus vegetans (a variant of P. vulgaris) 3. Pemphigus foliaceus 4. Pemphigus erythematosus (a variant of P. foliaceus) 5. Paraneoplastic pemphigus (associated with internal malignancy).
Pathogenesis Both pemphigus vulgaris and pemphigus foliaceus are caused by a type II hypersensitivity reaction (antibody directed against a fixed tissue antigen). Patient sera contain pathogenic IgG antibodies to intercellular desmosomal proteins of skin and mucous membranes.
Pathologic features The common histologic denominator in all forms of pemphigus is acantholysis (lysis of desmosomes) within a squamous epithelial surface. The detached acantholytic cells become rounded. In pemphigus vulgaris, acantholysis selectively involves the layer of cells immediately above the basal cell layer, giving rise to a suprabasal blister; the floor of the cavity is lined by a single layer of intact basal cells (tombstone effect). In pemphigus foliaceus, acantholysis selectively involves the superficial epidermis at the level of the stratum granulosum. Variable superficial dermal infiltration by lymphocytes, histiocytes, and eosinophils accompanies all forms of pemphigus.
P. Vulgaris
Extensive erosions and blistering on the front of the knee.P. Vulgaris intact and ruptured blisters
Umblical lesions showing intact blisters as well as raw erosionsPemphigus vulgaris
Suprabasal acantholysis results in an intraepidermal blister containing rounded keratinocytes that are separating from their neighbors. Initially, a single row of basal cells is present on the floor of the blister with dermal papillomatosis (tombstone effect). Follicular involvement by acantholysis is also common.P. Foliaceus
Blisters are much less erosive than those seen in pemphigus vulgaris, since the level of the blisters is more superficial (subcorneal). In this patient, the disease was induced by penicillamine therapy, and there are intact blisters, erosions, and crusting. Picture on Rt. & below are close-up views.
There is subcorneal acantholysis leading to suncorneal blister.
Pemphigus foliaceusA, Pemphigus vulgaris. There is uniform deposition of immunoglobulin and complement (green) along the cell membranes of keratinocytes, producing a characteristic "fishnet" appearance. B, The immunoglobulin deposits are more superficial in pemphigus foliaceus.
Pemphigus direct IF microscopy
2. Bullous Pemphigoid Generally affecting elderly individuals that typically presents with generalized cutaneous lesions and involvement of mucosal surfaces. It is an autoimmune disease in which the characteristic finding is linear deposition of IgG antibodies and complement in the basement membrane zone. Microscopically, it is characterized by a subepidermal, nonacantholytic blister. Early lesions show a perivascular infiltrate of lymphocytes and variable numbers of eosinophils. Clinically, lesions are tense bullae, filled with clear fluid, on normal or erythematous skin. The bullae do not rupture as readily as in pemphigus and, if uncomplicated by infection, heal without scarring. Sites of occurrence include the inner aspects of the thighs, flexor surfaces of the forearms, axillae, groin, and lower abdomen.
Bullous pemphigoid
Tense, fluid-filled blisters result from vacuolization of the basal layer, producing subepidermal blistersBullous pemphigoid
Bullous pemphigoid
The subepidermal vesicle has an inflammatory infiltrate rich in eosinophilsBullous pemphigoid
In bullous pemphigoid, both IgG antibody and complement can be detected by direct immunofluorescence as a linear band outlining the subepidermal basement membrane zone3. Dermatitis Herpetiformis (DH) is a rare disorder characterized by urticaria and grouped vesicles. The disease affects predominantly males, often in the 20 to 40 years of age. In some cases it occurs in association with intestinal celiac disease and responds to a gluten-free diet. Pathogenesis The association of dermatitis herpetiformis with celiac disease provides a clue to its pathogenesis. Genetically predisposed individuals develop IgA antibodies to dietary gluten (derived from the wheat protein gliadin). The antibodies cross-react with reticulin, a component of the anchoring fibrils that tether the epidermal basement membrane to the superficial dermis.
Microscopic features Early, fibrin and neutrophils accumulate selectively at the tips of dermal papillae, forming small microabscesses. The basal cells overlying these microabscesses show vacuolization and focal dermoepidermal separation that ultimately coalesce to form a true subepidermal blister. By direct immunofluorescence, dermatitis herpetiformis shows discontinuous, granular deposits of IgA selectively localized in the tips of dermal papillae. The lesions of DH are extremely pruritic. The lesions are bilateral, symmetric, and grouped involving preferentially the extensor surfaces, elbows, knees, upper back, and buttocks.
Upper Lt. Lesions consist of intact and eroded (usually scratched) erythematous blisters, often grouped (seen here on elbows and arms). Upper Rt. The blisters are associated with basal cell layer injury initially caused by accumulation of neutrophils (microabscesses) at the tips of dermal papillae. Lower Rt. Selective deposition of IgA autoantibody at the tips of dermal papillae is characteristic.
Dermatitis herpetiformis
Dermatitis herptiformis
Extensive lesions on the extensor aspects of the forearmsThe dermal papillae are distended by microabscesses of neutrophils and fibrin. there is evidence of early vesiculation.
Dermatitis herptiformis
Part of an established subepidermal blister containing edema fluid, fibrin and neutrophils.
Dermatitis herptiformis
Dermatitis herpetiformis. A, Papillary dermal microabscesses are associated with zones of dermoepidermal cleavage that eventually coalesce to form a clinical blister. B, By direct immunofluorescence, these abscesses are rich in IgA and fibrin deposits.
Dermatitis herptiformis
Erythema Multiforme (which progresses clinically from papular erythema to a characteristic target lesion) are subepidermal edema. Presence of basement membrane in the roof of the bulla, abundant nuclear dust in the dermis, and occasional vasculitis, epidermal spongiosis, and epidermal necrosis. Eosinophils can also be present. The bullae of erythema multiforme can be subepidermal, with the basal lamina at the top of the blister (as a result of dermal edema), or dermoepidermal, with the basal lamina at the floor of the bulla (as a result of epidermal damage).
Erythema multiformi
TUMORS AND TUMORLIKE CONDITIONS Seborrheic keratosesIs a common epidermal tumor that occurs mostly in middle-aged or older individuals. It arises spontaneously and may become particularly numerous on the trunk, although the extremities, head, and neck may also be involved. These neoplasms are exophytic and composed of sheets of small cells that most resemble monotonous basal cells of the normal epidermis. Variable melanin pigmentation is present within these basaloid cells, accounting for the brown coloration seen clinically. Hyperkeratosis occurs at the surface and the presence of small keratin-filled cysts (horn cysts) and down-growths of keratin into the main tumor mass (pseudo-horn cysts) are characteristic features.
A. This roughened, brown, waxy lesion almost appears to be "stuck on" the skin. B. The lesions consist of an orderly proliferation of uniform, benign basaloid keratinocytes with a tendency to form keratin microcysts (horn cysts).
Seborrheic keratosis
Actinic Keratosis This refers to dysplastic changes of the epidermis. Result of chronic exposure to sunlight and is associated with hyperkeratosis, hence the name. (actinic: sun-related). Mutation of p53 is often an early event with molecular changes suggestive of ultraviolet light injury. Lesions of actinic keratosis, very common in fair-skinned individuals, are usually less than 1 cm in diameter; tan-brown, red, or skin colored; and has a rough, sandpaper-like consistency. As would be expected, there is a predilection for sun-exposed areas (face, arms, and dorsum of the hands).
Microscopic features The lower portions of the epidermis show cytologic atypia, often with hyperplasia of basal cells or with early atrophy that results in diffuse epidermal thinning of the epidermis. There are thickened, blue-gray dermal elastic fibers (solar elastosis). There is hyper- and parakeratosis. Lymphocytes are present in superficial dermis Some but not all lesions progress to full-thickness atypia amounting to squamous cell carcinoma in situ.
Most lesions form subtle zones of redness or sandpaper-like keratinization as seen in the lesions on the cheek, nose, and chin of this woman
Actinic keratosis
Actinic keratosis with moderate dysplasia
The lower portions of the epidermis show cytologic atypia, often with hyperplasia of basal cells with moderate dysplasia. There is hyper- and parakeratosis. Lymphocytes are present in superficial dermisActinic keratosis with Severe dysplasia
Sun exposure damages the skin, primarily as the result of ultraviolet light. This actinic damage is seen as a collection of abnormal collagen fibers in the upper dermis, seen here with a pale bluish appearance (basophilic degeneration) (arrows). Note the epidermal atrophy.
Solar (actinic) keratosis
1. Squamous Cell Carcinoma (SCC) This is a common tumor arising on sun-exposed sites in older people. The following are considered predisposing factors 1. Sunlight 2. Industrial carcinogens (tars and oils) 3. Chronic ulcers 4. Old burn scars 5. Ingestion of arsenicals 6. Ionizing radiation 7. Immunosuppression 8. Inherited defects in DNA repair
Pathogenesis The most common exogenous cause of cutaneous squamous cell carcinoma is UV light exposure, with subsequent unrepaired DNA damage. In addition to inducing mutations, UV light (UVB in particular) may have a transient immunosuppressive effect on skin by impairing antigen presentation by Langerhans cells. This may contribute to carcinogenesis by weakening immunosurveillance. p53 mutations with associated UV mutation signatures are common, as are activating mutations in RAS. Immunosuppressed patients, particularly organ transplant recipients, are at increased risk because they are likely to have high-risk HPV infections. As with squamous cell carcinomas at other sites, those in the skin may be preceded by in situ lesions.
Microscopic features Squamous cell carcinoma in situ is characterized by highly atypical cells at all levels of the epidermis, with nuclear crowding and disorganization. When these cells break through the basement membrane, the process has become invasive. Invasive squamous cell carcinomas exhibit variable differentiation, ranging from well-differentiated tumors formed by atypical squamous cells arranged in orderly lobules showing large zones of keratinization to poorly-differentiated neoplasms formed by highly anaplastic, rounded cells with foci of necrosis and only abortive, single-cell keratinization (dyskeratosis).
Squamous cell carcinomas in situ appear as sharply defined, red, scaling plaques; many arise from prior actinic keratoses. More advanced, invasive lesions are nodular, and may ulcerate. The likelihood of metastasis is related to the thickness of the lesion and degree of invasion into the subcutis. Tumors arising in the context of actinic keratoses may behave in a less aggressive fashion.
A nodular and hyperkeratotic lesion occurring on the ear, unfortunately with early metastasis to a prominent postauricular lymph node (arrow).
Squamous cell carcinoma
Tumor of the face with rolled edges and depressed center.
SCC of the leg with exophytic appearance.
Well-differentiated SCC showing deep invasionThe tumor is formed by atypical squamous cells arranged in orderly lobules showing large zones of keratinization.
Poorly- differentiated Squamous cell carcinoma showing spindle metaplastic features (sarcomatoid SCC)
2. Basal Cell Carcinoma (BCC) This is the most common human cancer. It is a slow-growing tumor that rarely metastasizes. BCC tends to occur at sites exposed to chronic sun exposure and in lightly pigmented people. As with squamous cell carcinoma, the incidence of basal cell carcinoma increases with immunosuppression and in individuals with inherited defects in DNA repair.
Pathogenesis
Inherited defects in the PTCH gene with subsequent loss of heterozygosity in the numerous individual tumor foci cause the familial basal cell carcinoma syndrome, Gorlin syndrome. Thus, PTCH functions as a classic tumor suppressor gene. Some component of the PTCH pathway is also mutated in the great majority of sporadic basal cell carcinomas; mutations in p53 are also common.Gross (Clinical) features
Clinically, these tumors present as pearly papules, often containing prominent, dilated subepidermal blood vessels (telangiectasia). Some tumors contain melanin pigment (pigmented BCC) and thus appear similar to melanocytic nevi or melanomas. Advanced lesions may ulcerate, and extensive local invasion of bone or facial sinuses may occur after many years of neglect.
Microscopic features Because they arise from the epidermis or sometimes follicular epithelium, they are not encountered on mucosal surfaces. Tumor cells resemble the normal epidermal basal cell layer from which they are derived. Two common patterns are seen: either multifocal growths originating from the epidermis (superficial type), or nodular lesions growing downward into the dermis as cords and islands of basophilic cells with hyperchromatic nuclei, embedded in a fibrotic to mucinous matrix. Peripheral tumor cell nuclei align in the outermost layer (palisading) with separation from the stroma, creating a cleft or separation artifact.
This lesion is a prototypical pearly, smooth-surfaced papule with associated telangiectatic vessels The lesion is formed by multiple nodules of basaloid cells infiltrating a fibrotic stroma. The cells have scant cytoplasm, small hyperchromatic nuclei, and a peripheral palisade with clefting from the stroma. Note the similarity of these cells to the basal cells of normal epithelium.
Basal cell carcinoma
Nodular and pigmented basal cell carcinoma of forehead
Clinical appearance of pigmented basal cell carcinoma. Melanin is largely present in macrophages located in the stroma between tumor lobules.a pearly pink border and an ulcerated center.
Basal cell carcinoma lower lipNests of basaloid cells are dropping off into the upper dermis in this example of a basal cell carcinoma of the skin.
Basal cell carcinoma solid
MELANOCYTIC LESIONS1.Melanocytic Nevi: Melanocytic nevus refers to any benign, congenital or acquired, neoplasm of melanocytes Common Nevus /Pathological features Melanocytic nevi are derived from the transformation of highly dendritic melanocytes that are normally scattered among basal cells of the epidermis. They are initially composed of round-to-oval cells that grow in "nests" along the dermoepidermal junction. Nuclei are uniform and round, and contain inconspicuous nucleoli with little or no mitotic activity. Such lesions, believed to represent an early developmental stage, are called junctional nevi.
Eventually, most junctional nevi grow into the underlying dermis as nests or cords of cells (compound nevi). In older lesions the epidermal nests may be lost entirely to leave pure dermal nevi. It should be noted that progressive growth of nevus cells from the dermoepidermal junction into the underlying dermis is accompanied by maturation. Superficial nevus cells are larger and less mature, tend to produce melanin pigment, and grow in nests; deeper nevus cells are smaller and more mature, produce little or no pigment, and grow in cords. This sequence of maturation of individual nevus cells is of diagnostic importance, since melanomas usually show little or no maturation .
Gross (Clinical) features Compound and dermal nevi are often more elevated than are junctional nevi. The nevi are tan-to-brown, uniformly pigmented, small (usually ≤5 mm across), papules or macules with well-defined, rounded borders.
A. These are benign nevi. Small brown flat to slightly raised nevi. They are usually less than a centimeter in diameter. B. LP micro appearance of a benign pigmented nevus. Small amounts of dark pigment are seen near the skin surface. The small blue nevus cells can extend into the dermis and around adnexal structures, but this is not invasion. C. In this junctional nevus, there are nevus cells in nests in the lower epidermis as well as nests appearing to "drop off" into the upper dermis. Unlike a melanoma, there is no significant atypia and no inflammation.
A, Melanocytic nevi are relatively small, symmetric, and uniformly pigmented. B. This dermal nevus shows rounded melanocytes extending into the dermis with loss of pigmentation and cells becoming smaller and more separated with depth-all reassuring signs of appropriate maturation.
Melanocytic nevus
2. Dysplastic Nevus A subset of dysplastic nevi are precursors of melanoma. They form the precursors in familial cases of melanomas (familial melanoma syndrome) with a lifetime risk close to 100%. The number of dysplastic nevi correlates with the risk of developing melanoma. However, most melanomas arise de novo and not from a preexisting nevus. Activating RAS or BRAF mutations are encountered in dysplastic as well as in melanocytic nevi; additional complementing mutations occur in melanoma.
Microscopic features Dysplastic nevi are mostly compound in type, with both architectural and cytologic evidence of abnormal growth. Nevus cell nests within the epidermis may be enlarged and exhibit abnormal bridges with adjacent nests. As part of this process, single nevus cells begin to replace the normal basal cell layer along the dermoepidermal junction, producing so-called lentiginous hyperplasia. Cytologic atypia is frequent & consists of irregular nuclear contours and hyperchromasia. There is linear fibrosis surrounding epidermal nests of melanocytes.
Gross (clinical) features Dysplastic nevi are usually larger than most acquired nevi (often >5 mm across) and may occur as hundreds of lesions on the body surface. They are usually of variegated color with irregular borders. Unlike ordinary nevi, dysplastic nevi tend to occur on both sun unexposed as well exposed body surfaces.
4. Melanoma Today, as a result of increased public awareness of the earliest signs of skin melanomas, most melanomas are cured surgically. Pathogenesis As with other cutaneous malignancies, sunlight plays an important role in the development of melanoma. The incidence is highest in sun-exposed skin and in localities such as New Zealand and Australia where sun exposure is high and the protective mantle of melanin is sparse. The presence of preexisting nevi and hereditary predisposition also play a role. Most melanomas occur sporadically, but a few are hereditary (<5% to 10 %). Germ-line mutations in the CDKN2A gene are found in as many as 40% of those with familial melanoma. This gene encodes p16, an inhibitor that regulates the G1-S transition of the cell cycle. The CDNK2A gene can also be silenced by methylation.
Polymorphisms in the melanocortin-1-receptor (MC1R) locus, associated with red hair, fair skin, and easy freckling, are also markers of melanoma susceptibility. As with other tumors, malignant transformation of melanocytes is a multistep process with activating mutations in proto-oncogenes and loss of tumor suppressor genes. Clinico-pathologic features Individual melanoma cells are usually considerably larger than nevus cells. They contain large nuclei with irregular contours & chromatin clumping at the periphery of the nuclear membrane. There are prominent cherry red nucleoli. Malignant cells grow as poorly formed nests or individual cells at all levels of the epidermis and as dermal expansile, balloon-like nodules; these constitute the radial and vertical growth phases, respectively.
Radial and vertical growth concept: the radial growth indicates the initial tendency of a melanoma to grow horizontally within the epidermis (in situ) and superficial dermal layers. During this stage of growth, melanoma cells do not have the capacity to metastasize. With time, the pattern of growth assumes a vertical component, and the melanoma grows downward into the deeper dermal layers as an expansile mass lacking cellular maturation. This event is evident clinically by the development of a nodule in the relatively flat radial growth phase and correlates with the emergence of a clone of cells with metastatic potential. the biological aggressiveness.
The probability of metastasis is predicted by measuring the depth of invasion in millimeters of this vertical growth phase (Breslow thickness). Metastases involve not only regional lymph nodes but also liver, lungs, brain, etc,. Sentinel lymph node biopsy (first draining node(s) of a primary melanoma) at the time of surgery is an assessment of
The main clinical warning signs of melanoma are 1. Enlargement of a preexisting nevus 2. Itching or pain in a preexisting nevus 3. Development of a new pigmented lesion during adult life 4. Irregularity of the borders of a pigmented lesion 5. Variegation of color within a pigmented lesion. It is vitally important to recognize and intervene in melanoma as rapidly as possible. The vast majority of superficial lesions are cured surgically, while melanomas that become metastatic have a virtually uniformly poor prognosis, with no effective therapy in most cases.
A, Normal skin shows only scattered melanocytes. Top row: b, Junctional nevus. c, Compound nevus. d, Intradermal nevus. e, Intradermal nevus with neurotization (extreme maturation). Bottom row: B, Lentiginous melanocytic hyperplasia. C, Lentiginous compound nevus with abnormal architecture and cytologic features (dysplastic nevus). D, Early or radial growth-phase melanoma (large dark cells in epidermis) arising in a nevus. E, Melanoma in vertical growth phase with metastatic potential. Note that no melanocytic nevus precursor is identified in most cases of melanoma. They are believed to arise de novo, perhaps using the same pathway.
Possible steps in development of melanocytic nevi and melanoma
A, Radial growth, showing irregular nested and single-cell spread of melanoma cells in the epidermis. B, Vertical growth showing nodular aggregates of malignant cells extending deeply within the dermis.
Melanoma
C, Melanoma cells have hyperchromatic nuclei of irregular size and shape with prominent nucleoli. Mitoses, including atypical forms (arrow), are often encountered. D, Lesions clinically tend to be larger than nevi, with irregular contours and pigmentation. Macular areas are early superficial (radial) growth, while elevated areas often indicate dermal invasion (vertical growth).
Melanoma