OVERVIEW OF HISTOLOGY

Functions of Skin Protection (against UV light, chemical/thermal/mechanical insults, bacteria/fungi) Sensation (receptors for touch, pressure, pain & temperature) Thermoregulation (subcutaneous fat stores; sweating) Metabolism (synthesis of vitamin D3) Skin Structure 3 main layers Epidermis self-regenerating stratified squamous epithelium which produces a surface layer of the protein keratin (tough, protective, partially water-resistant) also contains non-epithelial cells which protect against sunlight (melanocytes), recognize external antigens (Langerhans cells) & provide touch receptors (Merkel cells) tightly bound to underlying dermis by a specialized basement membrane additional resistance to frictional shearing force is provided by a series of epidermal downgrowths (rete ridges) which penetrate the upper dermis to provide stronger tethering layers of epidermis stratum basale (basal layer): single layer of cuboidal or low columnar cells that rests upon the basement membrane; responsible for constant regeneration of other layers of epidermis via repeated mitotic division stratum spinosum (prickle cell layer): polyhedral keratinocytes w/ large palestaining nuclei & prominent nucleoli (indicative of active protein synthesis -cytokeratin) stratum granulosum (granular layer): cells lose their polyhedral shape & become progressively more flattened nearer to the surface; contain dense basophilic & electron-dense keratohyaline granules stratum lucidum stratum corneum (keratin layer): flat flakes & sheets of keratin Dermis layer of fibrocollagenous & elastic tissue containing blood vessels, nerves & sensory receptors Hypodermis/Subcutis mainly adipose tissue also contains larger vessels which supply & drain the dermal blood vasculature often compartmentalized by downward extensions of dermal collagen Skin appendages specialized structures such as hair follicles, eccrine glands & sebaceous glands which arise as downgrowths into the dermis from the epidermis during embryological development mainly occupy the dermis and, occasionally, the upper subcutis Melanocytes

produce pigment melanin responsible for coloration of skin & hair protective function against UV damage synthesize melanin from tyrosine within melanosomes, which are transferred to keratinocytes via complex network of melanocytes cytoplasmic processes present as scattered cells in the basal layer; more numerous in areas which are most exposed to light no difference in # of melanocytes between white- and dark-skinned races, but are considerably more synthetically active in darker-skinned people

PATHOLOGY
Definitions Macroscopic Terms excoriation: traumatic lesion breaking the epidermis & causing a raw linear area (i.e., deep scratch); often self-induced lichenification: thickened & rough skin characterized by prominent skin markings; usually the result of repeated rubbing macule: circumscribed lesion, 5mm or smaller in diameter, characterized by flatness & distinguished by coloration (patch: >5mm) onycholysis: separation of nail plate from nail bed papule: elevated dome-shaped or flat-topped lesion 5mm or less across (nodule: >5mm) plaque: elevated flat-topped lesion, usually greater than 5mm across (may be caused by coalescent papules) pustule: discrete, pus-filled, raised lesion scale: dry, horny, platelike excrescence; usually the result of imperfect cornification vesicle: fluid-filled raised lesion 5mm or less across (bulla: >5mm) wheal: itchy, transient, elevated lesion with variable blanching & erythema formed as the result of dermal edema Microscopic Terms erosion: discontinuity of the skin showing incomplete loss of the epidermis ulceration: discontinuity of the skin showing complete loss of the epidermis revelaing dermis or subcutis

exocytosis: infiltration of the epidermis by inflammatory cells acantholysis: loss of intercellular cohesion b/w keratinocytes acanthosis: diffuse epidermal hyperplasia hydropic swelling (ballooning): intracellular edema of keratinocytes, often seen in viral infections spongiosis: intercellular edema of the epidermis dyskeratosis: abnormal, premature keratinization within cells below the stratum granulosum hyperkeratosis: thickening of stratum corneum, often a/w qualitative abnormality of keratin parakeratosis: keratinization with retained nuclei in the stratum corneum (a normal process on mucous membranes) hypergranulosis: hyperplasia of stratum granulosum, often due to intense rubbing lentiginous: linear pattern of melanocyte proliferation within the epidermal basal cell layer papillomatosis: surface elevation caused by hyperplasia & enlargement of contiguous dermal papillae vacuolization: formation of vacuoles within or adjacent to cells; often refers to basal cell/basement membrane zone area Disorders of Pigmentation & Melanocytes Lentigo small (5-10 mm across), oval, tan-brown macules or patches do not darken when exposed to sunlight (vs. freckles) linear (non-nested) melanocytic hyperplasia restricted to the cell layer immediately above the basement membrane that produces a hyperpigmented basal cell layer may see elongation & thinning of rete ridges Melanocytic Nevus (Pigmented Nevus; Mole) tan to brown, uniformly pigmented, small (usually <6 mm across), solid regions of relatively flat (macules) to elevated skin (papules) with well-defined, rounded borders junctional nevus aggregates or nests of round cells grow along dermoepidermal junction nuclei of nevus cells are uniform & rounded in contour, contain inconspicuous nucleoli, & show little or no mitotic activity

Melanocytic nevus, junctional type. A, In clinical appearance, lesions are small, relatively flat, symmetric, and uniform. B, On histologic examination, junctional nevi are characterized by rounded nests of nevus cells originating at the tips of rete ridges along the dermoepidermal junction.

intradermal nevus nests & cords of nevus cells within the dermis compound nevus histo: combine the features of junctional & intradermal nevi

Melanocytic nevus, compound type. In contrast to the junctional nevus, the compound nevus (A) is more raised and dome-shaped. The symmetry and uniform pigment distribution suggest a benign process. Histologically (B), compound nevi combine the features of junctional nevi (intraepidermal nevus cell nests) with nests and cords of nevus cells in the underlying dermis.

Maturation progressive growth of nevus cells from the dermoepidermal junction into the underlying dermis is accompanied by a process called maturation whereas superficial nevus cells are larger, tend to produce more melanin, and grow in nests, deeper nevus cells are smaller, produce little or no pigment, and appear as cords & single cells the most mature nevus cells may be found at the deepest extent of lesions, where they often acquire fusiform contours & grow in fascicles resembling neural tissue (neurotization) correlates with enzymatic changes (progressive loss of tyrosinase activity & acquisition of cholinesterase activity in deeper, nonpigmented, nerve-like nevus cells) this sequence of maturation of individual nevus cells is of diagnostic importance in distinguishing some benign nevi from melanomas, which usually show little or no maturation

Maturation sequence of nondysplastic melanocytic nevi. A, Normal skin shows only scattered dendritic melanocytes within the epidermal basal cell layer. B, Junctional nevus. C, Compound nevus. D, Dermal nevus. E, Dermal nevus with neurotization (extreme maturation). Nevi may exist at any stage in this sequence for variable periods of time, although many are believed to progress through this sequence.

Nevus Variant Congenital

Diagnostic Architectural Features

deep dermal & sometimes subcutaneous growth around adnexa, neurovascular bundles & blood vessel walls non-nested dermal infiltration, often a/w fibrosis fascicular growth

Cytologic Features
identical to ordinary acquired nevi highly dendritic, heavily pigmented nevus cells large, plump cells w/ pink-blue cytoplasm; fusiform cells identical to ordinary

Clinical Significance
present at birth; large variants have risk of melanoma black-blue nodule; often confused w/ melanoma clinically common in children; red-pink nodule; often confused w/ hemangioma clinically host immune

Blue Spindle & Spitz

Halo

lymphocytic infiltration

surrounding nevus cells

acquired nevi

Dysplastic

coalescent intraepidermal nests

cytologic atypia

response against nevus cells & surrounding normal melanocytes potential marker or precursor of melanoma

Dysplastic Nevus larger than most acquired nevi (often >5 mm across) & may number in the hundreds in those with dysplastic nevus syndrome flat macules, slightly raised plaques with a "pebbly" surface, or target-like lesions with a darker raised center & irregular flat periphery recognized by their size, variability in pigmentation (variegation) & irregular borders seem to be acquired rather than congenital in most instances occur on both sun-exposed & protected body surfaces, unlike ordinary moles morphology usually compound exhibit both architectural & cytologic atypia nevus cell nests within the epidermis may be enlarged & often fuse or coalesce w/ adjacent nests as part of this process, single nevus cells begin to replace the normal basal cell layer along the dermoepidermal junction, producing lentiginous hyperplasia cytologic atypia: nuclear enlargement, irregular/angulated nuclear contours, & hyperchromasia associated alterations in the superficial dermis: lymphocytic infiltrates (usually sparse); release of melanin from dead nevus cells into the dermis (melanin incontinence), where it is phagocytosed by dermal macrophages; linear fibrosis surrounding the epidermal rete ridges that are involved by the nevus

Dysplastic nevus. A, Numerous clinically atypical nevi on the back. B, One such lesion (inset A) has a compound nevus component (left side of scanning field) and an asymmetric junctional nevus component (right side of scanning field). The former correlates grossly with the more pigmented and raised central zone and the latter with the less pigmented, flat peripheral rim. C, An important feature is the presence of cytologic atypia (irregularly shaped, dark-staining nuclei). The dermis underlying the atypical cells characteristically shows linear, or lamellar, fibrosis.

Melanoma

Potential steps of tumor progression in dysplastic nevi. A, Lentiginous melanocytic hyperplasia. B, Lentiginous junctional nevus. C, Lentiginous compound nevus with abnormal architectural and cytologic features (dysplastic nevus). D, Early melanoma, or melanoma in radial growth phase (large dark cells in epidermis). E, Advanced melanoma (vertical growth phase) with malignant spread into the dermis and vessels. The risk of malignant transformation of any single dysplastic nevus is extremely low but can occur.

Morphology Radial growth = horizontal spread of melanoma within epidermis & superficial dermis during this initial stage, the tumor cells seem to lack the capacity to metastasize tumors in radial growth phase fall into several clinicopathologic classes: lentigo maligna: usually presents as an indolent lesion on the face of older men that may remain in the radial growth phase for several decades superficial spreading (most common type of melanoma): usually involves sun-exposed skin acral/mucosal lentiginous: unrelated to sun exposure After a variable (and unpredictable) period of time, melanoma shifts from the radial phase to a vertical growth phase, during which the tumor cells invade downward into the deeper dermal layers as an expansile mass this phase is often heralded by the appearance of a nodule & correlates with the emergence of a clone of cells with metastatic potential unlike melanocytic nevi, maturation is absent from the deep invasive portion of melanoma probability of metastasis in such lesions correlates with the depth of invasion, which by convention is the distance from the superficial epidermal granular cell layer to the deepest intradermal tumor cells (the Breslow thickness) other histologic features that correlate with outcome include the number of mitoses & the presence of ulceration Individual melanoma cells usually considerably larger than normal melanocytes or cells found in

melanocytic nevi contain large nuclei with irregular contours, chromatin that is characteristically clumped at the periphery of the nuclear membrane, & prominent red (eosinophilic) nucleoli the appearance of the tumor cells is similar in the radial and vertical phases of growth.

Melanoma. A, Typically, lesions are irregular in contour and pigmentation. Macular areas correlate with the radial growth phase, while raised areas usually correspond to nodular aggregates of malignant cells in the vertical phase of growth. B, Radial growth phase, showing irregular nested and single-cell growth of melanoma cells within the epidermis and an underlying inflammatory response within the dermis. C, Vertical growth phase, demonstrating nodular aggregates of infiltrating cells. D, High-power view of melanoma cells. The inset shows a sentinel lymph node with a tiny cluster of melanoma cells (arrow) staining for the melanocytic marker HMB-45. Even small numbers of malignant cells in a draining lymph node may confer a worse prognosis.

Benign Epithelial Tumors Seborrheic Keratosis round, flat, coin-like, waxy plaques that vary in diameter from mms to several cm uniformly tan to dark brown & usually have a velvety to granular surface inspection with a hand lens usually reveals small, round, porelike ostia impacted with keratin, a feature helpful in differentiating these pigmented lesions from melanomas histology exophytic sharply demarcated from adjacent epidermis composed of sheets of small cells that most resemble basal cells of the normal epidermis

variable melanin pigmentation is present within these basaloid cells, accounting for the brown coloration exuberant keratin production (hyperkeratosis) occurs at the surface, and small keratin-filled cysts (horn cysts) and invaginations of keratin into the main mass (invagination cysts) are characteristic features when SKs become irritated & inflamed, they develop whirling foci of squamous differentiation resembling eddy currents in a stream

Seborrheic keratosis. A well-demarcated coinlike pigmented lesion containing dark keratin-filled surface plugs (inset) is composed histologically of benign basaloid cells associated with prominent keratin-filled "horn" cysts, some of which communicate with the surface (pseudo-horn cysts).

Acanthosis Nigricans thickened, hyperpigmented skin with a "velvet-like" texture that most commonly appears in the flexural areas benign type: about 80% of cases, develops gradually & usually occurs in childhood or during puberty; may occur (1) as an autosomal dominant trait with variable penetrance, (2) in association with obesity or endocrine abnormalities (particularly with pituitary or pineal tumors & diabetes), and (3) as part of several rare congenital syndromes malignant type: refers to lesions arising in middle-aged & older individuals in association with underlying cancers, most commonly GI adenocarcinomas histo: epidermis & underlying enlarged dermal papillae undulate sharply to form numerous repeating peaks & valleys; variable hyperplasia may be seen, along w/ hyperkeratosis & slight basal cell layer hyperpigmentation (but no melanocytic hyperplasia) Fibroepithelial Polyp (Acrochordon; Skin Tag) clinical: soft, flesh-colored, bag-like tumor often attached to the surrounding skin by a slender stalk histo: fibrovascular core covered by benign squamous epithelium not uncommon for a polyp to undergo ischemic necrosis due to torsion

Epithelial Cyst formed by the invagination and cystic expansion of the epidermis or a hair follicle filled with keratin & lipid-containing debris derived from sebaceous secretions clinically, they are dermal or subcutaneous, well-circumscribed, firm, and often moveable nodules when large, they may be subject to traumatic rupture inflammation & pain morphology epidermal inclusion cyst: wall resembles normal epidermis; filled with laminated strands of keratin pilar or trichilemmal cyst: wall resmbles follicular epithelium, without a granular cell layer; filled by a more homogeneous mixture of keratin & lipid dermoid cyst: similar to epidermal inclusion cyst but also contains multiple appendages (such as small hair follicles) budding outward from its wall steatocystoma simplex: wall resembles the sebaceous gland duct; numerous compressed sebaceous lobules originate from it Adnexal (Appendage) Tumors cylindroma: islands of cells resembling those of the normal epidermal or adnexal basal cell layer (basaloid cells); islands fit together like pieces of a jigsaw puzzle within a fibrous dermal matrix trichoepithelioma: proliferation of basaloid cells that forms primitive structures resembling hair follicles

Adnexal tumors. A, Multiple cylindromas (papules) on the forehead are composed of islands of (B) basaloid cells containing occasional ducts that fit together like pieces of a jigsaw puzzle. C, Perinasal papules and small nodules of trichoepithelioma are composed of (D) buds of basaloid cells that resemble primitive hair follicles.

sebaceous adenoma: lobular proflieration of sebocytes w/ increased peripheral basaloid cells & more mature sebocytes in the central portion, characterized by frothy or bubbly cytoplasm due to lipid vesicle content pilomatrixoma: composed of basaloid cells that show trichilemmal or hairlike differentiation similar to that seen in the germinal portion of the normal hair bulb in the anagen growth phase apocrine carcinoma: shows ductal differentiation with prominent decapitation

secretion similar to that seen in the normal apocrine gland; the infiltrative growth pattern is a hint of malignancy in this otherwise well-differentiated tumor

Adnexal tumors. A, Sebaceous adenoma; inset demonstrates sebaceous differentiation. B, Pilomatrixoma; inset shows hair matrical differentiation with characteristic maturation to anucleate "ghost cells." C, Apocrine carcinoma (well-differentiated); inset shows apocrine differentiation with characteristic luminal decapitation secretion.

Premalignant & Malignant Epidermal Tumors Actinic Keratosis usually less than 1cm in diameter, tan-brown, red or skin-colored, with rough, sandpaper-like texture some lesions may produce so much keratin that a cutaneous horn develops cytologic atypia is seen in the lowermost layers of the epidermis & may be associated with hyperplasia of basal cells, or alternatively, with atrophy that results in thinning of the epidermis the atypical basal cells usually have pink or reddish cytoplasm due to dyskeratosis intercellular bridges are present, in contrast to basal cell carcinoma, in which they are not visible the superficial dermis contains thickened, blue-gray elastic fibers (elastosis), a probable result of abnormal elastic fiber synthesis by sun-damaged fibroblasts the stratum corneum is thickened, and unlike normal skin, the cells in this layer often retain their nuclei (parakeratosis)

Actinic keratosis. A, Excessive scale formation in this lesion has produced a "cutaneous horn." B, Basal cell layer atypia (dysplasia) is associated with marked hyperkeratosis and parakeratosis. C, Progression to full-thickness nuclear atypia, with or without the presence of superficial epidermal maturation, heralds the development of squamous cell carcinoma in situ.

Squamous Cell Carcinoma SCCs that have not invaded through the basement membrane of the dermoepidermal junction (termed in situ carcinoma) appear as sharply defined, red, scaling plaques more advanced, invasive lesions are nodular, show variable keratin production (appreciated grossly as hyperkeratotic scale), and may ulcerate unlike actinic keratoses, in SCC in situ, cells with atypical (enlarged & hyperchromatic) nuclei involve all levels of the epidermis invasive SCC shows variable degrees of differentiation, ranging from tumors composed of polygonal cells arranged in orderly lobules & having numerous large areas of keratinization, to neoplasms a/w geographic necrosis consisting of highly anaplastic cells that exhibit only abortive, single-cell keratinization (dyskeratosis) the latter tumors may be so poorly differentiated that immunohistochemical stains for keratins are needed to confirm the diagnosis

Invasive squamous cell carcinoma. A, Lesions are often nodular and ulcerated as seen in this scalp tumor. B, Tongues of atypical squamous epithelium have transgressed the basement membrane, invading deeply into the dermis. C, A magnified image reveals invasive tumor cells showing enlarged nuclei with angulated contours and prominent nucleoli.

Keratoacanthoma: some regard it as a variant of well-differentiated SCC, while others consider it as a distinct entity differs from conventional SCC in that after a period of rapid growth, it usually regresses spontaneously gross: symmetric cup-shaped tumor with a central depression filled with keratin debris histo: lobules of squamous cells with glassy cytoplasm that undergo keratinization w/o an intervening granular layer once established, these lesions elicit a brisk lymphocytic & eosinophilic host response Basal Cell Carcinoma gross: pearly papule often containing prominent, dilated subepidermal blood vessels (telangiectasias) some contain melanin & thus appear pigmented advanced lesions may ulcerate extensive local invasion of bone or facial sinuses may occur after many years of neglect or in unusually aggressive tumors one common and important variant, the superficial basal cell carcinoma, presents as an erythematous, occasionally pigmented plaque that may resemble early forms of melanoma histo tumor cells resemble those in the normal basal cell layer of the epidermis cells arise from the epidermis or follicular epithelium & do not occur on mucosal surfaces two patterns are seen: multifocal growths originated from the epidermis & sometimes extending over several square cm or more of skin surface (multifocal superficial type) nodular lesions growing downward deeply into the dermis as cords & islands of variably basophilic cells with hyperchromatic nuclei, embedded in a

mucinous matrix, and often surrounding by many fibroblasts & lymphocytes cells at the periphery of the tumor cell islands tend to be arranged radially with their long axes in parallel alignment (palisading) in sections, the stroma retracts away from the carcinoma, creating clefts or separation artifacts that assist in differentiating basal cell carcinomas from certain appendage tumors that are also characterized by proliferation of basaloid cells, such as trichoepithelioma

Basal cell carcinoma. Pearly, telangiectatic nodules (A) are composed of nests of uniformly atypical basaloid cells within the dermis (B) that are often separated from the adjacent stroma by thin clefts (C), an artifact of sectioning.

Tumors of the Dermis Dermatofibroma (Benign Fibrous Histiocytoma) firm, tan to brown papules which are asymptomatic or tender & may and slightly in size over time most are less than 1cm in diameter, but actively growing lesions may reach several cm in diameter; with time they often become flattened tendency to dimple inward on lateral compression (vs. nodular melanomas, which protrude when squeezed) histo benign, spindle-shaped cells arranged in a well-defined, nonencapsulated mass within the mid-dermis extension of these cells into the subcutaneous fat is sometimes observed many cases demonstrate a peculiar form of overlying epidermal hyperplasia, characterized by downward elongation of hyperpigmented rete ridges (a pseudoepitheliomatous pattern) numerous histologic variants are noted, such as more cellular forms or tumors with pools of extravascular blood & hemosiderin (aneurysmal)

Benign fibrous histiocytoma (dermatofibroma). This firm, tan papule on the leg (A) shows a localized proliferation of benign-appearing spindle cells within the dermis (B). C, Note the characteristic overlying epidermal hyperplasia and the tendency of fibroblasts to surround individual collagen bundles.

Dermatofibrosarcoma Protuberans well-differentiated slow growing locally aggressive and can recur, but rarely metastasize clinical: firm, solid nodules that arise most frequently on the trunk; often develop as aggregated protuberant tumors within a firm (indurated) plaque or nodule that may sometimes ulcerate histo cellular, composed of fibroblasts arranged radially, reminiscent of blades of a pinwheel (storiform pattern) mitoses are rare overlying epidermis is generally thinned deep extension from the dermis into subcutaneous fat, producing a characteristic honeycomb pattern, is frequently present may extend down fibrous septae in the subcutis and thus require wider excision than would appear to be necessary to prevent local recurrence

Dermatofibrosarcoma protuberans. A, The tumor usually presents as a flesh-colored to erythematous nodule, and has a fibrotic appearance on sectioning. B, C, Characteristic storiform cellularity is noted histologically, and the lesion often infiltrates the subcutis in a manner that resembles "Swiss cheese" to some afficianados.

Tumors of Cellular Migrants to the Skin Mycosis Fungoides (Cutaneous T-Cell Lymphoma)

T-cell lymphoma that presents in the skin and may evolve into generalized lymphoma lesions usually involve truncal areas and include scaly, red-brown patches; raised, scaling plaques that may be confused with psoriasis; and fungating nodules prognosis is related to the % of body surface area involved & progression from patch to plaque to nodular forms eczema-like lesions typify early stages of disease when obvious visceral or nodal spread has not occurred raised, indurated, irregularly outlined, erythematous plaques may then supervene. development of multiple, large (10 cm or more in diameter), red-brown nodules correlates with systemic spread sometimes plaques & nodules ulcerate ultimately, lesions may affect numerous body surfaces, including the trunk, extremities, face, and scalp in some individuals, seeding of the blood by malignant T cells is accompanied by diffuse erythema & scaling of the entire body surface (erythroderma), a condition known as Szary syndrome histo histologic hallmark of CTCL of the mycosis fungoides type is the presence of the Szary-Lutzner cells T-helper cells (CD4+) that characteristically form bandlike aggregates within the superficial dermis & invade the epidermis as single cells & small clusters (Pautrier microabscesses) these cells have markedly infolded nuclear membranes, imparting a hyperconvoluted or cerebriform contour although patches & plaques show pronounced epidermal infiltration by SzaryLutzner cells (epidermotropism), in more advanced nodular lesions the malignant T cells often lose this epidermotropic tendency, grow deeply into the dermis, and eventually spread systemically

Cutaneous T-cell lymphoma. A, Several ill-defined, erythematous, often scaling, and occasionally ulcerated plaques. B, Microscopically, there is an infiltrate of atypical lymphocytes that show a tendency to accumulate beneath the epidermal layer and to invade the epidermis.

Mastocytosis urticaria pigmentosa: lesions are multiple and widely distributed, consisting of round to oval, red-brown, nonscaling papules and small plaques solitary mastocytomas: present as one or several pink to tan-brown nodules that may be pruritic or show blister formation

systemic mastocytosis: skin lesions similar to those of urticaria pigmentosa are accompanied by mast cell infiltration of bone marrow, liver, spleen, and lymph nodes many signs & symptoms of mastocytosis are due to effects of histamine, heparin, and other substances released as a result of mast cell degranulation Darier sign refers to a localized area of dermal edema and erythema (wheal) that occurs when lesion skin is rubbed Dermatographism refers to an area of dermal edema resembling a hive that occurs in normal skin as a result of localized stroking with a pointed instrument In systemic disease, all of the following may be seen: pruritus and flushing triggered by certain foods, temperature changes, alcohol, and certain drugs (morphine, codeine, aspirin); rhinorrhea; rarely, GI or nasal bleeding, possibly due to the anticoagulant effects of heparin; and bone pain as a result of osteoblastic & osteoclastic involvement histo varies from a subtle increase in the numbers of spindle-shaped and stellate mast cells around superficial dermal blood vessels, to large numbers of tightly packed, round to oval mast cells in the upper to mid-dermis variable fibrosis, edema, and small numbers of eosinophils may also be present mast cells may be difficult to differentiate from lymphocytes in routine, H&Estained sections, & special metachromatic stains (toluidine blue or Giemsa) must be used to visualize their granules even with these stains, extensive degranulation may result in failure to recognize these cells by light microscopy, but their identity can be readily confirmed with immunohistochemical stains for mast cell markers, such as mast cell tryptase

Mastocytosis. A, Solitary mastocytoma in a 1-year-old child. B, By routine histology, numerous ovoid cells with uniform, centrally located nuclei are observed in the dermis. C, Giemsa staining reveals purple, "metachromatic" granules within the cytoplasm of the cells.

Disorders of Epidermal Maturation Ichthyosis group of genetically inherited disorders is associated with chronic, excessive keratin buildup (hyperkeratosis) that results clinically in fish-like scales

most ichthyoses become apparent either at or around the time of birth acquired (noninherited) variants also exist; in the acquired ichthyosis vulgaris in adults, there can be an association with lymphoid & visceral malignancies clinical types of ichthyosis vary according to the mode of inheritance, histology, & clinical features; the primary categories include ichthyosis vulgaris (autosomal dominant or acquired), congenital ichthyosiform erythroderma (autosomal recessive), lamellar ichthyosis (autosomal recessive), & X-linked ichthyosis histo all forms exhibit a buildup of compacted stratum corneum that is a/w loss of the normal basket-weave pattern generally little or no inflammation variations in the thickness of the epidermis & stratum granulosum, and the gross appearance & distribution of lesions are used to subclassify these disorders

Ichthyosis. Note prominent fishlike scales (A) and compacted, thickened stratum corneum (B).

Acute Inflammatory Dermatoses Urticaria (Hives) localized mast cell degranulation & resultant dermal microvascular hyperpermeability pruritic edematous plaques (wheals) angioedema is closely related characterized by deeper edema of both dermis & subcutaneous fat individual lesions develop and fade within hours (usually <24 hours); episodes may last for days or persist for months lesions vary from small, pruritic papules to large edematous plaques individual lesions may coalesce to form annular, linear, or arciform configurations sites of predilection for urticarial eruptions include any area exposed to pressure, such as the trunk, distal extremities & ears histo

sparse superficial perivenular infiltrate of mononuclear cells & rare neutrophils eosinophils may be present collagen bundles are more widely spaced than in normal skin, a result of superficial dermal edema superficial lymphatic channels are dilated due to absorption of edema fluid epidermal changes are typically absent

Urticaria. A, Erythematous, edematous, often circular plaques are characteristic. B, Histologically, there is superficial dermal edema, manifested by spaces between collagen bundles, and dilated lymphatic and blood-filled vascular spaces; the epithelium is normal.

Acute Eczematous Dermatitis all forms of eczema are characterized by red, papulovesicular, oozing & crusted lesions that, if persistent, develop into raised, scaling plaques due to reactive acanthosis & hyperkeratosis

Stages of eczema development. A, Initial dermal edema and perivascular infiltration by inflammatory cells is followed within 24 to 48 hours by epidermal spongiosis and microvesicle formation (B). C, Abnormal scale, including parakeratosis, follows, along with progressive acanthosis (D) and hyperkeratosis (E) as the lesion becomes chronic.

based on initiating factors, eczematous dermatitis can be subdivided into the following categories: (1) allergic contact dermatitis, (2) atopic dermatitis, (3) drugrelated eczematous dermatitis, (4) photoeczematous dermatitis, and (5) primary irritant dermatitis example: acute contact reaction to topical antigens such as poison ivy/oak pruritic, edematous, oozing plaques, often containing small & large blisters (vesicles & bullae) such lesions are prone to bacterial superinfection, which produces a yellow crust (impetiginization) with time, persistent lesions become less wet (faii to ooze or form vesicles) & become progressively scaly (hyperkeratotic) as the epidermis thickens (acanthosis) histo prominent spongiosis edema seeps into the intercellular spaces of the epidermis, splaying apart keratinocytes, particularly in the stratum spinosum (unlike urticaria, in which edema is restricted to the superficial dermis) mechanical shearing of intercellular attachement sites (desmosomes) & cell membranes by progressive accumulation of intercellular fluid may result in the formation of intraepidermal vesicles during earliest stages, there is a superficial, perivascular, lymphocytic infiltrate a/w papillary dermal edema & mast cell degranulation pattern & composition of this infiltrate may provide clues to underlying cause eczema resulting from certain ingested drugs is marked by a lymphocytic infiltrate, often containing eosinophils, around deep as well as superficial dermal vessels by contrast, eczematous dermatitis resulting from contact antigens tends to produce an inflammatory rxn preferentially affecting the superficial dermal layer

Eczematous dermatitis. A, Acute allergic contact dermatitis, with numerous vesicles on erythematous skin due to antigen exposure (in this case, laundry detergent in clothing). B, Histologically, intercellular edema within the epidermis creates small, fluid-filled intraepidermal vesicles.

Erythema Multiforme seems to be a hypersensitivity rxn to certain infections & drugs a/w: (1) infections: herpes simplex, mycoplasma, histoplasmosis, coccidioidomycosis, typhoid, leprosy; (2) drugs: sulfonamides, penicillin, barbiturates, salicylates, hydantoins, antimalarials; (3) malignant disease

(carcinomas and lymphomas); and (4) collagen vascular diseases (SLE, dermatomyositis, and polyarteritis nodosa) presents with an array of "multiform" lesions, including macules, papules, vesicles, and bullae as well as the characteristic target lesion consisting of a red macule or papule with a pale, vesicular, or eroded center although lesions may be widely distributed, symmetric involvement of the extremities frequently occurs an extensive & symptomatic febrile form of the disease, which is often but not exclusively seen in children, is called Stevens-Johnson syndrome typically, erosions & hemorrhagic crusts involve the lips and oral mucosa, although the conjunctiva, urethra, and genital and perianal areas may also be affected secondary infection of involved areas due to loss of skin integrity may result in life-threatening sepsis. another variant, termed toxic epidermal necrolysis, results in diffuse necrosis & sloughing of cutaneous & mucosal epithelial surfaces, producing a clinical situation analogous to an extensive burn when both infection & fluid loss are clinical concerns histo early lesions show a superficial perivascular, lymphocytic infiltrate a/w dermal edema & accumulation of lymphocytes along the dermoepidermal junction, where they are intimately a/w degenerating & necrotic keratinocytes, a pattern termed interface dermatitis with time there is upward migration of lymphocytes into the epidermis discrete & confluent zones of epidermal necrosis occur with concomitant blister formation epidermal sloughing leads to shallow erosions the clinical targetoid lesion shows central necrosis surrounded by a rim of perivenular inflammation

Erythema multiforme. A, The target-like clinical lesions consist of a central blister or zone of epidermal necrosis surrounded by macular erythema. B, Early lesions show lymphocytes collecting along the dermoepidermal junction where basal keratinocytes have begun to become vacuolated. With time, necrotic/apoptotic keratinocytes accumulate in the overlying epithelium.

Chronic Inflammatory Dermatoses Psoriasis most frequently affects skin of the elbows, knees, scalp, lumbosacral areas, intergluteal cleft, and glans penis

typical lesion is a well-demarcated, pink to salmon-colored plaque covered by loosely adherent scale that is characteristically silver-white in color variations exist annular, linear, gyrate, or serpiginous configurations psoriasis is one cause of total body erythema & scaling known as erythroderma nail changes occur in 30% of cases and consist of yellow-brown discoloration (often likened to an oil slick), with pitting, dimpling, separation of the nail plate from the underlying bed (onycholysis), thickening, and crumbling in the rare variant called pustular psoriasis, multiple small pustules form on erythematous plaques; this type of psoriasis is either benign & localized (hands/feet) or generalized & life-threatening, with associated fever, leukocytosis, arthralgia, diffuse cutaneous & mucosal pustules, secondary infection & electrolyte disturbances histo epidermal cell turnover results in marked epidermal thickening (acanthosis), with regular downward elongation of the rete ridges sometimes described as appearing like test tubes in a rack mitotic figures are easily identified well above the basal cell layer, where mitotic activity is confined in normal skin stratum granulosum is thinned or absent, and extensive overlying parakeratotic scale is seen typical of psoriatic plaques is thinning of the portion of the epidermal cell layer that overlies the tips of dermal papillae (suprapapillary plates) and dilated, tortuous blood vessels within these papillae this constellation of changes results in abnormal proximity of vessels within the dermal papillae to the overlying parakeratotic scale, and accounts for the characteristic clinical phenomenon of multiple, minute, bleeding points when the scale is lifted from the plaque (Auspitz sign) neutrophils form small aggregates within slightly spongiotic foci of the superficial epidermis (spongiform pustules) and within the parakeratotic stratum corneum (Munro microabscesses) in pustular psoriasis, larger abscess-like accumulations of neutrophils are present directly beneath the stratum corneum

Clinical evolution of psoriasis. A, Early and eruptive lesions may be dominated by signs of inflammation, including small pustules and erythema (left). Established, chronic lesions demonstrate erythema surmounted by characteristic silver-white scale (right). B, Histologically, established lesions demonstrate marked epidermal hyperplasia, parakeratotic scale, and neutrophils within the superficial epidermal layers.

Seborrheic Dermatitis

classically involves regions with high density of sebaceous glands (scalp, forehead, external auditory canal, retroauricular area, nasolabial folds, presternal area) but is NOT a disease of the sebaceous glands individual lesions are macules & papules on an erythematous-yellow, often greasy base, typically in a/w extensive scaling & crusting fissures may be present, particularly behind the ears dandruff is the common clinical expression of SD of the scalp in infants, presents as cradle cap histo lesions of SD share histologic features with both spongiotic dermatitis & psoriasis, with earlier lesions being more spongiotic & later ones more acanthotic typically, mounds of parakeratosis containing neutrophils & serum are present at the ostio of hair follicles (so-called follicular lipping) a superficial perivascular inflammatory infiltrate generally consists of an admixture of lymphocytes & neutrophils with HIV infection, apoptotic keratinocytes & plasma cells may also be present Lichen Planus pruritic, purple, polygonal, planar papules & plaques usually self-limited & most commonly resolves spontaneously 1-2 yrs after onset, often leaving zones of postinflammatory hyperpigmentation oral lesions may persist for years squamous cell carcinoma has been noted to occur in chronic mucosal & paramucosal lesions of LP cutaneous lesions consist of itchy, violaceous, flat-topped papules that may coalesce focally to form plaques these papules are often highlighted by white dots or lines called Wickham striae, which are created by areas of hypergranulosis in darkly pigmented individuals, lesions may acquire a dark-brown color due to release of melanin into the dermis as the basal cell layer is destroyed multiple lesions are characteristic & 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 the Koebner phenomenon may be seen (as in psoriasis) histo dense, continuous infiltrate of lymphocytes along the dermoepidermal junction, a prototypic example of interface dermatitis lymphocytes are intimately a/w basal keratinocytes, which show degeneration, necrosis, and a resemblance in size & contour to more mature cells of the stratum spinosum (squamatization) as a consequence of this destructive infiltration of lymphocytes, there is a redefinition of the normal, smoothly undulating configuration of the dermoepidermal interface to a more angulated zigzag contour (sawtoothing) anucleate, necrotic basal cells may become incorporated into the inflamed papillary dermis, where they are referred to as colloid or Civatte bodies though characteristic of LP, these bodies may be detected in any chronic dermatitis in which basal keratinocytes are injured & destroyed although the lesions bear some similarities to those in erythema multiforme, LP

shows changes of chronicity, namely, epidermal hyperplasia (or rarely atrophy) & thickening of the granular cell layer & stratum corneum (hypergranulosis & hyperkeratosis, respectively) lichen planopilaris = LP preferentially affecting the epithelium of hair follicles

Lichen planus. A, This flat-topped pink-purple, polygonal papule has a white lacelike pattern that is referred to as Wickham stria. B, Biopsy specimen demonstrating a bandlike infiltrate of lymphocytes at the dermoepidermal junction, hyperkeratosis, hypergranulosis and pointed rete ridges (sawtoothing) as a result of chronic basal cell layer injury.

Blistering (Bullous) Diseases

Schematic representation of histologic levels of blister formation. A, In a subcorneal blister the stratum corneum forms the roof of the bulla (as in pemphigus foliaceus). B, In a suprabasal blister a portion of the epidermis, including the stratum corneum, forms the roof (as in pemphigus vulgaris). C, In a subepidermal blister the entire epidermis separates from the dermis (as in bullous pemphigoid).

Squamous cell adhesion molecules. Knowledge of the proteins composing desmosomes and hemodesmosomes is key to understanding blistering disorders. Desmogleins 1 and 3 (Dsg1, Dsg3) are functionally interchangeable components of desmosomes, but have different distributions within the epidermis (left panel). In pemphigus vulgaris, autoantibodies against Dsg1 and Dsg3 cause blisters in the deep suprabasal epidermis, whereas in pemphigus foliaceus, the autoantibodies are against Dsg1 alone, leading to superficial, subcorneal blisters. In bullous phemphigoid, autoantibodies bind BPAG2, a component of the hemidesomes, leading to blister formation at the level of the lamina lucida of the basement membrane. Dermatitis herpetiformis is caused by lgA autoantibodies to the fibrils that anchor hemidesmosomes to the dermis. The various forms of epidermolysis bullosa are caused by genetic defects in genes encoding proteins that either form or stabilize desmosomes or hemidesmosomes. 6/4, 6/4 integrin.

Inflammatory Blistering Disorders Pemphigus Bullous Pemphigoid Dermatitis Herpetiformis Noninflammatory Blistering Disorders Epidermolysis Bullosa Porphyria Disorders of Epidermal Appendages Acne Vulgaris Rosacea Panniculitis Erythema Nodosum Erythema Induratum Infection Verrucae (Warts) Molluscum Contagiosum Impetigo Superficial Fungal Infections Tinea capitis Tinea barbae Tinea corporis

Tinea cruris Tinea pedis (athletes foot) Tinea versicolor