THE SKIN DISEASESIntroductionDefinitions of macroscopic termsDefinitions of microscopic termsDisorders of Pigmentation and MelanocytesBenign Epithelial TumorsPremalignant and Malignant Epidermal TumorsTumors of the DermisDisorders of Epidermal MaturationAcute Inflammatory DermatosesChronic Inflammatory DermatosesDisorders of Epidermal Appendages

INTRODUCTION

Accurate description of the clinical appearance of the skin at a macroscopic level is critical, since lesions before biopsy are, in effect, the gross pathology. Correlation between the gross and histologic appearances is often essential in formulating diagnoses and in understanding pathogenesis. Accordingly, efforts are made in the following pages to depict and describe clinical lesions whenever possible and to relate these findings to the microscopic appearance of lesions. OBJECTIVES:1. Define a nevus in terms of its clinical manifestations.2. Describe the non-nevoid pigmented disorders of the skin.3. List the variant forms of nevocellular nevi. 4. Define a dysplastic nevus in terms of its architectural and cytological features and

its clinical significance. 5. Discuss the evidence for the concept that some dysplastic nevi are precursors of

malignant melanomas. 6. Define a malignant melanoma in terms of its architectural difference from a

nevocellular nevus.7. Describe the risk factors for the development of a malignant melanoma. 8. List the clinical warning signals of melanoma. 9. Know what factor is thought to be responsible for the numerous seborrheic

keratoses sometimes seen as a paraneoplastic syndrome.10.Know the common tumors arising from these adnexal structures.11.Define squamous cell carcinoma of the skin in terms of etiology, pathogenesis,

and prognosis. 12.Define a basal cell carcinoma in terms of frequency, pathogenesis, localization,

and clinical outcome. 13.Know which other disease is closely related to urticaria and how it differs from

urticaria. 14.Name some clinical features in patients with psoriasis and describe the areas of

the skin that are most commonly affected.

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KEY WORDS: Macule, patch, papule, vesicle, dysplastic nevus, melanoma, seborrheic keratoses, urticaria, psoriasis, verrucae, acanthosis, vitiligo.

CLINICAL OBJECTIVES:1. Know the most important histological factor that determines the prognosis of a

melanoma 2. Describe the gross and histological features of seborrheic keratoses.3. Describe the two most frequent histological growth patterns of basal cell

carcinoma 4. Describe the typical epidermal changes in psoriasis. 5. Describe the anatomic classification of verrucae.

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. Wheal Itchy, transient, elevated lesion with variable blanching and erythema formed as the result of dermal edema. 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. Onycholysis Separation of nail plate from nail bed.

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. On mucous membranes, parakeratosis is normal. Hypergranulosis Hyperplasia of the stratum granulosum, often due to intense rubbing. Acanthosis Diffuse epidermal hyperplasia. Papillomatosis Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae.

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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. Hydropic swelling (ballooning) Intracellular edema of keratinocytes, often seen in viral infections. Exocytosis Infiltration of the epidermis by inflammatory or circulating blood cells. Erosion Discontinuity of the skin exhibiting incomplete loss of the epidermis. Ulceration Discontinuity of the skin exhibiting complete loss of the epidermis and often of portions of the dermis and even subcutaneous fat. Vacuolization Formation of vacuoles within or adjacent to cells; often refers to basal cell-basement membrane zone area. Lentiginous Referring to a linear pattern of melanocyte proliferation within the epidermal basal cell layer. Lentiginous melanocytic hyperplasia can occur as a reactive change or as part of a neoplasm of melanocytes.

Disorders of Pigmentation and Melanocytes

Skin pigmentation has historically had major societal implications. Cosmetic desire for increased pigmentation (tanning) has resulted in many deleterious alterations that are described in the pages that follow. Focal or widespread loss of normal protective pigmentation not only renders individuals extraordinarily vulnerable to the harmful effects of sunlight (as in albinism), but has also resulted in severe emotional stress and, in some cultures, profound social and economic discrimination (as in vitiligo).

VITILIGO

Vitiligo is a common disorder characterized by partial or complete loss of pigment-producing melanocytes within the epidermis. All ages and races are affected, but lesions are most noticeable in darkly pigmented individuals. Vitiligo may be entirely unapparent in lightly pigmented skin until tanning occurs in the surrounding normal skin. In darkly pigmented individuals with extensive involvement, residual zones of normal skin may at first appear to represent hyperpigmented lesions.

Clinical lesions are asymptomatic, flat, well-demarcated macules and patches of pigment loss; their size varies from few to many centimeters. Vitiligo often involves the hands and wrists; axillae; and perioral, periorbital, and anogenital skin. A curious phenomenon called koebnerization often occurs in vitiligo (as well as in certain other conditions; see lichen planus), where lesions develop primarily at sites of repeated trauma.

Morphology. On histologic examination, vitiligo usually appears indistinguishable from normal skin. However, it is characterized by loss of melanocytes, as revealed by electron microscopy; it also may be diagnosed by immunohistochemistry for melanocyte-associated proteins (e.g., tyrosinase or Melan-A, or S-100). This is in contrast to some forms of albinism, in which melanocytes are

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present but melanin pigment is not produced because of a lack of or defect in tyrosinase. There are other causes of hypopigmentation that are unrelated to diminished expression of melanin or melanocytes (e.g., postinflammatory hypopigmentation, which represents redistribution of existing pigment within skin possibly coupled with diminished transfer of pigment to keratinocytes).

Pathogenesis. Why are melanocytes progressively lost or destroyed in vitiligo? Theories of pathogenesis include (1) autoimmunity, (2) neurohumoral factors toxic to melanocytes and released by nearby nerve endings, and (3) self-destruction of melanocytes by toxic intermediates of melanin synthesis. Most evidence supports autoimmune causation, focusing on the presence of circulating antibodies against melanocytes7 and the association of vitiligo with other autoimmune disorders, such as pernicious anemia, Addison disease, and autoimmune thyroiditis. Abnormalities in macrophages,8 and in T lymphocytes in skin9 and in the peripheral blood have been described recently, suggesting that aberrations in cell-mediated immunity may also be operative in the pathogenesis of vitiligo. Another interesting facet of vitiligo is its response to therapy with UV light of the A wavelength coupled with use of the photosensitizing drug, psoralen (a therapy known as PUVA). Lesions so treated may regain pigment initially at the ostia of hair follicles, suggesting that melanocyte precursors harbored within the uppermost follicular epithelium are stimulated by this therapeutic approach.

MelasmaMelasma is a mask-like zone of facial hyperpigmentation commonly seen in

association with pregnancy-hence its designation as the "mask of pregnancy." It also may occur in some individuals taking oral contraceptives. It presents as poorly defined, blotchy, tan-brown macules and patches involving the cheeks, temples, and forehead bilaterally. Sunlight may accentuate this pigmentation, which often resolves spontaneously, particularly with cessation of hormonal stimulation.

Morphology. Three histologic patterns have been recognized: an epidermal type, in which there is increased melanin deposition in the basal layers; a dermal type, characterized by macrophages in the superficial (papillary) dermis that have phagocytosed melanin from the adjacent epidermal layer (a process referred to as melanin pigment incontinence); and a mixed type, characterized by a combination of the changes seen in the epidermal and dermal types. These three types may be distinguished by the use of a Wood's light ("black light"), which permits distinction between epidermal versus dermal pigmentation on clinical inspection. This is important because melasma of the epidermal type, and partially of the mixed type, may respond to the topical bleaching agent hydroquinone.

The pathogenesis of melasma appears to relate to functional alterations in melanocytes resulting in enhanced pigment transfer to basal keratinocytes or to dermal macrophages. Apart from its association with pregnancy and oral contraceptives, melasma may occur during the administration of hydantoins, or it may be idiopathic.

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LentigoUntil now, we have been addressing disorders of pigmentation that do not

involve proliferation of melanocytes. The term lentigo (plural, lentigines) refers to a common benign localized hyperplasia of melanocytes occurring at all ages but often in infancy and childhood. There is no sex or racial predilection, and the cause and pathogenesis are unknown. These lesions may involve mucous membranes as well as the skin, and they appear as small (5 to 10 mm across), oval, tan-brown patches. Unlike freckles, lentigines do not darken when they are exposed to sunlight.

Morphology. The essential histologic feature of the lentigo is linear (non-nested) melanocytic hyperplasia (hyperplasia restricted to the cell layer immediately above the basement membrane) that produces a hyperpigmented basal cell layer. So characteristic is this linear melanocytic hyperplasia that the term lentiginous is often used to describe similar patterns of cellular proliferation within the basal cell layer in melanocytic tumors, such as in lentiginous nevi and in certain melanomas (termed acral lentiginous melanomas). Elongation and thinning of the rete ridges are also commonly seen in a lentigo. In contrast to ordinary lentigo (lentigo simplex) a variant termed solar or actinic lentigo occurs in sun-damaged skin in older adults and is associated with subtle alteration in keratinocyte maturation.

Melanocytic nevus (pigmented nevus, mole)Most of us have at least a few moles and probably regard them as mundane and

uninteresting. It may be surprising to learn, then, that moles or nevi represent one of the most diverse, dynamic, and biologically intriguing tumors of the skin! Strictly speaking, the term nevus denotes any congenital lesion of the skin (e.g., birthmark).

Melanocytic nevus, however, refers to any congenital or acquired neoplasm of melanocytes, and hence is somewhat of a misnomer.In clinical appearance, common acquired melanocytic nevi are 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. There are numerous clinical and histologic types of melanocytic nevi, and the clinical appearance may be variable.

Nevocellular 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.

Morphology. Melanocytic nevi are initially formed by melanocytes that have been transformed from highly dendritic single cells normally interspersed among basal keratinocytes to round cells that grow in aggregates, or "nests," along the dermoepidermal junction. Langerhans cells, the other type of dendritic cell within the epidermis, are unrelated to melanocytic nevi. Nuclei of nevus cells are uniform and rounded in contour, contain inconspicuous nucleoli, and show little or no mitotic activity. Such lesions are believed to represent an early developmental stage in melanocytic nevi and are called junctional nevi. Eventually, most junctional nevi grow into the underlying dermis as nests or cords of cells (compound nevi); in older

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lesions, the epidermal nests may be lost entirely to form pure intradermal nevi. Clinically, compound and dermal nevi are often more elevated than junctional nevi.Progressive growth of nevus cells from the dermoepidermal junction into the underlying dermis is accompanied by a process termed maturation. Whereas less mature, more superficial nevus cells are larger, tend to produce melanin, and grow in nests, more mature, deeper nevus cells are smaller, produce little or no pigment, and grow in cords. The most mature nevus cells may be found at the deepest extent of lesions, where they often acquire fusiform contours and grow in fascicles resembling neural tissue. This striking metamorphosis correlates with enzymatic changes (progressive loss of tyrosinase activity and acquisition of cholinesterase activity in deeper, nonpigmented, nervelike 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.

Variant Forms of Nevocellular Nevi

Nevus Variant

Diagnostic Architectural Features

Diagnostic Cytologic Features

Clinical Significance

Congenital nevus

Deep dermal and sometimes subcutaneous growth around adnexa, neurovascular bundles, and blood vessel walls

Identical to ordinary acquired nevi

Present at birth; large variants have increased melanoma risk

Blue nevus Non-nested dermal infiltration, often with associated fibrosis

Highly dendritic, heavily pigmented nevus cells

Black-blue nodule; often confused with melanoma clinically

Spindle and epithelioid cell nevus (Spitz nevus)

Fascicular growth Large, plump cells with pink-blue cytoplasm; fusiform cells

Common in children; red-pink nodule; often confused with hemangioma clinically

Halo nevus Lymphocytic infiltration surrounding nevus cells

Identical to ordinary acquired nevi

Host immune response against nevus cells and surrounding normal melanocytes

Dysplastic nevus

Large, coalescent intraepidermal nests

Cytologic atypia Potential precursor of malignant melanoma

Morphology. On histologic examination, dysplastic nevi consist of compound nevi with both architectural and cytologic evidence of abnormal growth. Nevus cell nests within the epidermis may be enlarged and exhibit abnormal fusion or coalescence 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 consisting of

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irregular, often angulated, nuclear contours and hyperchromasia is frequently observed. Associated alterations also occur in the superficial dermis. These consist of a usually sparse lymphocytic infiltrate, loss of melanin from presumably destroyed nevus cells, phagocytosis of this pigment by dermal macrophages (melanin pigment incontinence), and a peculiar linear fibrosis surrounding the epidermal rete ridges that are involved by the nevus. All of these features assist in the histologic recognition of a dysplastic nevus.

Several lines of evidence support the concept that some dysplastic nevi are precursors of malignant melanoma. In one study, it was shown that in a large number of families prone to the development of melanoma, more than 5% of family members developed melanoma during an 8-year follow-up period, and new melanomas occurred only in individuals with dysplastic nevi. From this database, it was concluded that the actuarial probability of persons with the dysplastic nevus syndrome developing melanoma is 56% at age 59 years! Dysplastic nevi also demonstrate expression of some abnormal cell-surface antigens, karyotypic abnormalities, and in vitro vulnerability to the mutagenic effects of UV light

Clark and associates have proposed steps whereby benign nevi may undergo aberrant differentiation to become dysplastic and eventually become metastasizing malignant tumors. Parallels may be found in neoplasia involving other organ systems, and thus dysplastic nevi represent a general model of tumor progression

Malignant melanomaMalignant melanoma is a relatively common neoplasm that not long ago was

considered almost uniformly deadly. The great preponderance of melanomas arises in the skin; other sites of origin include the oral and anogenital mucosal surfaces, esophagus, meninges, and notably the eye.

Today, as a result of increased public awareness of the earliest signs of skin melanomas, most are cured surgically. Nonetheless, the incidence of these lesions is on the rise, necessitating vigorous surveillance for their development.

As with epithelial malignant neoplasms of the skin, sunlight appears to play an important role in the development of skin malignant melanoma. For example, men commonly develop this tumor on the upper back, whereas women have a relatively high incidence on both the back and the legs. Lightly pigmented individuals are at higher risk for the development of melanoma than are darkly pigmented individuals.

The lesion is irregular in pigmentation and contour, very suspicious for a malignant melanoma. Melanocytic lesions like a nevocellular nevus, a dysplastic nevus, and a melanoma can present as pigmented lesions.

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Sunlight, however, does not seem to be the only predisposing factor, and the presence of a pre-existing nevus (e.g., a dysplastic nevus), hereditary factors, or even exposure to certain carcinogens (as in the case of experimental melanomas in rodent models) may play a role in lesion development and evolution.

Clinical Features. Malignant melanoma of the skin is usually asymptomatic, although itching may be an early manifestation. The majority of lesions are greater than 10 mm in diameter. The most important clinical sign of the disease is change in color, size, or shape in a pigmented lesion. Unlike benign (nondysplastic) nevi, melanomas exhibit striking variations in pigmentation, appearing in shades of black, brown, red, dark blue, and gray. On occasion, zones of white or flesh-colored hypopigmentation are also present. The borders of melanomas are not smooth, round, and uniform, as in nevocellular nevi, but irregular and often "notched." In summary, the clinical warning signs of melanoma are (1) enlargement of a pre-existing mole, (2) itching or pain in a pre-existing mole, (3) development of a new pigmented lesion during adult life, (4) irregularity of the borders of a pigmented lesion, and (5) variegation of color within a pigmented lesion.

Growth Patterns and Morphology. Central to understanding the complicated histology of malignant melanoma is the concept of radial and vertical growth. Simply stated, radial growth indicates the tendency of a melanoma to grow horizontally within the epidermal and superficial dermal layers, often for a prolonged time. During this stage of growth, melanoma cells do not have the capacity to metastasize. Specific types of radial growth phase melanoma include lentigo maligna, superficial spreading, and acral/mucosal lentiginous. These are defined on the basis of architectural and cytologic features of growth within the epidermal layer as well as biologic behavior. For example, lentigo maligna radial growth typically occurs on sun-damaged facial skin of the elderly and may continue for as long as several decades before the tumor develops the capacity to metastasize. With time, the pattern of growth assumes a vertical component, and the melanoma now grows downward into the deeper dermal layers as an expansile mass lacking cellular maturation, without a tendency for the cells to become smaller as they descend into the reticular dermis. This event is heralded 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 true metastatic potential.

The epidermis shows atypical melanocytic proliferation consisting of irregular nested and single melanocytes. Atypical melanocytes are visible in all layers of the epidermis from the basal layer to the granular layer. Normally, the epidermis is composed of different, interdependent cell types.

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Interestingly, the probability of metastasis in such lesions may be predicted by simply measuring in millimeters the depth of invasion of this vertical growth phase nodule below the granular cell layer of the overlying epidermis. Prediction of clinical outcome has been refined further by taking into account factors such as number of mitoses and degree of infiltrative lymphocytic response within the tumor nodule.

Individual melanoma cells are usually considerably larger than nevus cells. They contain large nuclei with irregular contours, having chromatin characteristically clumped at the periphery of the nuclear membrane and prominent red (eosinophilic) nucleoli. These cells proliferate as poorly formed nests or as individual cells at all levels of the epidermis in the radial phase of growth and, in the dermis, as expansile, balloon-like nodules in the vertical phase of growth. The nature and extent of the vertical growth phase determine the biologic behavior of malignant melanoma, and thus it is important to observe and record vertical growth phase parameters in a pathology report.

Diagnostic Criteria and Prognostic Attributes. While most nevi and melanomas are clearly separable according to reproducible diagnostic criteria, a minority of lesions exhibit hybrid features that defy definitive classification as entirely benign or potentially malignant. These lesions occupy a gray zone where morphologic characteristics may be insufficient to determine prognosis with accuracy. Such melanocytic proliferations have been termed melanocytic tumors of uncertain malignant potential (MELTUMP) Such descriptive names underscore the limits of morphology in predicting outcome for these rare lesions and signify to the clinician the importance of excision to minimize local recurrence as well as of frequent follow-up.

For the majority of melanomas that have entered vertical growth, histologic and clinical attributes that permit prediction of outcome have been defined based on studies of large numbers of patients. One model that has received widespread attention over the past decade involves assessment of prognosis based on application of multiple variables to a given lesion. These variables are (1) measurement of tumor depth in millimeters, (2) number of tumor cell mitoses per square millimeter, (3) evidence of an immune response to the superficial (radial) growth component (termed regression), (4) presence and degree of tumor infiltrating lymphocytes (TILs) at the base of the deep (vertical) growth component, (5) gender, and (6) location (central body or extremity). Determinants of a more favorable prognosis in this model include tumor depth of less than 1.7 mm, absence or low numbers of mitoses, presence of a brisk TIL response, absence of regression, female gender, and location on extremity skin. Because melanomas evolve over time from entirely curable lesions to tumors with progressive potential for metastasis as they enlarge and invade more deeply, early and complete excision is critical to minimizing the likelihood of systemic dissemination.

BENIGN EPITHELIAL TUMORSBenign epithelial neoplasms are common and usually biologically

inconsequential, although they may represent significant sources of psychologic

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discomfort for the patient. These tumors, derived from the keratinizing stratified squamous epithelium of the epidermis and hair follicles (keratinocytes) and the ductular epithelium of cutaneous glands, may recapitulate the cell layers from which they arise. They are often confused clinically with malignancy, particularly when they are pigmented or inflamed, and histologic examination of a biopsy specimen is frequently required to establish a definitive diagnosis. In rare instances they can be part of specific syndromes associated with potentially life-threatening visceral malignancies (e.g., multiple trichilemmomas as in Cowden syndrome or multiple, benign or malignant sebaceous neoplasms as in Muir-Torre syndrome). Precise diagnosis of epithelial tumors in these instances may facilitate recognition of a syndrome and implementation of appropriate intervention and follow-up.

Seborrheic keratosesThese common epidermal tumors occur most frequently in middle-aged or

older individuals. They arise spontaneously and may become particularly numerous on the trunk, although the extremities, head, and neck may also be involved. In people of color, multiple small lesions on the face are termed dermatosis papulosa nigra.

Seborrheic keratoses have characteristic clinical features. They appear as round, flat, coinlike, waxy plaques that vary in diameter from millimeters to several centimeters. They are uniformly tan to dark brown and usually show a velvety to granular surface. Lesions may give the impression that they are "stuck on" and may be easily peeled off. Inspection with a hand lens will usually reveal small, round, porelike ostia impacted with keratin, a feature helpful in differentiating these pigmented lesions from melanomas.

Morphology. On histologic examination, these neoplasms are exophytic and demarcated sharply from the adjacent epidermis.

The largest lesion is dark brown and the characteristic greasy-appearing, granular surface is clearly elevated above the surrounding skin level. The surrounding smaller lesions vary in color from light to deep tan. Over a period of years, seborrheic keratosis may become numerous, particularly on the trunk.

They are 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 clinically. Exuberant keratin production (hyperkeratosis) occurs at the surface of seborrheic keratoses, and small keratin-filled cysts (horn cysts) and invaginations of keratin into the main tumor mass (invagination cysts) are characteristic features. Interestingly, when seborrheic

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keratoses become irritated and inflamed, they undergo squamous differentiation27 and are characterized by foci of "whorling" squamous cells resembling eddy currents in a stream. A biologic explanation for this intriguing phenomenon awaits discovery. When seborrheic keratoses involve the epithelium of hair follicles, they may grow in an endophytic (downward) fashion, and they generally also show the effects of inflammation; such lesions are termed inverted follicular keratoses.

Seborrheic keratoses may occur explosively in large numbers, as part of a paraneoplastic syndrome (Leser-Trélat sign). Transforming growth factor-α produced by tumor cells is thought to contribute to the development of such lesions

Acantosish nigricansAcanthosis nigricans is used to describe thickened (acanthosis = hyperplasia of

the stratum spinosum of the epidermis), hyperpigmented zones of skin often with a "velvet-like" texture involving most commonly the flexural areas (axillae, skin folds of the neck, groin, and anogenital regions). It is an important cutaneous marker for associated benign and malignant conditions and, accordingly, is divided into two types. The benign type, which constitutes about 80% of all cases, develops gradually and usually occurs in childhood or during puberty. It may occur (1) as an autosomal dominant trait with variable penetrance, (2) in association with obesity or endocrine abnormalities (particularly with pituitary and pineal tumors and with diabetes), and (3) as part of a number of rare congenital syndromes. As with seborrheic keratoses, acanthosis nigricans may result from abnormal production of epidermal growth-promoting factors by a variety of tumors. This occurrence may account for many instances of the malignant type, in which lesions arise in middle-aged and older individuals, often in association with an underlying gastrointestinal adenocarcinoma.

Morphology. All forms of acanthosis nigricans have similar histologic features. The epidermis and underlying enlarged dermal papillae undulate sharply to form numerous repeating peaks and valleys. Variable hyperplasia may be seen, along with hyperkeratosis and slight basal cell layer hyperpigmentation (but no melanocytic hyperplasia).Because lesions of acanthosis nigricans may precede clinical symptoms and signs of the underlying disorder, knowledge and recognition of this entity may be of great diagnostic importance in early recognition of covert systemic disease.

Fibroepithelial polypThe fibroepithelial polyp has many names (acrochordon, squamous papilloma,

skin tag) and is one of the most common cutaneous lesions. It is generally detected as an incidental finding in middle-aged and older individuals on the neck, trunk, face, and intertriginous areas as a soft, flesh-colored, baglike tumor attached to the skin surface by a small, often slender stalk. Rarely, fibroepithelial polyps, along with tumors differentiating toward perifollicular mesenchyme, are part of a syndrome called Birt-Hogg-Dubé syndrome.

Morphology. On histologic examination, these tumors are merely fibrovascular cores covered by benign squamous epithelium. It is not uncommon to

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discover ischemic necrosis in histologic sections (the result of torsion that produced the pain and swelling that may precipitate their removal).

Fibroepithelial polyps are usually biologically inconsequential, although they have been associated with diabetes and intestinal polyposis. It is of interest that along with melanocytic nevi and hemangiomas, they often become more numerous or prominent during pregnancy. The pathogenesis of this is unclear but may be related to hormonal stimulation.

Epithelial cyst (wen)Epithelial cysts are common lesions formed by the invagination and cystic

expansion of the epidermis or of the epithelium forming the hair follicle. The lay term, wen, derives from the Anglo-Saxon wenn, meaning a lump or tumor. These cysts are filled with keratin and variable amounts of 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 dome shaped and flesh colored and often become painful on traumatic rupture.

Morphology. Epithelial cysts are divided into several histologic types according to the structural components of their walls. The epidermal inclusion cyst has a wall nearly identical to the epidermis and is filled with laminated strands of keratin. Pilar or trichilemmal cysts have a wall that resembles follicular epithelium, without a granular cell layer and filled by a more homogeneous mixture of keratin and lipid.

Epithelial cysts are common lesions, presenting as well-circumscribed, firm nodules. Traumatic rupture may cause pain. Epidermal inclusion cysts can be very small and multiple.

The dermoid cyst is similar to the epidermal inclusion cyst, but it also shows multiple appendages (such as small hair follicles) budding outward from its wall. Finally, steatocystoma multiplex

constitutes a curious cyst with a wall resembling the sebaceous gland duct, and from which numerous compressed sebaceous lobules originate. The importance of recognition of this cyst derives from the often dominantly heritable nature of the lesion.

Adnexal tumorsThere are literally hundreds of benign neoplasms arising from cutaneous

appendages. Although some show no aggressive behavior and remain localized, they may be confused with certain types of cutaneous cancers (e.g., basal cell carcinoma). Certain appendage tumors are associated with Mendelian patterns of inheritance and occur as multiple disfiguring lesions. In some instances, these lesions serve as

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markers for internal malignancy, as in the case of multiple trichilemmomas and breast carcinoma of Cowden syndrome. Selected examples are provided here to illustrate neoplasms of hair follicles, eccrine glands, and apocrine glands.

Appendage tumors are often clinically nondescript, flesh-colored solitary or multiple papules and nodules. Some have a predisposition for occurrence on specific body surfaces. For example, the eccrine poroma occurs predominantly on the palms and soles. The cylindroma, an appendage tumor with apocrine differentiation, usually occurs on the forehead and scalp, where coalescence of nodules with time may produce a hatlike growth, hence the name turban tumor. These lesions may be dominantly inherited and first appear early in life. Syringomas, lesions of eccrine differentiation, in comparison, usually occur as multiple, small, tan papules in the vicinity of the lower eyelids. Trichoepitheliomas, showing follicular differentiation, are dominantly inherited when they are seen as multiple, semitransparent, dome-shaped papules that involve the face, scalp, neck, and upper trunk.

Common Adnexal TumorsAdnexal Tumors Mature

CounterpartHistologic Features Clinical Significance

Trichoepithelioma Trichofolliculoma

Hair follicle Hair matrix, outer root sheath differentiation

Multiple trichoepitheliomas, dominant inheritance

Sebaceous adenoma Sebaceous epithelioma

Sebaceous gland

Cytoplasmic lipid vacuoles

Association with internal malignancy

Syringocystadenoma papilliferum

Apocrine gland

Apocrine type ("decapitation") secretion

May develop in mixed epidermal-adnexal hamartomas of face and scalp termed nevus sebaceous

Syringoma Eccrine gland

Eccrine ducts lined by membranous eosinophilic cuticles; tadpole-like epithelial structures

May be confused with basal cell carcinoma clinically

Morphology. The cylindroma is composed of islands of cells resembling those of the normal epidermal or adnexal basal cell layer (basaloid cells). These islands fit together like pieces of a jigsaw puzzle within a fibrous dermal matrix. The trichoepithelioma is a proliferation of basaloid cells that forms primitive structures resembling hair follicles. Mixed tumor (chondroid syringoma) is composed of variably dilated sweat gland-like ducts surrounded by a blue-gray matrix with features of true cartilage. The trichilemmoma is a localized proliferation of pale pink, glassy cells that resembles the uppermost portion of the hair follicle (infundibulum). Hidradenoma papilliferum is composed of ducts lined by apocrine-type cells that show characteristic decapitation secretion and a fibrous stroma.

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Although most appendage tumors are benign, malignant variants do exist. Sebaceous carcinoma, for example, arises from the meibomian glands of the eyelid and may follow an aggressive biologic course with systemic metastases. Eccrine and apocrine carcinomas are often confused with metastatic adenocarcinomas to the skin because of their tendency for abortive gland formation.

KeratoacanthomaKeratoacanthoma is a rapidly developing neoplasm that clinically and

histologically may mimic well-differentiated squamous cell carcinoma. Often it will heal spontaneously, without treatment! Men are more often affected than women, and lesions most frequently affect sun-exposed skin of whites older than age 50 years.

Keratoacanthomas appear clinically as flesh-colored, dome-shaped nodules with a central, keratin-filled plug, imparting a crater-like topography (Fig. 25-12 A ). Lesions range in size from 1 cm to several centimeters across and have a predilection for facial skin, including the cheeks, nose, and ears, and the dorsa of the hands.

Morphology. Keratoacanthomas are characterized histologically by a central, keratin-filled crater surrounded by proliferating epithelial cells that extend upward in a liplike fashion over the sides of the crater and downward into the dermis as irregular tongues. This epithelium is composed of enlarged cells showing evidence of reactive cytologic atypia. These cells have a characteristically "glassy" eosinophilic cytoplasm and produce keratin abruptly (without the development of an intervening granular cell layer). This mode of keratinization is analogous to that of the normal hair follicle and is similar to that seen in the pilar cyst described earlier, giving rise to speculation that the keratoacan thoma is a neoplasm of follicular epithelium. The early tumor infiltrates into the collagen and elastic fibers and entraps them. Little, if any, host inflammatory response is present during this rapidly proliferative phase, but as the lesion evolves, there is some stromal response that is fibrotic and contains numerous inflammatory cells.

There is growing belief that keratoacanthomas may represent a form of squamous cell carcinoma that regresses as a consequence of interactions with host tissues that fail to support inexorable growth. It is presently unclear whether this relates to factors in the host (e.g., immune response) or inherent to the tumor (e.g., expression of angiogenesis or cell-cycle inhibitors). Like most squamous cell carcinomas, the majority of keratoacanthomas have mutations in the p53 gene.

PREMALIGNANT AND MALIGNANT EPIDERMAL TUMORS

Actinic keratosisBefore the development of overt malignancy of the epidermis, a series of

progressively dysplastic changes occur, a phenomenon analogous to the atypia that precedes carcinoma of the squamous mucosa of the uterine cervix. Because this dysplasia is usually the result of chronic exposure to sunlight and is associated with build-up of excess keratin, these lesions are called actinic keratoses. As would be expected, they occur with particularly high incidence in lightly pigmented

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individuals. Exposure to ionizing radiation, hydrocarbons, and arsenicals may induce similar lesions.

Actinic keratoses are usually less than 1 cm in diameter; are tan-brown, red, or skin-colored; and have a rough, sandpaper-like consistency. Some lesions may produce so much keratin that a "cutaneous horn" develops. Such horns may become so prominent that they actually resemble the horns of animals! Skin sites commonly exposed to sun (face, arms, dorsum of hands) are most frequently affected. The lips may also develop similar lesions (termed actinic cheilitis).

Morphology. Cytologic atypia is seen in the lowermost layers of the epidermis and may be associated with hyperplasia of basal cells or, alternatively, with early atrophy that results in diffuse thinning of the epidermal surface of the lesion. The atypical basal cells usually have evidence of dyskeratosis with pink or reddish cytoplasm. Also, intercellular bridges are present, in contrast to basal cell carcinoma, in which the cytoplasm is usually basophilic and the cells lack intercellular bridges identifiable by light microscopy. The dermis contains thickened, blue-gray elastic fibers (elastosis), a probable result of abnormal dermal elastic fiber synthesis by sun-damaged fibroblasts within the superficial dermis. The stratum corneum is thickened, and unlike in normal skin, nuclei in the cells in this layer are often retained (a pattern termed parakeratosis).

This skin biopsy specimen shows a severely sun-damaged dermis and an epidermis with parakeratosis and cytologic atypia in the basal layers. A small amount of lymphocytic infiltrate is present around blood vessels in the upper dermis.

Whether all actinic keratoses would lead to skin cancer (usually squamous cell carcinoma), if given enough time, is conjectural. Many believe that certain lesions may regress or remain stable during a normal life span. However, enough do become malignant to warrant local eradication of these potential precursor lesions. This can usually be accomplished by gentle curettage, freezing, or topical application of chemotherapeutic agents.

Squamous cell carcinomaSquamous cell carcinoma is the second most common tumor arising on sun-

exposed sites in older people, exceeded only by basal cell carcinoma. Except for lesions on the lower legs, these tumors have a higher incidence in men than in

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women. Exposure to sunlight is the major predisposing factor; others include industrial carcinogens (tars and oils), chronic ulcers and draining osteomyelitis, old burn scars, ingestion of arsenicals, ionizing radiation, and (in the oral cavity) tobacco and betel nut chewing.

The most commonly accepted exogenous cause of squamous cell carcinoma is exposure to UV light with subsequent DNA damage. Individuals who are immunosuppressed as a result of chemotherapy or organ transplantation, or who have xeroderma pigmentosum, are at increased risk for developing neoplasms. A considerable proportion of these are squamous cell carcinomas. Sunlight, in addition to its effect on DNA, also seems to have a direct and, at least, a transient immunosuppressive effect on skin by affecting the normal surveillance function of antigen-presenting Langerhans cells in the epidermis. DNA sequences of certain viruses (e.g., human papillomavirus [HPV] type 36) have been detected in potential precursors of squamous cell carcinoma, suggesting a role for these agents in the evolution of certain, but not all, cutaneous epithelial neoplasms. Finally, certain chemical agents appear to have direct mutagenic effects by producing DNA adducts with subsequent oncogene activation.39 (See Molecular Genetics of Skin Cancers for additional details).

Morphology. Squamous cell carcinomas 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 clinically as hyperkeratosis, and may ulcerate. Well-differentiated lesions may be indistinguishable from keratoacanthoma. When the oral mucosa is involved, a zone of white thickening may be seen, an appearance caused by a variety of disorders and referred to clinically as leukoplakia.

Unlike actinic keratoses, squamous cell carcinoma in situ is characterized by cells with atypical (enlarged and hyperchromatic) nuclei at all levels of the epidermis. When these cells break through the basement membrane, the process has become invasive. Invasive squamous cell carcinoma exhibits variable differentiation, ranging from tumors formed by polygonal squamous cells, arranged in orderly lobules and exhibiting numerous large zones of keratinization, to neoplasms formed by highly anaplastic, rounded cells with foci of necrosis and only abortive, single-cell keratinization (dyskeratosis).

An atypical squamous epithelial proliferation is present in the dermis, surrounded by a lymphocytic infiltrate. This image is part of a well-differentiated squamous cell carcinoma.

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Invasive squamous cell carcinomas are usually discovered while they are small and resectable; less than 5% have metastases to regional nodes, and these lesions are generally deeply invasive.

Basal cell carcinomaBasal cell carcinomas are common, slow-growing tumors that rarely

metastasize. They have a tendency to occur at sites subject to chronic sun exposure and in lightly pigmented people. As with squamous cell carcinoma, the incidence of basal cell carcinoma rises sharply with immunosuppression and in patients with inherited defects in DNA repair (e.g., xeroderma pigmentosum).

These tumors present clinically as pearly papules often containing prominent, dilated subepidermal blood vessels (telangiectasias). Some tumors contain melanin 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 or in unusually aggressive tumors, explaining the past designation rodent ulcers. One common and important variant, the superficial basal cell carcinoma, presents as an erythematous, occasionally pigmented plaque that may resemble early forms of malignant melanoma. Careful inspection usually reveals characteristic pearly papules at the periphery of the plaque.

Morphology. On histologic examination, tumor cells resemble those in the normal basal cell layer of the epidermis. They arise from the epidermis or follicular epithelium and do not occur on mucosal surfaces. Two patterns are seen: multifocal growths originating from the epidermis and extending over several square centimeters or more of skin surface (multifocal superficial type) and nodular lesions growing downward deeply into the dermis as cords and islands of variably basophilic cells with hyperchromatic nuclei, embedded in a mucinous matrix, and often surrounded by many fibroblasts and lymphocytes.

In a superficial basal cell carcinoma, the tumor nests are much smaller than in a nodular basal cell carcinoma, and all the nests are connected with the epidermis.

The cells forming the periphery of the tumor cell islands tend to be arranged radially with their long axes in approximately parallel alignment (palisading). The stroma shrinks away from the epithelial tumor nests, creating clefts or separation artifacts

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that assist in differentiating basal cell carcinomas from certain appendage tumors also characterized by proliferation of basaloid cells (e.g., trichoepithelioma).

TUMORS OF THE DERMIS

The dermis is composed of a variety of different cellular elements, including smooth muscle, pericytes, fibroblasts, neural tissue, and endothelium. All of these components can give rise to neoplasia within the skin, but many of these tumors also arise in soft tissues and viscera (e.g., leiomyosarcoma) or occur as part of a syndrome primarily affecting another organ system (e.g., as with cutaneous neurofibromas in neurofibromatosis). In this section, therefore, we consider only representative dermal neoplasms that arise primarily in the skin, have unique characteristics in the skin, or have not been presented in other chapters.

Benign fibrous histiocytoma (dermatofibroma)Benign fibrous histiocytoma refers to a heterogeneous family of

morphologically and histogenetically related benign dermal neoplasms of fibroblasts and histiocytes. These tumors are usually seen in adults and often occur on the legs of young to middle-aged women. Their biologic behavior is indolent, and they should not be confused with the unrelated malignant fibrous histiocytoma, which arises de novo in skin and in extracutaneous sites and often has an aggressive clinical course.

On gross inspection, these neoplasms are firm, tan to brown papules). Lesions are asymptomatic or tender, and their size may increase and decrease slightly over time. Although the majority of lesions are less than 1 cm in diameter, actively growing lesions may reach several centimeters in diameter; with time, they often become flattened. The tendency for fibrous histiocytomas to dimple inward on lateral compression is helpful in distinguishing them from nodular melanomas, which protrude when they are similarly manipulated.

Morphology. The most common form of fibrous histiocytoma is referred to as a dermatofibroma. These tumors are formed by benign, spindle-shaped fibroblasts arranged in a well-defined, nonencapsulated mass within the mid-dermis. Extension of these cells into the subcutaneous fat is frequently observed. The majority of cases demonstrate a peculiar form of overlying epidermal hyperplasia, characterized by downward elongation of hyperpigmented rete ridges ("dirty fingers" pattern). Although foamy histiocytes (macrophages) may be seen in dermatofibromas, they are generally not conspicuous, but certain variants are composed predominantly of these foamy histiocytes and a small number of fibroblasts. Finally, variants containing numerous blood vessels and deposits of hemosiderin may be encountered.

The histogenesis of fibrous histiocytomas remains a mystery. Many cases have a history of antecedent trauma, suggesting an abnormal response to injury and inflammation, perhaps analogous to the deposition of increased amounts of altered collagen in a hypertrophic scar or keloid. Many of the cells that form dermatofibromas express coagulation factor XIIIa. These common yet curious tumors appear to be composed partially of factor XIIIa-positive dermal dendrocytes, described as normal dermal constituents at the beginning of this chapter.

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Dermatofibrosarcoma protuberansDermatofibrosarcoma protuberans is best regarded as a well-differentiated,

primary fibrosarcoma of the skin. These tumors are slow growing, and although they are locally aggressive, they rarely metastasize.

Clinically, they are firm, solid nodules that arise most frequently on the trunk. They often develop as aggregated "protuberant" tumors within a firm (indurated) plaque that may ulcerate.

Morphology. On microscopic examination, these neoplasms are cellular, composed of fibroblasts arranged radially, reminiscent of blades of a pinwheel, a pattern referred to as storiform. Mitoses are usually present but are not as numerous as in a moderately or poorly differentiated fibrosarcoma. In contrast to that in dermatofibroma, the overlying epidermis is generally thinned. Deep extension from the dermis into subcutaneous fat, producing a characteristic "honeycomb" pattern, is frequently present, hindering attempts at complete surgical removal.

Dermal vascular tumorsBenign vascular neoplasms (capillary and cavernous hemangiomas),

malformations (nevus flammeus or port-wine stain), multifocal angioproliferative lesions (Kaposi sarcoma, bacillary angiomatosis), vascularized variants of other tumors (e.g., the sclerosing hemangioma variant of benign fibrous histiocytoma), and malignant vascular tumors (angiosarcomas) are frequently encountered in the skin. The capillary hemangioma is by far the most commonly encountered form of cutaneous hemangioma. It appears clinically either in childhood (strawberry hemangioma) or with advancing age, as discrete, deeply erythematous papules. In adults, lesions may slowly enlarge and occasionally undergo thrombosis, whereas in young children, they usually regress by fibrosis.

Morphology. Cutaneous hemangiomas must be differentiated from dermal vascular hyperplasia (as may occur in venous stasis), reactive vascular proliferations (as in pyogenic granulomas), unregulated multifocal vascular proliferations (as seen in Kaposi sarcoma), and vascular malignant tumors (angiosarcoma). Typically, hemangiomas are represented histologically by well-formed, blood-filled vascular spaces lined by benign endothelial cells within the superficial and sometimes deep dermis.

DISORDERS OF EPIDERMAL MATURATION

IchthyosisOf the numerous disorders that impair epidermal maturation, ichthyosis is

perhaps one of the most striking. The term is derived from the Greek root ichthy-, meaning fishy, and accordingly, this group of genetically inherited disorders is associated with excessive keratin build-up (hyperkeratosis) that results clinically in fishlike scales. Most ichthyoses become apparent either at or around the time of birth. Acquired (noninherited) variants exist; in the acquired vulgaris type in adults, there is an association with lymphoid and visceral malignant neoplasms. The clinical types of

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ichthyosis vary according to the mode of inheritance, histology, and clinical features; the primary categories include ichthyosis vulgaris (autosomal dominant or acquired), congenital ichthyosiform erythroderma (autosomal recessive), lamellar ichthyosis (autosomal recessive), and X-linked ichthyosis.

Morphology. The general histology of all forms of ichthyosis is often subtle build-up of compacted stratum corneum, with loss of the normal basket-weave pattern seen in this layer when it involves hair-bearing skin. There is generally little or no inflammation, and subtle associated variations in the thickness of the epidermis and the stratum granulosum, along with the clinical picture, assist in assigning the correct diagnostic subclassification.

Pathogenesis. The primary abnormality in some forms of ichthyosis may reside in defective mechanisms of desquamation, leading to retention of abnormally formed scale. For example, in X-linked ichthyosis, affected homozygotes demonstrate a deficiency in steroid sulfatase, an enzyme important for the removal of proadhesive cholesterol sulfate secreted into the intercellular spaces along with adhesive organelles called Odland bodies, or membrane-coating granules. Accumulation of this nondegraded cholesterol sulfate results in persistent cell-to-cell adhesion within the stratum corneum, hindering the desquamation process. Compare this with pemphigus vulgaris (see later), in which dramatically different lesions form as a consequence of decreased cell-to-cell adhesion.

ACUTE INFLAMMATORY DERMATOSES

Inflammatory dermatoses are usually mediated by local or systemic immunologic factors, although the causes for many remain a mystery. Literally thousands of specific inflammatory dermatoses exist. In general, acute lesions last from days to weeks and are characterized by inflammation (often marked by mononuclear cells, not neutrophils), edema, and epidermal, vascular, or subcutaneous injury in some. Chronic lesions, on the other hand, persist for months to years and often show significant components of altered epidermal growth (atrophy or hyperplasia) or dermal fibrosis. The lesions discussed here are selected as examples of the more commonly encountered dermatoses within the acute category.

UrticariaUrticaria (hives) is a common disorder of the skin characterized by localized

mast cell degranulation and resultant dermal microvascular hyperpermeability, culminating in pruritic edematous plaques called wheals. Angioedema is closely related to urticaria and is characterized by deeper edema of both the dermis and the subcutaneous fat.

Urticaria most often occurs between ages 20 and 40, although all age groups are susceptible. Individual lesions develop and fade within hours (usually <24 hours), and 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,

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and ears. Persistent episodes of urticaria may simply be the result of inability to eliminate the causative antigen or may herald underlying disease (e.g., collagen vascular disorders, Hodgkin disease). In the majority of cases, no underlying cause can be identified.

Morphology. The histologic features of urticaria may be so subtle that many biopsy specimens at first resemble normal skin. There is usually a sparse superficial perivenular infiltrate consisting of mononuclear cells and rare neutrophils. Eosinophils may also be present. Collagen bundles are more widely spaced than in normal skin, a result of superficial dermal edema fluid that does not stain in routinely prepared tissue. Superficial lymphatic channels are dilated in an attempt to accommodate this transudated edema fluid. Epidermal changes are typically not present.

Acute eczematous dermatitisEczema is a clinical term that embraces a number of pathogenetically different

conditions. All are characterized by red, papulovesicular, oozing, and crusted lesions early on that, with persistence, develop into raised, scaling plaques. In time, acute spongiotic dermatitis may evolve to a more chronic form in which epidermal hyperplasia and excessive scale, rather than blistering, dominate the clinical and histologic picture. Clinical differences permit classification of eczematous dermatitis into the following categories: (1) allergic contact dermatitis, (2) atopic dermatitis, (3) drug-related eczematous dermatitis, (4) photoeczematous dermatitis, and (5) primary irritant dermatitis

The Greek word eczema, meaning "to boil over," vividly describes the clinical appearance of acute eczematous dermatitis. The most obvious example is an acute contact reaction to topical antigens such as poison ivy, characterized by pruritic, edematous, oozing plaques, often containing small and large blisters (vesicles and bullae). Such lesions are prone to bacterial superinfection, which produces a yellow crust (impetiginization). With time, persistent lesions become less "wet" (fail to ooze or form vesicles) and become progressively scaly (hyperkeratotic) as the epidermis thickens (acanthosis).

Morphology. Spongiosis-the accumulation of edema fluid within the intercellular spaces of the epidermis-characterizes acute eczematous dermatitis, hence the synonym spongiotic dermatitis. Whereas edema is localized to the perivascular spaces of the superficial dermis in urticaria, edema seeps into the intercellular spaces of the epidermis in spongiotic dermatitis, splaying apart keratinocytes located primarily in the stratum spinosum. Intercellular bridges appear prominent, giving a spongy appearance to the epidermis. Mechanical shearing of intercellular attachment sites (desmosomes) and cell membranes by progressive accumulation of intercellular fluid may result in the formation of intraepidermal vesicles

During the earliest stages of the evolution of spongiotic dermatitis, there is a superficial, perivascular, lymphocytic infiltrate associated with papillary dermal edema and mast cell degranulation. The pattern and composition of this infiltrate may provide clues to the underlying cause.92 For example, spongiotic dermatitis resulting from systemic antigens, such as those related to ingestion of certain drugs, will show

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a lymphocytic infiltrate, often containing eosinophils, and extending around deep as well as superficial dermal vessels. Spongiotic dermatitis resulting from surface contact with antigens tends to produce an inflammatory reaction that preferentially affects the more superficial dermal layer.

CHRONIC INFLAMMATORY DERMATOSES

This category focuses on those persistent inflammatory skin disorders that exhibit their most characteristic clinical and histologic features for many months to years. Unlike the normal cutaneous surface, the skin surface in some chronic inflammatory dermatoses is roughened as a result of excessive or abnormal scale formation and shedding. However, not all scaling lesions are inflammatory-witness the hereditary ichthyoses with fishlike scales as the result of some defect in the adhesive properties of cells in the stratum corneum.

PsoriasisPsoriasis is a common chronic inflammatory dermatosis affecting as many as

1% to 2% of people in the United States. Persons of all ages may develop the disease. Psoriasis is sometimes associated with arthritis, myopathy, enteropathy, spondylitic joint disease, or the acquired immunodeficiency syndrome. Psoriatic arthritis may be mild or may produce severe deformities resembling the joint changes seen in rheumatoid arthritis.

Clinically, psoriasis most frequently affects the skin of the elbows, knees, scalp, lumbosacral areas, intergluteal cleft, and glans penis. The most typical lesion is a well-demarcated, pink to salmon-colored plaque covered by loosely adherent scales that are characteristically silver-white in color. Variations exist, with some lesions occurring in annular, linear, gyrate, or serpiginous configurations.

Morphology. Established lesions of psoriasis have a characteristic histologic picture. Increased epidermal cell turnover results in marked epidermal thickening (acanthosis), with regular downward elongation of the rete ridges.

To make the correct diagnosis, a high magnification is necessary. Neutrophils are present in a thick layer of parakeratosis and the stratum granulosum is almost absent.

Mitotic figures are easily identified well above the basal cell layer, where mitotic activity is confined in normal skin. The 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

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the tips of dermal papillae (suprapapillary plates) and dilated, tortuous blood vessels within these papillae. This constellation of changes results in abnormal proximity of dermal vessels within the dermal papillae to the overlying parakeratotic scale, and it 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.

Lupus erythematosusThere is also a localized, cutaneous form of lupus erythematosus, with no associated systemic manifestations, called discoid lupus erythematosus (DLE). Patients who present with DLE usually do not go on to develop systemic disease. However, more than one-third of patients with SLE may exhibit, during their course, lesions that are clinically and histologically indistinguishable from those of the discoid type. Thus, it is often impossible to distinguish patients with SLE from those with DLE on the basis of clinical and histologic inspection of skin lesions alone.

Cutaneous lesions usually consist of either poorly defined malar erythema (typically seen in systemic disease) or large, sharply demarcated erythematous scaling plaques. These "discoid" plaques may occur in either pure cutaneous lupus erythematosus or SLE. Cutaneous manifestations of lupus erythematosus may develop or worsen with sun exposure. The epidermal surface of lesions is shiny or scaly, and lateral compression often produces wrinkling, a sign of epidermal atrophy. Through this thinned epidermis, dilated and tortuous blood vessels (telangiectasia) and small zones of hypopigmentation and hyperpigmentation may be seen. Small, keratotic plugs in follicular ostia may be observed with a hand lens.

Morphology. Lesions of DLE are characterized histologically by an infiltrate of lymphocytes along the dermoepidermal or the dermal-follicular epithelial junction, or both. Deep perivascular and periappendageal (e.g., around sweat glands) infiltrates are also observed, and preferential infiltration of subcutaneous fat is called lupus profundus. The basal cell layer generally shows diffuse vacuolization. The epidermal layer is markedly thinned or atrophied, with loss of the normal rete ridge pattern. Variable hyperkeratosis is present on the epidermal surface. Involved hair follicles may also show epithelial atrophy, and their infundibula are frequently dilated and plugged with keratin. Periodic acid-Schiff (PAS) stain of established lesions reveals marked thickening of the epidermal basement membrane zone, and direct immunofluorescence shows a characteristic granular band of immunoglobulin and complement along the dermoepidermal and dermal-follicular junctions (so-called lupus band test). Such bands are typically seen in lesional skin but not normal skin in DLE and in both lesional and normal skin in many cases of SLE.

DISORDERS OF EPIDERMAL APPENDAGES

Acne vulgaris

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Virtually universal in the middle to late teenage years, acne vulgaris affects both males and females, although males tend to have more severe disease. Acne is seen in all races, but is usually milder in people of Asian descent. Acne vulgaris in adolescents is believed to occur as a result of physiologic hormonal variations and alterations in hair follicle maturation. The clinical features of acne may be induced or exacerbated by drugs (corticosteroids, adrenocorticotropic hormone, testosterone, gonadotropins, contraceptives, trimethadione, iodides, and bromides), occupational contactants (cutting oils, chlorinated hydrocarbons, and coal tars), and occlusive conditions such as heavy clothing and tropical climates. Some families seem to be particularly affected by acne, suggesting a heritable factor.

Acne is divided into noninflammatory and inflammatory types, although the types may coexist. The former consists of open and closed comedones. Open comedones are small follicular papules containing a central black keratin plug. This color is the result of oxidation of melanin pigment (not dirt). Closed comedones are follicular papules without a visible central plug. Because the keratin plug is trapped beneath the epidermal surface, these lesions are potential sources of follicular rupture and inflammation. Inflammatory acne is characterized by erythematous papules, nodules, and pustules. Severe variants (e.g., acne conglobata) result in sinus tract formation and physical scarring, in addition to the emotional scars.

Morphology. Four key components contribute to the development of acne: (1) changes in keratinization of the lower portion of the follicular infundibulum with the development of a keratin plug blocking outflow of sebum to the skin surface; (2) increase in size of sebaceous glands with puberty or increased activity due to hormonal stimulation; (3) lipase-synthesizing bacteria (Propionibacterium acnes) colonizing the upper and midportion of the hair follicle, converting lipids within sebum to pro-inflammatory fatty acids; and (4) induction of inflammation in the follicle associated with release of cytotoxic and chemotactic factors. Depending on the stage of the disease, open or closed comedones, papules, pustules, or deep inflammatory nodules may develop. Open comedones have large, patulous orifices, whereas those of closed comedones are identifiable only microscopically. Variable lymphohistiocytic infiltrates are present in and around affected follicles, and extensive acute and chronic inflammation accompanies follicular rupture. Dermal abscesses may form in association with rupture, and gradual resolution, often with scarring, ensues.

Infection and InfestationAlthough the skin is a protective organ, it frequently succumbs to the attack of

microorganisms, parasites, and insects. We have already discussed the possible role of bacteria in the pathogenesis of common acne, and the dermatoses resulting from viruses are too numerous to list. In the setting of the immunocompromised patient, ordinarily trivial cutaneous infections may be life-threatening.

Many disorders, such as herpes simplex and herpes zoster, the viral exanthems, and deep fungal infections, are discussed in Chapter 8. In addition, immune reactions in skin provoked by infectious agents, such as the annular erythema termed erythema

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chronicum migrans, a harbinger of Lyme disease, are also discussed in Chapter 8. Here we address a representative sampling of common infections and infestations whose primary clinical manifestations are in the skin.

Verrucae (warts)Verrucae are common lesions of children and adolescents, although they may

be encountered at any age. They are caused by human papillomaviruses. Transmission of disease usually involves direct contact between individuals or autoinoculation. Verrucae are generally self-limited, regressing spontaneously within 6 months to 2 years.

The classification of verrucae is based largely on clinical morphology and location. Verruca vulgaris is the most common type of wart. The lesions of verruca vulgaris occur anywhere but most frequently on the hands, particularly on the dorsal surfaces and periungual areas, where they appear as gray-white to tan, flat to convex, 0.1- to 1-cm papules with a rough, pebble-like surface. Verruca plana, or flat wart, is common on the face or the dorsal surfaces of the hands. The warts are slightly elevated, flat, smooth, tan papules that are generally smaller than verruca vulgaris. Verruca plantaris and verruca palmaris occur on the soles and palms, respectively. Rough, scaly lesions may reach 1 to 2 cm in diameter, coalesce, and be confused with ordinary calluses. Condyloma acuminatum (venereal wart) occurs on the penis, female genitalia, urethra, perianal areas, and rectum. Venereal warts appear as soft, tan, cauliflower-like masses that in occasional cases reach many centimeters in diameter.

Morphology. Histologic features common to verrucae include epidermal hyperplasia that is often undulant in character (so-called verrucous or papillomatous epidermal hyperplasia and cytoplasmic vacuolization (koilocytosis) that preferentially involves the more superficial epidermal layers, producing halos of pallor surrounding infected nuclei. Electron microscopy of these zones reveals numerous viral particles within nuclei. Infected cells may also demonstrate prominent and apparently condensed keratohyaline granules and jagged eosinophilic intracytoplasmic keratin aggregates as a result of viral cytopathic effects. These cellular alterations are not as prominent in condylomas; hence, their diagnosis is based primarily on hyperplastic papillary architecture containing wedge-shaped zones of koilocytosis.

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