DEFINITIONS OF MACROSCOPIC TERMS

DEFINITIONS OF MICROSCOPIC TERMS

FRECKLE (EPHELIS)

Freckles are the most common pigmented lesions of childhood in lightly pigmented individuals. They are generally small (1 to several mm in diameter), tan-red or light brown macules that appear after sun exposure. Once present, freckles fade and darken in a cyclic fashion during winter and summer, respectively. This is not because of changes in the number of melanocytes, but in the degree of pigmentation.

LENTIGO

The term lentigo (plural, lentigines) refers to a common benign localized hyperplasia of melanocytes occurring at all ages, but often initiated 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 consist of small (5–10 mm across), oval, tan-brown macules or patches. Unlike freckles, lentigines do not darken when exposed to sunlight.

MELANOCYTIC NEVUS (PIGMENTED NEVUS, MOLE)

Most of us have at least a few moles and probably regard them as mundane and uninteresting. However, in truth moles (or nevi) are diverse, dynamic, and biologically intriguing. Strictly speaking, the term nevus denotes any congenital skin lesion (e.g., a birthmark). Melanocytic nevus refers specifically to any neoplasm of melanocytes and hence is somewhat of a misnomer, since most melanocytic nevi are acquired.

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 (Figs. 25-3A and 25-4A). There are numerous clinical and histologic types of melanocytic nevi, with variable clinical appearance. Table 25-1 provides a comparative summary of salient features of some commonly encountered forms of melanocytic nevi. Acquired melanocytic nevi (Figs. 25-3 and 25-4) are probably the most common type and virtually universal. They may become more prominent during pregnancy, indicating a degree of hormone sensitivity.

FIGURE 25-3 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.

FIGURE 25-4 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.

TABLE 25-1 Representative Variant Forms of Melanocytic Nevi

Morphology. Melanocytic nevi are thought to progress through a series of morphologic changes over time. The earliest lesions are believed to be junctional nevi, which consist of aggregates or nests of round cells that grow along the dermoepidermal junction (see Fig. 25-3B). Nuclei of nevus cells are uniform and rounded in contour, contain inconspicuous nucleoli, and show little or no mitotic activity. Eventually, most junctional nevi grow into the underlying dermis as nests or cords of cells to form compound nevi (see Fig. 25-4B). In older 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 (Fig. 25-5). Whereas superficial nevus cells are larger, tend to produce melanin, and grow in nests, deeper nevus cells are smaller, produce little or no pigment, and appear as cords and single cells. 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 (neurotization, see Fig. 25-5E). 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.

FIGURE 25-5 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.

Although melanocytic nevi are common, their clinical and histologic diversity necessitates thorough knowledge of their appearance and natural evolution, lest they be confused with other skin conditions, most notably melanoma. The biologic importance of some nevi, however, resides in their possible transformation to melanoma (see below).

DYSPLASTIC NEVI

The association of melanocytic nevi with melanoma was made more than 185 years ago,⁸ but a precursor of melanoma was not clearly identified until 1978 when Clark and colleagues described the lesions that are now referred to as dysplastic nevi.⁹ Several lines of evidence support the concept that dysplastic nevi are precursors of melanoma. One of the most compelling pieces of evidence involves studies of families affected by dysplastic nevus syndrome, ¹⁰ in which a tendency to develop multiple dysplastic nevi and melanoma are co-inherited. The probability that a person with dysplastic nevus syndrome will develop melanoma is over 50% by age 60,¹¹ and at-risk individuals sometimes develop several melanomas at different sites. Even more directly, transformation of dysplastic nevi to melanoma has been documented histologically.

Although dysplastic nevi can give rise to melanoma, the vast majority of such lesions are clinically stable and never progress. Conversely, not all melanomas in individuals with dysplastic nevus syndrome arise from dysplastic nevi, suggesting that these lesions are best viewed as indicators or markers of increased melanoma risk. Dysplastic nevi may also occur as isolated lesions in otherwise normal individuals, in which case the risk of malignant change is very low.

Dysplastic nevi are larger than most acquired nevi (often >5 mm across) and may number in the hundreds in those with the dysplastic nevus syndorme (Fig. 25-6A). They are flat macules, slightly raised plaques with a “pebbly” surface, or target-like lesions with a darker raised center and irregular flat periphery. They can be recognized by their size, variability in pigmentation (variegation) and irregular borders, and seem to be acquired rather than congenital in most instances. Unlike ordinary moles, dysplastic nevi occur on both sun-exposed and protected body surfaces.

FIGURE 25-6 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.

Pathogenesis.

Clark and associates have proposed stages in the development of dysplastic nevi and their eventual progression to melanoma (Fig. 25-7),¹² presumably through stepwise acquisition of mutations or epigenetic changes. Dysplastic nevus syndrome is inherited in an autosomal dominant pattern. Several mutated genes have been discovered in affected families, including CDKN2A on chromosome 9p21 and CDK4 (cyclin-dependent kinase 4) on chromosome 12q14, both of which are also associated with familial forms of melanoma (discussed later). However, linkage of these mutations to the dysplastic nevus phenotype is not straightforward, as not all patients with germline CDKN2A and CDK4 mutations have dysplastic nevi, and not all familial dysplastic nevi are associated with mutations in these genes. It is suspected that other genetic modifiers determine whether CDKN2A and CDK4 mutations cause dysplastic nevi in a particular individual; the identities of these modifier genes, as well as the other genes that are responsible for the syndrome, are being sought. Like conventional nevi, dysplastic nevi also frequently have acquired activating mutations in NRAS and BRAF.

FIGURE 25-7 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.

MELANOMA

Melanoma is a relatively common neoplasm that remains deadly if not caught at its earliest stages. The great preponderance of melanomas arises in the skin; other sites of origin include the oral and anogenital mucosal surfaces, esophagus, meninges, and the eye (see Chapter 29). The following comments apply to cutaneous melanomas.

Today, as a result of increased public awareness of the signs of cutaneous melanoma, most are cured surgically.¹³ Nevertheless, the reported incidence of melanoma is increasing; more than 60,000 cases and more than 8000 deaths are expected in the United States in 2008.¹⁴

Clinical Features.

Because melanomas evolve over time from localized skin lesions to aggressive tumors that metastasize and are resistant to therapy, early recognition and complete excision are critical. Melanoma of the skin is usually asymptomatic, although itching or pain may be early manifestations. The majority of lesions are greater than 10 mm in diameter at diagnosis. The most consistent clinical signs are changes in the color, size, or shape of a pigmented lesion. Unlike benign nevi, melanomas show striking variations in color, appearing in shades of black, brown, red, dark blue, and gray (Fig. 25-8A). On occasion, zones of white or flesh-colored hypopigmentation also appear, sometimes due to focal regression of the tumor. The borders of melanomas are irregular and often notched, not smooth, round, and uniform as in melanocytic nevi. To reiterate, the most important warning signs, sometimes called the ABCs of melanoma, are (1) asymmetry; (2) irregular borders; and (3) variegated color. Other features of pigmented lesions that should raise concern are a diameter greater than 6 mm, any change in appearance, and new onset of itching or pain.

FIGURE 25-8 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.

Morphology. Central to understanding the progression of melanoma is the concept of radial and vertical growth phases.¹⁵ Radial growth describes the horizontal spread of melanoma within the epidermis and superficial dermis (Fig. 25-8B). During this initial stage the tumor cells seem to lack the capacity to metastasize. Tumors in radial growth phase fall into several clinicopathologic classes, including: lentigo maligna, usually presenting as an indolent lesion on the face of older men that may remain in the radial growth phase for several decades; superficial spreading, the most common type of melanoma, usually involving sun-exposed skin; and acral/mucosal lentiginous melanoma that is 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 (Fig. 25-8C). The vertical growth phase is often heralded by the appearance of a nodule and 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. The 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; this measurement is known as the Breslow thickness.¹⁶ Other histologic features that correlate with outcome include the number of mitoses and the presence of ulceration;^17,18 these and other prognostic factors are discussed further below.

Individual melanoma cells are usually considerably larger than normal melanocytes or cells found in melanocytic nevi. They contain large nuclei with irregular contours, chromatin that is characteristically clumped at the periphery of the nuclear membrane, and prominent red (eosinophilic) nucleoli (Fig. 25-8D). The appearance of the tumor cells is similar in the radial and vertical phases of growth. While most nevi and melanomas are easily distinguished based on their appearance, a minority of “atypical” lesions occupy a histologic gray zone and have been termed melanocytic tumors of uncertain malignant potential;^13,19 such lesions require complete excision and close clinical follow-up.

Prognostic Factors.

Once a melanoma is excised, a number of clinical and pathologic features are used to gauge the probability of metastatic spread and prognosis. One model predicts outcome based on the following variables:²⁰ (1) tumor depth (the Breslow thickness); (2) number of mitoses; (3) evidence of tumor regression (presumably due to the host immune response); (4) the presence and number of tumor infiltrating lymphocytes (TILs); (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, no or very few mitoses, a brisk TIL response, absence of regression, female gender, and location on an extremity. In a retrospective multivariate study by the American Joint Committee on Cancer (AJCC), tumor thickness and presence or absence of ulceration had prognostic significance independent of clinical stage.^21,22 Because most melanomas initially metastasize to regional lymph nodes, additional prognostic information may be obtained by performing a sentinel lymph node biopsy; as in breast cancer (Chapter 23), this involves the identification, removal, and careful examination of the lymph node (or nodes) that is the initial site of drainage of intratumoral lymphatic vessels. Microscopic involvement of a sentinel node by even a small number of melanoma cells (micrometastases) confers a worse prognosis (Fig. 25-8D, inset).²³ The degree of involvement and the total number of lymph nodes involved correlate well with overall survival.

Pathogenesis.

The two most important predisposing factors are inherited genes and sun exposure. Melanomas most commonly arise on sun-exposed surfaces, particularly the upper back in men and the back and legs in women, and lightly pigmented individuals are at higher risk than are darkly pigmented individuals. However, the relationship between sun exposure and melanoma is not as straightforward as with other skin cancers (discussed later); some studies suggest that severe sunburns early in life are the most important risk factor. Since melanomas occur in dark-skinned individuals and at body sites that are not sun-exposed, sunlight is clearly not the only predisposing factor, and other environmental factors may also contribute to risk.²⁴

It is estimated that 10% to 15% of melanomas are familial, and many (but not all) of those with familial melanoma also have dysplastic nevi. Several of the genes responsible for familial melanoma encode well-characterized tumor suppressors and are also mutated in sporadic tumors (discussed below). Other genetic variants linked to melanoma risk in fair-skinned populations control melanin production; these pigmentation genes have weak effects, conferring a slightly elevated risk. They include MC1R, which encodes the melanocortin-1 receptor; ASIP (agouti signaling protein), which encodes a regulator of melanocortin receptor signaling, and TYR, which encodes tyrosinase, a melanocyte-specific enzyme that is required for melanin synthesis.²⁵

Mutations that diminish the activity of the retinoblastoma (RB) tumor suppressor proteins are common in both familial and sporadic melanomas. The CDKN2A gene (discussed earlier under dysplastic nevi) is mutated in approximately 40% of pedigrees with autosomal dominant familial melanoma. CDKN2A is a complex locus that encodes three different tumor suppressors, p15/INK4b, p16/INK4a, and p14/ARF. Of these, loss of p16/INK4a is clearly implicated in human melanoma, and experimental evidence also strongly supports a role for loss of p14/ARF. You will recall from Chapter 7 that p16/INK4a enhances the activity of tumor suppressor proteins of the RB family by inhibiting cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), while p14/ARF enhances the activity of the p53 tumor suppressor by inhibiting the activity of the MDM2 oncoprotein. CDKN2A is mutated in approximately 10% of sporadic melanomas,²⁶ and these mutations uniformly abolish the production of p16/INK4a and more variably affect p14/ARF. However, it is suspected that these mutations are the tip of the “oncogenic iceberg” with respect to molecular lesions affecting the function of RB proteins. For example, as many as 30% to 70% of melanomas show loss of p16/INK4a expression though varied mechanisms,²⁷ and other uncommon familial and sporadic melanomas have mutations in CDK4 that prevent its inhibition by p16/INK4a. The net effect of all of these alterations is the same; increased melanocytic proliferation and escape from oncogene-induced cellular senescence.

The second common group of molecular lesions in sporadic melanoma leads to aberrant increases in RAS and PI-3K/AKT signaling (Fig. 25-9), which you will recall are pathways that promote cell growth and survival (Chapter 7). Activating mutations in BRAF, which encodes a serine/threonine kinase that is downstream of RAS, are seen in 60% to 70% of melanomas, while activating mutations in NRAS (which is upstream of BRAF) occur in additional 10% to 15% of tumors. For reasons that are unclear, melanomas arising in non-sun exposed sites are much more likely to have activating mutations in the c-KIT receptor tyrosine kinase,^28,29 which sits upstream of both RAS and PI-3K/AKT, than in NRAS or BRAF. PTEN, a tumor suppressor that acts by downregulating PI-3K/AKT signaling, is epigenetically silenced in another 20% of melanomas.^30,31

FIGURE 25-9 Pathways important in melanoma. The PI-3K/PTEN/AKT and BRAF/ERK pathways regulate cell survival and proliferation. Proteins altered in melanoma are indicated by asterisks. Inhibitors of these pathways are being studied as therapeutic agents; some specific examples are listed in red.

Molecular lesions of these two kinds are probably necessary, but not sufficient, for the development of melanoma. As discussed earlier, melanocytic nevi have the same activating mutations in NRAS and BRAF that are found in melanomas, yet become malignant very rarely, probably because unbridled RAS signaling leads to cellular senescence. p16/INK4a appears to be essential for the oncogene-induced cellular senescence,³¹ and in its absence proliferation persists, placing melanocytes at risk for transformation into a melanoma. However, dysplastic nevi sometimes have lesions in both p16/INK4a and RAS or BRAF, yet transform into full-blown melanomas only somewhat more frequently than conventional nevi. Clearly, other pathways yet to be identified also contribute to the transformation process.

These molecular insights have spawned attempts to treat melanoma with new therapeutic agents that target the RAS and PI-3K/AKT pathways (Fig. 25-9). Such approaches are urgently needed, as metastatic melanoma is resistant to both conventional chemotherapy and radiation treatment. Ultimately, it is likely that these types of targeted therapies will be used in combinations tailored to the oncogenic leions found in individual tumors.³² For example, a tumor with an activating mutation in c-KIT will require treatment with different inhibitors than a tumor with an activating mutation in RAS or BRAF. Immunotherapeutic approaches for melanoma in which host lymphocytes are “trained” to recognize and kill melanoma cells have also generated considerable interest, sparked in part by the recognition that spontaneous remissions of metastatic melanoma occur sporadically that are presumably mediated by the host immune response. Excellent responses are obtained on occasion,³³ but the general applicability of such treatments has yet to be demonstrated.

SEBORRHEIC KERATOSES

These common epidermal tumors occur most frequently in middle-aged or older individuals. They arise spontaneously and are 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 characteristically appear as round, flat, coin-like, waxy plaques that vary in diameter from millimeters to several centimeters (Fig. 25-10, inset). They are uniformly tan to dark brown and 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.

FIGURE 25-10 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

Acanthosis nigricans is a condition marked by thickened, hyperpigmented skin with a “velvet-like” texture that most commonly appears in the flexural areas (axillae, skin folds of the neck, groin, and anogenital regions). It can be an important cutaneous marker of benign and malignant conditions and, accordingly, is divided into two types.³⁷ 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 or pineal tumors and diabetes), and (3) as part of several rare congenital syndromes. As with seborrheic keratoses, acanthosis nigricans sometimes occurs as a paraneoplastic process resulting from the production of growth factors by a variety of tumors. The malignant type refers to lesions arising in middle-aged and older individuals in association with underlying cancers, most commonly gastrointestinal adenocarcinomas.

FIBROEPITHELIAL POLYP

The 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, bag-like tumor often attached to the surrounding skin by a slender stalk. Rarely, fibroepithelial polyps and tumors of perifollicular mesenchyme (specialized fibroblasts associated with the hair bulb) are seen together in Birt-Hogg-Dubé syndrome, but the vast majority of polyps are sporadic.³⁹

Fibroepithelial polyps are usually inconsequential, but can occasionally be associated with diabetes, obesity, and intestinal polyposis. Of interest, like melanocytic nevi and hemangiomas they often become more numerous or prominent during pregnancy, presumably related to hormonal stimulation.

EPITHELIAL CYST (WEN)

Epithelial cysts are common lesions formed by the invagination and cystic expansion of the epidermis or a hair follicle. The lay term, wen, derives from the Anglo-Saxon wenn, meaning a lump or tumor. These cysts are filled with keratin and 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, which can lead to inflammation and pain.

ADNEXAL (APPENDAGE) TUMORS

There are literally hundreds of neoplasms arising from or showing differentiation toward cutaneous appendages. Their significance varies according to type and clinical context. Some are entirely benign, but may be confused with cutaneous cancers such as basal cell carcinoma. Other appendage tumors are associated with mendelian patterns of inheritance and occur as multiple disfiguring lesions. In some instances, these lesions warn of a predisposition for internal malignancy; such is the reationship between multiple trichilemmomas and Cowden syndrome, a disorder caused by germline mutations in the tumor suppressor gene PTEN that is associated with an increased risk of breast cancer and many other tumors.⁴² Selected examples are provided here to illustrate neoplasms of hair follicles and sebaceous, eccrine, and apocrine glands.

Appendage tumors are often 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. Cylindroma, an appendage tumor with ductal (apocrine or eccrine) differentiation, usually occurs on the forehead and scalp (Fig. 25-11A), where coalescence of nodules with time may produce a hat-like growth, hence the name turban tumor. These lesions may be dominantly inherited; in such cases they appear early in life and are associated with inactivating mutations in the tumor suppressor gene CYLD, which encodes a deubiquitinating enzyme that regulates NF-κB and the cell cycle.^43,44 Germline mutations in this gene are associated with several related genetic syndromes including familial cylindromatosis, multiple familial trichoepithelioma (a follicular tumor), and Brooke-Spiegler syndrome (showing both tumor types).⁴⁵ Syringomas, lesions with eccrine differentiation, usually occur as multiple, small, tan papules in the vicinity of the lower eyelids. Sebaceous adenomas can be associated with internal malignancy in the Muir-Torre syndrome, a subset of the hereditary nonpolyposis colorectal carcinoma syndrome (Chapter 17) associated with germline deficits in DNA mismatch repair proteins; some of these have mutations in genes involved in WNT signaling.^46,47 Pilomatricomas, showing follicular differentiation, are associated with activating mutations in CTNNB1, the gene encoding β-catenin.⁴⁸ Mutations in this gene are seen in numerous neoplasms but are of interest here since WNT signaling through β-catenin is critical for early hair development and regulates the hair cycle. Adnexal tumors can also show primarily apocrine differentiation; these usually arise in body areas where apocrine glands are most prevalent, such as the axilla and scalp. Some skin adnexal tumors may arise from multipotent cutaneous stem cells, which are believed to reside in a specialized niche associated with hair follicles.⁴⁹

FIGURE 25-11 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.

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 (Fig. 25-11B). Trichoepithelioma is a proliferation of basaloid cells that forms primitive structures resembling hair follicles (Fig. 25-11C, D). Sebaceous adenoma shows a lobular proliferation of sebocytes with increased peripheral basaloid cells and more mature sebocytes in the central portion, characterized by frothy or bubbly cytoplasm due to lipid vesicle content (Fig. 25-12A). Pilomatrixomas are 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 (Fig. 25-12B). Apocrine carcinoma shows ductal differentiation with prominent decapitation secretion similar to that seen in the normal apocrine gland (Fig. 25-12C). The infiltrative growth pattern is a hint of malignancy in this otherwise well-differentiated tumor.

FIGURE 25-12 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.

Although most appendage tumors are benign, malignant variants do exist. Apocrine tumors are unusual in that malignant forms seem to be more common than benign forms. Sebaceous carcinoma, for example, arises from the meibomian glands of the eyelid and may follow an aggressive course replete with systemic metastases. Eccrine and apocrine carcinomas are often confused with metastatic adenocarcinomas to the skin because of their tendency for abortive gland formation.

ACTINIC KERATOSIS

The development of epidermal malignancy is typically preceded by a period of progressively worsening dysplastic changes, which are analogous to the precursor lesions that give rise to carcinoma of the squamous mucosa of the uterine cervix (Chapter 22). In the skin, these precursor lesions are called actinic keratoses; as the name implies, these usually occur in sun-damaged skin and exhibit hyperkeratosis. As would be expected, they occur with particularly high incidence in lightly pigmented individuals. Exposure to ionizing radiation, industrial 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 (Fig. 25-13A). Such horns may become so prominent that they actually resemble the horns of animals! Sun-exposed sites (face, arms, dorsum of hands) are most frequently affected. The lips may also develop similar lesions (termed actinic cheilitis).

FIGURE 25-13 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.

Whether all actinic keratoses would inexorably lead to skin cancer (usually squamous cell carcinoma), if given enough time, is conjectural. Studies indicate that lesions may regress or remain stable during a normal life span. However, enough become malignant to warrant local eradication. This can usually be accomplished by gentle curettage, freezing, or topical application of chemotherapeutic agents. More recently, a reagent called imiquimod, which activates the innate immune system through stimulation of Toll-like receptors (TLRs), has been used to eradicate the abnormal cells that compose this tumor.⁵⁰

SQUAMOUS CELL CARCINOMA

Squamous 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 women. Invasive squamous cell carcinomas are usually discovered while they are small and resectable. Less than 5% of these tumors metastasize to regional nodes; these lesions are generally deeply invasive and involve the subcutis.

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 grossly as hyperkeratotic scale), and may ulcerate (Fig. 25-14A).

FIGURE 25-14 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.

Unlike actinic keratoses, in squamous cell carcinoma in situ, cells with atypical (enlarged and hyperchromatic) nuclei involve all levels of the epidermis (Fig. 25-13C). Invasive squamous cell carcinoma (Fig. 25-14B, C) shows variable degrees of differentiation, ranging from tumors composed of polygonal cells arranged in orderly lobules and having numerous large areas of keratinization, to neoplasms associated with 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.

Keratoacanthoma is a controversial lesion; some regard it as a variant of well-differentiated squamous cell carcinoma, while others consider it to be a distinct entity. It differs from conventional squamous cell carcinomas in that after a period of rapid growth, it usually regresses spontaneously. Grossly, it is a symmetric cup-shaped tumor with a central depression filled with keratin debris. Histologically, the tumor is composed of lobules of squamous cells with glassy cytoplasm that undergo kertinization without an intervening granular layer. Once established, keratoacanthomas elicit a brisk lymphocytic and eosinophilic host response.

BASAL CELL CARCINOMA

Basal cell carcinoma is the most common invasive cancer in humans, with nearly 1 million estimated cases per year in the United States.⁵⁶ These are slow-growing tumors that rarely metastasize. They have a tendency to occur at sun-exposed sites and in lightly pigmented people. As with squamous cell carcinoma, the incidence of basal cell carcinoma rises sharply with immunosuppression and in people with inherited defects in DNA repair such as xeroderma pigmentosum (Chapter 7).

These tumors present clinically as pearly papules often containing prominent, dilated subepidermal blood vessels (telangiectasias) (Fig. 25-15A). 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 archaic 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 melanoma.

FIGURE 25-15 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.

Pathogenesis.

Nevoid basal cell carcinoma syndrome (NBCCS; also known as basal cell nevus or Gorlin syndrome) is an autosomal dominant disorder characterized by multiple basal cell carcinomas.⁵⁷ Most of these tumors develop before age 20 and are accompanied by various other conditions including tumors (especially medulloblastomas and ovarian fibromas), odontogenic keratocysts, and pits of the palms and soles. Multiple systemic manifestations such as intracranial calcification, cleft lip and palate, abnormal segmentation of the vertebra, and rib anomalies (bifid, fused, missing, splayed ribs) may also be present.⁵⁸ Though quite rare (incidence of 1 in 56,000), this syndrome has helped to elucidate the molecular genetics of basal cell carcinoma, including the common sporadic type. Examples of other genetic syndromes associated with skin tumors are listed in Table 25-2.

TABLE 25-2 Survey of Familial Cancer Syndromes with Cutaneous Manifestations

The gene associated with NBCCS, located on chromosome 9q22.3, is PTCH, the human homologue of the Drosophila developmental gene patched.⁵⁹ The pathogenesis of basal cell carcinomas in NBCCS fits the classical Knudson “two-hit” hypothesis for familial retinoblastoma (Chapter 7). Individuals with NBCCS are born with a germline mutation in one of the PTCH alleles; the second normal allele is inactivated in tumors by a mutation acquired by chance or due to exposure to mutagens (such as UV light).

The PTCH gene encodes a receptor for the protein product of the sonic hedgehog gene (SHH), a member of the hedgehog (HH) family of genes that determine polarity during embryonic development.⁶⁰ The pathway is also involved in hair follicle formation and the hair cycle in skin.⁵ The PTCH protein forms a receptor complex with another transmembrane protein, known as SMO (for “smoothened”). In the absence of its ligand, SHH, PTCH inactivates SMO and sequesters it from transducing a down-stream signal. Binding of SHH to PTCH releases the suppression of SMO, causing the up-regulation of hedgehog target genes through a signal cascade that involves the GLI1 transcription factor (Fig. 25-16). Experimental work in mice has shown that animals with defects in the PTCH signaling pathway, including overexpression of GLI1, develop skin tumors resembling basal cell carcinomas.^61,62 In NBCCS the absence of PTCH causes constitutive activation of SMO, leading to the development of basal cell carcinoma.

FIGURE 25-16 Normal and oncogenic hedgehog signaling. Left, Normally, PTCH and SMO form a receptor complex that binds sonic hedgehog (SHH). In the absence of SHH, PTCH blocks SMO activity. When SHH binds PTCH, SMO is released to trigger a signal transduction cascade that leads to activation of GLI1 and other transcription factors. Right, Mutations in PTCH, and less often in SMO, allow SMO to signal without ligand binding and underlie the nevoid basal cell carcinoma (Gorlin) syndrome.

Mutations of genes belonging to the PTCH signaling pathway are also important for the development of the common sporadic form of basal cell carcinoma, as documented by the inactivation of PTCH and the presence of SMO activating mutations in these skin neoplasms.⁶³ PTCH mutations are found in approximately 30% of sporadic basal cell carcinomas, and of these about one third have mutations (C→T transitions) that are considered hallmarks of UV damage. Mutations in p53 occur in 40% to 60% of basal cell carcinomas, and 60% of these have “UV signature.”⁶⁴ Xeroderma pigmentosum, a disorder of DNA repair, presents a striking example of the connection between sun exposure and defects in PTCH and p53.⁶⁵ In these tumors the frequency of mutations in PTCH and p53 are, respectively, 90% and 40%, and the majority of these bear the UV signature.

BENIGN FIBROUS HISTIOCYTOMA (DERMATOFIBROMA)

Benign fibrous histiocytoma refers to a heterogeneous family of morphologically and histogenetically related benign dermal neoplasms of uncertain lineage. These tumors are usually seen in adults and often occur on the legs of young to middle-aged women. Their biologic behavior is indolent.

These neoplasms appear as firm, tan to brown papules (Fig. 25-17A). Lesions are asymptomatic or tender and may increase and decrease slightly in size over time. Most are less than 1 cm in diameter, but 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 can be helpful in distinguishing them from nodular melanomas, which protrude when squeezed.

FIGURE 25-17 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.

The cause of fibrous histiocytomas remains a mystery. Many cases have a history of antecedent trauma, suggesting an abnormal response to injury and inflammation,⁶⁶ perhaps analogous to the deposition of increased amounts of altered collagen in a hypertrophic scar or keloid. These common yet curious tumors appear to be composed at least partially of factor XIIIa–positive dermal dendrocytes.

DERMATOFIBROSARCOMA PROTUBERANS

Dermatofibrosarcoma protuberans is best regarded as a well-differentiated, primary fibrosarcoma of the skin. These tumors are slow growing, and although they are locally aggressive and can recur, 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 or nodule that may sometimes 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 rare. 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 (Fig. 25-18B, C). These tumors may extend down fibrous septae in the subcutis and thus require wider excision than would appear to be necessary to prevent local recurrence.

FIGURE 25-18 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.

MYCOSIS FUNGOIDES (CUTANEOUS T-CELL LYMPHOMA)

Cutaneous T cell lymphoma (CTCL) represents a spectrum of lymphoproliferative disorders affecting the skin (see also Chapter 13).⁷¹ Two different clinical types of malignant T-cell disorders were originally recognized: mycosis fungoides, a chronic proliferative process; and a more aggressive nodular eruptive variant, mycosis fungoides d’emblée. It is now known that a variety of presentations of T-cell lymphoma occur in the skin, but this section will focus on mycosis fungoides.

Mycosis fungoides is a T-cell lymphoma that presents in the skin and may evolve into generalized lymphoma.⁷² Most affected individuals have disease that remains localized to the skin for many years; a minority have rapid systemic dissemination. This condition may occur at any age, but most commonly it afflicts persons older than age 40.

Lesions of mycosis fungoides usually involve truncal areas and include scaly, red-brown patches; raised, scaling plaques that may even be confused with psoriasis; and fungating nodules. Prognosis is related to the percentage of body surface involved and 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 and nodules ulcerate (Fig. 25-19A). 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 and scaling of the entire body surface (erythroderma), a condition known as Sézary syndrome (Chapter 13).

FIGURE 25-19 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.

The proliferating cells in CTCL are clonal populations of lymphocytes of the CD4 subset.^2,73 The neoplastic cells are targeted to the skin by expression of CLA (see Fig. 25-2) and often express aberrant cell surface antigens as well as clonal T-cell receptor gene rearrangements. Detection of these features may be of diagnostic assistance in difficult cases. Topical therapy with steroids or UV light is often used for early lesions of CTCL, whereas more aggressive systemic chemotherapy is indicated for advanced disease.

MASTOCYTOSIS

The term mastocytosis refers to a spectrum of rare disorders characterized by increased numbers of mast cells in the skin and, in some instances, in other organs. A localized cutaneous form of the disease that affects predominantly children and accounts for more than 50% of all cases is termed urticaria pigmentosa. These lesions are multiple, although solitary mastocytomas may also occur, usually shortly after birth. About 10% of individuals with mast cell disease have systemic disease, with mast cell infiltration of many organs. These individuals are often adults, and unlike localized cutaneous disease, the prognosis may be poor.

The pathologic findings in mastocytosis are highly variable. In 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 (Fig. 25-20A). In 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 of the signs and symptoms of mastocytosis are due to the 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); watery nasal discharge (rhinorrhea); rarely, gastrointestinal or nasal bleeding, possibly due to the anticoagulant effects of heparin; and bone pain as a result of osteoblastic and osteoclastic involvement.

FIGURE 25-20 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.

ICHTHYOSIS

Of 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 chronic, excessive keratin buildup (hyperkeratosis) that results clinically in fish-like scales (Fig. 25-21A). 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 and visceral malignancies. The clinical types of 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.⁷⁶

FIGURE 25-21 Ichthyosis. Note prominent fishlike scales (A) and compacted, thickened stratum corneum (B).

URTICARIA

Urticaria (hives) is a common disorder of the skin characterized by localized mast cell degranulation and resultant dermal microvascular hyperpermeability. This gives rise to pruritic edematous plaques called wheals. 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 (Fig. 25-22A). 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, and ears. Persistent episodes of urticaria may herald an underlying disease (e.g., collagen vascular disorders, Hodgkin lymphoma), but in the majority of cases no underlying cause can be identified.

FIGURE 25-22 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

The Greek word eczema, meaning “to boil over,” vividly describes the appearance of acute eczematous dermatitis. All forms of eczema are characterized by red, papulovesicular, oozing, and crusted lesions that, if persistent, develop into raised, scaling plaques due to reactive acanthosis and hyperkeratosis (Fig. 25-23). Based on initiating factors, eczematous dermatitis can be subdivided into the following categories: (1) allergic contact dermatitis, (2) atopic dermatitis, (3) drug-related eczematous dermatitis, (4) photoeczematous dermatitis, and (5) primary irritant dermatitis.

FIGURE 25-23 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.

A striking example of eczema is an acute contact reaction to topical antigens such as poison ivy/oak (Rhus toxicodendron), characterized by pruritic, edematous, oozing plaques, often containing small and large blisters (vesicles and bullae) (Fig. 25-24A). 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). The clinical causes of eczema are sometimes broadly divided into “inside” and “outside” types: disease resulting from external application of antigen (such as poison ivy) or reaction to an internal circulating antigen (such as ingested food or drug).

FIGURE 25-24 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.

Treatment of eczema involves a search for offending substances that can be removed from the environment. Topical steroids can also be used that nonspecifically block the inflammatory response. Such treatments are palliative and not curative, but are helpful in interrupting acute exacerbations of eczema that can become self perpetuating if unchecked.

ERYTHEMA MULTIFORME

Erythema multiforme is an uncommon, self-limited disorder that seems to be a hypersensitivity reaction to certain infections and drugs. This disorder affects individuals of any age and is associated with the following conditions: (1) infections such as herpes simplex, mycoplasmal infections, histoplasmosis, coccidioidomycosis, typhoid, and leprosy, among others; (2) administration of certain drugs (sulfonamides, penicillin, barbiturates, salicylates, hydantoins, and antimalarials); (3) malignant disease (carcinomas and lymphomas); and (4) collagen vascular diseases (lupus erythematosus, dermatomyositis, and polyarteritis nodosa).⁸⁰

Affected individuals present 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 (Fig. 25-25A). Although lesions may be widely distributed, symmetric involvement of the extremities frequently occurs. An extensive and symptomatic febrile form of the disease, which is often but not exclusively seen in children, is called Stevens-Johnson syndrome. Typically, erosions and 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 and sloughing of cutaneous and mucosal epithelial surfaces, producing a clinical situation analogous to an extensive burn when both infection and fluid loss are clinical concerns.⁸¹

FIGURE 25-25 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.

PSORIASIS

Psoriasis 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.

Psoriasis most frequently affects the skin of the elbows, knees, scalp, lumbosacral areas, intergluteal cleft, and glans penis. The typical lesion is a well-demarcated, pink to salmon-colored plaque covered by loosely adherent scale that is characteristically silver-white in color (Fig. 25-26A). Variations exist, with some lesions occurring in annular, linear, gyrate, or serpiginous configurations. Psoriasis is one cause of total body erythema and scaling known as erythroderma. Nail changes occur in 30% of cases of psoriasis 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 and localized (hands and feet) or generalized and life-threatening, with associated fever, leukocytosis, arthralgia, diffuse cutaneous and mucosal pustules, secondary infection, and electrolyte disturbances.⁸⁴

FIGURE 25-26 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

Seborrheic dermatitis is a chronic inflammatory dermatosis even more common than psoriasis, affecting 1% to 3% of the general population.⁸⁴ It classically involves regions with a high density of sebaceous glands, such as the scalp, forehead (especially the glabella), external auditory canal, retroauricular area, nasolabial folds, and the presternal area. However, it is important to note that seborrheic dermatitis is not a disease of the sebaceous glands. The individual lesions are macules and papules on an erythematous-yellow, often greasy base, typically in association with extensive scaling and crusting. Fissures may also be present, particularly behind the ears. Dandruff is the common clinical expression of seborrheic dermatitis of the scalp. In infants, seborrheic dermatitis presents as cradle cap but can also be part of a disorder known as Leiner disease, in which the condition is generalized and associated with diarrhea and failure to thrive. A severe form of seborrheic dermatitis that is difficult to treat is seen in many HIV–infected individuals with low CD4 counts.⁸⁶

LICHEN PLANUS

“Pruritic, purple, polygonal, planar papules, and plaques” are the tongue-twisting “six p’s” of this disorder of skin and mucosa. Lichen planus is usually self-limited and most commonly resolves spontaneously 1 to 2 years 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 and paramucosal lesions of lichen planus, but a direct pathogenetic relationship has not been established.^89,90

Cutaneous lesions consist of itchy, violaceous, flat-topped papules that may coalesce focally to form plaques (Fig. 25-27A). 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 and are symmetrically distributed, particularly on the extremities, often about the wrists and elbows, and on the glans penis. In 70% of cases, oral lesions are present as white, reticulated, or netlike areas involving the mucosa. As in psoriasis, the Koebner phenomenon may be seen in lichen planus.⁹¹

FIGURE 25-27 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.

INFLAMMATORY BLISTERING DISORDERS

Pemphigus

Pemphigus is a blistering disorder caused by autoantibodies that result in the dissolution of intercellular attachments within the epidermis and mucosal epithelium. Though rare, without treatment it may be life-threatening, and its pathobiology provides important insight into the molecular mechanisms of keratinocyte adhesion. The majority of individuals who develop pemphigus are in the fourth to sixth decades of life, and men and women are affected equally. There are multiple variants: (1) pemphigus vulgaris, (2) pemphigus vegetans, (3) pemphigus foliaceus, (4) pemphigus erythematosus, and (5) paraneoplastic pemphigus.⁹³

Pemphigus vulgaris, by far the most common type (accounting for more than 80% of cases worldwide), involves the mucosa and skin, especially on the scalp, face, axilla, groin, trunk, and points of pressure. It may present as oral ulcers that may persist for months before skin involvement appears. Primary lesions are superficial vesicles and bullae that rupture easily, leaving shallow erosions covered with dried serum and crust (Fig. 25-30A). Pemphigus vegetans is a rare form that usually presents not with blisters but with large, moist, verrucous (wart-like), vegetating plaques studded with pustules on the groin, axillae, and flexural surfaces. Pemphigus foliaceus is a more benign form that is endemic in Brazil (where it is called fogo selvagem) and occurs sporadically in other geographic regions. Sites of predilection are the scalp, face, chest, and back, and the mucous membranes are only rarely affected. Bullae are so superficial that only zones of erythema and crusting, sites of previous blister rupture resulting in superficial erosions, are usually present on physical examination (Fig. 25-31A). Pemphigus erythematosus is considered to be a localized, less severe form of pemphigus foliaceus that may selectively involve the malar area of the face in a lupus erythematosus–like fashion. Paraneoplastic pemphigus occurs in association with various malignancies, most commonly non-Hodgkin lymphoma.

FIGURE 25-30 Pemphigus vulgaris. A, Eroded plaques are formed on rupture of confluent, thin-roofed bullae, here affecting axillary skin. B, Suprabasal acantholysis results in an intraepidermal blister in which rounded (acantholytic) epidermal cells are identified (inset). C, Ulcerated blisters in the oral mucosa are also common as seen here on the mucosal portion of the lip.

FIGURE 25-31 Pemphigus foliaceus. A, The delicate, superficial (subcorneal) blisters are much less erosive than seen in pemphigus vulgaris. B, Subcorneal separation of the epithelium is seen.

The mainstay of treatment is immunosuppressive agents, which decrease the titers of the pathogenic antibodies. In those with the most severe form of the disease, pemphigus vulgaris, this lowers but does not entirely prevent mortality.

Morphology. The common histologic denominator in all forms of pemphigus is acantholysis, the dissolution, or lysis, of the intercellular adhesions that connect squamous epithelial cells. Acantholytic cells dissociate from one another, lose their polyhedral shape and become rounded. In pemphigus vulgaris and pemphigus vegetans, acantholysis selectively involves the cells immediately above the basal cell layer. In the vegetans variant, there is also overlying epidermal hyperplasia. The suprabasal acantholytic blister that forms is characteristic of pemphigus vulgaris (see Fig. 25-30B). The single layer of intact basal cells that forms the blister base has been likened to a row of tombstones. In pemphigus foliaceus, a blister forms by similar mechanisms but, unlike the case with pemphigus vulgaris, selectively involves the superficial epidermis at the level of the stratum granulosum (Fig. 25-31B). Variable superficial dermal infiltration by lymphocytes, histiocytes, and eosinophils accompanies all forms of pemphigus.

Pathogenesis.

All forms of pemphigus are caused by IgG autoantibodies against desmogleins, and show linkage to specific HLA types.⁹⁴ By direct immunofluorescence, lesional sites show a characteristic net-like pattern of intercellular IgG deposits. IgG is usually seen at all levels of the epithelium in pemphigus vulgaris, but tends to be more superficial in pemphigus foliaceus (Fig. 25-32). The distribution of desmoglein 1 and 3 in the epidermis and the presence of autoantibodies to one or both proteins appear to explain the position and severity of the blisters (Fig. 25-29). The antibodies seem to function primarily by directly disrupting the intercellular adhesive function of the desmosomes and may activate intercellular proteases as well.⁹⁵ Paraneoplastic pemphigus most often arises in the setting of lymphoid neoplasms, and is caused by autoantibodies that may recognize desmogleins of other proteins involved in intercellular adhesion.⁹⁶

FIGURE 25-32 Direct immunofluorescence of pemphigus. A, In pemphigus vulgaris there is deposition of immunoglobulin along the plasma membranes of epidermal keratinocytes in a reticular or fishnet-like pattern. Also note the early suprabasal separation due to loss of cell-to-cell adhesion (acantholysis). B, In pemphigus foliaceus the immunoglobulin deposits are more superficial.

Bullous Pemphigoid

Generally affecting elderly individuals, bullous pemphigoid shows a wide range of clinical presentations. It may involve only the skin, either locally or generally, or the skin and mucosal surfaces. Clinically, lesions are tense bullae, filled with clear fluid, on normal or erythematous skin (Fig. 25-33A). Lesions are usually up to 2 cm in diameter but occasionally may reach 4 to 8 cm in diameter. The bullae do not rupture as easily as do the blisters seen in pemphigus and, if they are not secondarily infected, heal without scarring. Sites of involvement include the inner aspects of the thighs, flexor surfaces of the forearms, axillae, groin, and lower abdomen. Oral lesions are present in 10% to 15% of affected individuals, usually appearing after the cutaneous lesions.⁹⁷ Some patients may present with urticarial plaques, with extreme associated pruritus.

FIGURE 25-33 Bullous pemphigoid. A, Clinical bullae result from basal cell layer vacuolization, producing tense, intact subepidermal blisters that are difficult to rupture given the roof formed by the full thickness of the epidermis. Ulceration results upon rupture as the blisters are subepidermal. B, Histopathology shows an intact blister with eosinophils, as well as lymphocytes and occasional neutrophils, that may be intimately associated with basal cell layer destruction and the creation of the subepidermal cleft.

Morphology. The separation of bullous pemphigoid from pemphigus is based on the identification of subepidermal, nonacantholytic blisters. Early lesions show a superficial and sometimes deep perivascular infiltrate of lymphocytes and variable numbers of eosinophils, occasional neutrophils, superficial dermal edema, and associated basal cell layer vacuolization (Fig. 25-33B). Eosinophils showing degranulation are typically detected directly beneath the epidermal basal cell layer. The vacuolated basal cell layer eventually gives rise to a fluid-filled blister.

Pathogenesis.

Bullous pemphigoid features linear deposition of immunoglobulin and complement in the basement membrane zone (Fig. 25-34A). Reactivity also occurs in the basal cell–basement membrane attachment plaques (hemidesmosomes), where most of the bullous pemphigoid antigen (BPAG) is located. This protein is involved normally in dermoepidermal bonding. There are two forms of the antigen recognized by auto-antibodies—BPAG1, a 230-kD plakin protein, and BPAG2, a 180-kD protein also known as collagen type XVIII. Both BPAG1 and BPAG2 are recognized as normal constituents of the hemidesmosomes that bind basal cells at the dermoepidermal junction (Figs. 25-34B and 25-29). Only antibodies to BPAG2 are proven to cause blistering.⁹⁸ Generation of auto-antibodies to this hemidesmosome component results in continuous and linear deposition of IgG along the basement membrane and the fixation of complement with subsequent tissue injury by means of locally recruited neutrophils and eosinophils.

FIGURE 25-34 A, Linear deposition of complement along the dermoepidermal junction in bullous pemphigoid; the pattern has been likened to ribbon candy. B, Bullous pemphigoid antigen is located in the lowermost portion of the basal cell cytoplasm in association with hemidesmosomes (HD), with blister formation affecting the lamina lucida (LL) of the basement membrane zone. AF, anchoring fibrils; LD, lamina densa. (See also Fig. 25-31.)

DERMATITIS HERPETIFORMIS

Dermatitis herpetiformis is a rare disorder characterized by urticaria and grouped vesicles. The disease affects predominantly males, often in the third and fourth decades. In some cases it occurs in association with intestinal celiac disease and responds to a gluten-free diet.

Pathogenesis.

The association of dermatitis herpetiformis with celiac disease provides a clue to its pathogenesis. Genetically predisposed individuals develop lgA antibodies to dietary gluten (derived from the wheat protein gliadin). The antibodies cross-react with reticulin, a component of the anchoring fibrils that tether the epidermal basement membrane to the superficial dermis. The resultant injury and inflammation produce a subepidermal blister. Some people with dermatitis herpetiformis and gluten-sensitive enteropathy respond to a gluten-free diet.

Morphology. As an early event, fibrin and neutrophils accumulate selectively at the tips of dermal papillae, forming small microabscesses (Fig. 25-35A). The basal cells overlying these microabscesses show vacuolization and focal dermoepidermal separation that ultimately coalesce to form a true subepidermal blister. By direct immunofluorescence, dermatitis herpetiformis shows discontinuous, granular deposits of lgA selectively localized in the tips of dermal papillae (Fig. 25-35B).

FIGURE 25-35 Dermatitis herpetiformis. A, The blisters are associated with basal cell layer injury initially caused by accumulation of neutrophils (microabscesses) at the tips of dermal papillae. B, Selective deposition of IgA autoantibody at the tips of dermal papillae is characteristic. C, Lesions consist of intact and eroded (usually scratched) erythematous blisters, often grouped (seen here on elbows and arms).

(B, Courtesy of Dr. Victor G. Prieto, Houston, Texas.)

Clinical Features.

The urticarial plaques and vesicles of dermatitis herpetiformis are extremely pruritic. The lesions are bilateral, symmetric and grouped, involving preferentially the extensor surfaces, elbows, knees, upper back, and buttocks (Fig. 25-35C).

NONINFLAMMATORY BLISTERING DISORDERS

Epidermolysis Bullosa and Porphyria

Some primary disorders characterized by vesicles and bullae are mediated by non-inflammatory mechanisms. Two such diseases are epidermolysis bullosa and porphyria.

Epidermolysis bullosa constitutes a group of disorders caused by inherited defects in structural proteins that lend mechanical stability to the skin. The common feature is a proclivity to form blisters at sites of pressure, rubbing, or trauma, at or soon after birth.⁹⁹ In the simplex type, defects of the basal cell layer of the epidermis result from mutations in the genes encoding keratins 14 or 5. These two proteins normally pair with one another to make a functional keratin fiber, thus explaining the similar phenotype resulting from mutation of either gene. In the junctional type, blisters occur in otherwise histologically normal skin at precisely the level of the lamina lucida (Figs. 25-36 and 25-29). In the scarring dystrophic types, blisters develop beneath the lamina densa, in association with rudimentary or defective anchoring fibrils. Dystrophic epidermolysis bullosa is an inherited disease resulting from mutations in the COL7A1 gene that encodes type VII collagen (Chapter 3). Squamous cell carcinoma can sometime arise in these chronic blisters.¹⁰⁰ The histologic changes are so subtle that electron microscopy may be required to differentiate among these types in clinically ambiguous settings. Overall, approximately ten genes encoding structural proteins at the dermoepidermal junction have been implicated in the various forms of this disease.¹⁰¹ One form, termed non-Herlitz junctional epidermolysis bullosa is caused by a genetic defect (usually a point mutation) in the LAMB3 gene that encodes laminin Vβ3. Successful gene therapy has been carried out in one individual with this disease by inserting a normal LAMB3 gene into keratinocytes.

FIGURE 25-36 Epidermolysis bullosa. A, Junctional epidermolysis bullosa showing typical erosions in flexural creases. B, A noninflammatory subepidermal blister has formed at the level of the lamina lucida.

Porphyria refers to a group of uncommon inborn or acquired disturbances of porphyrin metabolism. Porphyrins are pigments normally present in hemoglobin, myoglobin, and cytochromes. The classification of porphyrias is based on both clinical and biochemical features. The five major types are (1) congenital erythropoietic porphyria, (2) erythrohepatic protoporphyria, (3) acute intermittent porphyria, (4) porphyria cutanea tarda, and (5) mixed porphyria. Cutaneous manifestations consist of urticaria and vesicles that heal with scarring and that are exacerbated by exposure to sunlight. The primary alterations by light microscopy are a subepidermal vesicle (Fig. 25-37) with associated marked thickening of the walls of superficial dermal vessels. The pathogenesis of these alterations is not well understood, although serum proteins, including immunoglobulins, typically form glassy deposits in the walls of superficial dermal microvessels.

FIGURE 25-37 Porphyria. A noninflammatory blister is forming at the dermoepidermal junction; note the seemingly rigid dermal papillae at the base that contain the altered superficial vessels.

ACNE VULGARIS

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 follicles, particularly the sebaceous gland. 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, cosmetics, and tropical climates. Some families seem to be particularly affected by acne, suggesting a hereditary component.

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 (Fig. 25-38A). Severe variants (e.g., acne conglobata) result in sinus tract formation and physical scarring.

FIGURE 25-38 Acne. A, Inflammatory acne associated with erythematous papules and pustules. B, A hair shaft pierces the follicular epithelium, eliciting inflammation and fibrosis. C, Open comedone.

ROSACEA

Rosacea is a common disease of middle age and beyond, affecting up to 3% of the US population, with a predilection for females. Four stages are recognized: (1) flushing episodes (pre-rosacea), (2) persistent erythema and telangiectasia, (3) pustules and papules, and (4) rhinophyma—permanent thickening of the nasal skin by confluent erythemaous papules and follicular prominence.¹⁰⁷

ERYTHEMA NODOSUM AND ERYTHEMA INDURATUM

Panniculitis is an inflammatory reaction in the subcutaneous adipose tissue that may preferentially affect (1) the connective tissue septa separating lobules of fat, or (2) the lobules of fat themselves. Panniculitis often involves the lower legs and usually has a subacute to chronic course. Erythema nodosum is the most common form and usually has an acute presentation. Its occurrence is often associated with infections (β-hemolytic streptococcal infection, tuberculosis and, less commonly, coccidioidomycosis, histoplasmosis, and leprosy), drug administration (sulfonamides, oral contraceptives), sarcoidosis, inflammatory bowel disease, and certain malignant neoplasms, but many times a cause cannot be identified.¹⁰⁹

Erythema nodosum presents as poorly defined, exquisitely tender, erythematous plaques and nodules that may be more readily palpated than seen. Fever and malaise may accompany the cutaneous signs. Over the course of weeks, lesions usually flatten and become bruiselike, leaving no residual clinical scars, while new lesions develop. Biopsy of a deep wedge of tissue to generously sample the subcutis is usually required for histologic diagnosis.

Erythema induratum is an uncommon type of panniculitis that affects primarily adolescents and menopausal women. Although the cause is not known, most observers regard this as a primary vasculitis affecting deep vessels supplying lobules of the subcutis, with subsequent necrosis and inflammation within the fat. Erythema induratum presents as an erythematous, slightly tender nodule that usually goes on to ulcerate. Originally considered a hypersensitivity response to tuberculosis, erythema induratum today most commonly occurs without an associated underlying disease.

Erythema nodosum and erythema induratum are but two of the many types of panniculitis. Weber-Christian disease (relapsing febrile nodular panniculitis) is a rare form of lobular, nonvasculitic panniculitis seen in children and adults. It is marked by crops of erythematous plaques or nodules, predominantly on the lower extremities, created by deep-seated foci of inflammation with aggregates of foamy histiocytes admixed with lymphocytes, neutrophils, and giant cells. Factitial panniculitis is a form of secondary panniculitis caused by self-inflicted trauma or injection of foreign or toxic substances. Rarely, T cell lymphomas (panniculitic T cell lymphoma) home to fat lobules, producing fat necrosis and superimposed inflammation that mimics panniculitis. Finally, disorders such as lupus erythematosus may occasionally have deep inflammatory components with associated panniculitis.¹¹⁰ The etiologies for all of these except the self-inflicted form and the rare T cell lymphomas are not understood.

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 auto-inoculation. Verrucae are generally self-limited, regressing spontaneously within 6 months to 2 years.

The classification of verrucae is based largely on appearance and location.¹¹¹ 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 (Fig. 25-39A). 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 occasionally reach many centimeters in diameter.

FIGURE 25-39 Verruca vulgaris. A, Multiple papules with rough pebble-like surfaces. B (low power) and C, (high power) histology of the lesions showing papillomatous epidermal hyperplasia and cytopathic alterations that include nuclear pallor and prominent keratohyaline granules. D, In situ hybridization demonstrating viral DNA within epidermal cells.

MOLLUSCUM CONTAGIOSUM

Molluscum contagiosum is a common, self-limited viral disease of the skin caused by a poxvirus. The virus is characteristically brick shaped, has a dumbbell-shaped DNA core, and measures 300 nm in maximal dimension, and thus represents the largest pathogenic poxvirus in humans and one of the largest viruses in nature. Infection is usually spread by direct contact, particularly among children and young adults.

Clinically, multiple lesions may occur on the skin and mucous membranes, with a predilection for the trunk and anogenital areas. Individual lesions are firm, often pruritic, pink to skin-colored umbilicated papules generally ranging in diameter from 0.2 to 0.4 cm. Rarely, “giant” forms occur measuring up to 2 cm in diameter. A curd-like material can be expressed from the central umbilication. Smearing this material onto a glass slide and staining with Giemsa reagent often shows diagnostic molluscum bodies.

Morphology. On microscopic examination, lesions show cuplike verrucous epidermal hyperplasia. The diagnostically specific structure is the molluscum body, which occurs as a large (up to 35 μm), ellipsoid, homogeneous, cytoplasmic inclusion in cells of the stratum granulosum and the stratum corneum (Fig. 25-40). In the H&E stain, these inclusions are eosinophilic in the blue-purple stratum granulosum and acquire a pale blue hue in the red stratum corneum. Numerous virions are present within molluscum bodies.

FIGURE 25-40 Molluscum contagiosum. A focus of verrucous epidermal hyperplasia contains numerous cells with ellipsoid cytoplasmic inclusions (molluscum bodies) within the stratum granulosum and stratum corneum.

IMPETIGO

Impetigo is a common superficial bacterial infection of skin. It is highly contagious and is frequently seen in otherwise healthy children as well as occasionally in adults in poor health. Two forms exist, classically referred to as impetigo contagiosa and impetigo bullosa; they differ from each other simply by the size of the pustules. Over the past decade a remarkable shift in etiology has been observed. Whereas in the past impetigo contagiosa was almost exclusively caused by group A β-hemolytic streptococci and impetigo bullosa by Staphylococcus aureus, both are now usually caused by Staphylococcus aureus.¹¹⁴

The infection usually involves exposed skin, particularly that of the face and hands. It presents as an erythematous macule, but multiple small pustules rapidly supervene. As pustules break, shallow erosions form, covered with drying serum, giving the characteristic clinical appearance of honey-colored crust. If the crust is not removed, new lesions form about the periphery and extensive epidermal damage may ensue. A bullous form of impetigo mainly occurs in children.

SUPERFICIAL FUNGAL INFECTIONS

As opposed to deep fungal infections of the skin, where the dermis or subcutis is primarily involved, superficial fungal infections of the skin are confined to the stratum corneum, and are caused primarily by dermatophytes. These organisms grow in the soil and on animals and produce a number of diverse and characteristic clinical lesions.¹¹⁶

Tinea capitis usually occurs in children and is only rarely seen in infants and adults. It is a dermatophytosis of the scalp characterized by asymptomatic, often hairless patches of skin associated with mild erythema, crust formation, and scaling. Tinea barbae is a dermatophyte infection of the beard area that affects adult men; it is a relatively uncommon disorder. Tinea corporis, on the other hand, is a common superficial fungal infection of the body surface that affects persons of all ages, but particularly children. Predisposing factors include excessive heat and humidity, exposure to infected animals, and chronic dermatophytosis of the feet or nails. The most common type of tinea corporis is an expanding, round, slightly erythematous plaque with an elevated scaling border (Fig. 25-41A). Tinea cruris occurs most frequently in the inguinal areas of obese men during warm weather. Heat, friction, and maceration all predispose to its development. The infection usually first appears on the upper inner thighs, with gradual extension of moist, red patches that have raised, scaling borders. Tinea pedis (athlete’s foot) affects 30% to 40% of the population at some time in their lives. There is diffuse erythema and scaling, often initially localized to the web spaces. Most of the inflammatory tissue reaction, however, has recently been shown to be the result of bacterial superinfection and not directly related to the primary dermatophytosis.¹¹⁷ Spread to or primary infection of the nails is referred to as onychomycosis. This produces discoloration, thickening, and deformity of the nail plate. Tinea versicolor usually occurs on the upper trunk and is highly distinctive in appearance. Caused by Malassezia furfur, a yeast rather than a dermatophyte, the lesions consist of groups of macules of all sizes, lighter or darker than surrounding skin, with a fine peripheral scale.⁸⁷

FIGURE 25-41 Tinea. A, Characteristic plaque of tinea corporis. Routine histology (B) shows a mild eczematous (spongiotic) dermatitis and focal neutrophilic abscesses. A periodic acid–Schiff stain (inset) reveals deep red hyphae within the stratum corneum.