Cutaneous Tumors and Pseudotumors of the Head and Neck

Benign Skin Tumors of Surface Epithelial Components

Benign neoplasms of the integument of the head and neck are relatively common, and malformative lesions that simulate neoplastic processes also occur in this body area. These basically are few in number and can be considered under the rubric of epidermal nevi.

Epidermal nevi typically assume gross and histological appearances that mimic those of verruca vulgaris or seborrheic keratosis . Hence, all of these benign proliferations can be considered together. Verrucae and verruca-like nevi demonstrate regular papillomatosis with a “spiky” surface aspect; acanthosis; regional parakeratosis; and variable degrees of nuclear atypia. A particularly important form of verruciform nevus is the nevus sebaceus , which is found on the scalp and neck. Its microscopic appearance is somewhat variable, depending on the age of the lesion. However, it regularly features the presence of localized epidermal papillomatosis, with hyperkeratosis, hypergranulosis, and fusion of rete pegs. With time, varying degrees of adnexal hyperplasia are superimposed on this description, such that excess numbers of sebaceous glands and apocrine glands are observed ( Fig. 14.1 ). Conversely, hair follicles are either lacking or embryonic in appearance within nevi sebaceus. True verrucae differ from verruciform epidermal nevi in also demonstrating multifocal koilocytosis, coarse clumping of keratohyaline cytoplasmic material, and regional “ground glass” homogenization of nuclear chromatin.

Secondary epithelial neoplasms of various types may arise from nevus sebaceus. These include syringocystadenoma papilliferum, basal cell carcinoma, squamous cell carcinoma, trichoblastoma, trichilemmoma, and apocrine adenocarcinoma.

Seborrheic keratoses (SKs) are characterized by a small polygonal cell constituency, an interanastomosing trabecular substructure that is based on the rete ridge pattern of the skin, and the presence of intercellular accumulations of keratin (so-called horn cysts ). There are several recognized microscopic variants of seborrheic keratosis, including acanthotic, hyperkeratotic, reticulated, clonal, and inflamed subtypes ( Fig. 14.2 ). The nuances of those lesions are implicit in their names. A special comment is in order, however, in reference to inflamed SK. That variant may demonstrate a rather alarming degree of nuclear atypia and mitotic activity, but because such lesions still retain the basic attributes of SK, they should be labeled as such. There are no convincing examples of true malignant transformation of seborrheic keratosis.

Warty dyskeratoma is another benign epidermal tumor with a distinctive histological appearance. Clinically, however, it takes the form of a nondescript 3 to 10 mm nodule, with a raised periphery and, often, a central pore-like opening ( Fig. 14.3 ). Keratinous debris may extrude from the latter structure, or the lesion may be pruritic. Under the microscope, one sees localized acanthosis of the infundibular portion of adjacent hair follicles, with acantholysis of the overlying epithelium and follicular keratin plugs. The acantholytic keratinocytes may demonstrate focal cytoplasmic hypereosinophilia and the formation of “corps ronds” as seen in Darier disease (a potentially systemic genodermatosis). However, the latter disease involves more than three adjacent hair follicles, whereas warty dyskeratoma does not.

Lichen planus-like keratosis (LPLK) is another benign proliferation that looks like the localized version of a disseminated dermatosis; namely, lichen planus. As such, one observes irregular “sawtooth” acanthosis, hypergranulosis, hyperkeratosis, lichenoid lymphoid or lymphoplasmacytic inflammation, basal vacuolar change in keratinocytes, and the presence of “cytoid” or “Civatte” bodies at the dermoepidermal junction. There are some subtle differences in the degrees of these changes between LPLK and lichen planus, but the most pragmatic way of separating these two entities is to ask the clinician whether the lesion is solitary or not. The answer is “yes” in LPLK and “no” in lichen planus.

Actinic keratosis is a premalignant alteration in the epidermis that clearly is related to actinic skin damage. It demonstrates disordered maturation of the epithelium, together with nuclear atypia, nucleomegaly, multifocal pyknosis, misplaced suprabasilar mitotic activity, and dyskeratosis. There is typically marked actinic elastosis in the subjacent corium. Variations on this general histologic picture include acantholytic (adenoid) and hypertrophic forms of actinic keratosis.

Malignant Skin Tumors of Surface Epithelial Components

Basal Cell Carcinoma

There is no question that basal cell carcinoma (BCC) is the most common cutaneous malignancy of the head and neck. Because of its relationship to actinic damage of the skin and the number of fair-skinned persons who are still refractory to wearing sun-blocking topical lotions during outside activities, the frequency with which BCC is seen in the general population is still increasing.

This tumor has a great number of clinical appearances, a description of which is beyond the scope of this discussion. However, it most commonly presents itself as a discrete ulcer with “rolled,” heaped-up, pearly-white edges, or as a gray-white or flesh-colored nodule in the skin of the face and neck.

Histopathology

As true of many carcinomas, BCC displays a considerable diversity of appearances under the microscope. These may be divided into nodulocystic, superficial-multifocal, adenoid, metatypical, morpheaform, infiltrative, keratotic, and pigmented forms, as well as rarer variants.

Nodulocystic BCC is the most frequent (approximately 70% of cases), and is composed of rounded or bluntly branched lobules of small hyperchromatic cells, which are connected to the overlying epidermis by narrow cords or broad trabeculae ( Fig. 14.4 ). These cellular clusters vary slightly or moderately in size and shape; however, they are typified by the roughly parallel alignment of peripheral nuclei at right angles to those in the center of the nodules, so-called peripheral palisading . The tumor cells themselves are uniform in size and polygonal in shape, with generally oval nuclei and inconspicuous nucleoli. Exceptionally, spindled or giant dysplastic nuclear forms may be observed; these appear to have no prognostic significance. Cytoplasm is scanty and amphophilic, and mitotic activity is variable. From 0 to 2 division figures are typically seen per high-power (×400) field, but up to 10 may be observed in selected neoplasms. The stroma in this form of BCC is fibromyxoid, and characteristically exhibits a retraction from tumor cell clusters, in specimens fixed in formalin. Peritumoral actinic elastosis is almost invariably seen in the surrounding dermis.

Not uncommonly, agminated centrilobular apoptosis in nodular BCCs accounts for their cystic quality, both clinically and microscopically. Degenerative areas in adjacent cellular lobules may become confluent, yielding broad areas of anucleate debris. The overlying epidermis may or may not be ulcerated. As stated, there are several distinctive histological variants of BCC, including the superficial-multifocal, nodulocystic, adenoid, infiltrative, morpheaform, adamantinoid, clear cell, signet ring cell, pilar-keratotic, organotypical, eccrine, apocrine, fibroepitheliomatous, basosebaceous, pigmented (melanotic), basosquamous, metatypical, and dedifferentiated (carcinosarcomatous) forms. These are discussed in detail in other textbooks and will not be recounted in detail here; however, it should be noted that the infiltrative, morpheaform, metatypical, and basosquamous variants of BCC do have an apparently greater propensity for local recurrence than other microscopic subtypes of the tumor.

Specialized Pathologic Features

Because of the prevalence of basal cell carcinoma and its corresponding familiarity to most pathologists and dermatologists, specialized pathologic studies are not usually necessary for diagnosis. Nevertheless, occasional cases of BCC may simulate adnexal carcinomas of the skin, such as adenoid cystic carcinoma of eccrine glands and basaloid sebaceous carcinoma. In such circumstances, histochemical special stains or immunohistochemistry can be used to resolve interpretative difficulties.

Histochemical Special Stains

Basal cell carcinoma contains a negligible amount of glycogen, as demonstrated by relative nonreactivity with a periodic acid-Schiff (PAS) stain. The mucicarmine reaction is seen focally in examples of apocrine BCC, as well as in tumors containing signet ring cells; the same neoplasms display diastase-resistant PAS positivity. Similarly, the colloidal iron technique can be used to label the epithelium-related mucosubstance in adenoid BCC, and will also stain the stroma of most basal cell carcinomas faintly. Hyaluronidase digestion will abolish the latter but not the former of these reactivities. The Movat stain also labels the contents of pseudoglandular profiles in adenoid neoplasms, but they are PAS negative. This constellation of results differs from that of true glandular tumors of the skin. Lipid stains (oil red O and Sudan IV) are nonreactive with conventional BCC, but amyloid can be detected by the Congo Red, Lieb, or thioflavine T techniques in up to 70% of such neoplasms. The latter finding appears to be independent of histologic subtype, and may be related to a relatively high degree of tumor cell apoptosis.

Immunohistochemistry

Among all malignant neoplasms of the skin, those showing cellular differentiation toward keratinocytes (BCC and squamous cell carcinoma) are relative immunohistochemical “have-nots.” They lack many specialized determinants other than cytokeratin polypeptides (the basic cytoskeletal proteins of epithelial cells and neoplasms) and a restricted group of other markers, such as Gli-1 protein. Specifically, epithelial membrane antigen (EMA), other human milk fat globule proteins, CD117, S100 protein, and carcinoembryonic antigen are not observed in BCCs.

Normal epidermal basal cells and BCCs display selective immunoreactivity for low-molecular-weight (40–46 kiloDalton [kD]) keratin proteins. In contrast, other keratinocytes, pilar tumors, and squamous cell carcinomas exhibit staining for a broad spectrum of cytokeratins (45–65 kD). These observations may be useful in separating small cell squamous cell carcinoma from BCC. However, they do not allow for a similar distinction between basal cell carcinomas and sudoriferous or sebaceous tumors because these adnexal lesions also have a typically restricted keratin profile. Immunostains for the other cell products listed in the previous paragraph attain their value in the latter differential diagnosis. Additions to that immunohistologic armamentarium of reagents include antibodies to BER-EP4, MOC-31, and the bcl -2 protein, all of which decorate BCCs (as well as various appendage tumors), but not squamous cell carcinomas. Similarly, alpha-isoform actin and CD10 are seen in a significant number of BCCs. It is also of interest that the intratumoral amyloid seen in many BCCs is apparently of keratinaceous origin, as documented immunocytochemically. This finding further supports the premise that BCC amyloid is related to apoptosis and degeneration of cytoskeletal protein.

Additional cell membrane determinants that have been detected in BCC are of little diagnostic use. These include markers of active cellular proliferation and beta-2-microglobulin (B2M), a component of human histocompatibility locus antigens. A proposal has been made that malignant tumors lacking B2M are more likely to exhibit an aggressive clinical course. In general, this premise has not proven to be valid; in specific reference to BCC, B2M has no relationship whatsoever to biological behavior.

Eccrine BCC may express EMA, S100 protein, or CD117 in the tubular profiles corresponding to adnexal differentiation, but carcinoembryonic antigen is absent in such lesions. The presence of gross cystic disease fluid protein 15 (a marker for apocrine differentiation) has not yet been assessed in apocrine BCC.

As a final note on this topic, it is of interest that many BCCs incite an inflammatory response in the surrounding dermis. Reactive hematopoietic cells consist primarily of lymphocytes, which have been shown to manifest a predominantly T cell immunophenotyped. Their presence explains the potentially beneficial therapeutic effect on BCC of topical imiquimod, which is an immunostimulant.

Differential Diagnosis

Several other primary cutaneous neoplasms enter into differential diagnosis with BCC variants. These include conventional (solitary) trichoepithelioma (which resembles keratotic BCC), desmoplastic trichoepithelioma (with similarities to morpheaform BCC), small cell squamous cell carcinoma and basaloid sebaceous carcinoma (both of which mimic nodulocystic BCC), and adenoid cystic eccrine adenocarcinoma (simulating adenoid or eccrine BCC).

In general, classic trichoepitheliomas exhibit a much more organoid growth pattern than BCC, with more equally sized cellular lobules. Also broad connections to the epidermis are rare in dermal hair sheath tumors (except via pilosebaceous units), whereas they are regularly observed in cases of BCC. Finally, the fibromyxoid stroma of BCC is not recapitulated by the fibrous matrix in trichoepithelioma, nor is cellular retraction as prominent a feature of the latter tumor. Some authors have used immunostains for various keratin peptides in an attempt to separate these lesions, and other markers such as bcl-2 and CD34 have been used in that context as well. However, all of those approaches may fail to make the distinction under consideration here, for reasons to be discussed subsequently.

Desmoplastic trichoepithelioma (DTE) can be distinguished from morphea-like BCC by the uniform observation of horn cysts in the former, along with an absence of expansile cell nests and the nearly universal presence of epidermal hyperplasia. Also, DTE occurs in a younger patient population than typical cases of morpheaform BCC. Moreover, DTE typically contains endocrine cells that label for chromogranin and CK20, whereas that finding is rare in BCC. Small cell squamous cell carcinoma is devoid of nuclear palisading, as well as the fibromyxoid stroma of BCC. Moreover, tumor cell nuclei in small cell squamous cell carcinoma are vesicular with prominent nucleoli, as opposed to the generally compact, nonnucleolated forms seen in BCC. Basaloid sebaceous carcinoma must be distinguished from basosebaceous BCC. This separation is particularly difficult, because the distribution of obvious areas of sebaceous differentiation may be similar in both lesions, and each has the capacity for nuclear palisading. Pagetoid involvement of the epidermis or conjunctiva favors an interpretation of sebaceous carcinoma, but it is not invariably present. Diagnosis may be facilitated by lipophilic stains on frozen tissue, or immunostains for EMA and adipophilin in difficult cases. Sebaceous carcinomas display diffuse positivity with those techniques, whereas basosebaceous BCC is reactive only in areas of obvious sebaceous differentiation.

Adenoid cystic sweat gland carcinoma typically, but not always, lacks the epidermal connections of adenoid or eccrine BCC. The distinction between these entities is extremely challenging, accounting for the fact that several reported examples of eccrine BCC actually appear to represent adenoid cystic carcinomas. The reverse of this situation holds true as well. Immunostains for carcinoembryonic antigen, EMA, and CD117 are helpful in this context because they are consistently positive in adenoid cystic carcinoma and negative in BCC. Very rarely, adenoid cystic carcinomas of salivary gland origin may metastasize to the skin. Those tumors also lack an epidermal connection and have a similar immunohistochemical profile to their primary cutaneous counterparts. Obviously, these comments make it apparent that the diagnostic distinction between such lesions must be accomplished by clinicopathologic correlation rather than by special studies.

There are several variants of cutaneous BCC that have a particular tendency for local recurrence. These include the morpheaform, metatypical (squamoid), micronodular, and infiltrative subtypes. Formal surgical (or chemosurgical [Mohs]) resection, with use of frozen sections to determine marginal status, is recommended for the latter lesions. Other forms of BCC can be managed with a variety of treatment modalities, including electrodessication, curettage, and conservative local excision.

Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) of the skin is capable of assuming a diversity of clinical and histologic growth patterns, like BCC, but it typically presents itself as a nonhealing ulcer or an irregular cutaneous nodule. From a morphological perspective, these include conventional, adenoid, spindled-pleomorphic, small cell, clear cell, and verrucous variants. Also, this neoplasm can be graded according to its level of nucleocytoplasmic differentiation and depth of dermal invasion.

SCC in situ (SCCIS; Bowen disease) has a distinctive clinicopathologic appearance, but it also may be confused with a number of other dermatopathologic entities. SCCIS usually appears clinically in middle age or adulthood, as an irregular, reddish, and scaly thickening of the skin. Both sun-exposed and protected cutaneous areas may be affected by this proliferation.

Histologically, SCCIS is characterized by global epidermal atypia, acanthosis, and elongation of the rete ridges ( Fig. 14.5 ). There is little or no maturation of neoplastic keratinocytes within the epidermis, and their nuclear-to-cytoplasmic ratios are greatly increased. The basement membrane is intact, but the atypical proliferation may involve the follicular infundibula fairly deeply. Nuclear chromatin is either hyperchromatic and uniformly distributed, or vesicular; nucleoli are often prominent. Tumor cell size varies significantly from case to case, and even within the same lesion. One of the hallmarks of this lesion is the irregular dispersal of dyskeratotic cells throughout the epidermis; these often show an artifactual retraction from their “neighbors” and contain hypereosinophilic cytoplasm and pyknotic nuclei. Also, random mitoses are regularly observed, which are commonly atypical in shape. The horny layer of the skin is moderately thickened and parakeratotic. Some cases of SCCIS show nests of atypical keratinocytes in an otherwise unremarkable epidermis, and still others manifest cytoplasmic clarity in the neoplastic cells. The first of these patterns was formerly included in the now-defunct concept of “intraepidermal epithelioma of Borst-Jadassohn.” Strayer and Santa Cruz also have described atrophic, psoriasiform, verrucous, and metaplastic forms of SCCIS. The last of these variants features the presence of intraepidermal amyloid, mucinous cells, or foci of sebaceous differentiation.

Invasive SCC has eventuated from SCCIS in less than 1% to 11% of cases, in various reports on this entity. When this occurs, the infiltrative component often manifests a more well-differentiated cytologic appearance than that which is present above the basement membrane. Foci of dermal fibrosis and chronic inflammation beneath apparently intraepidermal SCC should prompt examination of step sections to detect areas of microinvasion.

Conventional SCC

Conventional SCC features the interanastomosing growth of cords and nests of polygonal cells, with eosinophilic or amphophilic cytoplasm, and enlarged nuclei. The latter contain generally vesicular chromatin and prominent nucleoli; mitotic activity is variable, and mitoses may be atypical in shape. Dyskeratotic cells are regularly present, along with parakeratosis of the stratum corneum ( Fig. 14.6 ).

Well-differentiated neoplasms (Broders grade 1) have abundantly keratinized, glassy eosinophilic cytoplasm, and intercellular “bridges” on high-power microscopy. Tumor cells are often arranged focally in a concentric fashion, enclosing masses of anucleate keratin, so-called keratin pearls . Invasive growth extends downward into the dermis in a jagged fashion, and usually extends no deeper than the midreticular layer. Fibrosis and lymphoplasmacytic inflammation typically are evident at the interface between corium and tumor, but necrosis is unusual. The level of nucleocytoplasmic differentiation in these lesions roughly approximates that of the normal keratinocyte.

The lesion known as solitary keratoacanthoma (KA) is, in the author’s opinion and that of others, really a grade 1 squamous cell carcinoma. This tumor subtype is characterized by the potential for clinical regression; its low-power microscopic profile resembles a volcano, with a central keratin-filled crater and lateral, protuberant, epidermal “lips” comprising well-differentiated keratinocytes ( Fig. 14.7 ). The base of KAs often shows an irregular downward proliferation of rete ridges with subjacent fibrosis and inflammation. Small collections of neutrophils are scattered throughout the neoplastic epithelium, and perineural invasion can be observed in some examples. KA may grow rapidly, a trait which, together with its characteristic macroscopic appearance, allows the clinician to recognize it before excision. When this history is obtained and the typical histologic image is seen, current practice is to diagnose the lesion as well-differentiated SCC, with features of so-called keratoacanthoma . This interpretation simultaneously confirms the attending physician’s impression and conveys the truism that the pathologist cannot tell which KAs will regress spontaneously (through immunologic lysis) and which will not.

Moderately differentiated SCC (Broders grades 2 and 3) shows less propensity for pearl formation, is more deeply invasive, has less eosinophilic cytoplasm, and manifests more nuclear hyperchromasia and mitotic activity. Regional necrosis within cell nests makes its appearance at this level of differentiation, and invasion of blood vessels and perineural sheaths may be appreciated. Tumoral lobules tend to be less uniform in shape and size than those of well-differentiated SCC, and have a more irregular outline.

Poorly differentiated squamous carcinoma (Broders grade 4) commonly infiltrates the subcutis, and has little if any obvious keratinization. Cytoplasm is amphophilic, nuclei are more pleomorphic and hyperchromatic, and mitoses are abundant. Necrosis is typically prominent, and cellular lobules often become confluent and have extremely irregular borders. Lymphatic and perineurial invasion may be observed in roughly 50% of cases.

Surface ulceration becomes more likely as the level of differentiation lessens. Conversely, residual actinic keratosis-like changes in the surrounding epidermis are usually seen in well-differentiated tumors of sun-exposed skin areas. Regardless of grade, SCC in such locations is associated with prominent elastosis of the contiguous dermis.

A number of histological variants of SCC have been described, similar to BCC. These include adenoid (acantholytic; pseudoglandular); small cell; spindle cell/pleomorphic, hydropic (clear cell); and verrucous forms. Of these, spindle cell squamous carcinomas seem to behave more aggressively than conventional tumors of this type, whereas verrucous carcinoma is an indolent lesion that seldom, if ever, spreads outside the skin. Spindle cell (sarcomatoid) and verrucous SCC are overrepresented in the skin of the head and neck. Accordingly, those subtypes will be discussed further here.

Spindle Cell/Pleomorphic SCC

Some examples of grade 4 SCC are composed exclusively of fusiform and giant pleomorphic cells, with little or no keratinization ( Fig. 14.8 ). Necrosis is variable, but mitotic activity is regularly evident and focally atypical. The surrounding dermis often shows edema rather than fibrosis, and peritumoral inflammation may or may not be apparent. Continuity between these neoplasms and an intact overlying epidermis is observed in a minority of cases; most manifest surface ulceration.

Spindle cell and pleomorphic SCC characteristically occur in sun-damaged skin. In common with other poorly differentiated cutaneous squamous neoplasms, deep infiltration of the dermis, subcutis, and underlying fascia is frequently observed.

Verrucous SCC

Squamous carcinomas that grossly, and to some extent microscopically, simulate giant condylomas or verrucae have been diversely described as giant condyloma of Buschke and Loewenstein, micaceous balanitis, carcinoma cuniculatum, or verrucous carcinoma, depending on their anatomic locations. All of these lesions are very similar and can be considered as a group. Verrucous SCC (VSCC) displays marked papillomatosis and acanthosis, with “church-spiring” of the neoplastic epidermis. As a rule, cytological atypia is only slight in this neoplasm, mitotic activity is scant, and dyskeratosis is less marked than in other forms of SCC ( Fig. 14.9 ). Infiltration of the dermis occurs in broad, blunt cellular tongues, rather than the jagged profiles seen in conventional squamous carcinoma. Perilesional fibrosis and inflammation are minimal, and vascular or perineural invasion are seen only rarely.

The criteria just given should be rigorously met before labelling a squamous carcinoma as verrucous. This is so because other forms (such as conventional SCC) may occasionally demonstrate verrucoid growth, but do not behave as indolently as true verrucous carcinoma. In particular, tumors displaying marked cellular atypia and abnormal mitotic figures should not be classified as VSCC.

Special Pathologic Studies

Histochemical Special Stains

Conventional histochemical staining methods are of limited use in the diagnostic definition of SCC. The PAS method yields variable reactivity with this neoplasm; however, if a clear cell cutaneous tumor fails to contain glycogen, metastatic renal cell carcinoma may be excluded from consideration, and hydropic SCC assumes greater importance in differential diagnosis. Mucin stains are nonreactive with SCC, as are the alcian blue and colloidal iron techniques. These findings also may help in discriminating between adenoid squamous carcinoma and sweat gland tumors.

Immunohistochemistry

As noted earlier in the section on BCC, squamous cell carcinoma of the skin demonstrates reactivity for medium and high-molecular-weight cytokeratins. In particular, keratin 5/6 is commonly expressed in such lesions. Spindle cell/pleomorphic SCCs manifest the facultative ability to reexpress vimentin, the intermediate filament seen in virtually all embryonic cells and in mature mesenchymal tissues. Thus reliance upon vimentin immunostains alone is not a valid means of separating spindle cell SCCs from true sarcomas, especially because keratin reactivity in the former of those tumor groups can be very focal. Factor XIIIa and CD68, which have been touted as markers for fibrohistiocytic neoplasms, are also potentially present in pleomorphic SCC and should not be used exclusively in diagnosis.

An interesting trend in immunoreactivity may be seen with antibodies to epithelial membrane antigen (EMA), in the analysis of SCC of varying grades. Well-differentiated cutaneous tumors lack EMA, moderately differentiated SCC expresses it patchily, and high-grade neoplasms are often diffusely positive for this determinant.

Other antigens of interest in dermatopathology, such as S100 protein, carcinoembryonic antigen, CD10, MOC31, CD117, BER-EP4, and alpha-isoform actin, are absent in SCC of the skin, regardless of grade. Some publications on SCC have considered its expression of molecular moieties usually associated with normal keratinocytes, including involucrin, filaggrin, and peptidylarginine deiminase. As expected, such proteins are expressed in a progressively diminishing fashion as tumor differentiation lessens. They appear to have little utility in the diagnostic separation of pseudoepitheliomatous hyperplasia and keratoacanthoma from well-differentiated squamous carcinoma.

Differential Diagnosis

Because of its potential variability of appearance, SCC of the skin may be confused microscopically with several other cutaneous neoplasms and pseudoneoplastic proliferations, including extramammary Paget disease, pseudoepitheliomatous hyperplasia, sweat gland carcinoma, epithelioid angiosarcoma, atypical fibroxanthoma, spindle cell amelanotic melanoma, Merkel cell carcinoma, basal cell carcinoma, basaloid sebaceous carcinoma, and small cell eccrine carcinoma. Among these lesions, melanomas are distinguishable by their potential positivity with the Fontana-Masson stain and their immunoreactivity for S100 protein, melan-A, HMB45, SOX10, or tyrosinase in the absence of keratin. Sweat gland carcinoma morphotypes express carcinoembryonic antigen, with or without gross cystic disease fluid protein-15, and may be positive for S100 protein and CD117 as well. Merkel cell carcinoma shows a characteristic dot-like cytoplasmic keratin-staining pattern, particularly for CK20, and it is reactive for synaptophysin and chromogranin as well. Sarcomas typically lack keratin and instead express vimentin, and pseudoepitheliomatous hyperplasia does not demonstrate the degree of cytologic atypicality or disorganized basal growth that is observed in even well-differentiated SCC.

The treatment of cutaneous SCC is generally similar to that applied to BCC. Potentially aggressive variants of SCC, however, such as the sarcomatoid, adenoid, and injury-associated forms, should be formally resected with frozen section-directed assurance of marginal status. Regional lymph node dissection is also a possibility if clinical examination demonstrates lymphadenopathy. The overall survival of patients who are managed with these precepts approximates 90% at 5-years’ follow-up.

Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of the Skin)

Merkel cell carcinoma (primary neuroendocrine carcinoma of the skin) is characteristically seen in middle-aged to elderly patients, with a predilection for sun-exposed skin areas. It usually takes the form of an erythematous to violaceous nodule, but may occasionally demonstrate extensive ulceration and ill-defined borders.

Histopathology

Typical Merkel cell carcinoma is characterized by the medullary, organoid, or trabecular growth of small oval cells in the corium, with various degrees of intercellular cohesion. A grenz zone is usually present between the tumor and the epidermis; however, the latter structure may be involved focally in approximately 10% of cases. Dermal appendages are usually spared, but permeative growth into the subcutis is often apparent. Adipocytes may be entrapped by tumor cells, yielding an appearance simulating that of lymphoma cutis. Regional coagulative necrosis and apoptosis are common within Merkel cell carcinoma. Nuclei are round to oval, with evenly dispersed chromatin, inconspicuous nucleoli, and abundant mitoses (up to 15 per high-power field) ( Fig. 14.10 ). Cytoplasm is scanty and amphophilic, and cellular borders are indistinct. The stroma of Merkel cell carcinoma may be sclerotic focally (sometimes mimicking the appearance of amyloid), and it is richly endowed with capillary- or venule-sized vessels, which may be dilated. Lymphatic invasion is apparent in 20% of cases, and variably intense stromal lymphoplasmacytic inflammation is evident in many examples.

Variations on the histopathologic description just given include lesions showing scattered uninucleated tumor giant cells, formation of Homer Wright rosettes, myxoid stroma, spindle cell growth, foci of squamous or glandular differentiation, and focal desmoplasia. Another subtype of Merkel cell carcinoma is the “oat cell” variant, displaying nests of small, hyperchromatic, partially crushed tumor cells with prominent nuclear molding. The microscopic similarities between the latter and metastatic pulmonary small cell neuroendocrine carcinoma are obvious; however, I have only very rarely observed the Azzopardi phenomenon DNA encrustation of intratumoral blood vessels) in Merkel cell carcinoma, whereas it is common in metastatic small cell carcinoma of the lung. Gould et al. have documented a spectrum of differentiation in Merkel cell carcinoma, including intermediate and large cell subtypes. It is probable that cases of “primary cutaneous carcinoid” fall into the second of those categories.

Merkel Cell Carcinoma Associated With Other Skin Lesions

The association between Merkel cell carcinoma and SCC is now well recognized. Roughly 25% of patients with neuroendocrine skin cancer have had SCC in the same cutaneous region, either metachronously or synchronously with the former lesion. Both invasive SCC and Bowen disease have been documented in this context. In addition, Silva et al. described a case in which overt sweat gland carcinoma and Merkel cell carcinoma were admixed. I have observed one example of cutaneous neuroendocrine carcinoma arising in background of hypohidrotic ectodermal dysplasia; the patient also had multifocal basal cell carcinomas and trichoepitheliomas in the same skin field. Moreover, in one published series on this neoplasm, 9 of 67 cases showed the concurrence of Merkel cell carcinoma and adjacent BCC in the same skin field. Another example of Merkel cell carcinoma in my files occurred in a large congenital nevus, and one patient mentioned by Silva and colleagues had had a noncontiguous malignant melanoma.

Special Pathologic Studies

Histochemical Stains

The PAS method may demonstrate scanty glycogen in the cells of Merkel cell carcinoma, but this reactivity is seen in less than 15% of cases. The mucicarmine stain is consistently negative, but alcian blue and colloidal iron techniques sometimes result in labeling of the tumoral stroma. Argyrophil stains (e.g., Grimelius, Churukian-Schenk) are positive in less than 10% of Merkel cell carcinomas that have been formalin-fixed, but preservation in Bouin solution yields silver reactivity in the majority of cases. Argentaffin and amyloid stains are uniformly negative.

Immunohistochemistry

Merkel cell carcinoma is typified by consistent reactivity for pancytokeratin, in one of two patterns: diffuse or globular/paranuclear. The second of these is diagnostic of neuroendocrine differentiation in a cutaneous small cell tumor, in and of itself. Positivity for CK20 and neurofilament protein can be detected in 85% and 33% of cases, respectively, with a similar globular cytoplasmic distribution. Additional evidence for the epithelial differentiation of cutaneous neuroendocrine carcinomas is represented by immunopositivity for EMA. This determinant is less ubiquitous than cytokeratin in such tumors, but it is apparent in over 75% of cases. The most sensitive neuroendocrine marker for Merkel cell carcinoma is CD56 (neural cell adhesion molecule). Chromogranin, a specific indicator of neuroendocrine differentiation, is seen in most Merkel cell carcinoma cases ; in addition, a variable number shows reactivity for FLI-1, synaptophysin, PAX-5, CD99, vasoactive intestinal polypeptide, calcitonin, pancreatic polypeptide, adrenocorticotropic hormone (ACTH), gastrin, insulin, or somatostatin. S100 protein, thyroid-transcription factor-1, vimentin, and carcinoembryonic antigen are consistently lacking in Merkel cell carcinoma.

Differential Diagnosis

The differential diagnosis of small cell neoplasms of the skin is extensive. Small cell SCC, eccrine carcinoma, and malignant melanoma must be included in this group, as well as malignant lymphoma, metastatic neuroendocrine carcinoma from visceral sites (especially the lungs), cutaneous rhabdomyosarcoma, and primitive neuroectodermal tumor. Immunohistochemical studies are extremely useful in this context ( Fig. 14.11 ).

Treatment of Merkel cell carcinoma is predicated on complete surgical excision. Because of the aggressive nature of this tumor, heroic resections are sometimes necessary to gain local control and provide the best chance of cure. Regional lymph node dissection should be undertaken if the primary lesion is >0.5 cm in maximum dimension; shows >10 mitoses per 10 400× microscopic fields; demonstrates extensive lymphatic or vascular invasion; has an oat cell cytologic image or a diffuse growth pattern; shows a dense lymphocytic host response; involves the subcutis; or is associated with obvious lymphadenopathy. Irradiation and chemotherapy have been used as adjunctive treatments for Merkel cell carcinoma, but, in general, such interventions afford only palliative benefit. Roughly 75% of Merkel cell carcinomas recur locally or metastasize to local nodal chains, and approximately 55% of patients eventually succumb to their tumors because of additional visceral spread.

Benign Tumors of Sweat Gland Origin

Several adnexal tumors with sweat glandular differentiation are observed with some regularity in the skin of the face, neck, and scalp. Dermal cylindroma may be observed as a solitary sporadic lesion, or as a multifocal process in the context of the “turban tumor” (Brooke-Ancell-Spiegler) syndrome. In either of these contexts, the tumors are composed of two cell populations, with one being compact and basaloid and the other showing a polygonal shape with more abundant amphophilic cytoplasm. Nuclear chromatin is dispersed, without apparent nucleoli, and mitotic activity is sparse. There are two striking aspects of this neoplasm that allow for its ready recognition on low-power microscopy; these are represented by a “jigsaw puzzle” pattern of growth with angular cell nests molding to one another in a fibrous stroma, and the regular disposition of brightly eosinophilic, hyaline basement membrane material, throughout the cellular clusters, and immediately around them in the dermal connective tissue ( Fig. 14.12 ). Cylindroma quite often exhibits an irregular pattern of peripheral growth, with buds of tumor in the dermis or subcutis that are detached from the main mass. This finding has no adverse prognostic importance and should not be used to label such lesions as malignant. Similarly, rare examples of cylindroma that demonstrate brisk mitotic activity show no untoward behavior if the nuclear features and overall architecture are characteristic of that entity. Occasional tumors in this category may be associated with cutaneous trichoepitheliomas or spiradenomas in the same skin field, as well as basal cell adenomas or adenocarcinomas in major or minor salivary glands.

Eccrine spiradenoma differs in appearance only slightly from the description just given for cylindromas. The former of these two neoplasms lacks a jigsaw puzzle profile, and instead shows the presence of intralesional vascular channels that are often dilated and disposed toward the periphery of tumor cell clusters ( Fig. 14.13 ). Another characteristic of spiradenoma is the consistent dispersion of mature lymphocytes throughout the mass, much as one would expect in tumors of the thymic epithelium. Otherwise, the potential for basement membrane deposition and irregular, permeative, peripheral growth of the lesion is shared between spiradenoma and cylindroma. In occasional instances, it may, in fact, be difficult to distinguish between these two pathologic entities microscopically, and selected lesions may even demonstrate concurrent patterns of both tumor types.

Eccrine and apocrine hidrocystomas are limited almost exclusively to the facial skin. In actuality, they are probably not neoplasms at all but rather localized dilatations of the eccrine and apocrine ducts that are caused by traumatic obstruction. Microscopically, such lesions manifest a saccular space that is lined by variably proliferative polyhedral epithelial cells that may, on occasion, form micropapillae; anywhere from 1 to >10 layers of epithelium may be observed. In the eccrine form, the cells are compact with cuticle formation at the luminal aspect of the lesion ( Fig. 14.14 ). Apocrine hidrocystoma, on the other hand, exhibits a composition by large cells with granular eosinophilic cytoplasm and luminal decapitation secretion ( Fig. 14.15 ). Mitotic activity is absent.

Syringoma is another benign eccrine proliferation that is probably malformative rather than neoplastic in most cases. It commonly is multifocal and is relatively restricted to the skin of the upper face (particularly the lower eyelids) and the genital region. Small, comma-shaped tubules of cells, many of which contain central lumina and a luminal cuticle, are dispersed throughout a collagenous matrix in the dermis in this lesion. Syringomas are exquisitely circumscribed on low-power microscopy, and they are entirely devoid of nuclear atypia, mitotic activity, and permeative growth ( Fig. 14.16 ). Nevertheless, a small punch or shave biopsy through the center of such a tumor can provide an image, which is maddeningly similar to that of a form of appendageal carcinoma, making primary excision the preferred approach to the management of this proliferation. Extensive clear-cell change in a syringoma may be related to the presence of underlying diabetes mellitus.

Mixed tumors (MT, chondroid syringomas) of the skin are relatively common in the head and neck. They principally affect adults, as nondescript pink-tan nodules that may attain several centimeters in diameter. Microscopically, MT comprise variable numbers of tubular or solid epithelial-cell profiles with bland cytologic features, admixed with mucinochondroid matrix. The epithelium may have eccrine, apocrine, or pilar attributes, and the stroma also may contain myogenous, adipocytic, or osteoid-forming elements ( Fig. 14.17 ).

Hidradenomas of the eccrine and apocrine types are grouped together by many observers into two main categories: tubulopapillary hidradenomas (e.g., syringocystadenoma papilliferum and hidradenoma papilliferum) and acrospiromas (e.g., nodular hidradenoma and poroma) ( Figs. 14.18 and 14.19 ). Both of these clusters of tumors show a basic composition by uniform polygonal cells that are variably aggregated into solid nests, subdivided from one another by fibrovascular stroma of heterogeneous density, or which line the peripheral aspects of dermal microcysts or form intraductal tubulopapillary complexes. Both eccrine and apocrine cytologic features may be observed (see earlier) in such lesions, and communication between cellular nests in the corium and similar aggregates in the epidermis may occur via penetrating columns of cells that resemble the normal acrosyringia. Some neoplasms showing the last-cited of these attributes have the histologic profile that is associated with classical eccrine poroma ( Fig. 14. 20 ). Benign hidradenomas are circumscribed on low-power microscopy, and they are therefore not “allowed” to exhibit irregular budding into the adjacent stroma. The latter finding usually equates with low-grade malignancy. Similarly, zonal necrosis, extensive clear cell change, and areas of obvious nuclear atypia (with increased nucleocytoplasmic ratios and nucleoli) are indicators of malignant acrospiromas (hidradenocarcinomas).

Malignant Sweat Gland Tumors

In reference to the latter point, there are several malignant sweat gland tumors that have a propensity to affect the head and neck. One, malignant acrospiroma, has just been mentioned. Another is represented by ductal eccrine carcinoma (DEC), a lesion that bears a striking structural homology to ductal adenocarcinoma of the breast and salivary duct carcinoma ( Fig. 14.21 ). As such, DEC is comprised by epithelioid cells arranged in tubules or solid nests and cords, with at least modest nuclear atypia and randomly disposed infiltrative growth throughout a fibrotic dermis. The peripheral borders of such tumors are irregular and permeative; abnormal mitotic figures and foci of spontaneous necrosis are often found as well. There are no immunohistochemical or ultrastructural features of DEC that may be used to separate it definitively from metastatic mammary carcinoma. Thus careful examination of the breasts and thorough history-taking are paramount in resolving this differential diagnosis. Oddly, patients with DEC often state that a solitary skin lesion has been present for at least several months, and often for years. These are not the features of cutaneous metastases.

A third form of sweat gland carcinoma in this region is that of mucinous eccrine (primary colloid) carcinoma (MEC). This neoplasm shares the same relatedness to mammary tumors that were mentioned earlier in connection with DEC. Accordingly, MEC shows cords and nests of relatively uniform polygonal cells that are suspended in pools of epithelial mucin ( Fig. 14.22 ). The latter material stains with the periodic acid-Schiff and mucicarmine methods, and is resistant to diastase digestion. The tumor is further subdivided by fibrovascular stroma, which is variably collagenized. Nests of neoplastic cells usually infiltrate the dermis and subcutis irregularly, at the advancing edges of MEC. The degree of nuclear atypia seen in the constituents of this tumor is typically slight, and mitotic figures are typically limited in scope. Regional necrosis is only exceptionally observed. Some examples of MEC contain an admixture of more solidly cellular tissue that resembles DEC. This type of “hybrid” tumor is also mirrored in the breast. Yet another variant contains cytologically monomorphic solid cell nests that demonstrate neuroendocrine differentiation immunohistologically; that lesion is most often observed in the eyelids.

A fourth variety of adnexal carcinoma with at least partial eccrine differentiation is represented by microcystic adnexal carcinoma (MAC). This lesion manifests the haphazard proliferation of solid dermal cell nests, often with internal concentricity, or tubular dermal cellular profiles, some of which may resemble those seen in syringomas ( Fig. 14.23 ). The tumor cells show surprisingly bland nuclear features and only rare mitotic activity; similarly, necrosis is uncommon. However, the clearly aggressive nature of this neoplasm is reflected in its propensity to infiltrate perineural sheaths and vascular adventitia, as well as common invasion of the subcutis, or even underlying muscle and bone. The predominant architectural characteristics of MAC have led some observers to describe it using an alternate term, sclerosing sweat duct carcinoma . Nevertheless, this tumor regularly contains dermal microcysts that contain pilar-type keratin, and occasional examples show sebaceous, multivacuolar cytoplasmic differentiation. Hence the less committal nosological designation of MAC is preferred for routine diagnostic use.

Apocrine sweat gland carcinomas seen in the head and neck include ductal, ductopapillary, and signet ring-cell apocrine carcinoma (AC). These neoplasms are largely confined to the eyelids, axillae, and genitoperineal region, where apocrine glands are found in the highest density. Its cytoarchitectural features are quite similar to those of DEC, with some salient modifications. AC additionally exhibits the variable formation of tumoral papillae, which are supported by delicate fibrovascular cores and mantled by several layers of tumor cells. Moreover, the cytoplasm in that tumor is relatively copious and obviously eosinophilic, often containing a fine granularity as well. In those areas of the lesion in which tubule formation or papillae are apparent, the neoplastic cells, abutting glandular spaces, commonly show decapitation secretion with the elaboration of luminal “snouts” ( Fig. 14.24 ). Signet ring cell apocrine carcinoma is seen almost exclusively in the eyelids, and it may be bilateral ( Fig. 14.25 ). Those characteristics commonly engender concern over the possibility of metastasis from a visceral site.

Another form of sweat gland carcinoma with special relevance to the head and neck is primary dermal adenoid cystic carcinoma (ACC). The microscopic image of that lesion is identical to that of salivary glandular ACC ( Fig. 14.26 ); hence, skin lesions arising near the major salivary glands may create diagnostic difficulty. However, there have been no well-documented examples of salivary glandular ACC that have metastasized to the dermis in the absence of a known primary tumor. Thus worries about such an event are probably unjustified. A more real concern is the distinction between cutaneous ACC and adenoid BCC, which share many points of histologic similarity. Attention to the usual stromal changes seen in the latter of these tumors is capable of resolving this potential problem; in addition, immunostains for epithelial membrane antigen, carcinoembryonic antigen, and S100 protein are positive in ACC, but not in BCC.

Therapy and Prognosis

All of the forms of sweat gland carcinoma just cited have the ability to recur locally and pursue an aggressive course of regional growth, even after seemingly complete initial excision. Consequently, it has been arbitrarily decided that the surgical approach to such lesions should be like that which would be used for a similarly-sized malignant melanoma. MEC seldom metastasizes distantly and MAC never does so, but DEC and dutopapillary apocrine carcinoma (DPAC) have the capability to spread to regional lymph nodes, as well as internal viscera, such as the lungs, liver, and bone. This behavior is realized in anywhere from 15% to 50% of cases, and, unfortunately, there are no reliable morphologic or adjunctive biological markers that can be used to predict that eventuality.

Benign Pilosebaceous Neoplasms

Several tumors that show differentiation along sebaceous or follicular lineages show a preference to arise in the skin of the head and neck. These include sebaceous adenoma, trichofolliculoma, classical trichoepithelioma, desmoplastic trichoepithelioma, trichilemmoma, pilomatrixoma, proliferating pilar (trichilemmal) tumor, and tumor of the follicular infundibulum.

Sebaceous adenoma is comprised by mature sebocytes with abundant, finely vacuolated cytoplasm and central ovoid nuclei. Chromatin is compact, with inconspicuous nucleoli and no mitoses. The overall profile of this lesion is that of a lobulated, sharply circumscribed, upper to middermal mass without necrosis or budding of cellular nests into the adjacent corium. An arbitrary distinction from sebaceous hyperplasia (defined by >3 sebaceous lobules per pilosebaceous unit) is made in favor of adenoma, if a confluence of sebaceous glands is seen that fills at least one low-power microscopic field ( Fig. 14.27 ). Some examples of sebaceous adenoma demonstrate an admixed population of more basaloid cells that tend to be concentrated around the periphery of the constituent lobules, together with mature sebocytes. Such terms as sebaceoma and Muir-Torre adenoma have been used in reference to these neoplasms. With regard to the latter designation, it should be remembered that any sebaceous cutaneous lesion may be linked to the Muir-Torre syndrome, which features malignancies in several visceral organs, in concert with tumors of the skin. Immunostains for DNA mismatch-repair proteins, such as MLH1, MSH2, MSH6, and PMS2 , can be used to screen for that condition. In syndromic cases of sebaceous neoplasia, tumor cell nuclei will show deletion of one or more of the four markers.

Trichofolliculoma has been described as a “caricature” of the normal hair follicle. It shows a constellation of several maturing keratinocytic projections that emanate from a central follicular lumen and often embrace a diminutive or aberrantly-formed hair shaft. The tumor cells are polyhedral rather than basaloid, and they contain relatively voluminous eosinophilic cytoplasm.

On the other hand, trichoepithelioma does not exhibit nearly as high a level of follicular differentiation. In classical form, it is a sharply delimited, dermal mass that is composed of islands and cords of uniformly basaloid cells that are punctuated by pilar microcysts. In contrast to most basal cell carcinomas, trichoepitheliomas do not demonstrate retraction artifacts between cellular nests and the surrounding stroma, and the intratumoral dermal matrix is collagenized rather than mucomyxoid ( Fig. 14.28 ). Lastly, there are no appreciable areas of apoptotic cell loss in the cell clusters of trichoepithelioma, again unlike BCCs. Immature trichoepithelioma shares all of these attributes except for the presence of pilar microcysts. Some immunohistochemical studies have suggested that bcl-2 protein is unique to BCC in this narrow context ; however, our laboratory has observed reactivity for the latter marker in both basal cell carcinomas and classical trichoepitheliomas. In light of that information, as well as shared expression of GLI-1 (a protein in the hedgehog gene pathway) in the two tumor types, it is highly probable that solitary “trichoepitheliomas” are, in fact, highly differentiated forms of basal cell carcinoma. A familial condition in which multiple trichoepitheliomas are seen, the adenoides cysticum syndrome, also accounts for a small proportion of cases.

Desmoplastic trichoepithelioma (DTE) differs substantially at a histological level from the description just given. This neoplasm is a plate-like, sharply outlined growth in the upper dermis, composed of solid cords and tubules of mature keratinocytes (more like those seen in trichofolliculoma) that tend to interlock with one another. Dystrophic calcification is commonly superimposed on the contents of pilar microcysts, which are again randomly distributed throughout the lesion ( Fig. 14.29 ). Differential diagnosis in small samples of DTE primarily concerns trichofolliculoma and MAC. The last of these three tumors may be recognized by immunoreactivity for carcinoembryonic antigen, and DTE does not contain hair shafts, as seen in trichofolliculoma. Another consideration is that of sclerosing basal cell carcinoma, but that neoplasm expresses GLI-1 protein, whereas DTE and MAC do not.

The neoplastic nature of trichilemmoma has been called into question by some investigators, who prefer the interpretation that it instead represents a folliculocentric verruca vulgaris. It is a lobulated, clear/polygonal cell proliferation that is indeed centered on hair follicles, with extensions into the adjacent dermis, manifesting a zone of nuclear palisading at the peripheral aspects of constituent lobules, and sometimes demonstrating foci of pilar keratinization as well ( Fig. 14.30 ). Multiple trichilemmomas (sometimes termed trichilemmomatous hamartomas ) have been found in some patients with Cowden syndrome, a disease complex caused by mutations in the PTEN gene, which potentially includes visceral carcinomas. A desmoplastic form of trichilemmoma has also been described, in which narrow outgrowths of mitotically active tumor cells project from the lesional epicenter and are surrounded by fibroblastic stromal elements. Fears over a diagnosis of malignancy in this context may be assuaged by attention to the low-power microscopic image of the tumor, which demonstrates circumscription.

Pilomatrixoma (calcifying epithelioma of Malherbe) is a germinal follicular neoplasm that shows an exclusively intradermal origin and a distinctive cellular composition. It comprises multiple rounded or slightly irregular lobules of basaloid cells with slightly open chromatin, small nucleoli, and notable mitotic activity. The central aspects of the cell nests are variably replaced by ghost cell clusters, representing groups of effete keratinizing epithelium, in which only the faint outlines of the nuclear contours are seen within a brightly eosinophilic cytoplasmic background ( Fig. 14.31 ). The ghost cell foci often become dystrophically calcified and may even be metaplastically ossified, and they are rather commonly surrounded by foreign body-type giant cells. A particular danger in the interpretation of this lesion is presented by requests for frozen section examination. This procedure accentuates the nucleolar size and vesicular nature of the tumor cells of pilomatrixoma; these features, together with the presence of keratinization and mitotic figures, have resulted in an erroneous interpretation of squamous cell carcinoma on more than one occasion. However, attention to the zonal nature of the tumor and the particular features of the ghost cells will avoid such errors. Locally infiltrative and perforating variants of pilomatrixoma also have been described.

Proliferating pilar tumor (PPT) is a neoplasm that has been alternatively designated as proliferating trichilemmal tumor or proliferating trichilemmal cyst . It typically forms a multilobulated nodular mass in the dermis that protrudes into the overlying epidermis and commonly elevates it, sometimes with ulceration. PPT is composed of mature keratinocytes with copious eosinophilic cytoplasm, vesicular nuclei, and discernible small nucleoli ( Fig. 14.32 ). Mitotic activity is often brisk, mild nuclear pleomorphism is present, and zones of spontaneous degeneration and calcification in the lesion may be mistaken for necrosis. Thus it is easy to understand why PPT is so often confused with SCC. Nonetheless, the low-power architectural profile of proliferating pilar tumors is again reassuringly discrete. Rounded, pushing interfaces with the adjacent corium and subcutis are indicative of benignancy despite the aforementioned atypicality of the tumor cells.

Tumor of the follicular infundibulum (TFI) is a peculiar small upper dermal lesion which may be mistaken for superficial-multifocal BCC. That is because the former tumor is composed of horizontally disposed plates of slightly basaloid epithelial cells that bud into the corium from the bases of the follicular ostia, and are interconnected by vertically aligned bars of cells with similar cytologic features. There is no stromal retraction surrounding such lesions, nor is the intratumoral matrix myxoid in character as it is in BCC. TFI does not show immunoreactivity for Ber-EP4 or MOC-31, both of which are expressed in BCC.

Malignant Pilosebaceous Neoplasms

Malignancies of the sebaceous glands and pilar apparatus are more limited in number. They include ocular and extraocular sebaceous carcinoma, trichilemmal carcinoma, pilomatrix carcinoma, malignant PPT, and pilar carcinoma not otherwise specified.

Sebaceous carcinomas are most common in the modified skin of the eyelids, where they often present in a manner which clinically simulates that of a chalazion. Hence surgical pathologists should react with alarm if the surgeon consigns excised “chalazions” to the waste bin without pathologic examination. Extraocular lesions of this type may arise in many skin fields, but they have a predilection for the central and upper facial skin. Histologically, sebaceous carcinomas (SCs) show quite a range of differentiation, ranging from obviously multivacuolated epithelium to basaloid or squamoid populations of cells with more occult cytoplasmic lipid content ( Fig. 14.33 ). These are arranged in infiltrative cords and clusters in the dermis, but roughly 50% of cases will also manifest the Pagetoid spread of tumor cells into the surface epithelium, with or without regional in situ carcinoma in intact pilosebaceous units. Nuclei are much like those of squamous tumors, with common mitotic forms, but the cytoplasm of SC generally has a more amphophilic or basophilic quality than that seen in surface-keratinocytic neoplasms. Overt sebaceous differentiation, with complex, “bubbly” intracellular compartmentalization, is generally most obvious in the central aspects of dermal cell nests. Occasional examples of SC exhibit comedo-type central necrosis inside tumor cell aggregates; organoid carcinoid-like growth ; or extensive formation of keratin pearls. In reference to differential diagnosis with other clear cell cutaneous neoplasms, it should be emphasized that SC shows myriad delicate cytoplasmic vacuoles within the tumor cells, whereas elements of clear cell lesions having sweat glandular, pilar, surface-epithelial, or melanocytic derivation contain large, generally solitary intracytoplasmic zones of lucency. These patterns can often be accentuated using fat stains on wet tumor tissue, or immunostains for epithelial membrane antigen and adipophilin, if only paraffin-embedded specimens are available for further study. Differential diagnostic alternatives include basosebaceous basal cell carcinoma; malignant acrospiroma with clear cell features; hydropic squamous cell carcinoma; trichilemmal carcinoma; and balloon cell malignant melanoma. Application of selected immunostains and attention to histomorphological nuances are capable of separating these lesions from one another.

Trichilemmal carcinoma was first described by Headington in 1976 ; other reports have characterized that tumor further. It is characterized by a lobulated proliferation of atypical clear cells that partially or completely replace pilosebaceous units, as well as adjacent segments of the surface epithelium ( Fig. 14.34 ). Nuclear atypia is easily appreciated in this tumor; mitotic activity, multifocal pilar-type keratinization, and limited areas of necrosis are regularly observed as well. The lesion commonly exhibits nuclear palisading at the peripheral aspects of cellular lobules. Foci of dermal invasion may emanate from either the epidermal or follicle-based components of the tumor, and these are attended by stromal desmoplasia.

Pilomatrix carcinoma has the same general architectural features as those described earlier in reference to pilomatrixoma. Overtly malignant pilomatrical tumors have a low-power microscopic image, which is identical to that of invasive pilomatrixoma, with clusters and cords of cells budding from the main mass into the surrounding dermis and subcutis. However, it differs from the latter entity in showing obvious cytologic features of malignancy ( Fig. 14.35 ). These include high nucleocytoplasmic ratios; vesicular chromatin; prominent eosinophilic nucleoli; brisk mitotic activity; and foci of spontaneous tumor necrosis. Indeed, many areas of pilomatrix carcinomas are reminiscent of primary lymphoepithelioma-like carcinoma of the skin, which, in turn, strongly resembles nasopharyngeal carcinoma. The principal difference between these neoplasms is the regular presence of ghost cell clusters in pilomatrix carcinomas.

Malignant proliferating pilar tumor similarly may be separated from ordinary PPT, based on established histological criteria. These primarily include a more uniformly high-grade cytological appearance and, most importantly, the presence of irregular invasion of the surrounding corium and hypodermis by tongues of tumor cells that bud from the main mass.

Pilar carcinoma, not otherwise specified (PCNOS; also called high-grade malignant proliferating pilar tumor ) is extremely similar histologically to high-grade SCC, except for two important points. The first difference is the presence of pilar-type (“abrupt”) keratinization in the former of these two lesions, and the other is a lack of a broad connection between the dermal tumor mass and the surface epithelium, which may nonetheless be ulcerated. Some lesions with this appearance may arise in transition from obvious lower-grade PPTs.

General Clinical Features

The clinical characteristics of cutaneous mesenchymal neoplasms are rather nondescript in most instances. Such tumors may present as plaque-like or nodular lesions that are only uncommonly ulcerated, and which have generally been present for months or years. Some, such as the common dermatofibroma, are superficial, circumscribed, firm dermal lesions that are freely mobile on palpation. More deeply seated neoplasms are fixed to underlying structures and more ill-defined on clinical examination.

The age of the patient is important in the formulation of a tenable clinical differential diagnosis in this context. Children under the age of 1 year virtually never develop sarcomas of the skin and superficial soft tissues. Likewise, malignant tumors of this type are uncommon in other pediatric patients as well. On the other hand, de novo mesenchymal neoplasms in elderly individuals are biologically aggressive in a sizable proportion of cases.

The color and consistency of tumors in this category may contribute to clinical interpretation. For example, vascular neoplasms are red or violaceous, whereas others of a myofibroblastic nature commonly have a pale, white-tan, translucent appearance. Lymphangiomas and lipomas are often fluctuant, while sarcomas of various types may be “woody” on palpation. Even though the “dimple sign” (downward retraction of a lesion induced by lateral compression) is equated by many clinicians with a diagnosis of dermatofibroma, this finding is nonspecific and is observed in association with any tumor that forms a connection between the dermis and superficial subcutis. Similarly, overlying hyperpigmentation of the epidermis is seen as a reaction to many slowly growing and localized mesenchymal tumors of the corium, both benign and malignant in nature.

Multiplicity of such neoplasms offers another clue to proper diagnosis in some instances. Neurofibromatosis may feature the presence of multiple cutaneous lesions, and this potential is shared by tumors with myofibroblastic, smooth muscular, and endothelial differentiation.

Pain on palpation or after minor trauma is a characteristic that is peculiar to a relatively limited set of cutaneous mesenchymal tumors. These are included among the lesions represented by the acronym ANGEL : angiolipoma, posttraumatic neuroma, glomus tumor, eccrine spiradenoma, and leiomyoma cutis.

Finally, the topographic location of such proliferations is sometimes a helpful point of differential diagnosis. For example, sporadic angiosarcomas and atypical fibroxanthomas are largely confined to the skin of the face and scalp, whereas other malignant mesenchymal neoplasms are rare in those sites.

Predisposing Conditions

Several heritable conditions may predispose individuals who have them to cutaneous mesenchymal neoplasia. These include neurofibromatosis (neurofibromas, vascular proliferations, neurilemmomas, and striated muscle tumors); tuberous sclerosis (angiofibromas; lipomas; connective tissue hamartomas); the Klippel-Trenauney-Weber, blue rubber bleb, Sturge-Weber, and Maffuci syndromes (vascular neoplasms); Gardner syndrome (fibromatoses; lipomas); Bannayan syndrome (hemangiomas and lipomas); the basal cell nevus syndrome (fetal rhabdomyomas and rhabdomyosarcomas); and familial lipomatosis. All of these afflictions are autosomal dominant traits.

Ambient conditions can also play a role in the genesis of mesenchymal tumors or tumor-like conditions. For example, exposure to megavoltage irradiation, occupational or otherwise, is linked to the potential subsequent development of undifferentiated pleomorphic sarcoma, malignant nerve sheath tumor, and angiosarcoma in the affected field of skin and soft tissue.

Lastly, past experience has witnessed the association between a particular infectious agent, the human immunodeficiency virus (HIV), and mesenchymal neoplasia of the skin. The relationship between HIV infection, the resulting acquired immunodeficiency syndrome (AIDS), and the development of mucocutaneous Kaposi sarcoma is now familiar to physicians everywhere.

Immunohistologic Findings In Cutaneous Mesenchymal Neoplasms

Paraffin section immunohistochemistry represents a useful tool in the distinction between mesenchymal proliferations. The detection of keratin proteins with this technique can generally be equated with the presence of epithelial differentiation, as also true of cell membrane-based immunoreactivity for epithelial membrane antigen (EMA). Muscle-specific actin (MSA), desmin, and smooth muscle (alpha-isoform) actin (SMA) are expected in myogenous lesions. S100 protein, glial fibrillary acidic protein, and the CD56 and CD57 antigens may be expressed by Schwannian neoplasms, although a final interpretation of the significance of these markers is dependent upon the histologic context and an absence of the other antigens mentioned thus far. The latter caveats also apply to “endothelial” determinants, which potentially include ERG protein, podoplanin, FLI-1, thrombomodulin, and the CD31 and CD34 antigens.

Neuroendocrine and neuroectodermal lineage-markers are represented by CD56, CD57, CD99, chromogranin, and synaptophysin. They are typically interpreted in the context of a small round cell neoplastic proliferation.

Vimentin is ubiquitous among mesenchymal proliferations of all types because it represents the “primordial” intermediate filament class of such lesions. Nevertheless, this marker is indeed useful as a sort of “internal control” for tissue antigenicity in general. Also if it represents the only determinant seen in a mesenchymal proliferation, a diagnosis of fibroblastic or “fibrohistiocytic” neoplasia is indicated. With these points of information in mind, a directed discussion of such lesions is undertaken in the remainder of this chapter.

Biologically benign and borderline cutaneous mesenchymal neoplasms are sufficiently distinctive on clinicopathologic grounds that they can be considered individually as distinctive entities. However, overtly malignant tumors in this category have a propensity to demonstrate overlapping microscopic features. Therefore they shall be grouped together in four generic categories: small round cell tumors, spindle cell neoplasms, epithelioid lesions, and pleomorphic tumors.

Benign Neoplasms

Fibrous Papule

Fibrous papules are common lesions that occur in the midfacial skin of adults, the majority of whom are Caucasian. These tumors are small, firm, tan or light brown papules that are largely cosmetic nuisances. Simple excision is curative.

Whether fibrous papules are truly neoplastic is an unresolved question at present, and has remained so since the original description of these lesions. They are characterized by a localized proliferation of bland fusiform fibroblasts in the reticular and papillary dermis, often forming concentric densities around hair follicles ( Fig. 14.36 ). Stellate cells, which often contain melanin pigment, are commonly interspersed throughout these proliferations; the surrounding skin demonstrates a proliferation of telangiectatic capillaries and venules, and may contain melanophages as well. Guitart et al. have reported examples in which small foci of epithelioid granular cells were apparent.

Some authors prefer the view that fibrous papule is merely a form of regressed intradermal nevus. Based on results of immunostaining for Factor XIIIa (a putative marker for dermal dendrocytes) in such lesions, others have advanced the premise that they represent unique dermal mesenchymal neoplasms.

Myofibroblastic Proliferations

Myofibroblastic neoplasms in the skin of the head and neck may be solitary or multifocal, and they are classically placed into one of several discrete clinicopathologic categories. Infantile (congenital) myofibromatosis is a condition affecting newborn children and those under the age of 1 year. They present with firm, tan-pink nodular lesions of the dermis and superficial subcutis, with no particular topographic predilection. The lesions are often multiple, and may be associated with similar proliferations in the viscera and bones. If the latter are present (disseminated myofibromatosis), the prognosis is guarded because multiorgan failure may supervene as a result of the growing tumefactions. On the other hand, restricted cutaneous infantile myofibromatosis is a relatively innocuous condition.

Hyaline fibromatosis primarily affects children, who have masses in the scalp and the mucosal surfaces. It is often observed as firm tan-pink plaques in the gingiva, and may have a familial distribution. Multifocality of the lesions is common, and therefore surgical removal may be followed by development of new masses in contiguous sites.

Desmoid-type (aggressive) fibromatosis (DTF) typically involves the skin only secondarily because it is centered in the aponeuroses of deep muscle groups. This lesion develops during pregnancy or the immediate postpartum period in some women, where it characteristically arises in the abdominal wall. Extraabdominal examples of DTF can be seen in patients of all ages and both sexes, with a predilection for the extremities. The condition is typified by firm, ill-defined, slowly growing nodular masses that may be multifocal and slightly painful on palpation. It can attain a maximum size of several centimeters and has a stubborn tendency to recur after surgical removal. Rare cases are fatal because of their location in a vital, but relatively inaccessible body site, with recalcitrant local growth.

Solitary adult myofibromas are nodular masses that are virtually identical to the individual lesions of infantile myofibromatosis, except that they appear in postpubertal patients. Conservative surgical removal constitutes sufficient treatment, with only rare examples of recurrence. Kamino et al. also have reported a lesion dubbed dermatomyofibroma , which has many clinical similarities to solitary myofibromatosis. It shows a striking tendency to arise only in the proximal extremities, and is more plaque-like grossly and microscopically.

With minor alterations, the appearance of the fibromatoses is a consistent one. It features the presence of interweaving fascicles of cytologically bland spindle cells with slightly fibrillar cytoplasm, set in a myxocollagenous matrix and punctuated by a distinctive vascular network ( Fig. 14.37 ). The latter is composed of venule-sized blood vessels with thick pericytic cuffs. Despite the fact that the stroma of the fibromatoses is often sclerotic, the lesional vascular lumina are typically open and slightly branched. The latter characteristics may lead to confusion with solitary fibrous tumors.

Myxoid change is also frequent in the matrix around intralesional vessels, and these areas typically contain cells that are more stellate than fusiform. Cellularity is variable in the myofibromatoses; hypodense zones with abundant collagenous or myxoid stroma are admixed with others that manifest closely apposed spindle cells, which may assume rounded contours. Peripheral interfaces between these tumors and surrounding tissues are indistinct, and the lesions typically blend imperceptibly with the surrounding dermis or deeper soft tissue. Mitotic activity in the myofibromatoses is characteristically limited, and observation of more than 1 to 2 mitoses per 10 high power (40×) microscopic fields should therefore lead one to consider an alternative diagnosis.

Specialized histologic findings typify selected members of this lesional category. Infantile myofibromatosis and solitary myofibroma of adults are characterized by multinodular or fascicular plaque-like proliferations of spindle cells, set in a variably myxoid stroma ( Fig. 14.38 ). Alternation between hypocellular and densely cellular zones in such lesions yields a distinctively dimorphic appearance to them, and supporting blood vessels may be “staghorn” shaped. Hyaline fibromatosis manifests cytoplasmic lucency in proliferating myofibroblasts and zones of extreme paucicellularity, where the stroma takes on a glassy, eosinophilic, hyaline character. Dermatomyofibroma also is a unique member of this group on histologic grounds, in that it has a more diffuse growth pattern in the dermis, with entrapment of cutaneous adnexae and extension into the subcutis via fibrous septa ( Fig. 14.39 ). Parallel fascicles of fusiform cells in this plaque-like lesion are arranged in parallel with the skin surface, and the individual cells are invested by delicate cuffs of collagen. The cytoplasm is delicately fibrillar, and the tumor cells often assume a serpiginous contour. However, dermatomyofibroma does not appear to have the tendency toward nodular growth or alternation in cellular density that characterizes solitary adult myofibromatosis.

Immunohistologic studies of myofibroblastic proliferations are generally limited in utility with regard to differential diagnosis. Virtually all of the lesions in this category have overlapping immunophenotypes, characterized by reactivity for vimentin, and potentially for actins, caldesmon, calponin, and desmin. Those features are shared by scars, nodular fasciitis, and smooth muscle tumors. Bhattacharya et al. have shown that among that group of lesions, only fibromatoses exhibit nuclear immunolabeling for beta-catenin.