There are one or several dilated follicles from which radiate numerous small follicles of varying degrees of maturity (Fig. 33.1). The central follicle, which opens on to the surface, usually contains keratinous material and sometimes vellus hairs. The follicles that branch off the central follicle may in turn give rise to secondary or even tertiary follicles. Sometimes only rudimentary pilar structures or epithelial cords are formed. In older lesions, catagen and telogen follicles are present. ²⁸ Trichofolliculomas have a relatively cellular connective tissue stroma. This complex pattern is quite different from the hair follicle nevus (see above), which is composed of mature vellus follicles. Merkel cells are found in the outer sheath of the small follicles. ²⁹

Scattered vacuolated cells representing sebaceous differentiation may be present within the follicles or the rudimentary structures. Sebocytes are seen more often in late stage lesions. Epidermolytic hyperkeratosis has been found as an incidental change. ³⁰ A variant of trichofolliculoma in which large sebaceous follicles connect to a central cavity or sinus has been reported as a sebaceous trichofolliculoma. ³¹ It has some similarities to the folliculosebaceous cystic hamartoma (see p. 773), which appears to be a trichofolliculoma at a late stage in its evolution.^{28.32. and 33.}

The secondary follicles in trichofolliculoma express CK14 but not CK1 and CK10. CK15 is present in the basal layers. ³⁴

Trichoadenoma is a well-defined dermal tumor composed of epithelial islands, most of which have a central cystic cavity containing keratinous material. The multilayered squamous epithelium shows epidermoid keratinization toward the central cavity. The appearances resemble multiple cross-sections of the infundibular portion of hair follicles (Fig. 33.2). There are no hair shafts present. Collagen fibers are present between the follicular structures. The presence of CK10 and 15 in these tumors further suggests that trichoadenoma differentiates towards the follicular infundibulum and follicular bulge regions. ⁴¹

Trichoadenomas contain cytokeratin 20-positive Merkel cells but lack Ber-EP4 and androgen receptor expression. ⁴²

Verrucous trichoadenoma is a variant of trichoadenoma which clinically resembles a seborrheic keratosis. ⁴³ It is composed of small epidermoid cysts, some of which contain vellus hairs. There is abundant keratin on the epidermal surface. ⁴³

Trichoepitheliomas are dermal tumors with focal continuity with the epidermis in up to one-third of cases. They are composed of islands of uniform basaloid cells, sometimes showing peripheral palisading. This may lead to a mistaken diagnosis of basal cell carcinoma if features of pilar differentiation are not noted. In addition, there are usually branching nests of basaloid cells. Epithelial structures resembling hair papillae or abortive hair follicles may be seen (Fig. 33.3). A tumor with giant and multinucleated epithelial cells has been reported. ⁹¹ Small keratinous cysts lined by stratified squamous epithelium are quite common. Rupture of these cysts with liberation of the keratinous debris results in a small foreign-body granuloma in the stroma. Foci of calcification are often present; amyloid is generally considered to be uncommon although it was present in 33% of cases in one study.^{92. and 93.} Melanocytes are common in most pilar neoplasms. ⁹⁴ The stroma is prominent and loosely arranged. Aggregations of fibroblasts, representing abortive attempts to form papillary mesenchyme (papillary-mesenchymal bodies), are characteristic of trichoepithelioma. ⁹⁵ A trichoepithelioma with ‘monster’ stromal cells resembling an atypical fibroxanthoma has been reported. ⁹⁶ A trichoepithelioma-like basal cell carcinoma has also been documented. ⁹⁷ LeBoit has editorialized on the morphological overlap of these two tumors. ⁹⁸

Immunohistochemical staining of trichoepitheliomas resembles that seen in the outer root sheath, with strong reactions for keratins (CK) 5/6 and CK8. Some CK17 is present in cells surrounding horn cysts. ⁹⁹ Conflicting views have been expressed on the specificity of cytokeratin types in the distinction between trichoepithelioma and trichoblastoma. Although one study concluded that there were no differences, ¹⁰⁰ another study found CK7 in trichoblastomas but not trichoepithelioma. ¹⁰¹ Trichoepitheliomas express CK15, whereas only a subset of basal cell carcinomas do this. ¹⁰² Basal cell carcinomas differ from trichoepitheliomas by having stronger and more diffuse expression of PCNA and Ki-67. ¹⁰³ They also show greater expression of p53 than trichoepitheliomas. ¹⁰⁴

CD10 expression varies but a small number of cases show overlap features. As a rule, trichoepithelioma shows CD10 stromal immunoreactivity while in basal cell carcinoma the staining involves basaloid cells, but some stromal staining is sometimes seen. ¹⁰⁵ Both basal cell carcinomas and trichoepitheliomas express p27^kip1 but staining tends to be patchy in trichoepithelioma and more diffuse in basal cell carcinoma. ¹⁰⁶ Peritumoral stromal cells expressing CD34 are almost invariably present in pilar tumors. ⁹⁴

Desmoplastic trichoepitheliomas are reasonably well-circumscribed tumors in the upper and mid dermis, with an overlying central depression. They are composed of cords and small nests of basaloid cells with scanty cytoplasm (Fig. 33.4). Tumor strands may be attached to the epidermis. There are usually many keratinous (horn) cysts, with a peripheral basaloid layer and several layers of stratified squamous epithelium with central loosely laminated horn. ¹²³ Sometimes this epithelial lining is attenuated and one cell thick. Tadpole- or comma-shaped epithelial projections extend from the peripheral layer of some of the keratinous cysts. Sometimes, structures resembling eccrine ducts are present.

The desmoplastic stroma is dense and hypocellular, with fewer elastic fibers and more acid mucopolysaccharides than in the normal dermis. Other features which are frequently present include foreign-body granulomas, usually related to ruptured cysts, and calcification. Stromal ossification is rare. Occasionally foci of sebaceous cells or shadow cells are present. Rarely, a nevocellular nevus is also present.^{110. and 124.}

The tumor cells do not contain carcinoembryonic antigen, unlike the cells in a syringoma, which are usually positive. ¹¹¹ In contrast, involucrin is expressed in desmoplastic trichoepitheliomas but not in syringomas. ¹¹² The spindle-shaped cells surrounding the cellular islands in desmoplastic trichoepithelioma are focally strongly positive for CD34, whereas the stromal cells around basal cell carcinomas and microcystic adnexal carcinomas are usually negative.^{125.126. and 127.} Epithelial membrane antigen (EMA) is negative in desmoplastic trichoepitheliomas. ⁹⁷ Whereas bcl-2 is expressed in most basal cell carcinomas, it is found only in the basal layer of trichoepitheliomas. Ber-EP4 is positive at least focally in most trichoepitheliomas, contrasting with the usual diffuse staining in basal cell carcinoma. ⁹⁷ Up to 80% of basal cell carcinomas express androgen receptors, whereas trichoepitheliomas are typically negative.^{128.129. and 130.} Merkel cells (CK20⁺) are present in desmoplastic trichoepitheliomas but uncommon in basal cell carcinoma.128. ^{and 131.} Unfortunately these markers do not always differentiate reliably between basal cell carcinoma and desmoplastic trichoepithelioma as Merkel cells are sometimes sparse in desmoplastic trichoepitheliomas.^{129.130. and 132.} The cord-like basaloid cells in desmoplastic trichoepitheliomas express CK1/5/10/14, CK5/8, CK14, and CK15, but not CK6. ¹³³

The differential diagnosis includes syringoma and morphea-like basal cell carcinoma.^{114.122. and 134.} Syringomas rarely have horn cysts, foreign-body granulomas, or calcification. ¹²² Narrow strands of tumor cells are also unusual in syringomas. Furthermore, syringomas are usually periorbital and multiple. Basal cell carcinomas of morpheic type may form clefts between the nests and the stroma. ¹¹⁴ There is often coexisting nodular basal cell carcinoma. Mitoses and apoptotic bodies are also quite common in basal cell carcinomas, whereas foreign-body granulomas and ruptured keratinous cysts are uncommon. ¹¹⁴ The staining pattern for CD34 and bcl-2 (see above) is also of use in the differentiation of these two tumors.

The low-power view is usually quite striking: a large, circumscribed basaloid tumor with no epidermal connection. It is usually situated in the mid and lower dermis, with extension into the subcutis. The tumor shows irregular nests of basaloid cells resembling a basal cell carcinoma, but with variable stromal condensation and pilar differentiation (Fig. 33.5). The variant reported as trichogerminoma was composed of closely packed lobules of basaloid cells resembling hair bulbs, with little intervening stroma.^{143. and 153.} It has also been regarded as a variant of (large nodular) trichoblastoma with less overt follicular differentiation. ⁹⁷ Foci of necrosis may be present in this variant. ¹⁵³ At the other end of the spectrum is the trichoblastic fibroma, with an intimate relationship between basaloid nests and strands, and a fibrocellular stroma.^{154.155. and 156.} A desmoplastic stroma has been reported. ¹⁵⁷ So-called ‘stromal induction’, with the formation of primitive hair bulbs, is present. Keratinous cysts may be present in this group of trichoblastomas but they are not seen in the cellular, basaloid variants that may resemble basal cell carcinoma.

Ackerman and colleagues have used ‘trichoblastoma’ as a generic term for all neoplasms of the skin and subcutaneous fat that are composed mostly of follicular germinative cells. Trichoepitheliomas are included in this definition. ¹³ They have reported nodular, retiform, cribriform, racemiform, and columnar patterns of trichoblastoma. ¹³

Stromal amyloid and Merkel cells are quite common in trichoblastomas.^{46.97. and 158.} Rare variants include clear cell, ¹⁵⁹ pigmented (pigmented trichoblastoma),^{160. and 161.} and adamantinoid lesions (Fig. 33.6). ¹³⁹ A variant of pigmented trichoblastoma colonized by abundant dendritic melanocytes has been called a melanotrichoblastoma. ¹⁶² Focal sebaceous and apocrine differentiation are rare.^{163.164. and 165.} It is generally agreed that the cutaneous lymphadenoma is an adamantinoid variant of trichoblastoma with lymphocytic infiltration of the basaloid nests (see below). Trichoblastomas with basal cell carcinoma-like foci have been reported. Such tumors do not express CK15 as do other trichoblastomas. Furthermore, they lose their Merkel cells. ¹⁶⁶ A trichoblastoma arising within an apocrine poroma, which also showed sebaceous differentiation, has been reported. ¹⁶⁷ The cells in a trichoblastoma express CK8 and CK19. ¹⁶⁸ CK7 is often expressed, in contrast to trichoepithelioma. ¹⁰¹ Both trichoblastomas and trichoepitheliomas are characterized by papillary mesenchymal bodies which express CD10. ⁹⁷ Trichoblastomas and trichoepitheliomas do not express androgen receptors; they are expressed in basal cell carcinomas. ¹⁶⁹ Neither trichoblastomas nor basal cell carcinomas express hair keratins. ¹⁷⁰

The rippled-pattern trichoblastoma has a palisaded arrangement of epithelial ribbons with areas of nuclear palisading resembling Verocay bodies. Focal sebaceous differentiation may occur. The expression of cytokeratins is similar to the more usual trichoblastoma. ¹⁷¹

Cutaneous lymphadenoma is composed of multiple rounded lobules of basaloid cells with some degree of peripheral palisading, embedded in a fibrous stroma of variable density (Fig. 33.7). The stroma may rarely be desmoplastic. ¹⁸³ There is an intense infiltrate of small mature lymphocytes within the lobules, with some spillage into the stroma. ¹⁷⁶ A hint of follicular differentiation and focal sebaceous differentiation is sometimes present. ¹⁷⁷ Some nests may show adamantinoid features, but this does not appear to be a universal change, a strong point against cutaneous lymphadenoma being synonymous with adamantinoid trichoblastoma. ¹⁸⁴ Focal stromal mucinosis is an uncommon finding. ¹⁷⁹

Both T and B lymphocytes are found within the lobules, as well as some S100-positive dendritic cells.^{174. and 182.} The pattern of staining with CD34 and bcl-2 is similar to that seen in trichoblastomas and trichoepitheliomas. ¹⁸⁵ There are scattered CD30-positive cells within the tumor nests.^{185.186. and 187.} Focal staining with CD15 has also been reported. ¹⁸⁷ The epithelial cells are usually positive for cytokeratin and EMA. ¹⁸⁸

The growth pattern resembles that of a superficial basal cell carcinoma. There is a plate-like fenestrated subepidermal tumor composed of pale or pink-staining glycogen-containing cells, with a peripheral palisade of basal cells. Some of the cords are basaloid without pale-staining cytoplasm. The tumor connects at intervals with the undersurface of the epidermis by slender pedicles. Hair follicles entering the tumor from below lose their identity and merge with it. Small follicular bulbs and papillary mesenchymal bodies may be found. Focal sebaceous differentiation is rare. ²²³ Ductal structures, resembling eccrine ducts, have been reported in the tumor strands. ²²⁴ The surrounding loose connective tissue stroma contains a network of elastic fibers.^{216. and 217.} The histological features sometimes overlap those of tricholemmoma, but the low-power architecture is quite different.

The tumor of the follicular infundibulum appears to be the same as that reported as a basal cell hamartoma with follicular differentiation. ²²⁵ However, it is histologically dissimilar to the cases reported as multiple infundibular tumors of the head and neck. ²²⁶ In these latter cases clusters of enlarged follicular infundibula comprised each lesion, somewhat similar to the appearances of prurigo nodularis. The illustrations in the report of a tumor called an infundibular keratosis showed some features of the multiple infundibular tumor referred to above, and others of an inverted follicular keratosis (see below) but without squamous eddies. ²²⁷

There is a markedly dilated follicular pore, which may extend to the mid or lower dermis. The follicle is lined by outer root sheath epithelium in which there is infundibular keratinization with the formation of keratohyaline granules. The epithelium shows acanthosis and finger-like projections that radiate into the surrounding dermis (Fig. 33.9). There is sometimes heavy melanin pigmentation of the follicular wall; pigmentation may also involve the central horny plug. The pilary unit of the involved follicle and the sebaceous gland are absent or rudimentary.

There is a central, cystically dilated follicle containing keratinous material which opens onto the surface (Fig. 33.10). Tumor lobules composed of outer root sheath epithelium extend from the wall of the cystic cavity into the adjacent dermis. Lobules sometimes reach the subcutis. Occasional abortive hair follicles may be present. The tumor epithelium shows infundibular keratinization, although it is of isthmic origin. There may be abundant glycogen in some of the tumor cells.

The condition may be distinguished from the dilated pore of Winer, in which there is a patulous follicle with only small projections of epithelium extending into the surrounding connective tissue. In trichofolliculoma, well-formed follicles radiate from the central keratin-filled sinus and there is a well-formed stroma, which is absent in pilar sheath acanthoma.

Inverted follicular keratoses are predominantly endophytic tumors with large lobules or finger-like projections of tumor cells extending into the dermis. An exophytic growth pattern is present in some lesions, and it is occasionally the dominant feature. Mehregan has described four growth patterns:

Each tumor lobule is composed of basaloid and squamous cells, with the basaloid cells at the periphery and larger keratinizing cells toward the center. Mitoses are not uncommon in the basaloid cells.

A characteristic feature is the presence of squamous eddies, which are formed by concentric layers of squamous cells in a whorled pattern and which may become keratinized with the formation of keratohyalin and sometimes keratin at the center of these islands (Fig. 33.11). There is sometimes clefting at the periphery of the squamous eddies, and even focal acantholysis. Melanin pigment is usually inconspicuous. The surrounding dermis sometimes contains a mild inflammatory cell infiltrate which is predominantly lymphohistiocytic. Telangiectatic vessels may be found in the dermal papillae in the filiform lesions.

Overlying the tumor there is variable hyperkeratosis and parakeratosis. Funnel-shaped keratinous plugs may form. Occasionally a prominent cutaneous horn is present.

Bcl-2-positive dendritic cells are present in increased numbers in the suprabasal areas of inverted follicular keratoses compared to seborrheic keratoses. This density of cells in inverted follicular keratoses correlates with the density of CD1a-positive cells. ²³⁹

Tricholemmomas are sharply circumscribed tumors composed of one or more lobules which extend into the upper dermis and are in continuity with the epidermis or follicular epithelium at several points. In small lesions follicular concentricity is apparent. ²⁴⁷ The tumor is composed of squamoid cells showing variable glycogen vacuolation, this change being most marked deeply (Fig. 33.12). Centrally, there may be foci of epidermal keratinization and occasionally small squamous eddies. Keratinous microcysts may form in large lesions. There is a peripheral layer of columnar cells with nuclear palisading resembling the outer root sheath of hair follicles. A thickened glassy basement membrane surrounds the tumor in part. This is PAS positive, and diastase resistant. The stroma is occasionally hyalinized or desmoplastic.^{241. and 248.} The term ‘desmoplastic tricholemmoma’ is used for this histological variant. A case of desmoplastic tricholemmoma arising in an organoid nevus has been reported. ²⁴⁹ Another case, on the eyelid, was misdiagnosed as sebaceous carcinoma. ²⁵⁰

The overlying epidermis shows hyperkeratosis, mild acanthosis, and sometimes a prominent granular layer. Uncommonly, a cutaneous horn will form (tricholemmomal horn). ²⁵¹ This differs from the tricholemmal horn, in which a horn showing tricholemmal keratinization overlies a depression in the epidermis which usually has a prominent basement membrane. ²⁵² Warts, basal and squamous cell carcinomas, and inverted follicular keratoses and seborrheic keratoses sometimes contain areas of tricholemmal differentiation.^{242. and 253.}

CD34 has been reported in tricholemmomas and also in the external root sheath of normal hair follicles. ²⁵⁴ Its presence in desmoplastic tricholemmoma may be of diagnostic value; it is not present in basal cell carcinoma²⁵⁵ or sebaceous carcinoma. ²⁵⁰ The cytokeratin expression of tricholemmomas has been studied. ²⁵⁶ CK1 and CK10 are present in keratinizing ductal epithelium. CK14 is present in the whole layer, while CK16 is present in the suprabasal layer but absent in keratinizing ductal epithelium. ²⁵⁶

Most of the facial lesions are tricholemmomas or tumors of the follicular infundibulum. The tricholemmomas are cylindrical or lobular in configuration. ²⁸⁷ Sometimes the lesions keratinize with squamous eddies, resembling an inverted follicular keratosis. Non-specific verrucous acanthomas and lesions resembling digitate warts may also be present. ²⁸⁷

The extrafacial lesions are mostly hyperkeratotic papillomas that resemble either verruca vulgaris, acrokeratosis verruciformis, or a nondescript hyperkeratotic acanthoma. ²⁸⁸ This latter change may take the form of hyperplasia of the follicular infundibulum. ²⁸⁸ No evidence of a viral etiology has been found on electron microscopy,^{269. and 291.} or with immunoperoxidase studies.

Distinctive dermal fibromas (sclerotic fibromas) with interwoven fascicles of coarse collagen, sometimes showing marked hyalinization, are not uncommon in Cowden’s disease.^{288. and 292.} They may have a plywood-like appearance histologically (see p. 815).

The tumors are multilobulate, infiltrative growths connected to the epidermis and pilosebaceous structures and showing features reminiscent of the outer root sheath. ²⁹⁷ The lobules often show peripheral palisading, hyaline basement membranes, and tricholemmal keratinization (Fig. 33.13). ²⁹⁷ A high mitotic rate is often present.^{296. and 298.} Neuroendocrine differentiation and melanocyte colonization were present in one case. This tumor expressed EMA, cytokeratin 15/20, chromogranin, synaptophysin, and CD56. ³⁰⁸ The usual tricholemmal carcinoma expresses CK7, ³⁰⁶ and podoplanin, detected by the D2-40 antibody. ³⁰⁹

The tumor reported as ‘clear cell pilar sheath tumor of scalp’ had some histological similarities to the tricholemmal carcinoma. The reported case was composed of small nests of glycogen-containing clear cells infiltrating the dermis and subcutis. ³¹⁰ There was no underlying cyst or evidence of tricholemmal keratinization. ³¹⁰

The appearances vary according to the age of the lesion. Established lesions are sharply demarcated tumors in the lower dermis, extending quite often into the subcutis. There are masses of epithelial cells of various shapes, with an intervening connective tissue stroma containing blood vessels, a mixed inflammatory cell infiltrate, foreign-body giant cells, and sometimes hemosiderin, melanin, bone, and rarely amyloid.^{10. and 358.}

There are two basic cell types, basophilic cells and eosinophilic shadow cells (Fig. 33.14). The basophilic cells tend to be at the periphery of the cell islands and have little cytoplasm, indistinct cell borders, hyperchromatic nuclei and plentiful mitoses. They resemble the cells of a basal cell carcinoma. They are sometimes the predominant cell in lesions removed from elderly patients. The term ‘proliferating pilomatricoma’ has been proposed for this variant (Fig. 33.15).^{359. and 360.} Follicular germinative cells have been reported in a palisaded arrangement at the edges of collections of matrical cells in cases of pilomatrixoma. ³⁶¹ The eosinophilic shadow cells in the usual form are found toward the central areas of the cell masses. They have more cytoplasm and distinct cell borders, but no nuclear staining. These shadow (mummified) cells form from the basophilic cells, and the transition may be relatively abrupt or take place over several layers of cells (transitional cells). The intermediary cells develop progressively more eosinophilic cytoplasm and the nucleus becomes pyknotic. The mode of cell death has been reported as apoptotic^{362. and 363.} but it is more likely that the shadow cells represent terminal differentiation rather than apoptosis.^{364. and 365.} Hyalinization of the cells, squamous change, or disruption into amorphous debris may result.

Calcification occurs in more than two-thirds of the tumors and is usually in the shadow cells. Ossification of the stroma occurs in about 13%; ³⁶⁶ hemosiderin is found in about 25% of cases; ³⁶⁷ and melanin is present in nearly 20% of lesions and may be in the shadow cells as well as in the stroma.^{367. and 368.} Extramedullary hematopoiesis may occur adjacent to the spicules of bone. ³⁶⁹ Bone morphogenetic protein (BMP)-2, which plays an important role in ectopic bone formation, has been found in the shadow cells, suggesting that it may play a role in generating bone formation in pilomatrixomas. ³⁷⁰ It results in the deposition of type II collagen at the dermoepidermal junction. ³⁷¹ Dendritic cells are sometimes seen among the basophilic cells in the cases with pigmentation.

The bullous (lymphangiectatic) lesions have marked dilatation of superficial lymphatics overlying the tumor. ³⁴⁵ There may be some loss of elastic fibers, as seen in the anetodermic variant.^{343. and 347.} The surrounding dermis may be edematous in these bullous variants. ³⁴⁷

In early lesions there is often a small cyst with basophilic cells in the wall. ³⁷² Rarely, a pilomatrixoma appears to arise in an established epidermal cyst³⁷³ or hair follicle. ³⁷⁴ Pilomatrixoma-like changes can also develop in the epidermal cysts in Gardner’s syndrome (see above). As the lesion ages, the number of basophilic cells decreases as the process of mummification outstrips the proliferation of the basophilic cells. About 20% of lesions are fully keratinized (mummified) at the time of removal and have no basophilic cells remaining.367. ^{and 372.} Transepidermal elimination of the tumor is a rare outcome.^{375.376.377.378.379.380. and 381.} In one case, perforation was present in the anetodermic variant. ³⁴⁴

The immunohistochemical pattern indicates a tumor differentiating into both the hair cortex and outer root sheath. ³⁸² The hard keratins hHa1, a2, and a5 are expressed in pilomatrixomas but not in other tumors of follicular origin.^{383. and 384.} Maturation to shadow cells is associated with a gradual loss of differentiation-specific hair keratins. ³⁸⁵ CK15, found in trichoepitheliomas, some basal cell carcinomas and proliferating tricholemmal cysts, inter alia, is not found in pilomatrixomas. ¹⁰² The basaloid cells of all pilomatrixomas express β-catenin, but the shadow cells do not stain.^{386.387. and 388.} The transitional cells show strong staining for involucrin³⁸² and bcl-2. ³⁸⁹ The S100 proteins S100A2, S100A3, and S100A6, which specifically label certain cells within the normal hair follicle, are all expressed in different parts of a pilomatrixoma. ³⁹⁰

Pilomatrix dysplasia was the term used for a histologically distinctive pattern seen in a patient with facial dysmorphism and follicular papules who was receiving four immunosuppressive drugs. ³⁹¹ Hair follicles were dilated and contained hyperkeratotic and parakeratotic debris in place of hair shafts. There were hyperplastic areas of differentiation into hair matrix with cellular disorganization and loss of nuclear polarity. ³⁹¹ These changes are now known as trichodysplasia spinulosa (see p. 405). This description is left in this chapter in case readers unfamiliar with the entity read this section looking for clues to the diagnosis of a problem case.

Matricoma is the designation used by Ackerman and colleagues for a tumor with the same constituent cells as a pilomatrixoma but with a different silhouette. ¹³ The lesions are well circumscribed, not fundamentally cystic (although cystic areas can be present in some lobules), and composed of discrete aggregations. Some of these cases have probably been included with the ‘proliferating pilomatricoma’ (see above).

Pilomatricomal horn is a verruca-like horn characterized by replacement of the epidermis by basaloid cells, with masses of cornified material containing shadow cells that form a cutaneous horn. ³⁹² This lesion is the matrical equivalent of the tricholemmal horn. Anetodermic changes, as seen in some cases of pilomatrixoma, were present in the dermis in one case. ³⁹²

Pilomatrix carcinoma is a poorly circumscribed, asymmetrical tumor that is often ulcerated. ⁴¹⁰ It is centered on the dermis but extension into the subcutaneous tissue often occurs. The tumor is composed of pleomorphic basaloid cells with prominent nucleoli and frequent mitoses. Necrosis is sometimes present. Keratotic material and shadow cells may be present in the center of the basaloid islands. Vascular and/or lymphatic invasion are rare.^{394. and 398.}

Melanin pigment and intralesional melanocytes have been present in several cases.^{414. and 415.} Such cases can be regarded as the malignant counterpart of the melanocytic matricoma (see below). ⁴¹⁴ The case reported as a pilomatrical carcinosarcoma was composed of a large pilomatrixoma lying within a spindled, sarcomatoid stroma. ³¹¹

It should be remembered that shadow cell differentiation can occur in some visceral tumors, such as tumors of the colon and uterus. ⁴¹⁶

Immunohistochemical studies have demonstrated the hair matrix and precortex keratins hHa5 and hHa1. ⁴¹⁷β-catenin is also expressed, as in pilomatrixomas. ⁴¹⁷

Melanocytic matricoma is a well-circumscribed dermal nodule composed of variably melanized, pleomorphic, and mitotically active matrical and supramatrical cells with islands of shadow cells (Fig. 33.16). ⁴¹⁸ The shadow cells are not always plentiful. Admixed with these cells are numerous dendritic melanocytes containing melanin pigment. There has been no discernible connection with the overlying epidermis or a hair follicle. Pigmented matrical cells are sometimes seen in normal hair follicles (Fig. 33.17).

The melanocytes express S100 protein and HMB-45, while the basaloid cells express β-catenin. ⁴²⁴

It is now accepted that the fibrofolliculomas and trichodiscomas of the Birt–Hogg–Dubé syndrome are the same entity (fibrofolliculoma), but with a spectrum of morphological changes. It is inferred, but not proven, that sporadic cases may have either of these two morphologies. Furthermore, some cases reported as trichodiscomas have illustrations showing fibrofolliculomas. ⁴⁶⁰

The fibrofolliculoma end of the spectrum consists of cords and strands of epithelial cells, 2–4 cells thick, radiating from a follicular structure with infundibular features. This may be dilated and contain keratin. The strands may anastomose or rejoin the infundibulum at several points. One or more sebocytes may be seen within the epithelial cords. They may form tiny lobules. Sebaceous ducts may also be present. The term ‘mantleoma’ has also been used for these tumors. Around the epithelial cords there is a well-circumscribed proliferation of loose connective tissue composed of fine fibers with some intervening mucin. Elastic fibers are scant or absent.

The trichodiscoma component is usually a well-demarcated and non-encapsulated tumor, which often has a folliculosebaceous collarette of variable maturity. Areas resembling fibrofolliculoma may be seen, particularly at the periphery. Trichodiscomas are composed of fascicles of loose, finely fibrillar connective tissue with intervening mucinous ground substance (Fig. 33.18). There is a moderate increase in fibroblasts, with occasional stellate forms. Elastic fibers are sparse or absent. There are prominent small vessels, some of which are telangiectatic. Sometimes, blood vessels with a concentric arrangement of PAS-positive collagen, forming a thickened wall, have been present toward the lower edge of the tumor. The term ‘perivascular fibroma’ has been used for these changes. ⁴⁶¹ Nerve fibers have been described at the periphery of the lesions, and also extending into the base. Neurofollicular hamartoma (see below) is now regarded as a spindle-cell predominant trichodiscoma. ⁴⁶²

Both syndromic-associated and sporadic types of fibrofolliculomas and trichodiscomas have identical immunophenotypic features with perifollicular vimentin and CD34, but not factor XIIIa.^{463.464.465. and 466.}

Multiple giant tumors with the appearances of a trichodiscoma have been reported as ‘giant fibromyxoid tumors of the adventitial dermis’.

The lesion consists of hyperplastic pilosebaceous units with an intervening stroma of spindle cells arranged in broad, haphazard fascicles. The stroma has features of both an angiofibroma and a neurofibroma. It also resembles a trichodiscoma.

It has been suggested that the neurofollicular hamartoma, trichodiscoma, and fibrofolliculoma are part of the same spectrum of hamartomas, ⁴⁶⁷ and, as stated above, that the neurofollicular hamartoma should be recategorized as a spindle-cell predominant trichodiscoma. The folliculosebaceous cystic hamartoma is closely related (see p. 773). ⁴⁷¹

The spindle-cell predominant trichodiscoma and the usual trichodiscoma express an identical CD13⁺/CD34⁺ fibrocytic immunophenotype without co-expression of neural/perineural, myogenic, or melanocytic markers. ⁴⁶² It is composed of cellular fascicles of spindle cells set in a loosely textured stroma with a moderate mucinous background. ⁴⁶²

Immunohistochemistry of the neurofollicular hamartoma shows scattered cells that are positive for S100 and factor XIIIa. Diffuse staining for S100 has also been reported. ⁴⁷⁰ Most of the connective tissue cells are positive for vimentin. ⁴⁶⁷

The lesion is composed of infundibular structures, sometimes cystic, with numerous radiating sebaceous lobules. Occasional rudimentary hair structures and even apocrine glands may be present. The pilosebaceous units are embedded in a mesenchymal stroma composed of variable proportions of fibrous, adipose, vascular and neural tissue. There are usually spindle-shaped cells in the stroma, and some of these stain for CD34 or factor XIIIa. ⁴⁸⁴ Smooth muscle was the only mesenchymal component in one case, leading to the diagnosis of folliculosebaceous smooth muscle hamartoma. ⁴⁹³

The case reported with a prominent neural component in the stroma has some features in common with the neurofollicular hamartoma (see p. 772), although this latter entity lacks the haphazard cystic infundibular structures. ⁴⁷¹ The morphologically related sebaceous trichofolliculoma (see p. 759) lacks a mesenchymal stromal component. ⁴⁸⁷ Trichofolliculoma differs from folliculosebaceous cystic hamartoma by the presence of secondary follicles in trichofolliculoma. ⁴⁹⁴

Large, mature sebaceous lobules are grouped around a central dilated duct, which is usually filled with debris, bacteria and occasionally a vellus hair. The lobules usually lack the indentations by fibrous septa that characterize the normal gland (Fig. 33.20). The sebocytes are smaller than usual and there are more basal cells per unit basement membrane length than in normal glands. Autoradiographic studies have shown a lower labeling index. ⁵²⁹ Sebaceous hyperplasia may be a clue to an underlying dermatofibroma. In shallow shave biopsies, sebaceous glands may be the most conspicuous feature. ⁵³⁰

In juxtaclavicular beaded lines there may be isolated sebaceous lobules in the upper dermis, not obviously connected with hair follicles. ⁵²¹

The tumor is composed of multiple sharply circumscribed sebaceous lobules separated by compressed connective tissue septa. It is usually centered on the mid dermis, but may adjoin the epidermis or exhibit multiple openings onto the skin surface, with partial replacement of the epidermis by basaloid epithelium showing sebaceous differentiation (Fig. 33.22). The sebaceous lobules have a peripheral germinative layer of small basaloid cells, with mature sebaceous cells centrally and transitional forms in between. This maturation is not as orderly or as well developed as in normal sebaceous glands. Nevertheless, mature cells still outnumber the darker germinative cells. ³¹³ This expansion of basaloid cells is a key feature in distinguishing this lesion from sebaceous hyperplasia. ⁴⁹⁹ There is variable central holocrine degeneration, with granular debris scattered in the area of cystic change. Cystic sebaceous tumors are now regarded as a marker for the mismatch repair-deficient subtype of the Muir–Torre syndrome. The connective tissue stroma may contain a patchy chronic inflammatory cell infiltrate. An overlying cutaneous horn is a rare occurrence. ⁵³⁶ The term ‘steatosebocystadenoma’ has been used for a sebaceous adenoma arising in the wall of a steatocystoma simplex. ⁵³⁷

On immunohistochemistry, CD10 staining of the cytoplasmic membrane occurs in nearly half of the cases. ⁵³⁸ CK15 is expressed in the basal cells; it is also present in other sebaceous tumors and sebaceous hyperplasia. ⁵³⁹

The sebaceous tumors resemble to varying degrees those already described. ⁵⁷⁴ Often they appear ‘unique’ and difficult to classify.^{551. and 555.} There may be solid sheets of basaloid cells in some lobules, or an intermingling of these cells and sebaceous cells without any orderly maturation. It has been suggested that these atypical features are predictive of malignant transformation, if not completely removed. ⁵⁷⁵ Sometimes the tumors resemble a basal cell carcinoma, but with focal sebaceous differentiation. Mucinous and cystic areas may be present (Fig. 33.23). Cystic lesions are an important component of this syndrome (see above). ⁵⁷⁶ Other tumors may connect with the surface and have a central debris-filled crater resembling, in part, a keratoacanthoma. Typical keratoacanthomas also occur. The lesion reported as a keratoacanthoma-like squamous cell carcinoma on the basis of its venous invasion was probably a keratoacanthoma with venous invasion. ⁵⁷⁷ All sebaceous tumors should be screened for the presence of MSH-2, MSH-6, MLH-1, and PMS-2, the respective gene products of MSH2, MSH6, MLH1, and PMS2. The diagnosis of Muir–Torre syndrome is made when nuclear staining for the particular gene product is absent in the tumors. ⁵⁷⁸ As MSH-2 and MSH-6 proteins normally form a stable heterodimer, mutations in the MSH2 gene can produce an instability of this heterodimer, with secondary lack of expression of MSH-6 protein. ⁵⁵⁹ False positive and negative results are uncommon. ⁵⁷⁹

The cells express epithelial membrane antigen and nuclear androgen receptor. ⁵⁸⁰

There are multiple nests of basaloid cells with a random admixture of sebaceous cells, either solitary or in clusters (Fig. 33.24). The tumor is centered on the upper and mid dermis, but some nests may be continuous with the basal layer of the epidermis. The small basaloid cells of the tumor outnumber the mature sebaceous component. Cysts and duct-like structures containing the debris of holocrine degeneration may be present. ⁵⁸² There are scattered mitoses, but the tumor lacks the atypia of sebaceous carcinoma.

The sebaceoma can exhibit an amazing diversity of patterns. ⁴⁷³ Sebocytes and sebaceous ducts may be plentiful or scarce, and the sebocytes may show variable vacuolation. Apocrine differentiation has also been reported.^{584. and 585.} Adenoid, reticulated, cribriform, cystic, and cornified areas may be present.^{586. and 587.} A rippled or carcinoid-like architecture in the basaloid component has also been described.^{499. and 588.} The cytokeratin expression in this variant (CK19) indicates an undifferentiated and pluripotent component.^{589. and 590.} Trichoblastoma can also have a rippled pattern, ⁵⁹¹ although Ackerman believes this pattern is always indicative of a sebaceoma. ⁵⁹² Sometimes, areas resembling a seborrheic keratosis with sebaceous differentiation may be present. ⁵⁹³ Furthermore, a sebaceoma has been reported arising in association with a seborrheic keratosis. ⁵⁹⁴ Such cases merge with the variant of sebaceoma with surface changes of verruca/seborrheic keratosis. ⁵⁹⁵

There exist tumors with close morphological resemblance to basal cell carcinoma which may show focal sebaceous differentiation. Such tumors are best classified as basal cell carcinomas with sebaceous differentiation. It is acknowledged that there is some overlap of this tumor with what has been designated sebaceoma, ⁵⁸¹ but this basal cell carcinoma variant shows peripheral basal-cell palisading, and sometimes tumor–stroma separation, and a loose fibromucinous stroma. ⁴⁹⁹ Rare variants have been reported with sweat gland differentiation in part of the lesion. ⁵⁹⁶

Cytokeratin 7 (CK7) is present in most sebaceous tumors, but it is usually absent in basal cell carcinomas. ⁴⁹⁹ Sebaceous cells express EMA, but not carcinoembryonic antigen (CEA). Only mature sebaceous cells express EMA, not the germinative cells. In contrast, expression of EMA is uncommon in basal cell carcinomas; they invariably express Ber-EP4 whereas sebaceomas do not. ⁵⁹⁷ Sebaceomas express CK15, and D2-40 in the basaloid, germinative cells.^{472. and 598.}

The tumor is characterized by a superficial plate-like proliferation of basaloid to squamoid cells with broad attachments to the overlying epidermis. ⁵⁹⁹ Clusters of mature sebaceous cells are present within the tumor. The low-power pattern is somewhat analogous to that seen in basaloid follicular hamartoma, an entity that lacks sebaceous differentiation. ⁶⁰⁵ There is also some resemblance to seborrheic keratosis but it lacks pigment and horn cysts, and infundibular tunnels stuffed with cornified cells are rare. ⁶⁰⁶

The mantleoma consists of cords and columns of undifferentiated cells that radiate from the infundibulum of a hair follicle. The cords may interweave into a retiform pattern. Varying degrees of vacuolization of the cells, representing sebocyte formation, can be seen. Some sebaceous ductal structures may be present. ⁶⁰⁷

The folliculocentric basaloid proliferation of Leshin and White⁶⁰⁸ is a hyperplasia of mantle epithelium that may become so pronounced that the term ‘mantleoma’ would be appropriate (Fig. 33.25). It would probably be best to regard the two as variants of the same lesion. It may be confused with basal cell carcinomas, particularly on frozen section. It is a common and largely neglected entity.

The tumor is composed of lobules or sheets of cells separated by a fibrovascular stroma. The cells extend deeply and often involve the subcutaneous tissue and even the underlying muscle. There is infiltration at the edges. The cells show variable sebaceous differentiation, manifest as finely vacuolated or foamy rather than clear cytoplasm (Fig. 33.26). In one study, 48% of the cases had cytoplasmic vacuoles. ⁶³¹ There is usually more differentiation at the center of the nests. The nuclei are large, with large nucleoli. There are scattered mitoses. Smaller basaloid cells and cells resembling those in a squamous cell carcinoma may be present; even focal keratinization does not negate the diagnosis. Less than 10% of cases resemble in some way a basal cell carcinoma. ⁶³¹ Focal necrosis is not uncommon and this may have a ‘comedo-like’ pattern. ⁶³¹ Sometimes pseudoglandular formation occurs. The vacuolated cells show abundant lipid if a frozen section is stained with oil red O or Sudan black. There may be a very small amount of PAS-positive diastase-resistant material in some cells. Focal apocrine differentiation is sometimes present.^{584. and 632.} This is not surprising in view of the common embryological origin of the folliculosebaceous–apocrine unit. A carcinoid-like pattern is another rare histological variant. ⁵⁸⁸ It has also been reported in sebaceomas. ⁵⁸⁸

The periocular lesions often show a pagetoid or, less commonly, a carcinoma-in-situ change in the overlying conjunctiva or epidermis of the eyelid (Fig. 33.27).^{617. and 618.} This feature was seen in one-third of all cases in one series. ⁶³¹ Such changes are not usually seen in extraocular cases. The presence of such a change above extraocular tumors should prompt reassessment of the lesion in case it is invasive Bowen’s disease, which may rarely mimic sebaceous carcinoma. ⁶³³ On the other hand, it is easy to misdiagnose intraepithelial sebaceous carcinoma of the eyelid as Bowen’s disease. Sebaceous carcinoma should be thought of in any lesion of the upper eyelid or if multivacuolated cytoplasmic clear cell changes are seen. ⁶³⁴

Adverse prognostic features for tumors of the ocular adnexa include vascular and lymphatic invasion, orbital extension, poor differentiation, an infiltrative growth pattern, and large tumor size. ⁶¹⁸

Immunohistochemically, the tumor cells show positive reactions for epithelial membrane antigen (EMA) and androgen receptor (AR), but not for carcinoembryonic antigen (CEA), S100 protein, or gross cystic disease fluid protein-15 (GCDFP). ⁶³⁵ CAM5.2 and BRST-1 have also been positive. ⁶³¹ In one report, two cases reacted with CD36. ⁶³⁶ It should be noted that EMA staining is often absent in poorly differentiated tumors but nuclear staining for AR is present, making it the more reliable marker. ⁵⁸⁰ Approximately 60% of basal cell carcinomas show focal positivity for AR. ⁵⁸⁰ A recent immunohistochemical review concluded that an EMA-positive, Ber-EP4-positive immunophenotype supports sebaceous carcinoma, an EMA-positive, Ber-EP4-negative profile supports squamous cell carcinoma, and an EMA-negative, Ber-EP4-positive result supports basal cell carcinoma. ⁶³⁷ Ocular sebaceous carcinomas contain cytokeratin 7 (CK7) but ocular basal cell carcinomas and squamous cell carcinomas do not.^{638. and 639.} Basaloid and undifferentiated cells express the keratin 15 (CK15) stem cell marker. ⁵³⁹ Cytokeratin 19 requires further studies before its use can be assessed.^{589. and 640.} Sebaceous carcinomas express statistically significant, increased levels of p53 and Ki-67 compared to benign lesions, and reduced levels of bcl-2 and p21 compared to adenomas. ⁵³⁵ Survivin, an inhibitor of apoptosis, is expressed more often in sebaceous carcinomas than adenomas and hyperplasia, but as the number of cases expressing this protein is low, it is not of any diagnostic use. ⁶⁴¹ Bcl-X appears to be a marker of sebocytes. ⁶⁴² Telomerase expression occurs in all sebaceous neoplasms and is of no value in distinguishing adenomas from carcinomas. ⁶⁴³

The cysts are lined by two layers of cells: an inner lining of large columnar cells with eosinophilic cytoplasm often showing luminal decapitation secretion, and an outer flattened layer of myoepithelial cells. Papillary projections of epithelium into the lumen are found in about one-half of cases. The term ‘papillary apocrine gland cyst’ has been used for these cases. ⁶⁵¹ The cytokeratin expression suggests that it is a complex tumor, differentiating into each portion of the apocrine gland. ⁶⁶⁴ There is a suggestion from immunohistochemistry that lesions with a proliferative component (apocrine cystadenoma) are different from the pure cystic form. ⁶⁶⁵ This was confirmed by the recent study (see above) which showed that apocrine cystadenomas, in which true papillae were found, had increased Ki-67 staining. ⁶⁶³

Two cases of an apocrine gland cyst with a hemosiderotic dermatofibroma-like stroma have been reported. ⁶⁶⁶

The tumor is composed of duct-like structures that extend as invaginations from the surface epithelium into the underlying dermis (Fig. 33.28A). These may be lined by squamous epithelium near the epidermal surface, with a transition to double-layered cuboidal and columnar epithelium below. Sometimes this latter epithelium partly replaces the overlying epidermis. At other times the surface is composed of irregular papillary projections covered by stratified squamous epithelium. Rarely, there is no connection with the epidermis. Such cases are thought to be connected to the follicular infundibulum. ⁶⁹⁶ An unusual keratotic lesion, thought to be derived from the apocrine acrosyringium, has been reported in association with syringocystadenoma papilliferum. ⁶⁹⁷ It showed hyperkeratotic columns surrounded by acanthotic epidermis with features of tricholemmal keratinization. The term ‘apocrine acrosyringeal keratosis’ was used for this associated proliferation. ⁶⁹⁷

The dilated and contorted ducts may lead into cystic spaces, into which villous projections of diverse size and shape protrude. The ducts and papillary projections are usually covered by an inner layer of columnar epithelium and an outer layer of cuboidal or flattened cells. Goblet cells may be present. ⁶⁹⁸

The stroma of the papillary processes contains connective tissue, dilated vessels, and, characteristically, numerous plasma cells admixed with a few lymphocytes. The underlying dermis also contains a few inflammatory cells.

There may be underlying dilated sweat glands and, occasionally, dilated apocrine glands. In those cases associated with an organoid nevus, apocrine glands are said to be always present. ⁶⁹⁹ This apocrine component may resemble a tubular apocrine adenoma. Sebaceous differentiation has been reported in an apocrine adenoma associated with syringocystadenoma papilliferum. ⁷⁰⁰

Carcinoembryonic antigen is usually present in the epithelial cells.^{701. and 702.} Gross cystic disease fluid protein-15 (GCDFP-15) is variably positive in the tumor cells. ⁷⁰³ The luminal columnar cells express CK7 and more than 70% are positive for CK19. The basal cuboidal cells usually express CK7 also, but the expression of CK19 by these cells is variable. ⁶⁸⁸ IgA and secretory component have also been demonstrated in these cells, and it has been suggested that the cells attract plasma cells by a similar mechanism to that utilized by glands of the secretory immune system. ⁶⁸⁶ Further evidence for the existence of an eccrine variant comes from a study of the eccrine-specific marker IKH-4 which has labeled one case. ⁶⁵⁴

Although Hashimoto has found evidence ultrastructurally for an eccrine origin, ⁷⁰⁴ Niizuma has suggested that the tumor differentiates toward the intrafollicular and intradermal duct of the embryonic apocrine gland. ⁶⁸⁵ Apocrine differentiation was also found in another ultrastructural study. ⁶⁸⁸

Syringadenocarcinoma papilliferum lacks precise morphological definition, but some have a close but cytologically malignant similarity to their benign counterpart (Fig. 33.28B). ⁶⁹² Solid areas of tumor may be present, in addition to the cystic and papillary areas.^{691. and 693.} In one instance a ductal sweat gland carcinoma was reported arising in syringocystadenoma papilliferum; ⁷⁰⁵ another case has subsequently been challenged.^{706. and 707.} They express CEA and BRST-1. ⁶⁹⁵ GCDFP-15 may also be positive.

The tumor is usually partly cystic and has both papillary and glandular areas (Fig. 33.29). The papillae often have an arborizing trabecular pattern; the glandular structures vary in size. Two types of epithelium are noted in both the papillary and glandular areas. Usually, the cells are tall and columnar with pale eosinophilic cytoplasm and nipple-like cytoplasmic projections on the surface. An underlying thin myoepithelial layer is often present. In about one-third of lesions, cuboidal cells with eosinophilic cytoplasm and small round nuclei, resembling apocrine metaplasia as seen in the breast, are present in some areas of the tumor. Oxyphilic metaplasia is uncommon; it may lead to a misdiagnosis of malignancy. ⁷¹⁶ The mitotic index is variable, but can be high. However, it does not predict a more aggressive outcome. ⁷¹⁷

A case of hidradenoma papilliferum with mixed histological features of syringocystadenoma papilliferum and anogenital mammary-like glands has been reported. ⁷¹⁸ It was postulated that the tumor might have developed from these mammary-like glands.

PAS-positive diastase-resistant granules are present in the apices of the large cells, and material in the glandular spaces stains with the colloidal iron method for acid mucopolysaccharides. GCDFP-15, a sensitive marker for apocrine differentiation, is usually positive. ⁷¹⁸

The tumor is composed of circumscribed lobules of well-differentiated tubular structures situated in the dermis but sometimes extending into the subcutis (Fig. 33.30). A transition to normal apocrine glands may be present. The tubules have apocrine features with an inner layer of cylindrical cells, often showing ‘decapitation’ secretion. Papillae devoid of stroma project into the lumina of some tubules. There is often an outer layer of flattened cuboidal cells. Follicular and sebaceous differentiation are rare, but their presence adds support to the view that this tumor is derived from the folliculosebaceous–apocrine germ. ⁷³³ Occasional comedo-like conduits extend into the epidermis and form a communication with some of the tubules of the tumor. ⁷³⁴ The epidermis may be hyperplastic. The stroma consists of fibrous tissue with only a paucity of inflammatory cells, in contrast to syringocystadenoma papilliferum, in which inflammatory cells, particularly plasma cells, are prominent. However, cases of tubular adenoma have been reported with features of syringocystadenoma papilliferum in the upper part of the lesion.^{726.735.736.737. and 738.}

Apocrine cystadenomas are part of this spectrum. They are simpler lesions, always cystic, with one or several cystic apocrine structures with true papillae (papillae with a fibrous core) protruding into the lumen. They are more cystic and less complex than cases of tubular adenoma. ⁶⁶³

These tumors differ from apocrine adenocarcinomas by lack of infiltration of surrounding tissues, and by less marked cytological atypia. Myoepithelial cells are usually present in adenomas, whereas they are absent in adenocarcinomas. ⁷²¹

Immunoperoxidase studies have shown that the tumor cells contain cytokeratin; human milk protein and CEA are localized to the apical region of the cells. ⁷³⁶

Hidradenomas are usually circumscribed non-encapsulated multilobular tumors, centered on the dermis but sometimes extending into the subcutis. Epidermal connections are present in up to one-quarter of cases. ⁷⁴⁶ Mucinous syringometaplasia has been described in one case, overlying a clear cell variant of hidradenoma. ⁷⁴⁷ Hidradenomas may be solid or cystic in varying proportions. Uncommonly they are pedunculated. Sometimes, large cystic spaces are present and may contain sialomucin attached to the surface of the lining cells. The closely arranged tumor cells, which may be round, fusiform, or polygonal in shape, are biphasic in cytoplasmic architecture, with one type having clear and the other eosinophilic cytoplasm (Fig. 33.31). There are variable proportions of each cell type in different tumors, but clear cells predominate in less than one-third.^{741. and 746.} Sometimes, only a few clear cells can be seen. They contain glycogen and some PAS-positive diastase-resistant material, but no lipid. The nuclei of the clear cells tend to be smaller than those in the eosinophilic cells. The nuclei of the non-clear cells are often elongated and about one-third of these cells often contain nuclear grooves. ⁷³⁹ Focal goblet-cell metaplasia is sometimes seen. ⁷⁴⁸ A diffuse proliferation of mucinous epithelium (mucinous hidradenoma) is rare. ⁷⁴⁹ Mitoses are variable in number; their presence does not necessarily indicate malignancy. ⁷⁵⁰ However, in one study mitoses and atypical nuclear changes were associated with an increased local recurrence rate, and even subsequent malignant transformation. ⁷⁵¹ Other cellular variations include an oncocytic variant, ⁷⁵² an epidermoid variant^{753.754. and 755.} with large polyhedral cells having a squamous appearance, and a pigmented variant with some melanocytes and melanin pigment in cells and macrophages.^{756. and 757.} A racemiform and reticulated pattern of growth has been recorded. ⁷⁵⁸

Immunohistochemistry demonstrates low molecular weight cytokeratin (CAM5.2) in most tumors. Some also express CEA and EMA. ⁷⁵⁹ There is some variability in the expression of the various keratin subtypes in different parts of the tumor.^{760. and 761.} Smooth muscle actin and S100 protein were co-expressed in one case. ⁷⁶²

The malignant variant has an infiltrative growth pattern, frequent mitoses (although some overlap exists in the mitotic rate between benign and malignant variants),^{750. and 763.} and sometimes angiolymphatic invasion.

Apocrine mixed tumors are circumscribed dermal tumors with an epithelial component distributed through a myxoid, chondroid, and fibrous stroma (Fig. 33.32). The epithelial component includes clusters and solid cords of cells as well as ductal structures, sometimes branching, lined by two layers of cuboidal cells. ⁷⁷² Some of the ducts are variably dilated, and keratinous cysts may form. ⁷⁷³ The finding of an apocrine duct in continuity with this tumor is further support for an apocrine origin. ⁷⁷⁴ Eosinophilic globules composed of collagen (collagenous spherulosis) may be found in the lumina of the glandular elements. This change was present in the stroma in one case. ⁷⁷⁵ Solid islands of squamous epithelium may be present. Focal calcification, ossification, ⁷⁷⁶ adipose metaplasia, and sebaceous and matrical differentiation are sometimes present.^{777.778.779. and 780.} When adipose tissue is a conspicuous component, the term lipomatous (apocrine) mixed tumor is used.^{781.782.783.784. and 785.} Hyaline epithelial cells are uncommon.^{786. and 787.} Rare cases are composed almost exclusively of these hyaline cells, which have a ‘plasmacytoid’ appearance because of the peripheral displacement of the nucleus.^{788. and 789.} Such cases have been called hyaline-cell rich chondroid syringomas, but hyaline-cell rich apocrine mixed tumor would now be more appropriate (Fig. 33.33).

In a large series of 244 cases of apocrine mixed tumor of the skin (mixed tumor of the folliculosebaceous–apocrine complex), all types of differentiation along the lines of the folliculosebaceous–apocrine unit were found. ⁷⁸⁰ The spectrum of metaplastic changes in the epithelial component included squamous, mucinous, oxyphilic, columnar, and hobnail metaplasia, as well as clear cell change, and cytoplasmic vacuolization. ⁷⁸⁰ Myoepithelial variability was also demonstrated. These changes have already been discussed. ⁷⁹⁰

The term ‘atypical mixed tumor’ has been suggested for tumors with borderline features of malignancy such as an infiltrative edge, but which do not develop metastasis after follow-up. ⁷⁹¹ The series of 18 cases with architectural and/or cytological atypia, referred to above, was characterized by good circumscription, lack of capsular breach or hypercellularity. ⁷⁷¹ Pushing borders were sometimes seen. All but one case were of the hyaline-cell rich type. ⁷⁷¹ There were multinucleated, bizarre, hyperchromatic cells in hyaline cell areas. Cells were negative for p53. Ultrastructurally, hyaline cells exhibited features consistent with myoepithelial differentiation. ⁷⁷¹

The cells express CEA and cytokeratin, whereas cells in the outer layer of the tubular structures contain vimentin and S100 protein.^{766.792.793. and 794.} This co-expression of CEA and cytokeratins suggests that the keratin cysts may contain cells differentiating toward the intrafollicular portion of the apocrine duct. ⁷⁹⁵ Extracellular matrix components, such as type IV collagen, laminin, fibronectin, and tenascin, are prominently expressed in the chondromyxoid matrix. ⁷⁹⁶ Type II collagen, which is expressed almost exclusively in cartilage, has been found not only in the stroma but also in epithelial portions of the tumor. ⁷⁹⁷ The chondroid matrix expresses BM-1. ⁷⁹⁸ Scattered Merkel cells are uncommon, as demonstrated by CK20 staining. ⁷⁹⁹ The monoclonal antibody G-81 which recognizes a component of dermcidin, a constituent of eccrine sweat glands, has stained some cases of apocrine mixed tumor. This suggests either dual eccrine/apocrine differentiation in some of these tumors or lack of specificity of the antibody. ⁸⁰⁰

Myoepitheliomas are circumscribed, non-encapsulated tumors situated in the dermis or subcutis. Dermal tumors may extend into the subcutis. They are composed of spindle-shaped, epithelioid, histiocytoid, and plasmacytoid (hyaline) cells. ⁸¹³ The cells usually have pale eosinophilic cytoplasm and relatively monomorphous ovoid nuclei. Mitoses are usually uncommon or absent. The mitotic rate is relatively high in cases that recur, or are frankly malignant. ⁸⁰⁷ Some tumors have very little stroma, while others have a myxoid or collagenous hyalinized stroma.

Immunohistochemistry shows that the cells express vimentin, S100 protein, EMA, and often, smooth muscle actin, muscle specific actin (HHF35), glial fibrillary acid protein (GFAP), and calponin.^{804.806. and 807.} Keratin staining is quite variable. ⁸¹⁴ In the cutaneous cases reported by Hornick and Fletcher, all five cases without keratin staining were diffusely positive for EMA. ⁸⁰⁷

The rare adenomyoepithelioma combines glandular sweat gland elements with myoepithelial cells.^{815. and 816.} Adipose tissue is rarely a predominant element in another variant. ⁸⁰⁷

The exceedingly rare myoepithelial carcinoma is usually a larger tumor with cellular atypia and a high mitotic rate. Central necrosis is often present. ⁸¹²

Anastomosing lobules of small uniform basaloid cells form small ductular structures lined by eosinophilic cuticles. ⁸¹⁷ Focal hair follicle and/or sebaceous differentiation are common. ⁸²⁰ In one case, follicular differentiation was a major feature of the lesion. ⁸²¹ One case resembled hidroacanthoma simplex with underlying sebaceous glands. ⁶⁴⁴ Similar cases were regarded by Steffen and Ackerman as seborrheic keratoses with sebaceous differentiation. ⁴⁷³

Cytokeratin expression has not assisted in the differentiation of apocrine and eccrine poromas. ⁸²²

Cylindromas are poorly circumscribed dermal tumors composed of irregularly shaped islands and cords of basaloid cells surrounded by conspicuous eosinophilic hyaline bands which are PAS positive and diastase resistant (Fig. 33.34). Droplets of similar hyaline material may be present in the cell nests. The hyaline basement membrane contains type IV and type VII collagen.^{844. and 845.} There is usually a thin band of uninvolved connective tissue beneath the epidermis; however, the large turban tumors will ulcerate. Subcutaneous extension may also occur.

Most of the tumor islands have two cell types: a peripheral cell with a dark-staining nucleus and a tendency for palisading, and a larger cell with a vesicular nucleus more centrally located. Small duct-like structures are sometimes present.

The stroma is composed of loosely arranged collagen containing an increased number of fibroblasts. A more compact stroma is occasionally present. Stromal ossification is a rare phenomenon. ⁸⁴⁶

Areas resembling spiradenoma (see below) will sometimes be present, and there may also be tumor lobules with overlap features between these two entities.^{829.847. and 848.} A patient with the Brooke–Spiegler syndrome had a tumor with features of cylindroma, spiradenoma, and trichoepithelioma in the same lesion. ⁵⁷ In another patient with this syndrome, hybrid lesions containing two or more of these already mentioned components and/or trichoblastomatous, lymphadenomatous, and sebaceous features were present. ⁸⁴⁹

Aggressive or malignant behavior is characterized by loss of the hyaline sheath and expanded cellular islands composed predominantly of larger cells, devoid of peripheral palisading. ⁸³⁹

Although the expression of cytokeratins could be interpreted as indicating an eccrine origin, the presence of lysozyme, human milk factor globulin 1, α-smooth muscle actin, and α₁-antichymotrypsin favors an apocrine origin. CEA and EMA are also expressed. ⁸⁴² Both cylindroma and spiradenoma express cytokeratins 7, 8, and 18. ⁸⁴⁸ In a comparative study of cylindroma of the skin and of the breast, both tumors did not express CK20, gross cystic disease fluid protein-15, or estrogen or progesterone receptor. ⁸⁵⁰ Both tumors expressed CK7 in the central basaloid cells, while ducts were highlighted by EMA and CEA. ⁸⁵⁰

The tumor is composed of one or more large, sharply delineated basophilic nodules in the dermis, unattached to the epidermis and sometimes extending into the subcutis. Small satellite lobules may be present. The tumor nodules are composed of aggregates of cells in sheets, cords, or islands, or with a trabecular arrangement (Fig. 33.35). Two cell types are present: small dark basaloid cells with hyperchromatic nuclei, and a more frequent larger cell with a pale nucleus which tends to be near the center of the clusters. The cells are PAS negative, but droplets of PAS-positive hyalin may be present in some areas of the tumor. A few duct-like structures are often present (Fig. 33.36). Other findings include squamous eddies, small cysts, and lymphocytes infiltrating the tumor nests. Irregular, thin bands of fibrous tissue containing blood vessels are present within the tumor lobules. Perivascular spaces, containing some lymphocytes, sometimes form between the blood vessels and the tumor cells. ⁸⁷⁷ The stroma between lobules may be edematous and sometimes there are prominent vessels with telangiectasia and even hemorrhage.^{858. and 878.} Dilated vessels rimmed by sclerosis have been called ‘ancient’ changes. ⁸⁷⁹ Cylindromatous areas are sometimes present.^{829.847. and 848.} Adenomatous elements have also been described. ⁸⁸⁰

The strands of cells are cytokeratin positive and the lumina are CEA positive. ⁸⁵⁸ The pattern of cytokeratin expression mirrors that seen in the transitional portion between the secretory segments and the coiled ducts of sweat glands. ⁸⁸¹ In another report there was co-expression of CK17 and SMA suggesting myoepithelial differentiation in this case. ⁸⁸² Abundant T lymphocytes and Langerhans cells are found within the tumor lobules. ⁸⁸³

There is great variability between tumors, and even in different areas of the same tumor. Apocrine adenocarcinomas are non-encapsulated and centered on the lower dermis and subcutaneous tissue. There is a complex glandular arrangement which includes papillary, tubular, solid, and cord-like areas. Small lumina may be present in some of the solid areas. The cells have abundant eosinophilic cytoplasm, which may be granular and sometimes partly vacuolated. Cases with signet-ring cells have been reported, but their apocrine derivation has been doubted by some authors.896.^{897. and 898.} Some cells may show decapitation secretion, but this may be absent. There is variable nuclear pleomorphism and mitotic activity. The latter features, together with the degree of invasion, have been used to distinguish these tumors from apocrine adenomas. ⁷²¹ Normal or hyperplastic apocrine glands may be seen in the vicinity; the lumen of these glands may contain foamy macrophages. ⁸⁹⁹ A variant with a cribriform pattern has been called ‘primary cutaneous cribriform carcinoma’. ⁹⁰⁰ Solid aggregations of basaloid cells have been reported. ⁹⁰¹ Neuroendocrine differentiation was present in one case. ⁹⁰² Pagetoid epidermal spread is uncommon in apocrine adenocarcinoma. ⁸⁹⁶

Tumor cells have PAS-positive diastase-resistant granules in the cytoplasm; in contrast to eccrine tumors, glycogen is virtually absent. Cytoplasmic granules of hemosiderin are present in about one-third of cases. ⁷²⁰ The tumor cells express cytokeratin and gross cystic disease fluid protein-15, but, not usually, CEA.^{885. and 899.} S100 protein and EMA have been reported in some cases,^{885. and 891.} but not others. ⁸⁸⁷ Tumor cells also express CK7.^{888. and 901.} Estrogen receptors (ER) are not usually found immunohistochemically, but ER mRNA may be demonstrated by the reverse transcription PCR method in many of these negative cases. ⁹⁰³ However, 62% of cases in a recent study expressed ER, and about the same percentage expressed androgen receptor. ⁸⁹⁶

A tumor resembling a basal cell carcinoma but with histochemical and ultrastructural features of apocrine cells has been reported. ⁹⁰⁴ It is best regarded as a variant of basal cell carcinoma.

The tumor cells in Paget’s disease have abundant pale cytoplasm and large pleomorphic nuclei, sometimes with a prominent nucleolus (Fig. 33.37). Occasional cells have an eccentric nucleus and the appearance of a signet ring. ⁹⁸⁵ Mitoses are usually present. In early lesions the cells are arranged singly or in small groups, sometimes with glandular formation, in the basal and parabasal regions of the epidermis. Later, the entire thickness of the epidermis may be involved, although the greatest concentration of tumor cells is in the lower epidermis. ⁹⁸⁵ They usually spread into the contiguous epithelium of hair follicles and eccrine ducts. Uncommonly, Paget cells may invade the dermis. ⁹⁰⁸ Rarely, an invasive microacinar adenocarcinoma may develop.^{986. and 987.} The epidermis is usually hyperplastic and there is often overlying hyperkeratosis and parakeratosis. The epidermal hyperplasia has been categorized into three types – squamous hyperplasia, fibroepithelioma-like hyperplasia, and papillomatous hyperplasia.^{988. and 989.} The rare pigmented form has melanocytic colonization. The dendritic cells stain for both S100 protein and HMB-45. ⁹³³ A chronic inflammatory cell infiltrate is found in the upper dermis. An underlying in-situ or invasive adnexal carcinoma may be present. This may show apocrine differentiation, but in other cases it is not possible to determine the cell of origin. Attempts to divide this disease into cutaneous and endodermal types on the basis of their immunohistochemical profile have already produced non-conforming cases. ⁹⁹⁰ An unusual variant of anogenital Paget’s disease has the concurrence of a dermal mucinous carcinoma and fibroepithelioma (of Pinkus)-like changes. This latter phenomenon may represent an unusual form of eccrine duct spread of the Paget’s cells. ⁹⁵¹ Another case mimicked pemphigus vulgaris with prominent acantholysis due to scant desmosomes in the tumor cells. ⁹⁹¹

Metastatic Paget’s disease is a rare occurrence in inguinal lymph nodes. In one case, the node contained a mixture of Paget’s cells and squamoid cells, probably derived by metaplasia of the Paget’s cells. ⁹²⁶

Unlike the great majority of cases of mammary Paget’s disease, the tumor cells in extramammary Paget’s disease contain abundant mucin, which may be confirmed by positive staining with mucicarmine, Alcian blue at pH 2.5, Hale’s colloidal iron, and the PAS method.^{985.992.993. and 994.} Zirconyl hematoxylin is a useful alternative for Alcian blue when it is not available. ⁹⁹⁵ However, small ‘skip areas’, devoid of mucin, have been described. ⁹⁹⁶ Such areas may resemble Bowen’s disease. ⁹⁶³ The cells of clear cell papulosis (see p. 675) do not contain mucin or show cytological atypia. ⁹⁹⁷ With immunoperoxidase techniques the Paget cells stain for CEA,^{963.994.998.999. and 1000.} CA15.3 and KA-93, ¹⁰⁰¹ CD5, ¹⁰⁰² CD23, ¹⁰⁰³ low molecular weight cytokeratins,^{994.996.1000.1004.1005.1006. and 1007.} and epithelial membrane antigen.^{963.972.1000. and 1008.} In one study, all 15 cases of primary extramammary Paget’s disease had the cytokeratin immunophenotype CK7⁺/CK20⁻, while only some cases secondary to underlying carcinomas were CK7⁺; furthermore, some were CK20⁺. ¹⁰⁰⁹ Interestingly, CK7 is also found in Toker cells, mammary Paget cells, and Merkel cells.^{966.1010. and 1011.} Others have confirmed these findings.^{942.988.1012.1013. and 1014.} The Paget cells also contain apocrine epithelial antigen, ⁹⁹⁸ MUC1, MUC2, and gross cystic disease fluid protein (GCDFP), which was thought to be specific for apocrine cells.^{703.914.962. and 1014.} However, GCDFP sometimes localizes in eccrine cells.^{653. and 985.} GCDFP is not always expressed in Paget cells. Variable staining of cells has been reported for human milk fat globulin. ¹⁰¹⁵ HER-2 protein is expressed in some cases. ¹⁰¹⁶ There is a consistent lack of estrogen and progesterone receptors but, in about half the cases, androgen receptors are expressed.^{944. and 1017.} However, they involve from only 1% of cells to more than 75% of them. ¹⁰¹⁸ Prostate-specific antigen is expressed in the pagetoid cells of many cases associated with an underlying adenocarcinoma of the prostate (Fig. 33.38). ⁹⁵⁴ It may also be expressed in cases without any associated carcinoma of the prostate. ¹⁰¹⁷ The cells do not contain CD44 or S100 protein.^{992.1000.1001. and 1006.} Matrix metalloproteinases (MMP-7, MMP-19) are often expressed in cases with an underlying carcinoma. ¹⁰¹⁹ Recently, various other proteins have been demonstrated in this condition. They include insulin-like growth factor-1 receptor, p-AKT, p-ERK1/2, Stat3, Stat5a, E-cadherin, cyclin D₁, and Bcl-xL.1020.^{1021. and 1022.} Overexpression of p53 is correlated with stromal invasion. ¹⁰²³ There is also differential expression of two new members of the p53 family, p63 and p73. Overexpression of p73 occurs, while there is decreased expression of p63. ¹⁰²⁴

The various immunoperoxidase markers can be used to distinguish Paget’s disease from Bowen’s disease and superficial spreading melanoma in situ, should any difficulty be experienced on examining hematoxylin and eosin-stained sections. ¹⁰²⁵ As some cases of Bowen’s disease express CK7, it has been suggested that Ber-EP4 should be added to the panel of markers as it labels all cases of extramammary Paget’s disease but none of the other pagetoid neoplasms. ¹⁰²⁶ The possibility of combined Paget’s disease and Bowen’s disease should be kept in mind.^{964. and 1027.} Immunolabeling for syndecan-1 shows cell-membrane staining in Bowen’s disease, cytoplasmic expression in extramammary Paget’s disease, and no expression in melanoma in situ. ¹⁰²⁸

The tumor is composed of islands and cords of basaloid cells showing cribriform and some tubular areas. There is abundant basophilic mucin (hyaluronic acid) in the small cysts and between cells. Mitoses are uncommon. Perineural invasion is almost invariably present. ¹⁰⁴⁶ The histological features closely resemble those of the corresponding tumor in salivary glands. ¹⁰⁴⁷ The tumor cells express epithelial membrane antigen and, sometimes, CEA.^{1030. and 1047.} There is focal staining for cytokeratin, vimentin, and S100 protein.^{1041.1042. and 1048.}

Mucinous carcinomas are dermal tumors that sometimes extend into the subcutis and deeper tissues. There are large pools of basophilic mucin separated by thin fibrovascular septa. Small islands of epithelial cells appear to float in these mucinous pools (Fig. 33.39). The epithelial component is denser at the periphery of the lesion. The tumor cells are small and cuboidal, and some have vacuolated cytoplasm. Rarely, signet-ring cells comprise a major component of the tumor. ¹⁰⁵⁴ The cell nests in some areas have a cribriform appearance, whereas other cells form small glandular or tubular spaces containing mucin. Some of these cases originate from an in-situ component, as seen in the corresponding mammary carcinoma. ¹⁰⁵⁴ Focal neuroendocrine differentiation was present in a lesion removed from the vulva, ¹⁰⁶⁸ suggesting that it may have been an endocrine mucin-producing sweat gland carcinoma (see below). Another uncommon component may mimic infiltrating mammary carcinoma. ¹⁰⁶⁹ A sarcomatous component was present in one case. ¹⁰⁷⁰ Epidermotropism, resembling Paget’s disease, has been reported. ⁹⁵¹Microcalcification is sometimes present. Psammoma bodies are rare.1054. ^{and 1071.}

The mucin is PAS positive and stains with mucicarmine and colloidal iron. It is hyaluronidase resistant and sialidase labile, indicating that it is a sialomucin. This feature assists in differentiating this tumor from a metastatic mucinous carcinoma, which it may closely mimic on histological examination. ¹⁰⁷² Metastatic mucinous carcinomas of intestinal origin show characteristic ‘dirty necrosis’. ¹⁰⁵⁴ Some mucinous carcinomas express apocrine markers.^{653. and 1073.} MUC1 and MUC2 stain various components of the tumor. ¹⁰⁵⁴ They also express low molecular weight cytokeratins (CK7, CAM5.2), CEA, epithelial membrane antigen and, sometimes, S100 protein.^{1054.1061.1073.1074. and 1075.} CD15 and 34βE12 are sometimes positive. ¹⁰⁷⁶ There is strong nuclear expression of estrogen receptors, but a more variable pattern for progesterone receptors.^{1077. and 1078.} Focal expression of human milk fat globulin 1 (HMFG) in the luminal or outer surface of the nests is seen in one-third of all cases. ¹⁰⁷⁹ CK20 is not expressed but it may be present in metastatic colorectal tumors. ¹⁰⁷⁹ The myoepithelial cells in any in-situ component express p63, CK5/6, calponin, smooth muscle actin, and HHF-35. ¹⁰⁸⁰ Lymphatic permeation is best visualized with the D2-40 antibody. ¹⁰⁸¹

The tumors have a lobulated appearance. They are composed of an epithelial and a mesenchyme-like component, the latter consisting of myxomatous and cartilaginous areas.^{1087. and 1089.} The epithelial component predominates at the periphery of the tumor, where there are cords and nests of cuboidal or polygonal cells with some glandular structures. There is variable pleomorphism (Fig. 33.40). Scattered mitoses are present. Mesenchymal elements are progressively more abundant toward the center. ¹⁰⁸⁸ They may also be present in lymph node metastases (Fig. 33.41). Ossification is occasionally present. ¹⁰⁸⁷ The histological appearance may be a poor indicator of the biological behavior of a particular tumor in this category.^{692. and 1094.}

The epithelial cells express cytokeratins (AE1/AE3). ¹⁰⁹² The luminal epithelial cells show binding to the lectin Ulex europaeus; intraluminal cells are CEA positive. ¹⁰⁹⁵ Androgen receptors have not been detected. ¹⁰⁹⁶ The chondroid areas express S100 protein. ¹⁰⁹⁵ GFAP may also be expressed. ¹⁰⁹²

The tumor is composed of sheets of cells with glycogen-containing pale cytoplasm and distinct cell membranes. ¹¹⁰⁸ The term ‘clear cell eccrine carcinoma’ has been used in the past for those with a prominent clear cell component. ¹¹⁰⁹ In some cases there is little clear cell change and the cells have a basaloid or even squamoid appearance. Sometimes, squamous differentiation is widespread. ¹¹¹⁰ Cytoplasmic vacuoles, representing intracellular lumina formation, are an important feature. ⁶⁹² Peripheral lobules of the tumors are often irregular and appear invasive. ¹¹¹¹ Focal necrosis is sometimes present. ¹¹¹² An occasional malignant tumor is deceptively bland in appearance¹¹⁰⁵ whereas others have numerous mitoses. ⁶⁹² Melanocytes are sometimes present in the tumor lobules. ⁶⁹²

The cells express the high molecular weight cytokeratins CK5 and CK7, as well as p63, androgen receptor, estrogen receptor, and sometimes Her-2/neu. ¹¹⁰¹ In a larger series, all cases stained positively for keratin AE1/3, and cytokeratin 5/6. ¹¹⁰⁰ Ki-67 and p53 staining was strongly positive in five of six tumors, but the neoplasms expressed CEA, S100 protein, GCDFP-15, and EMA in no consistent pattern. ¹¹⁰⁰

The tumor is composed of nests and cords of basaloid cells showing frequent mitoses, focal necrosis and loss of the PAS-positive hyaline membrane. It has been suggested that the rare variants that have partially preserved hyaline membranes have a good prognosis. ¹¹¹⁹ Foci of squamous differentiation occur. A contiguous benign cylindroma is usually present. ¹¹²⁰

There are solid islands of tumor cells, which may show either a squamous or a basaloid pattern. Glandular and sarcomatous areas have also been reported.^{692.870. and 1131.} The diagnosis depends on finding a contiguous spiradenoma, as the malignant component usually lacks any distinguishing features. Sometimes, an abrupt transition between the benign and malignant components is present. ¹¹²⁵

The tumor cells express cytokeratins, epithelial membrane antigen, ¹¹²⁴ and p53. ¹¹³²

The tumors resemble apocrine adenocarcinoma with architectural and cytological features of malignancy. There may be iron granules in the cytoplasm of the tumor cells. Cases reported in the past with pagetoid epidermal involvement have been regarded as possibly sebaceous rather than apocrine tumors. ¹¹³⁴

This dermal tumor is a well-circumscribed non-encapsulated lesion with an adenomatous configuration (Fig. 33.42). Some of the ducts have papillary projections into the lumen, and a few show cystic dilatation. The lining epithelium is of apocrine secretory type and there is usually a backing of myoepithelial cells. Some ducts connect with the surface epithelium; squamous epithelium may extend into them.

The fibrous stroma sometimes contains a mild inflammatory infiltrate, which may be rich in plasma cells.

In the AFIP series (see above), 36 cases were classified as ceruminous adenomas, 4 as ceruminous pleomorphic adenomas, and 1 case as syringocystadenoma papilliferum. ¹¹⁴⁵ The tumors were composed of a tubuloglandular proliferation of inner ceruminous cells subtended by a spindled to cuboidal myoepithelial layer. The luminal cells expressed CK7 and CD117, while the basal cells were highlighted with CK5/6, S100 protein, and p63. ¹¹⁴⁵

The cysts are unilocular and lined by two layers of cuboidal epithelium. Cytokeratins 7, 8, and 19 were present in some cases. On this basis they were regarded as being of eccrine origin. ¹²⁴⁷

Papillary eccrine adenoma is a circumscribed dermal tumor composed of multiple variably dilated duct-like structures lined by two or more layers of cells. ¹²⁵⁰ The inner layer often forms intraluminal papillations of variable complexity (Fig. 33.45). ¹²⁴⁹ This latter feature is not always prominent in all areas of the tumor. There is no decapitation secretion. The epithelial cells may show focal clear cell change and even focal squamous differentiation. Some of the lumina contain an amorphous eosinophilic material. ¹²⁵⁵ Immunoperoxidase studies have demonstrated the presence of CEA, cytokeratins, particularly CK8 and CK14, and S100 protein.^{1250.1252.1253.1256. and 1257.} The unique pattern of some cases, which are devoid of apocrine features, together with the positive staining with the eccrine-specific antibody IKH-4 are reasons for the retention of an eccrine variant of tubular adenoma. It is acknowledged that apocrine variants are far more common. The stromal connective tissue may show hyalinized collagen and a focal increase in fibroblasts. Inflammatory cells are usually sparse.

Syringomas are dermal tumors composed of multiple small ducts lined usually by two layers of cuboidal epithelium (Fig. 33.46). Sometimes, the ducts have a comma-like tail resembling those seen in desmoplastic trichoepithelioma. Solid nests and strands of cells, sometimes having a basaloid appearance, may be present. Some ducts are dilated and contain eosinophilic material. There is usually a dense fibrous stroma.

In the clear cell variant the ducts are lined by larger epithelial cells with pale or clear cytoplasm (Fig. 33.47).^{1290. and 1297.} This clear cell change may involve only part of the tumor or be limited to the cells adjacent to the duct lumina. The clear cells contain abundant glycogen. It is regarded as a ‘metabolic’ variant of the conventional syringoma. ¹²⁹⁸

Rare variants include the presence of numerous mast cells in the stroma¹²⁹⁹ or of nevus cells admixed with the syringomatous elements.^{854. and 1300.} Syringoma-like sweat duct proliferation is found as an incidental finding in scalp biopsies taken for the histological evaluation of alopecia.1301. ^{and 1302.} It has also been found in prurigo nodularis. ¹³⁰³ Malignant degeneration is very rare, and the tumors designated as malignant syringoma (syringoid eccrine carcinoma) are probably malignant ab initio. Syringomas differ from microcystic adnexal carcinoma by their lack of deep extension and of perineural infiltration.^{1259. and 1304.} They are easily distinguished from the exceedingly rare change known as sclerosing adenosis of sweat ducts.^{650. and 1305.}

Staining with monoclonal anti-eccrine gland antibodies has shown positivity for EKH-6 (eccrine secretory and ductal structures), but the tumor cells are negative for EKH-5 and SKH1, which label eccrine secretory elements.^{1170. and 1306.} The cytokeratin pattern has been further characterized: the cells express CK1/5/10/11/19, and CK14 variably.^{1298. and 1307.} Syringomas usually contain CEA, whereas desmoplastic trichoepitheliomas do not. ¹¹¹ Ferritin is present in the outermost layer of cells in the epithelial elements of the syringoma, in a similar pattern to that seen in normal eccrine ducts. ¹¹⁷¹ Progesterone receptors are expressed in most syringomas, supporting the view that they are under hormonal control.^{1308. and 1309.} They were not expressed in all 15 cases on the vulva, in one series. ¹²⁹⁶