Tumors of the sweat glands

Clinical features

Apocrine nevus as defined by an excess of normal apocrine glands (apocrine hamartoma, hamartomatous apocrine gland hyperplasia) is a very rare and clinically heterogeneous condition. Most often it presents with a fleshy axillary swelling. Erythematous or brown nodules on the neck, chest, and inguinal region, a plaque on the cheek, and multiple papules on the chest have also been documented. Lesions are present at birth or develop in adulthood. Hyperhidrosis is not usually a feature. There is generally no underlying systemic disease, although one patient with a background of focal dermal hypoplasia (Goltz syndrome) and another with axillary apocrine carcinoma have been documented. In addition, the development of syringocystadenoma papilliferum has been described within apocrine nevi.

Histologic features

The lesion is characterized by excess mature apocrine glands in the reticular dermis, sometimes extending into the subcutaneous fat. Glands and ducts are represented.

Clinical features

Apocrine hidrocystoma is an uncommon cystic lesion and is most often solitary. Despite its apocrine differentiation, it is rare at sites rich in normal apocrine glands. It is usually found on the head and neck, commonly affecting the cheek ( Fig. 33.1 ). Multiple lesions have also been documented. Those on the face are sometimes known as the Robinson variant, and these present most often in middle-aged females. Multiple apocrine hidrocystomas are a feature of ectodermal dysplasia (Schöpf-Schulz-Passarge syndrome) and focal dermal hypoplasia (Goltz syndrome). Similar lesions on the eyelids are also known as Moll gland cysts. Rarely, it may present on the chest, shoulder, axilla, umbilicus, prepuce, vulva, penis, and the finger. The diagnosis of an apocrine hidrocystoma or cystadenoma should be made with great caution on distal extremities as most represent digital papillary adenocarcinoma. Penile variants are now thought at least in part to represent median raphe rather than true apocrine cysts. The cyst shows an equal sex incidence and arises most often in the middle aged. Exceptionally, it has been described in childhood.

It presents as an intradermal, moderately firm, dome-shaped, translucent, blue, bluish-black or purple cystic nodule measuring up to about 1 cm across. Giant variants measuring up to 7.0 cm in diameter are exceptionally encountered. Apocrine hidrocystoma is not associated with a familial incidence. Although solitary apocrine hidrocystoma is said not to show seasonal variation, multiple lesions in some patients worsen in summer or with excessive heat and decrease during the winter months. Apocrine hidrocystoma is an occasional feature of nevus sebaceous.

Histologic features

Apocrine hidrocystoma consists of a large unilocular or multilocular cystic space situated within the dermis ( Fig. 33.2 ). A fibrous pseudocapsule is often present. Typically, the cystic spaces are lined by a double layer of epithelial cells: an outer layer of flattened vacuolated myoepithelial cells and an inner layer of tall columnar cells with eosinophilic cytoplasm and basally located, round or oval vesicular nuclei. Ultrastructural observations have confirmed the presence of myoepithelial in addition to secretory cells. Decapitation secretion is usually present ( Fig. 33.3 ). In lesions with prominent cystic change, the lining cells appear flattened. Diastase-resistant periodic acid-Schiff (PAS)-positive granules may be evident in the cytoplasm of the inner lining cells, and occasionally iron or melanin is also demonstrable. In about 50% of lesions, numerous papillary projections are seen growing into the central cavity. Occasionally, the cyst cavity is partially replaced by a papillary or adenomatous proliferation (apocrine cystadenoma) ( Fig. 33.4 ).

Moll gland cyst is lined in part by apocrine-type epithelium and elsewhere by keratinizing squamous epithelium.

The myoepithelial layer can be highlighted with smooth muscle actin (SMA), calponin and p63 immunohistochemistry ( Fig. 33.5 ). Staining with S100 protein is variable.

Differential diagnosis

There is often difficulty in distinguishing between apocrine hidrocystoma and eccrine hidrocystoma. This results largely from atrophy of the epithelial lining of the apocrine hidrocystoma due to cyst distension by excessive secretions. Eccrine hidrocystoma is thought to derive from cystic dilatation of a sweat duct. Whether such a cyst is of eccrine or apocrine derivation is a moot point, since the two ductal systems are generally thought to be identical. Some authors have proposed the alternative term ductal hidrocystoma to reflect this possible dual histogenesis. Apocrine ducts, however, have been reported as expressing human milk fat globulin 1 (HMFG-1) whereas eccrine ducts are negative for this protein. This may help separate true apocrine duct hidrocystoma from that of eccrine derivation. In any event, in hidrocystomas where decapitation secretion is unapparent, S100 protein and α-SMA immunohistochemistry will readily resolve the problem since eccrine hidrocystoma is negative for both antibodies. In addition, the luminal epithelial layer in apocrine hidrocystoma expresses keratins K7, K8, and K18, whereas in eccrine hidrocystoma the luminal layer expresses K1, K5, K10, and K14.

Clinical features

This rarely documented entity presents as a usually less than 1.0 cm bluish or flesh-colored cystic papule or nodule. Lesions have been described on the nipple, eyelid, and lip.

Histologic features

The cyst (which contains keratin debris) is lined in part by apocrine epithelium with decapitation secretion admixed with squamous epithelium showing a well-developed granular cell layer.

Clinical features

Syringocystadenoma papilliferum is usually a solitary lesion, which may be present at birth or develop in childhood, and most commonly occurs on the scalp. It can also be found on the face, neck, trunk, and rarely the lower limbs ( Fig. 33.6 ). Surprisingly, it is not often present in the axilla, a site where apocrine glands are abundant. Rarely, lesions have been described on the eyelid, breast, arm, thigh, popliteal fossa, vulva, and scrotum. Scalp involvement is commonly associated with nevus sebaceous ( Fig. 33.7 ). Syringocystadenoma papilliferum is thus found in between 5% and 19% of cases of nevus sebaceous, sometimes in association with trichilemmoma. It has also been described in association with nevus comedonicus and in a patient with focal dermal hypoplasia (Goltz syndrome).

Syringocystadenoma papilliferum most often presents as a gray or dark-brown papillary or rather warty, sometimes crusted, excrescence with a moist appearance. Less commonly, multiple small papules, occasionally in a linear or segmental distribution sometimes following Blaschko lines are seen. Lesions may be excoriated due to pruritus, and those that develop on the scalp sometimes bleed due to the trauma of hair brushing or combing. Occasionally, there is central umbilication with drainage of serosanguinous secretions. Multifocal disease is exceptional.

Occasionally, syringocystadenoma papilliferum has been described in association with apocrine hidrocystoma, apocrine cystadenoma, hidradenoma papilliferum, tubular apocrine adenoma, apocrine poroma, mixed tubulopapillary hidradenoma, as well as apocrine nevus. It may also present with condyloma accuminatum, apocrine acrosyringeal keratosis, papillary eccrine hidradenoma, cutaneous horn, verrucous carcinoma, verrucous cyst, giant comedone, and poroma folliculare.

Pathogenesis and histologic features

Although syringocystadenoma papilliferum is generally classified within the apocrine group, the results of electron microscopy, enzyme histochemistry, and immunocytochemistry are conflicting, variably offering support for both eccrine and apocrine derivation/differentiation.

Genetically, deletion at 9q22 (PTCH) and at 9p21 (p16) have been identified in a subset of cases of syringocystadenoma papilliferum. Sequencing analysis revealed frequent BRAF and HRAS mutations.

Syringocystadenoma papilliferum has a characteristic and readily recognizable appearance. On low-power examination, it appears as an invagination from the overlying epidermis or else has an exophytic configuration ( Fig. 33.8 ). Central to the diagnosis are superficially located epithelium-covered papillae, which communicate with ductlike structures in the deeper aspect of the lesion. At the surface, residual squamous epithelium is often hyperplastic and may show hyperkeratosis and parakeratosis. Superficially, the villi can be covered by stratified squamous epithelium, but this soon gives way to a typical double-layered epithelium consisting of an inner zone of small cells with scant cytoplasm and oval hyperchromatic nuclei, and an outer zone of tall columnar cells with abundant eosinophilic cytoplasm and fairly large vesicular nuclei ( Fig. 33.9 ). Decapitation secretion is often a feature. The glandular spaces are also lined by a double layer of epithelium. The papillary processes are supported by a fibrovascular core, which typically contains large numbers of plasma cells ( Fig. 33.10 ). Although the histologic features of syringocystadenoma papilliferum are quite classic and characteristic, the morphological spectrum appears to be broad, and there may be at least some morphological overlap with tubular apocrine adenoma. Syringocystadenoma papilliferum can show areas reminiscent of classic tubular apocrine adenoma as well as apocrine hidrocystoma and clear cell syringoma, and a tumor with focal sebaceous differentiation has also been reported to arise within a nevus sebaceous.

Syringocystadenoma papilliferum expresses AE1/AE3, CAM 5.2, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). The inner layer is positive for SMA. The results of markers of apocrine differentiation are variable. Some authors have found gross cystic disease fluid protein 15 (GCDFP-15) and HMFG-1 negative. Others have found GCDFP-15 and/or HMFG-2 present.

Clinical features

Only very rare cases of syringocystadenocarcinoma have been described. These have included three in situ variants. There are insufficient cases to allow for meaningful clinical data other than documenting that they have been described particularly on the scalp, but the forehead, temple, neck, chest, breast, back, and perianal region have also been affected. The sex incidence is equal and patients have been middle aged or elderly (range 46–81 years). Patients presented with verrucous nodules or large plaques, usually of many years' duration. When documented, an episode of sudden rapid growth and tumor fixation to the underlying tissues has been evidence of malignant transformation. Occasionally, an association with nevus sebaceous has been documented.

Thus far, these tumors appear to be low grade, with only one case having metastasized to regional lymph nodes.

Histologic features

The majority of carcinomas have arisen in clearly recognizable benign precursor lesions. The malignant component may be recognized by nuclear atypia, multilayering, increased mitotic activity including abnormal forms, and dermal involvement in those cases associated with an invasive component. Intraepidermal pagetoid spread may be observed, and the invasive component may show additional differentiation toward squamous cell carcinoma.

Rarely, the development of mucinous adenocarcinoma or apocrine ductal carcinoma presenting in a syringocystadenoma papilliferum which had arisen in a nevus sebaceous has been documented.

The tumor epithelial cells express AE1/AE3, EMA, and CEA. HMFG-2 and GCDFP-15 are variably positive.

Clinical features

Hidradenoma papilliferum (papillary hidradenoma) in the vast majority of cases has been described in females. Almost all cases have been reported in white women. Patients are generally young or middle-aged adults (range 20–89 years). There are only very rare documented cases reported in males, and some authors would regard such lesions as representing apocrine papillary cystadenomas. The same might also be said for at least some examples of so-called ectopic hidradenoma papilliferum which have been described on the eyelid, nose, cheek, axilla, upper and lower limbs, chest, back, and external auditory canal. The examples arising on the eyelid and external auditory meatus are likely derived from the gland of Moll and ceruminous gland, respectively.

The tumor presents as a small (1–2 cm in diameter), solitary, usually asymptomatic papule or nodule in a vulval, perineal, or perianal location. Very occasionally, pain, tenderness, pruritus, burning, discharge, or bleeding may be encountered. The tumor typically arises at sites of the anogenital mammary-like glands. Most often it affects the labium majus, but on occasion it has been described as involving the lateral aspect of the labium minus, the interlabial sulcus, the clitoris, posterior fourchette, and mons pubis ( Fig. 33.11 ). Lesions are round, solid, or cystic and sometimes umbilicated or ulcerated.

Pathogenesis and histologic features

Hidradenoma papilliferum arises from apocrine glands or possibly the anogenital mammary-like glands, and it may represent the genital equivalent to intraductal papilloma of the breast with which it shares many morphological similarities.

The epidermis may be normal, acanthotic, or ulcerated. The tumor forms a fairly well-demarcated nodule in the dermis or lamina propria and may sometimes show foci of continuity with the overlying epithelium ( Fig. 33.12 ). The lesion consists primarily of epithelium-covered papillary processes that project into cystic spaces. The epithelial lining is typically double layered, comprising inner small myoepithelial cells with oval hyperchromatic nuclei and outer tall columnar cells with eosinophilic cytoplasm, sometimes manifesting decapitation secretion ( Fig. 33.13 ). Prominent oxyphilic metaplasia of the epithelial cells, in areas showing mild nuclear pleomorphism, may be a focal feature. Occasionally, the lining is only one cell thick (columnar). Diastase-resistant, PAS-positive intracytoplasmic granules are usually present. The presence of normal mitotic activity has no sinister implication ( Fig. 33.14 ). The larger villi have a fibrous core in which occasional ductular structures may be identified, sometimes forming a cribriform pattern. Often, the fibrous tissue surrounding the tumor is compressed to form a pseudocapsule. An inflammatory cell component is not a significant feature although aggregates of lymphocytes and plasma cells have been described in the stroma of ectopic lesions. The tumors may show overlapping histologic features with syringocystadenoma papilliferum. Rare observations include a focally solid growth pattern composed of small monomorphous cells with lumen formation, a spindle cell population as well as areas resembling sclerosing adenosis, usual and atypical ductal hyperplasia in the breast. Uncommonly, focal sebaceous differentiation may be a feature.

Exceptionally rarely, a malignant variant may be encountered including intraductal carcinoma. In the single example encountered by the authors, focal areas showing an extensive infiltrative growth pattern accompanied by marked nuclear pleomorphism and conspicuous, sometimes abnormal, mitotic activity were identified against a background of typical benign morphology. The outcome in this case is unfortunately not known. Coincidental hidradenoma papilliferum in a patient with vulval Paget disease has been described.

Ultrastructurally, hidradenoma papilliferum shows features of apocrine differentiation.

Immunohistochemically, the epithelial cells express low molecular weight keratin, EMA, CEA, HMFG, and GCDFP-15. Estrogen and, to a lesser extent, progesterone receptors are positive, and androgen receptor is expressed in up to 20% of tumors. The myoepithelial cells express S100 protein and SMA.

Genetically, the tumors may show mutations in the PIK3Ca and AKT1 genes, similar to intraductal papilloma of the breast.

Human papillomavirus (HPV) types 16, 31, 33, 53, and 56 have been detected in a subset of anogenital lesions, but no definite causal role in the pathogenesis of this tumor has been established as yet and the significance of this finding is unclear.

Clinical features

Tubular apocrine adenoma (apocrine adenoma, tubulopapillary hidradenoma, papillary tubular adenoma) is a rare benign tumor which shows a female predominance (2:1) and a wide age distribution (18–78 years). The scalp is most commonly affected although lesions have been described at a variety of other sites including the face, eyelid, axilla, leg, and genitalia. The last, however, may represent an adenoma of the anogenital mammary-like glands. Those that present on the scalp often arise in a background of nevus sebaceous and are sometimes associated with syringocystadenoma papilliferum. The tumor generally presents as a dermal nodule 1–2 cm in diameter or pedunculated lesion, frequently of many years' duration, particularly those developing within a nevus sebaceous. The lesion is benign, and recurrence following excision is uncommon.

Histologic features

Histologically, tubular apocrine adenoma presents most often as a circumscribed intradermal nodule although in some cases the subcutaneous fat is involved. Sometimes the tumor communicates with the epidermis through ductlike structures or dilated follicular infundibula ( Fig. 33.15 ). As mentioned above, there may be continuity with a syringocystadenoma papilliferum or an organoid nevus. It is composed of variably sized, well-formed tubules lined by a double- or multilayered epithelial cell layer comprising cuboidal or columnar forms with abundant eosinophilic cytoplasm and uniform round to oval nuclei ( Fig. 33.16 ). There is no pleomorphism and mitoses are scanty. In those tubules showing glandular differentiation, the inner lining cells often show decapitation secretion while the outer layer is composed of flattened myoepithelial cells. Cystic change is common, and in many tumors intraluminal papillae are present although usually these are devoid of a fibrovascular core. True papillae are, however, sometimes seen although these are generally evident in lesions associated with a syringocystadenoma papilliferum. The tumor has a well-developed connective tissue stroma in which only small numbers of chronic inflammatory cells are present. Areas of follicular and/or sebaceous differentiation may rarely be encountered.

The luminal surface of the tubular lining epithelial cells shows strong expression of EMA and CEA ( Fig. 33.17 ). The cytoplasm is also sometimes weakly EMA positive. HMFG-1 and GCDFP-15 may be present. The myoepithelial cells can be highlighted with SMA or S100 protein immunohistochemistry.

Ultrastructurally, the tubules are lined by cuboidal to columnar epithelial cells with conspicuous luminal microvilli and sometimes showing apical pinching or frank decapitation secretion. The cytoplasm contains prominent Golgi, conspicuous mitochondria, and lipid-rich secretory vacuoles. The outer layer shows features of myoepithelial cells.

Differential diagnosis

Tubular apocrine adenoma must be distinguished from syringocystadenoma papilliferum, papillary eccrine adenoma, and papillary apocrine carcinoma.

Some tumors, particularly those arising in a background of an organoid nevus, develop in association with a syringocystadenoma papilliferum. Those that are wholly intradermal differ from syringocystadenoma papilliferum by the absence of true papillae with fibrovascular cores and by the absence of a plasma cell-rich inflammatory cell infiltrate. There may, however, be a morphological continuum between the two entities, and reliable separation is not always possible.

Tubular apocrine adenoma can be distinguished from papillary eccrine adenoma in many cases by the presence of apocrine decapitation secretion and the common location on the scalp, especially when developing in association with syringocystadenoma papilliferum or organoid nevus. In some cases, however, the distinction is difficult or impossible ( Figs 33.18 and 33.19 ). Occasional tumors show features of both lesions. This has led some authors to suggest the alternative terms tubulopapillary hidradenoma and papillary tubular adenoma.

Tubular apocrine adenoma differs from papillary apocrine carcinoma by the absence of an infiltrative growth pattern and cytological atypia. Mitoses are generally sparse and abnormal forms are absent.

Clinical features

Nipple adenoma (erosive adenomatosis, florid papillomatosis, superficial papillary adenomatosis) is a benign tumor which most often presents in middle-aged females with a peak incidence in the fifth decade. Rarely, however, girls may be affected, and there are exceptional reports of the condition in males. Patients present with erythematous, scaly or crusted, and sometimes eroded lesions clinically mistaken for eczematous dermatitis or Paget disease ( Fig. 33.20 ). ^, Pruritus, irritation, pain, and burning are variable complaints. A 0.5- to 1.5-cm tumor nodule and/or an increase in size of the nipple are sometimes present. Some patients complain of nipple discharge or bleeding.

Histologic features

The tumor is unencapsulated and consists of adenomatous and papillary areas in varying proportion. It usually communicates with the surface epithelium where cysts lined by an admixture of squamous and columnar epithelium are sometimes evident. The glandular spaces are lined by tall columnar eosinophilic cells which invariably show decapitation secretion. A myoepithelial cell layer is present. Intraluminal papillomatosis is generally evident, and giant cells are sometimes seen. Normal mitoses may be present. The papillae are devoid of a fibrovascular core and cytological atypia is absent. The stroma can be fibrotic or hyalinized, and in some tumors this compresses the epithelium to give rise to a pseudoinfiltrative growth pattern. A plasma cell-rich inflammatory cell infiltrate is sometimes evident in the surrounding connective tissue.

Genetically, the tumors show mutations in the PIK3CA gene in approximately 50% of cases.

Clinical features

Syringomatous adenoma of the nipple is a rare tumor presenting as a firm unilateral mass of few centimeters on the breast predominantly affecting the nipple and subareolar area. Bilateral presentation is rare, and the development within a supernumerary breast has also been reported. It is a tumor of adulthood with a peak incidence in the fourth decade and a strong female predilection. Presentation in males is exceptional. Syringomatous adenoma of the nipple is a locally aggressive tumor with potential for recurrence if inadequately excised. However, no distant metastasis or disease-related mortality has been documented, and complete excision with negative margins appears to be curative.

Histologic features

The histologic features are reminiscent of microcystic adnexal carcinoma to which it may be closely related. The tumor shows an infiltrative growth pattern within dermis, along nipple ducts, and extending into breast parenchyma. Infiltration of smooth muscle is a frequent feature and perineural infiltration may rarely be observed. The tumor is composed of small, well-formed ducts and basaloid epithelial strands within a fibrous stroma showing only little or no cytological atypia. Tubular and squamous differentiation may be seen and keratocysts as well as dystrophic calcification are common.

By immunohistochemistry, the syringomatous adenoma of the nipple is composed of p63, CK5, and CK14 positive tumor cells and CK8 and CK18 positive glandular cells similar to low-grade adenosquamous carcinoma. It has recently been proposed that these may be closely related entities.

Clinical features

Apocrine poroma (poroma with divergent differentiation, complex poroma-like adnexal adenoma, sebocrine adenoma, sebaceous and apocrine adenoma, and poroma with sebaceous differentiation) is an uncommon tumor, which presents as an often slowly growing flesh-colored, erythematous papule, nodule, or plaque. There is no site predilection, lesions having been described on the lip, cheek, eyelid, nose, abdomen, back, and limbs. No cases presenting on the palms and soles have been documented to date. A wide age range may be involved (19–76 years). The sexes are affected equally.

The tumor is benign and recurrences are rare.

Histologic features

Apocrine poroma in essence is defined as a poroma showing sebaceous differentiation with the occasional presence of follicular differentiation and foci of apocrine-like features. In terms of nomenclature, although sebaceous differentiation is the common link, the literature has focused on the apocrine element – hence the designation apocrine poroma. The presence of sebaceous, follicular, and apocrine features reflects the common embryological ancestry of the three units (the folliculosebaceous-apocrine unit).

Apocrine poroma – in common with its eccrine counterpart – is composed of anastomosing trabeculae, displaying multiple points of origin from the epidermis and located largely in the papillary and upper reticular dermis. The individual cells are small and uniform with scanty cytoplasm and round to oval nuclei united by inconspicuous intercellular bridges. Foci of ductal differentiation with a well-developed eosinophilic cuticle are present. An example showing follicular infundibular origin in a patient with nevoid basal cell carcinoma has been reported.

An infrequent feature is the presence of sebaceous cells, singly and in clusters with bubbly cytoplasm and crenated nuclei. Sebaceous ductlike tubular or cystic structures lined by squamous epithelium with an eosinophilic, scalloped cuticle and containing eosinophilic debris with pyknotic nuclei may also be present. In some examples, hair germlike structures manifest as small collections of basaloid cells with peripheral palisading, and perifollicular sheathlike connective tissue are seen. Occasional reports have described tubules lined by cells with intensely eosinophilic cytoplasm reminiscent of apocrine epithelium. Although frank decapitation has generally been absent, it is well illustrated in the series of Yamamoto and coworkers.

Wholly intraepidermal hidroacanthoma simplex-like and largely intradermal variants have been documented. In addition, there is a report of an example associated with trichoblastoma.

A case presenting on the areola has also been documented. In it, however, there was no evidence of sebaceous, follicular, or apocrine differentiation. Although close proximity to the follicular infundibula was demonstrated, it is unclear whether the tumor might not have been better regarded as eccrine poroma.

A metaplastic or sarcomatoid carcinoma has been shown to arise within an apocrine poroma (sarcomatoid apocrine porocarcinoma).

Differential diagnosis

Diagnosis of apocrine poroma depends on exclusion of entrapped normal adnexae.

Intraepidermal variants may be differentiated from seborrheic keratoses with sebaceous differentiation by the presence of ducts, which may be highlighted with diastase–PAS staining or EMA/CEA immunohistochemistry.

Clinical features

Oncocytomas rarely affect the skin. They are more commonly seen in the kidney, thyroid, parathyroid, and salivary glands. In the skin, they show a predilection for the lacrimal areas and they typically occur on the canthus, the eyelid, and rarely on the cheek as a small nodule. The patients are elderly adults without significant gender predilection. The clinical behavior is benign.

Histologic features

Cutaneous oncocytomas are well-circumscribed tumors within the dermis occasionally showing a connection with the overlying epidermis ( Fig. 33.21 ). Their growth pattern is solid and cystic with additional papillary and tubular areas. They are composed of large polygonal cells with abundant finely granular eosinophilic cytoplasm containing uniform nuclei with eosinophilic nucleoli ( Fig. 33.22 ). Nuclear pleomorphism and mitotic activity are not a feature.

By immunohistochemistry, tumor cells express pancytokeratin AE1/AE3 but they are negative for S100 and CD68. Luminal staining is noted for EMA and CEA.

Clinical features

Apocrine adenocarcinoma is rare, and most documented cases have affected the axilla. Occasionally, the tumor may present at a variety of other sites including the scalp, eyelid (Moll gland carcinoma), ear (ceruminous gland adenocarcinoma), anogenital region, chest, lip, and wrist, in descending order of frequency. Tumors have also been described on the cheek, nipple, and fingertip. Clinical data are limited in the majority of published cases, but most tumors present as single or multiple, sometimes ulcerated, often slowly growing nodules or plaques covered by erythematous or purple skin. A presentation as carcinoma erysipeloides has also been documented. In some instances, tumors have been present for 30 years before diagnosis. Occasional tumors have arisen within a nevus sebaceous, and invasive as well as in situ carcinoma has been documented to arise in association with apocrine adenoma in the perianal area. Patients with bilateral axillary apocrine carcinomas and associated apocrine hyperplasia have been reported in the Japanese literature. Telangiectatic and inflammatory cutaneous metastatic disease similar to that described with breast carcinoma has been described. Age at presentation is variable (18–91 years, mean 60 years) and the sex incidence is approximately equal. There is no racial predilection.

Apocrine carcinoma is often characterized by a prolonged course and, although recurrences (28%) and nodal metastases (50%) are common, the overall mortality is low. Bone and lung secondary deposits or more disseminated disease and tumor-related deaths have, however, been described. Disease-related mortality was 24% in one study. The median survival is 51.5 months, and positive lymph node status and metastatic disease are associated with poor overall survival. In some patients, metastases are a very late development and therefore a very careful, prolonged follow-up is indicated.

Histologic features

Apocrine carcinoma is characterized by a variable glandular, tubular, papillary, tubulopapillary, or diffuse or solid growth pattern centered on the deeper dermis and frequently involving the subcutaneous fat ( Figs 33.23–33.26 ). Occasional tumors are cystic, and foci of necrosis are sometimes evident. In contrast to apocrine adenoma, the tumor is usually poorly circumscribed, and typically an infiltrating border is present. Epidermotropism is sometimes a feature, and in some tumors frank Paget disease is present ( Fig. 33.27 ).

The epithelial cells have abundant eosinophilic cytoplasm, and decapitation secretion (albeit often focal) is invariably present ( Fig. 33.28 ). Nuclei are round or oval and vesicular and commonly contain a solitary prominent nucleolus ( Figs 33.29–33.31 ). Focal squamous differentiation may occasionally be seen. Exceptionally, sebaceous differentiation has been described. Pleomorphism and mitotic activity are variable features, but become more prominent in poorly differentiated variants. The tumor is commonly accompanied by a dense hyaline stroma. A single filing growth pattern may be encountered in poorly differentiated tumors. Apocrine carcinoma is characterized by intracytoplasmic diastase-resistant, PAS-positive granules, and intracytoplasmic iron is sometimes demonstrable. Alcian blue (pH 2.5) and mucicarmine may also be positive but glycogen is uniformly absent.

Normal apocrine glands are often found in close proximity to the tumor, and occasionally longstanding preexistent benign apocrine lesions (including hyperplasia, cystadenoma, cylindroma, syringocystadenoma papilliferum, and tubular adenoma) may be evident, raising the possibility of malignant transformation. The apocrine glands sometimes show tumor infiltration/in situ carcinoma. Perineural infiltration and lymphovascular invasion is occasionally seen.

A small number of apocrine carcinomas showing signet ring cells reminiscent of invasive lobular carcinoma of breast have been reported. These show a striking predilection for elderly males (10:1). Although these have most frequently been described on the eyelids, they may also present in the axilla. Apocrine carcinoma with focal mucinous carcinoma-like features has been documented. An unusual tumor characterized by more circumscribed borders, epidermal connection, and atypical basaloid cells with duct formation and decapitation secretion has been reported.

It has been proposed that tumors should be graded histologically according to the modified Bloom-Richardson method used in breast cancer as grade III lesions are associated with worse survival than those classified as grade I or II.

Immunocytochemically, the tumor shows cytokeratin CAM 5.2, AE1/AE3, CK5/6, EMA, CEA, GATA3, and GCDFP-15 expression. Lysozyme, α ₁ -antitrypsin, α ₁ -antichymotrypsin, and in some tumors S100 protein, are also present. Myoepithelial cells as demonstrated by SMA or p63 are usually lost. Androgen receptor is typically expressed and expression of estrogen receptor and progesterone receptor is seen in a significant subset of tumors. In contrast, no HER2/neu expression is seen. If fresh tissue is available, assessment of apocrine enzymes, including acid phosphatase and non-specific esterase, may be of diagnostic value.

Electron microscopic findings, including luminal microvilli, conspicuous mitochondria, and large electron dense granules, have supported apocrine differentiation.

Differential diagnosis

Primary cutaneous apocrine carcinoma is indistinguishable from metastatic mammary ductal apocrine carcinoma. With the exception of those rare lesions arising in a nevus sebaceous or showing focal continuity with an associated apocrine adenoma, careful breast assessment should be advised before accepting the diagnosis of primary cutaneous apocrine carcinoma, particularly for those lesions that present at an atypical location. By immunohistochemistry, primary cutaneous tumors are commonly adipophilin and HER2/neu negative and estrogen receptor (ER) and progesterone receptor (PR) positive. In contrast, mammary tumors are more likely to express adipophilin and HER2/neu with negative staining for ER and PR. Androgen receptor expression is nondiscriminatory.

Clinical features

Primary cutaneous cribriform apocrine carcinoma is a rare and poorly documented but distinctive neoplasm ^, currently regarded as a morphological variant of apocrine carcinoma. It is, however, unclear whether this tumor has potential for malignant behavior and if it should be regarded as a carcinoma. As yet no recurrences, metastases or disease-related deaths have been reported. The tumor presents as firm 1- to 3-cm large nodules with a strong predilection for the limbs of middle-aged adults with a female predominance. The trunk and head and neck region are rarely involved.

Histologic features

The tumors are circumscribed and symmetrical dermal based nodules, which may also extend into superficial subcutis ( Fig. 33.32 ). They are composed of interconnecting nests and islands of basaloid cells with prominent duct formation giving rise to a cribriform architecture ( Fig. 33.33 ). The tumor cells show hyperchromatic nuclei but nuclear pleomorphism is limited. Mitoses are sparse and necrosis is rare. Focal decapitation secretion is noted as evidence of the apocrine differentiation. The tumor nests are separated by a fibrous stroma.

By immunohistochemistry, the tumor cells express cytokeratins AE1/AE3, MNF116, CAM 5.2 and CK7. CEA and EMA are expressed in the luminal cells. Patchy S100 staining has also been reported in tumor cells. No staining is seen for CK20 and GCDFP-15 and no surrounding myoepithelial cell layer can be identified by p63, SMA, and calponin staining.

Differential diagnosis

Nodular basal cell carcinoma may show a prominent cribriform pattern. It can be separated by the absence of duct differentiation and the presence of a peripheral palisade and stromal cleft artifact. Similarly, adenoid cystic carcinoma is characterized by a cribriform pattern and it shows additional duct differentiation. It shows however a more plaquelike architecture with a diffusely infiltrative growth pattern and almost invariable perineural invasion. In addition, the cribriform areas are composed of mucin filled pseudocysts rather than the florid ductal differentiation seen in primary cutaneous cribriform apocrine carcinoma. Papillary eccrine adenoma may show many low power similarities. It is however composed of well-formed tubules with a retained myoepithelial layer. In addition, cystic elements and papillary projections are also found. Finally, metastatic cribriform carcinoma of visceral origins, especially from the prostate and breast, needs to be considered. Definitive separation is possible only on clinical grounds.

Clinical features

Ceruminous gland tumors (ceruminoma) are rare and present as an often pedunculated nodule or cystic lesion in the external auditory canal, often associated with deafness and less commonly with tinnitus or otorrhea. Pain is sometimes a feature as a result of otitis externa, ulceration, or malignancy. Facial nerve palsy has occasionally been documented. The age distribution is wide but tumors are most commonly seen in adulthood. The sex incidence is equal.

In the earlier literature, the term ceruminoma was often applied to all glandular tumors arising in the external auditory meatus. This resulted in considerable confusion since it lumped together both benign and malignant variants, the latter being the more common. Currently, ceruminous gland tumors are classified as benign, including apocrine adenoma and mixed tumor (pleomorphic adenoma), and malignant – ceruminous gland adenocarcinoma and adenoid cystic carcinoma. In addition, cylindroma, syringocystadenoma papilliferum, and mucoepidermoid carcinoma have exceptionally been documented.

Histologic features

The ceruminous glands are apocrine glands found predominantly within the dermis of the cartilaginous part of the external auditory canal.

Ceruminous apocrine adenoma presents as a circumscribed nodule composed of glands lined by a double layer of epithelium ( Fig. 33.34 ). The inner are cuboidal to columnar with eosinophilic cytoplasm often showing decapitation secretion. The outer are myoepithelial cells. Cystic change is sometimes present. Solid, acinar, and trabecular variants have been described. Pleomorphism is absent and mitoses are scarce. Abnormal forms, by definition, are not a feature.

Ceruminous gland adenocarcinoma is characterized by an infiltrating growth pattern. Pure glandular and papillary variants are recognized. The cytology varies from deceptive, well-differentiated forms to high-grade tumors with marked pleomorphism and conspicuous mitotic activity ( Fig. 33.35 ). Perineural infiltration is sometimes a feature and rarely extramammary Paget disease is seen.

Differential diagnosis

Well-differentiated ceruminous gland adenocarcinoma may be difficult to distinguish from adenoma if the infiltrative border is not visible, as may be the case in small biopsy specimens. If there is any doubt, it is recommended that tumors be reported as having uncertain malignant potential with the final diagnosis deferred until the full excision specimen is available for study.

Clinical features

Mixed tumor of the skin (chondroid syringoma) is not uncommon and presents as a slowly growing, firm, circumscribed, lobulated nodule within the dermis or subcutaneous fat. It is usually solitary and asymptomatic and most often affects the head and neck, particularly the nose, cheek, upper lip, scalp, forehead, chin, eyelids, and ear including the external auditory meatus, in descending order of frequency, although on occasions it may involve the axillae, trunk, or extremities ( Figs 33.36 and 33.37 ). Scrotal involvement has rarely been described. Exceptional giant variants affecting the cheek and axilla have been documented. Males are more commonly affected than females and the tumor typically presents in the middle aged. Recurrences are rare.

Histologic features

Although the earlier literature argued variably for an eccrine or apocrine derivation, variants differentiating toward both (including follicular differentiation) are recognized.

Most tumors are currently classified as apocrine type (apocrine chondroid syringoma). This is usually multilobulated and situated within the deep dermis and/or subcutaneous fat ( Fig. 33.38 ). It forms a well-circumscribed mass in which a dominant component has a chondroid appearance ( Figs 33.39 and 33.40 ). The lobules are separated by fibrous septa. The epithelial component is composed of nests and cords of cuboidal or polygonal cells with copious eosinophilic cytoplasm and basophilic nuclei. They are distributed singly, in cords and nests or as irregular tubuloalveolar and ductal structures.

The tubuloalveolar foci, which are believed to represent differentiation toward the secretory coil, are lined by two or more rows of epithelial cells, the outer layer being somewhat flattened and of myoepithelial derivation ( Fig. 33.41 ). Apocrine decapitation secretion is sometimes evident and occasionally the epithelium has a lacelike pattern ( Fig. 33.42 ). PAS-positive, diastase sensitive, glycogen-rich clear cells may be present ( Fig. 33.43 ). One or occasionally two layers of cells line the ducts, which represent differentiation toward the dermal sweat gland duct ( Fig. 33.44 ). Cystic dilatation is common ( Fig. 33.45 ). Occasionally, keratinous cysts and foci of squamous differentiation are present ( Fig. 33.46 ). In addition, clear cell change as well as mucinous, columnar, oxyphilic, and hobnail metaplasia of the epithelial component may be evident. There is, however, no pleomorphism, mitoses are sparse, and necrosis is absent.

Not uncommonly, mixed tumor shows additional foci of follicular and sebaceous differentiation. The former is characterized by the presence of infundibulocystic, isthmic as well as tricholemmal differentiation, hair bulbs and papillary mesenchyme in addition to foci of ghost cells reminiscent of pilomatrixoma. Some tumors may be almost exclusively follicular. Sebaceous differentiation is present as foci of cells showing granular or bubbly cytoplasm and scalloped nuclei or as sebaceous ductlike structures with an eosinophilic, wavy, laminated, keratinized lining. Rarely, pigmented dendritic melanocytes are a feature.

The myoepithelial component may show hyaline (plasmacytoid), spindled cell, or clear cell differentiation. The hyaline (plasmacytoid) cells are characterized by abundant ground-glass eosinophilic cytoplasm and an eccentric nucleus. They are present singly within the stroma or as distinct noncohesive aggregates ( Fig. 33.47 ). Spindled cell myoepithelial cells are also present within the chondroid matrix and are responsible for its production. Clear cell change of the myoepithelial component may be an additional finding. Transition between polyhedral cells and spindled cells or foci of squamous differentiation may be seen. The stroma is of variable appearance. Characteristically, it is composed of homogeneous bluish chondroid ( Fig. 33.48 ). In other areas it is myxoid or densely collagenous, eosinophilic, and hyalinized ( Fig. 33.49 ). Positive Alcian blue or green staining at pH 2.5 indicates the presence of acid mucopolysaccharides ( Fig. 33.50 ). Sometimes, abundant mature fat is present (‘lipomatous mixed tumor’) ( Fig. 33.51 ). Some tumors may show foci of calcification, and on rare occasions osteoid with marrow spaces has been described.

Less often, the tumor is composed of small glandular and tubular structures lined by a single layer of cuboidal epithelium dispersed in a mucinous and/or chondroid stroma ( Figs 33.52 and 33.53 ). This is sometimes referred to as the eccrine variant (eccrine chondroid syringoma). Occasionally, these tumors may show a cribriform architecture and clear or hyaline cell change of the epithelial component and cartilaginous or sclerotic stromal change with ossification, lipomatous metaplasia and ossification.

Exceptionally, hidrocystoma-like features have been described.

Cutaneous mixed tumors with atypical histologic features but benign clinical behavior have been described. Atypical architectural features include lesional asymmetry and slightly infiltrative tumor edges without capsular invasion. More often, the atypical findings relate to the cytological features. Mild cytological atypia of epithelial cells in ductular structures may be present but the most frequent finding is the presence of scattered multinucleated pleomorphic and bizarre-appearing cells within the myoepithelial component of the tumor. By immunohistochemistry, these cells are characterized by a myoepithelial phenotype.

There are occasional reports of diagnosis of mixed tumor by fine needle aspiration cytology. In view of the difficulty sometimes encountered in distinguishing between benign and malignant variants, a complete excision with histologic study should always be performed.

Immunocytochemically, the inner epithelial cell layer is characterized by high and low molecular weight keratin (AE1/AE3), EMA, CEA, and GCDFP-15 expression ( Fig. 33.54 ). The outer cells express vimentin, S100 protein, SOX10, and sometimes SMA and muscle-specific actin (MSA) ( Fig. 33.55 ). Stromal cells are vimentin and S100 protein positive.

A more detailed immunohistochemical study of stromal cells in mixed tumor has shed some light on their likely nature. The authors classified them into the following three subtypes:

• Hyaline cells express CAM 5.2, but not cytokeratin 10 (CK10), CK14, SMA, or MSA, indicative of simple epithelium. A rim of CK14+ cells possibly representing ductal basal cell or myoepithelial differentiation may surround them. The additional presence of S100 and focal GFAP expression, however, argues for myoepithelial differentiation.

• Polyhedral cells express CK14, but not CK10, SMA, or MSA, and may represent myoepithelial cells or sweat duct basal cells.

• Spindled cells express CK14, SMA, and MSA, but not CAM 5.2 or CK10, and are therefore thought to be of myoepithelial derivation.

A number of in-depth investigations of keratin expression in mixed tumor have been published. The results suggest that all elements of the sweat gland are represented although whether the tumor arises in or differentiates toward the apocrine or eccrine sweat gland apparatus remains uncertain.

Genetically, most cutaneous mixed tumors show rearrangement of the PLAG1 gene and immunohistochemical expression of PLAG1 analogous to pleomorphic adenomas of the salivary gland. A small subset of tumors show EWSR1 gene rearrangement as seen in myoepitheliomas of the skin.

Clinical features

Malignant mixed tumor (malignant chondroid syringoma) is an extremely rare tumor. Approximately 50 cases have been described to date. Although the majority of tumors have developed de novo, there are some documented examples which appear to have arisen within a preexistent benign mixed tumor. The tumor predominantly affects the distal extremities (the foot being the common site), shows a predilection for females (2:1), and most often arises in the sixth decade although there is a wide age range (18–89 years). Clinically, the tumor is not distinctive and presents as a flesh-colored or erythematous nodule.

Malignant mixed tumor is an extremely high-grade neoplasm with a metastasis rate of approximately 60% and a mortality of roughly 25%. The lymph nodes, lungs, and bone are predominantly affected.

Histologic features

Ideally, the diagnosis of malignant mixed tumor should depend upon the identification of a benign precursor lesion ( Figs 33.56–33.60 ). This, however, has only rarely been histologically documented. In the majority of cases, diagnosis depends upon identification of foci of mucoid stroma and chondroid differentiation as with its benign counterpart. Criteria suggestive of malignant potential include an infiltrative growth pattern, epithelial nuclear and cytoplasmic pleomorphism, excessive or abnormal mitotic activity, and tumor necrosis ( Figs 33.61–33.63 ). Vascular and lymphatic invasion or metastases obviously confirm the diagnosis. Impaired tubular differentiation, excessive mucoid matrix, and abundant, poorly developed chondroid elements may also point toward a diagnosis of malignancy, and frank chondrosarcomatous or osteosarcomatous differentiation may be present. Some tumors which have metastasized have been deceptively bland. An infiltrative growth pattern or evidence of satellite lesions in such tumors should be viewed with concern and the tumor widely excised, with careful follow-up recommended.

The tumor often shows multiple satellite lesions in the adjacent dermis or subcutaneous tissue, which may result in incomplete excision and account for the high risk of recurrence.

There is one instance of malignant mixed tumor recognized by fine needle aspiration cytology.

Immunohistochemically, the epithelial cells express pankeratin, AE1/AE3, CAM 5.2, EMA, CEA, and variably S100 protein. Intracytoplasmic lumina may be outlined with CEA. The stromal cells are S100 protein positive and variably express keratin. SMA has been variably reported as present or absent.

Differential diagnosis

Malignancy in mixed tumor relates solely to the epithelial proliferation. If nuclear pleomorphism and mitotic activity affect the chondroid component, a diagnosis of metaplastic carcinoma (carcinosarcoma) is more appropriate. Other tumors in which a mucinous or chondroid matrix is evident, including mucinous carcinoma, extraskeletal myxoid chondrosarcoma, and metastatic skeletal chondrosarcoma, may occasionally have to be excluded.

Clinical features

Myoepithelioma is a rare tumor which arises in the dermis, subcutaneous fat or soft tissues. Analogous to salivary gland tumors, cutaneous myoepitheliomas are composed of the myoepithelial and stromal components of mixed tumors but lack the ductal epithelial component. The age range at presentation is wide (newborn–93 years) but there is a predilection for adolescents and young adults. Males appear more frequently affected than females. Cutaneous tumors present as firm or hard, well-circumscribed, flesh-colored, gray, or violaceous nodules ranging in size from 0.5 to 2.5 cm (mean 1.1 cm). Tumors located within soft tissue may present as larger masses measuring up to 12 cm (mean 3.8 cm) while malignant myoepithelioma may reach up to 20 cm. There is a predilection for the extremities and limb girdles but the head, neck, and trunk are also affected. Local recurrence may be a complication, but distant metastasis and disease-related death are rare. While few data are available regarding morphologically malignant tumors of skin, those presenting in soft tissue show an increased risk of local recurrence (40–50%), high metastatic potential of 30% to 50%, and high disease-associated mortality.

Histologic features

Myoepithelioma is composed of an unencapsulated, often dome-shaped, circumscribed nodule consisting of a pure population of myoepithelial cells with no evidence of glandular or ductal differentiation as is seen in the more commonly encountered mixed tumor ( Figs 33.64 and 33.65 ). The overlying epidermis may be hyperplastic and sometimes a well-developed collarette is present. A variety of cell types are encountered, including epithelioid, spindled, histiocytoid, and plasmacytoid (hyaline) cells; occasionally clear cells are a feature. These may show a solid sheetlike, reticular, or whorled and occasionally fascicular arrangement. Some tumors are characterized by a multinodular growth pattern. There is generally no significant nuclear pleomorphism, nucleoli are inconspicuous, and mitoses usually scanty ( Fig. 33.66 ). Intranuclear cytoplasmic pseudoinclusions are sometimes present. The stroma is typically myxoid or hyaline ( Figs 33.67 and 33.68 ). Cartilagenous differentiation or osseous metaplasia is only rarely present. In some tumors conspicuous mature adipocytes are present. Occasionally, radially orientated collagenous crystalloid inclusions are a feature. These are composed predominantly of type I collagen with type III collagen at their periphery. Rarely, colonization by dendritic melanocytes may be a feature. A subset of tumors is known as cutaneous syncytial myoepithelioma. The tumors present in dermis and are less well circumscribed. They are characterized by a sheetlike growth of ovoid to spindle cells with palely eosinophilic cytoplasm, syncytial cell borders, and vesicular nuclei with small nucleoli ( Figs 33.69 and 33.70 ). Occasional mitoses are present, but there is no significant cytological atypia. Adipocytic metaplasia is frequently noted in this subtype of myoepithelioma.

Malignant myoepithelioma is characterized by marked nuclear pleomorphism, conspicuous nucleoli, a high mitotic rate, and necrosis. Lymphovascular invasion or perineural infiltration may also be present. The behavior of cutaneous and soft tissue myoepitheliomas is, however, unpredictable and local recurrence and even distant metastasis as well as disease-related mortality have been documented in tumors lacking cytological features of malignancy. Reliable criteria for malignancy are therefore difficult to establish.

Ultrastructurally, intermediate filaments with focal densities are prominent and the tumor cells are surrounded by a well-developed basal lamina. Desmosomes may be present.

By immunohistochemistry, expression of cytokeratin and/or EMA together with S100, SOX10, and/or GFAP in tumor cells is required to document their myoepithelial phenotype. The cutaneous syncytial variant is typically cytokeratin negative and EMA positive. In addition, expression of calponin and SMA may be seen ( Fig. 33.71 ). Nuclear staining for p63 may be seen but desmin is only rarely expressed. INI1 expression is lost in a subset of tumors. Malignant variants show an identical profile.

Cytogenetic studies on one case of malignant myoepithelioma have revealed complex findings with deletion of 3p, gain of 16q, and monosomy of chromosomes 13 and 15. EWSR1 gene rearrangements are present in around 45% of soft tissue myoepitheliomas and myoepithelial carcinomas and in 80% of cutaneous syncytial myoepitheliomas. As yet identified translocation partners include POU5F1, ATF1, PBX1, PBX3, and ZNF444. PLAG1 gene rearrangements are rare in myoepithelial tumors without duct differentiation.

Clinical features

Eccrine nevus (nevus sudoriferous, sudoriferous hamartoma) is a rare hamartoma of the eccrine unit which typically presents in childhood or adolescence. Clinical manifestations are variable and include localized areas of hyperhidrosis (localized unilateral hyperhidrosis). The condition may also develop in association with cutaneous lesions including solitary papules, nodules, patches, or plaques frequently showing brownish discoloration. These cutaneous findings may also present in the absence of hyperhidrosis. There is a predilection for the upper extremities. Lesions may be grouped in a linear arrangement but are rarely multiple, and congenital presentation is infrequent.

Pathogenesis and histologic features

Histologically, eccrine nevi are characterized by increased sized or number of eccrine coils. Infrequently, abundant mucin or an angiomyxoid stroma surrounds the coils, when the term mucinous eccrine nevus is applied.

Clinical features

Adnexal polyp of neonatal skin presents as a small congenital polypoid and typically solitary cutaneous lesion. It is skin colored and regresses within a few days of birth. The incidence reported in a large Japanese study is estimated at 4%. It almost exclusively affects the areola of the breast, but other sites such as the eyelid, cheek, periauricular and scapular regions, axilla, arm, hypochondrium, scrotum, and labium majus may also be involved.

Pathogenesis and histologic features

Histologically, the polyp consists of centrally located adnexal structures including hair follicles, sebaceous glands, and well-formed eccrine units. Arrector pili muscle and apocrine structures are absent. Keratinous cysts are sometimes present.

Clinical features

Eccrine syringofibroadenoma (acrosyringeal nevus) is uncommon. It may show a variable presentation, ranging from solitary lesions to multiple papules and nodules arranged in a symmetrical or linear nevoid pattern. Distribution is wide and includes the face, back, abdomen, buttock, extremities, and rarely the nail. The age of onset ranges from 16 to 80 years; most patients, however, were in their seventh or eighth decade. A stratification according to five clinically distinct subgroups has been proposed :

• Solitary eccrine syringofibroadenoma : this variant presents as a single, often verrucous-like lesion in the middle aged or elderly. The anatomical distribution is wide with a predilection for the lower extremity.

• Multiple eccrine syringofibroadenoma associated with ectodermal dysplasia : patients in this subgroup typically present with multiple erythematous papules predominantly affecting the limbs and especially the palms and soles. Presentation is in adolescence and is associated with ectodermal dysplasia. The accompanying cutaneous manifestations frequently include eyelid hidrocystoma, hypotrichosis, hypodontia, and nail hypoplasia, a constellation also referred to as the Schöpf-Schulz-Passarge syndrome.

• Multiple eccrine syringofibroadenoma without associated cutaneous findings : the lesions typically occur on the palms and soles of the elderly without associated cutaneous anomalies.

• Nonfamilial unilateral linear eccrine syringofibroadenoma : this extremely infrequent presentation is nonfamilial and lesions are present unilaterally as multiple papules and plaques in a linear arrangement. A wide age range is affected but patients typically present in adolescence or early adulthood and there is a predilection for the extremities.

• Reactive eccrine syringofibroadenoma : eccrine syringofibroadenoma may also be present as an unusual reactive epithelial change complicating other cutaneous disease including inflammatory dermatoses in addition to neoplasia. It has been associated with longstanding venous stasis, nail trauma, chronic ulceration of the foot, burn scar ulcer, leprosy, nevus sebaceous, enterostomy site, bullous pemphigoid, epidermolysis bullosa, erosive palmoplantar lichen planus, epithelioid hemangioendothelioma, and squamous cell carcinoma.

Recurrences are not a feature, but malignant transformation within a longstanding eccrine syringofibroadenoma has been postulated.

Pathogenesis and histologic features

Whether presenting as a solitary tumor or in a nevoid distribution, the histologic features are remarkably similar. Arising from the epidermis at multiple points are thin anastomosing strands of uniform, small epithelial cells enclosing a fibrovascular stroma, which is often rich in acid mucopolysaccharides and sometimes contains a prominent lymphocytic and plasma cell infiltrate ( Fig. 33.72 ). The epithelial strands characteristically show ductal differentiation, often associated with a well-formed cuticle ( Figs 33.73 and 33.74 ). Aggregates of clear cells may rarely be noted. The epithelial cells are PAS positive and, in keeping with their eccrine derivation, contain oxidative enzymes, including succinic dehydrogenase, phosphorylase, and leucine aminopeptidase.