The classification of cutaneous sweat gland lesions is very complex (table 1), as these lesions have a wide histological spectrum, and the pathogenesis and exact origin of many lesions is still under investigation and not clear.^1,2 Many different terms are often used to describe the same tumour (table 2), making this subject more difficult for pathologists to reach a uniform terminology for the diagnosis of these lesions. Furthermore, the issue is complicated by the coexistence of eccrine and/or apocrine lesions within cutaneous hamartomas or within adnexal lesions with composite/mixed differentiation, which also includes those with follicular and sebaceous differentiation. A detailed practical approach to different skin adnexal lesions has been illustrated in the first review article of this series.³ Nonetheless, some important general features of sweat glands are reviewed here.

Eccrine sweat glands are widely distributed almost everywhere in the skin. The cells in the excretory coil express positivity for low molecular weight keratin (LMWK), epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), as well as S100 protein in the basal layer only. The myoepithelial cell layer may be highlighted by smooth muscle actin (SMA), p63 and calponin. Acrosyringeal cells (intraepidermal portion) stain for high molecular weight keratin (HMWK) and cytokeratin (CK) 14. A subpopulation of cells also expresses positivity to bcl-2. Skin tumours with eccrine differentiation often also express positive immunohistochemical staining for oestrogen and progesterone receptors.⁴ The positivity of some eccrine carcinomas to oestrogen receptors has important clinical implications, as affected patients may be partially treated with hormonal therapy.⁵ Unfortunately, positivity for oestrogen receptors and progesterone receptors does not distinguish cutaneous eccrine tumours from cutaneous metastases of breast carcinoma,⁶ in which case clinical and radiological correlation is critical.

Apocrine lesions of the skin are rare and are found mainly in body folds including the axillary, groin and anogenital regions, where apocrine glands are most concentrated, as well as in the umbilicus, eyelid (Moll’s glands), areola and in external auditory meatus. They also occur as heterotopic lesions elsewhere in the body, exemplified by tubular apocrine adenoma and within hamartomatous adnexal lesions such as in nevus sebaceous of Jadassohn (NSJ) in the scalp. In lesions of apocrine origin, the cells have abundant eosinophilic cytoplasm and eccentric, basally located nuclei. In addition, there is usually evidence of decapitation secretion in the luminal cells, and the tumour cells contain periodic acid Schiff (PAS)-positive diastase-resistant granules, and iron pigment (best illustrated with Prussian blue stain). The luminal cells are immunoreactive to CEA and EMA. The secretory cells are positive for LMWK, and the glandular epithelium often also expresses gross cystic disease fluid protein 15 (GCDFP-15) and androgen receptors, which may be useful in the assessment of lesions suspicious of apocrine carcinoma. However, oestrogen receptors/progesterone/bcl-2 negativity is more consistent, and is considered more helpful to confirm the diagnosis of apocrine carcinoma than GCDFP-15/androgen receptor positivity.⁷

Apoeccrine glands are mostly found in the axillary region, and within lesions of NSJ.⁸ Their presence helps to explain the existence of some adnexal lesions that have both eccrine and apocrine components, including syringocystadenoma papilliferum (SCAP)¹ and Fox–Fordyce disease.⁹ Some authors¹⁰ believe that these glands are synonymous with cutaneous mammary-like glands (MLG), which are now recognised to be a normal component of the skin in the anogenital region, including the perianal skin.¹¹ MLG are unique in having features of apocrine, eccrine and mammary glands. The previous assumption that these glands represent ectopic/accessory breast tissue lying along the milk line (mammary ridge) is now believed to be incorrect.¹² Many adnexal lesions of the anogenital area are now recognised to be of MLG origin, including “apocrine” adenoma/fibroadenoma, hidrocystoma, hidradenoma papilliferum, extramammary Paget’s disease and adenocarcinoma.^11–14 These lesions often have papillary/cribriform growth pattern and a fibrous stroma reminiscent of fibroepithelial lesions of the breast. A helpful feature in attributing MLG origin to an adnexal tumour is the presence of normal MLG in the deep dermis and subcutaneous fatty tissue, in the vicinity of the lesion of interest,¹³ with a transition zone between benign and lesional areas.¹²

Tumours of pure apocrine origin appear to be much less common than those of eccrine origin, by virtue of the localisation of apocrine glands in the body. However, it is important to mention at the outset of this review that many of the sweat gland tumours traditionally assumed to have an eccrine origin are now recognised to have apocrine counterparts as well, as evidence of apocrine differentiation has been elucidated in many of them. These tumours include hidrocystoma, poroma, cylindroma, spiradenoma and chondroid syringoma. In addition, many sweat gland lesions have both eccrine and apocrine differentiation (as well as pilosebaceous occasionally) within the same tumour. Examples of this are the many composite/mixed adnexal tumours and hamartomas that continually appear in the literature. Therefore, it was felt necessary in this review to drop the prefix “eccrine” from many of these terms.

This review will concentrate on common and/or important benign as well as malignant tumours of cutaneous sweat glands (tables 3 and 4, respectively), with emphasis on a diagnostic approach. Many benign sweat gland tumours have malignant counterparts, which are discussed under the same subheading. Some entities are referred to only in the tables, but not considered in the text. After reading this review, the practising pathologist will be able to diagnose most of the entities considered herein. However, when a tumour is difficult to classify, it is more important to differentiate between benign and malignant lesions, and in that setting it may be sufficient to describe the tumour as a benign or malignant cutaneous sweat gland tumour, with predominant eccrine or apocrine differentiation. Furthermore, complete excision of all skin adnexal lesions is always advisable. The differentiation of sweat gland tumours from metastatic carcinomas is discussed where appropriate.

POROMAS

Most of these tumours originate from the outer cells of the intraepidermal (acrosyringeal) excretory ducts of eccrine sweat gland. They usually occur in adults, with predilection to palms and soles, and less frequently in the head and neck, and trunk regions. Clinically they can be solitary or multiple, and can present as superficial plaques or dermal nodules, with tendency to ulceration and bleeding. Histologically, three main benign tumours are recognised and distinguished according to their location in relation to the epidermis:^15,16 (1) poroma (fig 1A), involving both epidermis and dermis; (2) hidroacanthoma simplex, also known as intraepidermal poroma, confined within the epidermis; and (3) dermal duct tumour, limited to the dermis, with no epidermal attachment. These tumours consist of solid sheets and nodules of basaloid poroid cells with pushing borders that emanate from the epidermis. The neoplastic cells are small, monomorphous and polyhedral cuboidal, with well-defined cell membrane. They have small, centrally located bland nuclei, and a variable amount of cytoplasm that ranges from scant to ample, eosinophilic to clear glycogenated PAS positive and diastase sensitive. Variable numbers of mitotic figures can be identified. The tumour cells are sharply delineated from adjacent keratinocytes. Foci of squamous differentiation and clear cell change are commonly seen. The intervening stroma is characteristically very vascular. Inconspicuous to prominent CEA-positive small ducts lined by cuboidal cells, and PAS-positive eosinophilic cuticle material are present in most tumours. Poroma cells are also reactive for cytokeratin 17.¹⁷ More recently, there have been reports of poromas with sebaceous, follicular and apocrine differentiation, suggesting a possible apocrine origin. These cases have been labelled as “apocrine” poromas.¹⁸

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Figure 1

 (A) Poroma: multiple epidermal attachments with downgrowth into the dermis. (B) Porocarcinoma, with clear cell change. (C) Higher power of porocarcinoma demonstrating cellular atypia, tumour necrosis, infiltration and budding into adjacent desmoplastic stroma. (D) In situ component adjacent to the invasive porocarcinoma depicted in (B) and (C).

Porocarcinomas (malignant eccrine poromas; fig 1B) are usually found on the lower extremities. They usually arise in pre-existing benign poroid tumours, and are histologically characterised by asymmetrical, solid, nodular growth pattern, with infiltrative or pushing borders. The neoplastic cells in porocarcinoma may have basaloid features, resembling those of poroma, but show varying degrees of cytonuclear atypia, hyperchromatic nuclei, and prominent nucleoli. Large polyhedral cells with abundant clear cytoplasm can be present. Foci of squamous and spindle cell differentiation are common. Evidence of eccrine differentiation in the form of CEA-positive ductal formation is present in most of the cases. Brisk mitotic activity, necrosis and desmoplastic stromal reaction can be prominent (fig 1C). Continuity with a benign pre-existing poroma and prominent intraepidermal component, occasionally showing severe cellular pleomorphism and resembling Paget’s disease, can be present (fig 1D).^19,20 A pure “porocarcinoma in situ” adjacent to a benign poroma may also occur. Porocarcinomas are aggressive tumours with potential for local recurrence, and nodal and distant metastases.²¹ It has been suggested that more than 14 mitoses per high power field, tumour depth >7 mm and presence of lymphovascular invasion are associated with more aggressive clinical course.²⁰ The main differential diagnosis of porocarcinoma is squamous cell carcinoma, which lacks intracytoplasmic lumina and ductal formation. The differential diagnosis of porocarcinoma in situ includes clonal seborrhoeic keratosis, clonal squamous cell carcinoma in situ (Bowen’s disease), melanoma in situ and Paget’s disease.²² The presence of an adjacent benign poroid component is a helpful feature in establishing the diagnosis. In clonal Bowen’s disease, the tumour cells are more atypical and there is more severe architectural abnormality. Clonal seborrhoeic keratosis and Bowen’s disease are negative for CEA, cytokertain 7 and S100, which are often positive in porocarcinoma.¹⁶ Negativity for melan-A and HMB45 helps rule out melanoma in situ. In Paget’s disease, the cells are large, with clear PAS-positive cytoplasm.

HIDRADENOMA AND HIDRADENOCARCINOMA

Hidradenoma is a benign tumour, which usually presents as a solitary, skin-coloured lesion and occurs more commonly in females.¹⁶ Hidradenoma may have variable histomorphological patterns (fig 2A–C), reflected by the various terms used to describe this entity: nodular hidradenoma, eccrine acrospiroma, solid-cystic hidradenoma clear cell hidradenoma, and clear cell acrospiroma. It shows variably sized nests and nodules of neoplastic epithelial cells, with small ductular lumens, confined within the upper dermis. The tumour cells are small, monomorphous and polyhedral, resembling those of poroma cells. In fact, some tumours have epidermal attachment, and occasionally may also have features overlapping with those of typical poromas.²³ Clear cell change and/or squamous metaplasia may be prominent. However, squamoid change does not seem to denote a worse prognosis. Occasionally, focal apocrine components may also be present. The lesion is also characterised by its pushy, but well-circumscribed, peripheral border. Nodular hidradenoma should be fully excised, as malignant transformation may be present in other areas of the lesion. Furthermore, hidradenoma has a recurrence rate of approximately 12% if not fully excised,²⁴ especially in lesions with irregular peripheral margins.²³

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Figure 2

 (A) Hidradenoma—solid-cystic variant. (B) Hidradenoma—solid variant. (C) Hidradenoma—tubular/ductal differentiation and clear cell change (clear cell hidradenoma). (D) Hidradenocarcinoma—cellular atypia and tumour necrosis (arrow).

Although most cases of hidradenocarcinoma arise de novo, the tumour may also arise in pre-existing hidradenoma.²³ Hidradenocarcinoma is also often referred to as malignant nodular/clear cell hidradenoma, malignant clear cell acrospiroma, clear cell eccrine carcinoma or primary mucoepidermoid cutaneous carcinoma. Histologically (fig 2D), it is a multinodular solid malignant neoplasm, showing ductal structures and intracytoplasmic tubular vacuoles, with areas of tumour necrosis. The tumour cells have similar morphology as those of nodular hidradenoma, but may also show cytonuclear atypia and increased mitotic activity. Apocrine differentiation is frequently seen. Evidence of nodular hidradenoma remnants may be present. An infiltrative growth pattern is not universally seen, and the carcinoma is distinguished from benign hidradenoma by the presence of brisk mitotic activity and cellular pleomorphism. The tumour cells stain positively for LMWK, and the ductal structures/luminal surfaces are highlighted by EMA and CEA. Although these rare tumours do not always behave aggressively, they may have an aggressive course with metastasis and/or local recurrence. The primary treatment is wide local excision with or without lymph node dissection.^25,26

Interestingly, clear cell hidradenoma and hidradenocarcinoma may occasionally mimic metastatic clear cell carcinomas including thyroid, lung or renal cell carcinomas. However, the first two are usually distinguished by their positivity to thyroid transcription factor-1 (TTF-1), and the latter by its prominent vascularity, and the presence of haemorrhage and focal granular necrosis within the lesion.²² Renal cell carcinoma also expresses both EMA and CD10.

SYRINGOMA AND SYRINGOID ECCRINE CARCINOMA

Syringomas constitute a spectrum of benign sporadic tumours that arise from the straight segment of the intradermal eccrine sweat duct. They predominantly affect middle-aged women, and most commonly involve the head and neck region, with a predilection for the eyelids. An uncommon variant is eruptive syringoma, a clinical condition characterised by multiple yellow–brown-coloured, firm papules, with no specific site predilection in young adults.²⁷ The pathogenesis of eruptive syringoma is controversial, and it has been suggested that it represents a reactive eccrine gland ductal proliferation following cutaneous inflammatory conditions.²⁸ There is also an increased incidence of eruptive syringoma in patients with Down’s syndrome, and, rarely, syringomas can occur in familial form.²⁹

Histologically, syringomas are symmetrical, well circumscribed, confined to the upper dermis, and usually have no connection with the overlying epidermis. The tumours consist of proliferation of epithelial cells, and are arranged in nests, cords or tubules, in which some display a “comma” or “tadpole” shape (fig 3A). The tubules are lined by single or double layers of bland, monomorphous, cuboidal epithelial cells with small normochromic nuclei, and small to moderate amount of pale eosinophilic cytoplasm. In some tumours, the neoplastic cells predominantly exhibit abundant clear cytoplasm³⁰ (clear cell syringoma; fig 3B). A PAS-positive eosinophilic material is often present within the tubular lumina. Syringoma should be distinguished from the extremely rare malignant counterparts, syringoid eccrine carcinoma and microcystic adnexal carcinoma. In contrast with benign syringomas, syringoid eccrine carcinoma (fig 3C) exhibits cytonuclear atypia, mitotic activity, lymphovascular and perineural invasion, and infiltrative growth pattern, with tumour extension into the deep dermis and subcutaneous tissue, and potential for local recurrence and distant metastases.^31,32 In superficial skin biopsies, microcystic adnexal carcinoma may be misdiagnosed as syringoma (see below). Therefore, re-evaluation of these tumours and especially their base after complete excision is important.

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Figure 3

 (A) Syringoma: typical eccrine ducts with comma shape and intraductal eosinophilic material. (B) Clear cell syringoma. (C) Syringoid eccrine carcinoma: hyperchromatic nuclei, ductular/tubular structures (arrows), infiltrating into a desmoplastic stroma are illustrated.

Chondroid syringoma (mixed tumour of the skin) and malignant chondroid syringoma

This uncommon tumour presents as a slowly growing, painless, firm nodule, generally occurring in the head and neck region, but most commonly affecting the nose, cheek and upper lip.^1,33 Less frequently, the extremities, trunk or back may also be affected. Histologically, chondroid syringoma is similar to the benign mixed tumour of the salivary glands, having both epithelial and mesenchymal stromal components. The tumour shows a circumscribed nodule, consisting of bland epithelial cells, arranged in cords, ducts (fig 4A), or tubules (fig 4B). The stromal component is most often myxoid-cartilaginous (chondromyxoid), but may also be hyalinised/fibrous, fatty, osteoid, or may even be minimal or absent.¹⁶ The stromal cells show myoepithelial differentiation, illustrated by positivity to S100, vimentin and neurone-specific enolase, and less commonly by glial fibrillary acid protein, SMA, calponin or p63. Desmin is usually negative.^1,33 Chondroid syringoma is classified into apocrine and eccrine types, based on the histopathological appearance of the sweat gland lumina within the tumour. In the apocrine type, lesions incorporating areas with pilar and sebaceous differentiation have been described repeatedly,³⁴ suggesting that some tumours are best viewed as hamartomatous lesions of the pilosebaceous-apocrine unit. Chondroid syringoma is best completely excised because of the possibility of local recurrence and malignant transformation.

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Figure 4

 (A) Chondroid syringoma: proliferating ductuloglandular eccrine epithelium in chondromyxoid stroma. (B) Chondroid syringoma with prominent tubular proliferation in chondroid stroma.

Malignant chondroid syringoma is very rare, and may arise de novo or from a pre-existing chondroid syringoma which has undergone malignant transformation.^35,36 Histologically, there is cellular atypia, increased mitotic activity, infiltrative margins, satellite tumour nodules and tumour necrosis.¹ Haematogenous and lymphatic spread to lymph nodes, lungs and bone may occur. The term “atypical chondroid syringoma” is used to describe tumours with histological features of malignancy as well as recurrence, local invasion and satellite tumour nodules, but without proved metastases.³⁷

SYRINGOFIBROADENOMA (ACROSYRINGEAL ADENOMATOSIS)

This is a rare benign eccrine tumour of acrosyringeal origin, with variable clinical presentation. Histologically, there are reticulated and irregularly anastomosing epithelial cords and strands extending from the epidermis into the superficial dermis (fig 5), usually embedded in a fibrovascular stroma. The cells are basophilic and monomorphous, and are smaller than adjacent epidermal keratinocytes. They are positive for HMWK and cytokertain 14. Occasional ductal structures may be identified, and enhanced with CEA or EMA. Areas of clear cell change may also occur. This lesion has indeterminate pathogenesis, and is labelled variously as a neoplasm, hamartoma, nevus or reactive hyperplasia; therefore, it probably represents a group of heterogeneous disorders.^38,39

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Figure 5

 Syringofibroadenoma reticulated and irregularly anastomosing epithelial cords with areas of ductal differentiation (arrows).

SPIRADENOMA AND SPIRADENOCARCINOMA

Spiradenomas are commonly encountered benign tumours originating from the straight intradermal eccrine duct. They usually present as a solitary, painful, nodular lesion in young adults, with a predilection to the trunk and upper extremities. Spiradenomas can rarely be associated with Brooke–Spiegler syndrome, a rare autosomal dominant inherited disorder, characterised by the development of multiple skin adnexal tumours.⁴⁰ Microscopically, they involve a well-circumscribed nodular tumour in the dermis and subcutaneous tissue, encapsulated by a well-defined fibrous capsule, and lacking a connection to the epidermis. The neoplastic nodules are solid, variable in size and characteristically formed of two epithelial cell types (fig 6A,B): (1) large cells with round vesicular nuclei prominent nucleoli, and abundant pale cytoplasm, located in the centre of the neoplastic nodules; (2) small cells with hyperchromatic nuclei and scant cytoplasm rimming the periphery of the neoplastic nodules. Mitotic figures can be present. The cells can be arranged in cords, or exhibit tubular and alveolar differentiation. Globules of dense eosinophilic PAS-positive basement membrane material are present within the tumour lobules. Richly vascular stroma with occasional thrombi, foci of squamous differentiation, fibrosis and cystic degenerative changes are commonly seen. Apocrine differentiation has also been reported in spiradenomas, leading some authors to suggest that not all spiradenomas are of eccrine origin.⁴¹

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Figure 6

 (A) Spiradenoma: a lobulated mass composed of multiple nests of small basophilic cells, admixed with squamoid cells and clear cells, with hyalinised basement membrane. (B) Spiradenoma, high power: focal ductal differentiation is evident (arrow). (C) Spiradenocarcinoma: cellular atypia and increased mitotic activity. The lesion is seen adjacent to benign spiradenoma.

Spiradenocarcinoma (fig 6C) is a very rare malignant neoplasm arising from a pre-existing spiradenoma and histologically characterised by loss of nodular growth pattern, infiltrative borders, cytonuclear pleomorphism, increased mitotic activity and tumour necrosis.⁴² The presence, at least in focal parts within the lesion, of dual population (central basaloid cells and larger peripheral cells) is required for the diagnosis of spiradenocarcinoma, which has a high recurrence rate, and can occasionally metastasise to lymph nodes and distant organs.

CYLINDROMA

Cylindromas are benign neoplasms, usually affect adult females, with 90% occurring in the head and neck region, particularly the scalp and face. They can be sporadic and present as a solitary lesion, or less commonly as a variably sized, multiple coalescing tumour causing marked disfiguring of the scalp and face (turban tumour). Rarely, multiple cylindromas can be associated with familial cylindromatosis; an autosomal dominant disorder, and Brook–Spiegler syndrome, in which case there are multiple tumours that may also involve the trunk and extremities in children or young adults. Mutations in the cylindromatosis tumour suppressor gene (CYLD1) on chromosome 16q12–13 play an essential role in the pathogenesis of hereditary and sporadic cylindromas.⁴³ This mutation is also associated with developing spiradenoma, trichoepithelioma, milia or a membranous variant of salivary gland basal cell adenoma. The histogenesis of cylindroma is controversial; where as accumulated evidences favour an eccrine origin from the coiled part of the intradermal duct,⁴⁴ others suggest an apocrine differentiation.⁴⁵ Histologically, these tumours are readily recognised and characterised by numerous well-defined, non-encapsulated variably sized islands and nodules of epithelial cells, lined by thick PAS-positive basement membrane-like, hyalinised material, and arranged in a characteristic “jigsaw puzzle” pattern (fig 7). Two populations of cells are usually identified within the tumour epithelial islands: (1) large cells with pale-staining nuclei and moderate amount of amphophilic cytoplasm, located at the central zone, and (2) peripherally located, small, basaloid cells with dark-staining nuclei and scant cytoplasm that exhibit a palisading pattern. Ductulotubular structures, lined by cuboidal or columnar cells and containing intraluminal eosinophilic material, are usually present. PAS-positive hyaline globules are also found in the tumour islands. Some tumours, termed spiradenocylindromas, have features of both cylindromas and eccrine spiradenomas,⁴⁶ the existence of which may suggest that both entities represent a continuous morphological spectrum of a single entity, or a transitional or maturing phase from one lesion to the other.³² In addition to the morphological similarity between cylindroma and spiradenoma, both entities express immunopositivity for S100 protein within the tubular and large, pale-staining cells, human milk fat globulin and lysosome in tubular cells, SMA in small basaloid cells, and CK 7, 8, and 18.⁴⁷

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Figure 7

 Cylindroma: jigsaw puzzle appearance and eosinophilic peripheral basement membrane.

Malignant cylindroma is a rare tumour arising from pre-existing benign cylindroma, both in solitary sporadic and in autosomal dominant multiple forms. Malignant cylindroma is clinically characterised by rapid growth, long-standing ulceration or bleeding, and aggressive clinical behaviour, with local recurrence and potential for distant metastases.^48,49 Histologically, there is an infiltrative growth pattern with cytonuclear pleomorphism, increased mitotic activity, and loss of jigsaw appearance, hyaline sheath and peripheral palisading.

SCAP AND SYRINGOCYSTADENOCARCINOMA PAPILLIFERUM

SCAP is a benign hamartomatous tumour usually affecting the young adults, and occurs as a solitary or less commonly multiple lesion, most commonly in the face and scalp. They can arise within a pre-existing NSJ,⁵⁰ and on rare occasions can be associated with papillary eccrine adenoma,⁵¹ tubular apocrine adenoma⁵² and hidradenoma papilliferum.¹³ Mutations in tumour suppressor gene p16 may contribute to the pathogenesis of SCAP.⁵³ The tumour is variably denoted to be derived from eccrine, apocrine or apoeccrine origins.^1,2 Histologically, SCAP is a verrucous tumour that displays multiple epithelial invaginations extending down from the epidermis, and contains numerous papillae (fig 8A,B). These papillary structures consist of a dermal fibrovascular core, lined by two layers of epithelial cells, luminal columnar cells with decapitation secretion and outer cuboidal cells. A characteristically marked plasmacytic inflammatory cell infiltrate is present within the fibrous cores.⁵⁴ Apocrine sweat glands are often identified at the deep part of the tumour. Immunohistochemically, the luminal columnar cells express GCDFP-15, CEA, and CK 7 and 19, whereas the basal cuboidal cells express CK 5, 7, 8 and 14.⁵⁵ Syringocystadenocarcinoma papilliferum (fig 8C,D) is very rare, and as characterised histologically by disorderly arrangement of papillary projections, cytological atypia and loss of double-layered epithelium.⁵⁶

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Figure 8

 (A) Syringocystadenoma papilliferum (SCAP): papillary epithelial projections with opening into the surface. (B) Decapitation secretion and prominent plasma cell stromal component in SCAP. (C) Syringocystadenocarcinoma papilliferum. (D) Syringocystadenocarcinoma papilliferum: cellular atypia, tumour necrosis and mitoses.

HIDRADENOMA PAPILLIFERUM

Hidradenoma papilliferum is a benign tumour, and occurs almost exclusively in females, with predilection to the vulva and perianal region. Rare cases of hydradenoma papilliferum have been reported in males,⁵⁷ and in extra-anogenital locations, particularly in the head and neck.⁵⁸ The tumours are solitary, and are usually small and asymptomatic. Occasionally, the tumours can be large and elevated, forming a reddish-brown mass with an ulcerated and bleeding surface.⁵⁹ Human papilloma virus may have a potential role in the pathogenesis of hydradenoma papilliferum,⁶⁰ an observation that needs to be confirmed by further study. Histologically (fig 9), hidradenoma papilliferum is a well-circumscribed solid or cystic dermal nodular lesion, not connected to the epidermis. It is formed of frond-like papillae or tubulopapillary structures that are lined by a two-cell layer: luminal cuboidal or low columnar epithelial cells with apical secretions, resting on an outer myoepithelial cell layer. The epithelial cells typically have histochemical characteristics in keeping with an apocrine origin. hidradenoma papiulliferum lacks cytonuclear atypia, mitotic activity or tumour necrosis. Morphological features analogous to benign breast diseases can be frequently encountered, and include oxyphilic (apocrine) metaplasia, sclerosing adenosis-like changes, atypical apocrine adenosis-like changes, ductal epithelial hyperplasia, clear cell change of the myoepithelium, foamy histiocyte reaction and stromal fibrosis.⁶⁰ Rare malignant transformation in hidradenoma papiulliferum (apocrine adenocarcinoma) is characterised by cytological pleomorphism, mitoses and necrosis with or without epidermal pagetoid spread of the malignant cells.⁶¹ Immunohistochemically, the tumour cells often express CEA,⁶² GCDFP-15,⁶³ lysosome and CD-15 (Leu M1)⁶⁴ Furthermore, oestrogen receptors, progesterone receptors, and androgen receptors are commonly expressed in hidradenoma papiulliferum.⁶⁵ This and the presence of histomorphological features analogous to benign breast diseases lend further evidence to a possible origin of hidradenoma papiulliferum from MLG.

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Figure 9

 Hidradenoma papilliferum: a cystic and papillary dermal neoplasm demonstrating decapitation secretion characteristic of apocrine differentiation.

TUBLOPAPILLARY HIDRADENOMA WITH ECCRINE/APOCRINE DIFFERENTIATION (INCLUDING PAPILLARY ECCRINE ADENOMA, TUBULAR APOCRINE ADENOMA, AND PAPILLARY APOCRINE FIBROADENOMA)

Papillary eccrine adenoma (PEA) and tubular apocrine adenoma (TAA) occur most commonly on the scalp, but rare variants of TAA have also been described in the vulva⁶⁶ and in the perianal skin.⁶⁷ In the anogenital skin, apocrine adenoma is believed to arise from MLG.^11,68 As TAA may be histologically indistinguishable from PEA (fig 10), the term “tubulopapillary hidradenoma” was recently introduced to describe benign sweat gland tumours characterised by combining ductal as well as apocrine and eccrine glandular differentiation, incorporating features of TAA and/or PEA, with a predominance of eccrine or apocrine differentiation.^45,69 This incorporates entities previously designated as PEA, TAA and other related lesions. Clinically, these lesions appear as well-circumscribed superficially located solitary dermal/subcutaneous nodules. Microscopically, the tumour is composed of dilated tubular/ductular structures of varying size, lined by a double layer of epithelial cells and a peripheral myoepithelial cell layer. Delicate intraluminal papillary projections are commonly seen. Immunohistochemical evidence of both eccrine and apocrine differentiation may be found,⁴⁵ raising the possibility that such lesions have dual origin or arise from apoeccrine glands⁷⁰ or MLG (in lesions of the anogenital area).^45,69 The lumina are usually filled by eosinophilic amorphous material. In lesions of tubulopapillary hidradenoma with apocrine differentiation, irregularly shaped tubular structures lined by two layers of epithelial cells with decapitation secretion in the lumina are evident in many areas.⁶⁹ Immunohistochemically, the tumour is reactive to S100 protein, CEA and EMA.⁷¹ The coexistence of SCAP with TAA⁷² and with PEA⁵¹ has been reported, suggesting that TAA, PEA and SCAP may represent a spectrum of inter-related tumours.

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Figure 10

 (A) Tubulopapillary hidradenoma. (B) Tubulopapillary hidradenoma with eccrine differentiation (papillary eccrine adenoma). (C) Tubulopapillary hidradenoma with apocrine differentiation (tubular apocrine adenoma).

Hidradenoma papilliferum is distinguished from these tumours by its more closely arranged tumour cells and glands,¹³ and by its almost consistent presence in the female anogenital area.

MICROCYSTIC ADNEXAL CARCINOMA

Microcystic adnexal carcinomas (MACS; sclerosing sweat duct carcinomas) are uncommon malignant neoplasms. They are widely believed to be of eccrine origin. However, the issue is complicated by the presence of keratinous cysts and the description of apocrine and sebaceous differentiation in many cases.⁷³ This may suggest that the tumour has a mixed adnexal lineage with eccrine, apocrine and pilosebaceous features. Microcystic adnexal carcinoma occurs as a solitary lesion in middle-aged adults, commonly in the face, with predilection to the upper and lower lip.³² Risk factors include previous radiation therapy and immunosuppression.⁷⁴ Histologically (fig 11), microcystic adnexal carcinoma consists of poorly circumscribed proliferation of deceptively bland epithelial neoplastic cells infiltrating the dermis and subcutaneous tissue, and exhibits prominent perineural and intraneural invasion. The neoplastic cells are small, uniform and basaloid, or less commonly clear, and have no or minimal cytological atypia and mitotic activity. Keratin-filled microcysts are often present in the superficial dermis. Tubular and ductal structures lined by a single layer of neoplastic cells dominate the deeper parts of the lesion. Small, solid clusters and single tumour cells often infiltrate the subcutaneous and skeletal muscle tissues, as well as into the perichondrium and periosteum. The tumour stroma is characteristically sclerotic. The ductal elements are usually positive for EMA and CEA. Recently, CD5 was found to stain the epithelial component in most cases.⁷⁵ MAC is locally aggressive, with propensity to invade the nerves and cause local tissue destruction, and has a high recurrence rate. Occasionally, nodal and distant metastases also occur.⁷⁶ The differential diagnosis of microcystic adnexal carcinoma includes syringoma, desmoplastic trichoepithelioma, sclerosing/morpheic basal cell carcinoma and papillary eccrine adenoma (table 5).^22,77 In all cases, the base of the lesion must be observed to rule out this tumour. If a syringoma-like lesion infiltrates deeply into the underlying tissues with/without perineural involvement, it is highly suspicious for MAC.

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Figure 11

 Microcystic adnexal carcinoma: deceptively benign-looking epithelial proliferation reaching the subcutis.

PRIMARY CUTANEOUS MUCINOUS CARCINOMA

Primary cutaneous mucinous carcinoma (PCMC) is a rare low-grade malignancy tumour that affects older adults, and occurs most frequently in the head and neck, and axillary regions, with a predilection to the eyelids. Histologically, the tumour has a morphological spectrum comparable to its mammary counterpart,^22,78 and usually appears as a well-demarcated, lobular dermal lesion, with frequent extension into the subcutaneous tissue and no connection with the overlying epidermis. It consists of PAS-positive, diastase-resistant multilocular pools of mucin, in which nests of bland, monotonous, polygonal epithelial cells are embedded (fig 12). The tumour cells possess round, hyperchromatic nuclei, inconspicuous nucleoli, moderate amount of pale eosinophilic to clear cytoplasm and well-defined cell membrane. Secretory snouts may be present. Mitotic figures are rare. Solid sheets of tumour cells and single neoplastic cells arranged in an Indian-file pattern can be seen.⁷⁹ Immunohistochemically, the tumour cells are often immunoreactant to EMA, LMWK and CEA,¹⁹ as well as to GCDFP-15, CK 7, oestrogen receptors and progesterone receptors.⁸⁰ PCMC should be differentiated from metastasising mucinous carcinoma originating in extracutaneous organs; therefore, an extensive clinical examination to exclude metastasis from breast or visceral mucinous carcinoma is essential. Histologically, an in situ component in the form of epithelial islands bounded by a myoepithelial layer, and highlighted by CK 5/6, p53, calponin and SMA, is frequently present in PCMC in comparison to metastatic mucinous carcinoma.⁷⁸ In comparison, breast mucinous carcinoma metastatic to the skin mostly presents with lesions on chest wall, breast and axillae, and these locations can serve as clue to the breast origin. In addition, these metastatic lesions lack an in situ component histologically. PCMC is typically an indolent tumour with tendency for local recurrence; however, distant metastasis is rare.²²

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Figure 12

 Primary cutaneous mucinous carcinoma in pools of mucinous stroma.

ADENOID CYSTIC CARCINOMA

Adenoid cystic carcinoma (ACC) is a very rare malignant tumour affecting older adults, with female predominance. It can occur in different anatomical sites, most commonly in the scalp.⁸¹ The tumour has a 50% local recurrence rate,⁸¹ but metastasis to regional lymph nodes and distant organs is exceedingly rare.⁸² Histologically, ACC is indistinguishable from its salivary gland counterpart, usually presenting as a dermal tumour that consists of bland, monomorphous basaloid cells with round or angulated hyperchromatic nuclei, indistinct nucleoli and inconspicuous cytoplasm, arranged in cribriform, solid or trabecular growth patterns (fig 13). A basement membrane-like PAS-positive, diastase-resistant eosinophilic material is often present within the microcystic spaces. The tumour cells are immunoreactant to LMWK and pankeratin (AE1/AE3). EMA and CEA are frequently expressed in the luminal cells.⁸³ Inconstant expression of actin was described previously, which is possibly an indication of the presence of a myoepithelial cell population.⁸¹ Before diagnosing primary cutaneous ACC, it is essential to clinically rule out the presence of salivary gland ACC and exclude other cutaneous basaloid tumours, especially adenoid BCC. The lack of epidermal connection and absence of peripheral palisading of neoplastic cells, and the presence of PAS-positive material and perineural space invasion favour the diagnosis of adenoid cystic carcinoma over adenoid BCC.¹⁹ In addition, CEA and CD117 (c-kit protein) are seen in adenoid cystic carcinoma but not in BCC.⁸⁴ Adenoid cystic carcinoma may have squamous metaplasia, in which case it must also be distinguished from squamous cell carcinoma with adenoid (pseudoglandular) features. The positivity for CEA and S100 protein, and negativity for p63 favour the diagnosis of ACC.

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Figure 13

 Adenoid cystic carcinoma, with perineural invasion (inset).

DIGITAL PAPILLARY ADENOCARCINOMA (AGGRESSIVE DIGITAL PAPILLARY TUMOUR, AGGRESSIVE DIGITAL PAPILLARY ADENOMA/CARCINOMA, AGGRESSIVE DIGITAL PAPILLARY ADENOMA)

These are rare sweat gland neoplasms, largely accepted to be of eccrine origin, that occur in middle-aged adults (with male predominance) and have a mostly digital location (most frequently on fingers, but also on toes, palms and soles).⁸⁵ They typically have clinically aggressive growth behaviour. Histologically (fig 14), the tumour shows intradermal multinodular solid and cystic growth pattern, composed of cuboidal/low columnar epithelial cells, with back-to-back/cribriform glands. Multiple cystic spaces, containing eosinophilic material, with luminal papillary projections are characteristically present. Not uncommonly, there may be cytonuclear atypia, increased mitotic activity or tumour necrosis. Rarely, decapitation secretion (traditionally attributed to apocrine glands) may be seen in parts of the lesion. Areas of squamous, clear cell or spindle cell change are less frequently observed. There is no connection to the overlying epidermis. The tumour expresses CEA within the luminal cells and S100 protein within other tumour cells. The presence of poor glandular differentiation, necrosis, cytological atypia, increased mitotic rate, and invasion of soft tissue, bone and blood vessels was deemed important in labelling these tumours as adenocarcinomas. However, the distinction between adenoma and carcinoma on histological grounds alone does not seem to predict the clinical progression of these tumours,⁸⁶ which often have a high rate of local recurrence and potential for metastasis.⁸⁷ Therefore, all these tumours are best considered malignant, and they should be completely excised with or without amputation of the affected digit, as they may recur in 50% of cases, with 14% risk for metastasis. Sentinel lymph node biopsy has also been suggested in the staging of these tumours.⁸⁸ All patients should be followed up for potential local recurrence/metastatic disease, even after apparent complete excision, in which case the risk of local recurrence is estimated at 5%.

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Figure 14

 Digital papillary adenocarcinoma. Tumour necrosis is more evident in the inset.

The differential diagnosis of this tumour includes spiradenocarcinoma, which should have at least the foci of a two-cell population, and hidradenocarcinoma, which is usually less circumscribed and lacks the papillary pattern and back-to-back glandular differentiation.⁸⁶ Papillary eccrine adenoma is well circumscribed and lacks the back-to-back glandular differentiation and the cystic component of digital papillary adenocarcinoma. This tumour may also resemble breast carcinoma; however, it is unusual for an invasive papillary breast carcinoma to metastasi

APOCRINE CARCINOMA

Apocrine carcinoma is a rare and highly aggressive cutaneous adenocarcinoma, more commonly seen in middle-aged women, and mostly occurs in areas rich in apocrine glands, especially the axilla.^89,90 Other possible sites include eyelid (in Moll’s glands), ear and scalp.⁹¹ These tumours have also been described in NSJ.⁹² Histologically (fig 15), the tumour shows an asymmetric poorly demarcated malignant tumour, composed of conspicuous tubular and ductal structures. Papillary projections within the lumina may be present. The tumour has infiltrative margins, occupies the dermis and may extend to the subcutis. Cytonuclear pleomorphism, increased mitotic activity and areas of tumour necrosis are also noted. Decapitation secretion, as a sign of apocrine differentiation, is often present. PAS-positive diastase-resistant material is identified in the cells or lumen. The tumour cells are positive for LMWK, and the luminal cells are reactive for CEA, EMA and GCDFP-15. S100 protein is also occasionally positive.⁹¹ Although positivity to androgen receptors and GCDFP-15 is considered helpful, negativity of these tumours to ER and PR is more relevant from a practical point of view. The use of calponin and SMA as markers for the peripheral myoepithelium is helpful in delineating invasion.¹

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Figure 15

 Apocrine carcinoma, with infiltrative growth and tumour necrosis (left side), and cellular atypia, prominent nucleoli and mitotic activity (right side).

Of interest is the possible association between apocrine carcinoma and benign apocrine lesions (apocrine hyperplasia and apocrine adenoma), which is reported in the axillary region in five elderly male Japanese patients,⁹⁰ and a single case in the perianal region reported from the Department of Laboratory Medicine and Pathobiology (University of Toronto and University Health Network, Toronto, Ontario, Canada).⁹³ In another case we encountered, in a perianal skin tag, the lesion was present within an apocrine tubulopapillary hidradenoma and showed features reminiscent of breast lesions, specifically ductal carcinoma in situ, with no break-up of the peripheral myoepithelial layer, possibly arising in MLG.⁹⁴ Helpful features in distinguishing tubular apocrine carcinoma from metastatic visceral carcinoma are the presence of decapitation secretion and attachment of the lesion to the neighbouring follicular epithelium, or the presence of benign apocrine component within the lesion.

EXTRAMAMMARY PAGET’S DISEASE

Extramammary Paget’s disease (EMPD) is an uncommon cutaneous malignant neoplasm arising in areas rich in apocrine glands, most commonly in the vulvar and perianal region of middle-aged females. It has also been described in the axillae, eyelids, external auditory canal, penis and scrotum. Apocrine gland origin or apocrine differentiation of cells in EMPD has been generally accepted. However, some authors believe that EMPD arises from the intraepidermal stem cell of sweat ducts.²³ An alternative origin from Toker cells, with possible association to MLG, has also been suggested.¹⁴ Lesions usually present with erythematous eczematoid plaques and erosive ulceration. Histologically, there is proliferation in a Pagetoid pattern within the epidermis of single and small clusters of large malignant cells (fig 16), which have less defined intercellular bridges and exhibit glandular differentiation,²² occasionally showing intracytoplasmic luminal and ductal formation. The tumour cells contain alcian blue, mucicarmine and PAS-positive mucin in most cases. AE1/AE3, LMWK and CK 7 are typically positive,⁹⁵ with variable positivity seen for EMA and CEA. GCDFP-15, androgen receptors and Her2/neu are also commonly expressed in EMPD, whereas oestrogen receptors and progesterone receptors are not.^96,97

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Figure 16

 Extramammary Paget’s disease: Single units and small clusters of atypical cells scattered throughout epidermal layers.

In contrast with mammary Paget’s disease, EMPD is most commonly a primary intraepidermal lesion, with only 20% of cases demonstrating a dermal invasive element.¹² When the invasive component is <1.0 mm in depth, this is considered minimally invasive disease, and complete excision is usually curative.⁹⁸ EMPD may also be associated with an underlying cutaneous adnexal carcinoma, usually an apocrine adenocarcinoma.²³ In up to 30% of cases, it represents metastatic spread from a regional visceral malignancy, such as cervical⁹⁹ rectal,¹⁰⁰ prostate¹⁰¹ or transitional cell carcinoma,¹⁰² in which case the tumour cells are positive to CK 7 and possibly GCDFP-15,⁹⁸ but they also demonstrate immunohistochemical profile similar to the original carcinoma, including positivity to CK 20 or CA19.9 in genitourinary or gastrointestinal carcinomas,²³ or prostate-specific antigen in prostate cancer.¹⁰¹ An underlying regional visceral malignancy or cutaneous adnexal carcinoma is more commonly seen in perianal EMPD compared with the vulvar variant. Primary intraepidermal EMPD typically has a CK 7+/GCDFP-15+/CK 20–/prostate-specific antigen−immunohistochemical profile.

Anaplastic cases of Paget’s disease have also been described, in which there is full-thickness epidermal atypia, loss of nuclear polarity, marked cytologic anaplasia and inconspicuous glandular differentiation.^22,103 It is distinguished from Bowen’s disease by sparing the basal cell layer and the presence of mucin-containing cells. Furthermore, the lesion in Bowen’s disease is positive for HMWK but not for CK 7. In contrast, EMPD expresses positivity to CEA, CK 7, GCDFP-15, AR and CD5.²² In addition to Bowen’s disease and metastatic visceral malignancy, the differential diagnosis of EMPD also includes other lesions that exhibit Pagetoid spread. In melanoma, the tumour cells usually have melanin granules in their cytoplasm, and are positive for melan-A and HMB45 immunostains.

OTHER SWEAT GLAND CARCINOMA

Apart from the well-defined entities aforementioned, there are many malignant adnexal tumours that have prominent eccrine component/differentiation. These tumours have no characteristic clinical picture, and it is usually very difficult to differentiate them from metastatic carcinomas, as they usually lack an epidermal connection and simulate carcinomas from other parts of the body, including thyroid, breast, salivary glands and renal cell carcinomas. This group includes eccrine ductal carcinoma, basaloid eccrine carcinoma, clear cell eccrine carcinoma and other non-specified sweat gland carcinomas.

Eccrine ductal carcinoma (fig 17A) resembles breast ductal carcinomas, with different growth patterns possibly seen in isolation or in combination, including solid, papillary, tubular and cribriform. On most occasions, only a clinical history may help differentiate these tumours from their mammary counterparts. In eccrine carcinomas with basaloid morphology, the tumour cells are small, with scanty cytoplasm and prominent nuclei. Apoptotic cells, geographical necrosis and desmoplastic stroma are usually seen. The differential diagnosis of basaloid eccrine carcinoma is wide, and includes Merkel cell carcinoma, Ewing’s sarcoma, metastatic carcinoma, as well as small cell melanoma and squamous cell carcinoma. Immunohistochemically, the eccrine carcinomas are positive for AE1/AE3 and CEA, and occasionally for S100 protein. Typically, chromogranin, melan-A, HMB45 and CD45 are negative.¹⁶ Occasionally, eccrine carcinomas may exhibit squamous differentiation, and in some of them CK14 is positive, suggesting that such cases originate from the acrosyringium (acrosyringeal eccrine carcinoma; fig 17B).

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Figure 17

 (A) Eccrine ductal carcinoma. (B) Eccrine ductal carcinoma with cellular atypia, brisk mitotic activity and squamous differentiation, probably arising from the syringeum (acrosyringeal carcinoma). (C) Eccrine carcinoma with clear cell change.

Prominent clear cell change may be seen in benign as well as malignant sweat gland tumours, including poroma/porocarcinoma, hidradenoma/hidradenocarcinoma, syringoma, spiradenoma, microcystic adnexal carcinoma and other eccrine carcinomas (fig 17C). Furthermore, clear cell change may also be present in metastatic carcinomas, including thyroid, lung, urogenital and renal cell carcinomas. Differentiating these entities from each other is very important, but not always possible. Clinical history, other histomorphological features and immunohistochemical stains are very important in this regard. CK 5/6 is expressed by most skin adnexal carcinomas, but only in 33% of metastatic adenocarcinomas.¹⁰⁴ CA125 may be helpful in identifying urogenital carcinomas, and positivity for thyroid transcription factor-1 may be seen in thyroid and lung carcinomas.

COMPOSITE/MIXED ADNEXAL TUMOURS

Cutaneous adnexal tumours may display a varied composition with a mixture of eccrine, apocrine, sebaceous and pilar differentiation.^105–108 The diagnosis of these mixed lesions relies on histological evaluation, and they are usually classified according to the predominant morphological component. If no component is predominant, a different terminology is used to describe these lesions, including “combined adnexal tumours of the skin”,¹⁰⁵ “benign adnexal tumour with multi-directional differentiation”,¹⁰⁸ “benign adnexal tumour of mixed lineage”^2,16 and “composite adnexal tumours of the skin”.¹⁰⁹ Clinically, these tumours are located in the head and neck and the extremities, and rarely elsewhere in the body, as in a case we diagnosed recently from the ventral aspect of the penis (fig 18A).¹⁰⁹ They present as slowly enlarging solitary dermal/subcutaneous nodules.^2,108 Histologically, they are characterised by well-circumscribed, non-encapsulated nodules composed of a lobular proliferation of epithelial cells displaying a spectrum of eccrine, apocrine, sebaceous and follicular differentiation. Figure 18B illustrates another example of these lesions.

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Figure 18

 (A) Composite adnexal tumour on penis, combining features of syringocystadenoma, trichilemmoma and benign eccrine ductal proliferation. (B) Composite adnexal tumour showing a mixed follicular cyst with infundibular and papillary apocrine components (insets).

The occurrence of these different elements together in one lesion may be explained by the common embryological origin of these structures in the primary epithelial germ of the superficial ectoderm.¹ The existence of these cases highlights the difficulties encountered in the classification of some benign skin adnexal neoplasms, where more than one cell lineage is encountered. In our opinion, the term “composite adnexal tumours of the skin” better reflects the common embryological origin of these lesions, and the potential variable combination of eccrine, apocrine, sebaceous and pilar differentiation.