Cutaneous adnexal tumors

INTRODUCTION — Cutaneous adnexal tumors are a large group of benign and malignant neoplasms that exhibit morphologic differentiation towards one of the four primary adnexal structures present in normal skin: hair follicles, sebaceous glands, apocrine glands, and eccrine glands [1,2]. They may occur sporadically or may be markers of rare genetic syndromes, including Birt-Hogg-Dubé syndrome, Brooke-Spiegler syndrome, Cowden syndrome, and Muir-Torre syndrome [3].

This topic will review the clinical features, diagnosis, and treatment of cutaneous adnexal tumors and associated syndromes. Brooke-Spiegler syndrome, microcystic adnexal carcinoma, sebaceous carcinoma, Muir-Torre syndrome, and Cowden syndrome are discussed separately.

●(See "Brooke-Spiegler syndrome (CYLD cutaneous syndrome)".)

●(See "Microcystic adnexal carcinoma".)

●(See "Sebaceous carcinoma".)

●(See "Muir-Torre syndrome".)

●(See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)

CLASSIFICATION — Cutaneous adnexal tumors are classified based upon their differentiation toward one of the primary appendageal skin structures (table 1) [1]. Some tumors display differentiation toward more than one cell lineage, making their precise classification difficult. However, it is important to remember that hair follicles, sebaceous glands, and apocrine glands derive from the same epidermal bud in fetal development, explaining why some adnexal tumors show differentiation of some or all of these adnexal structures in the same neoplasm. Eccrine glands develop from a distinct embryologic anlage.

EPIDEMIOLOGY — Adnexal tumors represent a minority of cutaneous neoplasms. Data on their overall incidence and prevalence in the general population are lacking. With the exception of patients with syndromes associated with adnexal tumors and adnexal tumors arising in nevus sebaceus, most adnexal tumors occur in the fourth to sixth decade [4-6]. A female predilection has been noted for sweat duct tumors [4,7].

Malignant cutaneous adnexal tumors are rare. An analysis of data from 18 United States population-based registries in the Surveillance, Epidemiology, and End Results (SEER) database of primary tumors diagnosed from 2000 to 2018 found 9646 tumors, with an estimated age-adjusted incidence rate of 5.9 per million person-years [8]. The median age at diagnosis was 64, with a slight male predominance. In a previous analysis of the SEER database for the years 1988 to 2006, the estimated 10-year, disease-specific survival was 97 percent [9].

A higher incidence of malignant adnexal tumors occurs in patients with germline mutations predisposing to such tumors. As an example, 5 to 10 percent of patients with Brooke-Spiegler syndrome develop malignant adnexal tumors [6]. (See 'Brooke-Spiegler syndrome' below.)

CLINICAL FEATURES — Adnexal tumors typically present as pink, skin-colored, or slightly bluish papules or nodules ranging in size from a few millimeters to several centimeters (picture 1A-C). Lesions are typically asymptomatic and slow growing over several years. Malignant adnexal tumors have a similar clinical appearance but exhibit rapid growth and can ulcerate. Adnexal tumors can be pigmented and may clinically resemble a melanocytic tumor.

Follicular and sebaceous neoplasms occur most frequently on the head and neck, where the greatest density of folliculosebaceous units is found. Eccrine neoplasms can arise in any area of skin but are most frequently found on the palms and soles. Apocrine tumors have a predilection for the axilla, anogenital region, and eyelids.

Patients with multiple adnexal tumors should be evaluated for possible syndromes associated with adnexal tumors. (See 'Syndromes associated with cutaneous adnexal tumors' below.)

DIAGNOSIS

Biopsy — Because of the extensive overlap in clinical features of cutaneous adnexal tumors, biopsy is essential for proper diagnosis. Excisional or punch biopsies are preferred to shave biopsies for the diagnosis because superficial shave biopsies may miss important diagnostic findings. As an example, the surface of fibrofolliculomas and trichodiscomas can resemble an angiofibroma, and a superficial shave biopsy may lead to a misdiagnosis. However, a deep-shave biopsy that captures a majority of the dermis with the lesion may be acceptable. (See "Skin biopsy techniques".)

Pathology — The histopathologic characteristics of benign and malignant adnexal tumors are discussed in the sections on specific tumor types below.

●(See 'Eccrine and apocrine tumors' below.)

●(See 'Follicular tumors' below.)

●(See 'Tumors with sebaceous differentiation' below.)

Immunoperoxidase stains — Most adnexal tumors can be diagnosed accurately with routine hematoxylin and eosin-stained (H&E) sections from an adequate biopsy. When small, partial biopsies are performed or tumors have ambiguous histopathologic features, immunohistochemical stains are a valuable adjunct:

●Ber-Ep4, cytokeratin 15, and T cell death-associated gene 51 (TDAG51) – Markers of hair follicle differentiation, but also variably positive in some eccrine and apocrine tumors.

●Cytokeratin 20 and androgen receptor – The presence of cytokeratin 20 positive-Merkel cells colonizing benign hair follicle tumors (eg, trichoblastoma) and absence of androgen receptor positivity helps distinguish those tumors from basal cell carcinoma. Androgen receptor is frequently expressed in sebaceous carcinoma as well.

●CD34 – Marker of trichilemmal differentiation and positive in the stroma in trichodiscoma.

●Epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) – Useful markers of sweat gland/ductal differentiation.

●Myoepithelial markers (eg, smooth muscle actin, p63, S100, SOX10, calponin) – Used to assess for loss of myoepithelial cells in invasive adenocarcinomas or to assess for myoepithelial differentiation in cutaneous mixed tumors.

●Beta-catenin – Positive in hair matrical tumors (eg, pilomatricoma).

●PTEN – Complete loss of PTEN staining occurs in >80 percent of trichilemmomas in patients with Cowden syndrome and in only 3 percent of sporadic trichilemmomas [10].

●Adipophilin – Marker of sebocytic lineage.

●CD117 (c-kit) – Positive markers for sweat gland tumors, including adenoid cystic carcinoma, cylindroma, and spiradenoma.

●Phosphohistone H3 and Ki-67 (MIB-1) – Immunostains to assess the mitotic and proliferative rate of tumors, respectively.

●Cytokeratin 7 or CAM 5.2 – Positive in many sweat gland tumors, including extramammary Paget disease.

●MSH2, MLH1, MSH6, and PMS2 – Screening stains for loss of protein expression in sebaceous tumors associated with Muir-Torre syndrome.

●Immunostains detecting protein products of gene fusions – MYB for adenoid cystic carcinoma and cylindroma, YAP1 and NUT for poroma/porocarcinoma, pan-TRK for secretory carcinoma, PLAG1 and HMGA2 for mixed tumors.

Differentiation of primary cutaneous adnexal carcinoma from metastatic adenocarcinoma — Significant histopathologic overlap exists between primary cutaneous adenocarcinomas of apocrine or eccrine derivation and various internal adenocarcinomas that metastasize to the skin. Clinical history of prior cancer is the most useful information when confronted with this differential diagnosis.

Immunostaining can also be helpful in distinguishing primary cutaneous tumors from cutaneous metastases. Since no single stain is fully sensitive or specific, a combination of these stains provides the best results. Positive staining for p63 or p40, D2-40 (podoplanin), cytokeratin 5/6, and cytokeratin 15 is supportive of primary cutaneous origin [11,12]. Additional staining with cytokeratin 7, cytokeratin 20, estrogen receptor, progesterone receptor, thyroid transcription factor 1, prostate specific antigen, renal cell carcinoma antigen, and various other stains can be used in appropriate settings to exclude various forms of metastatic carcinomas. (See "Adenocarcinoma of unknown primary site", section on 'Immunohistochemistry'.)

In cases of cutaneous metastases of unknown origin, molecular assays that assess gene expression profiles can also be used to identify potential candidates for the primary site of the tumor. (See "Adenocarcinoma of unknown primary site", section on 'Molecular cancer classifier assays'.)

ECCRINE AND APOCRINE TUMORS

Benign

Syringoma — Syringomas are small tumors of eccrine or apocrine origin that present as multiple discrete, skin-colored papules 2 to 4 mm in diameter [13,14]. They occur most frequently in the periorbital area (picture 2) but they may involve any body site. Eruptive syringomas appear during childhood or early adulthood on the anterior neck (picture 3A-B), chest, shoulders (picture 4), abdomen, and genital areas (picture 5).

Multiple or eruptive syringomas may be associated with Down's syndrome [15], anti-epileptic medications [16], and hyperthyroidism [17]. Reports of eruptive syringomas at the sites of prior inflammatory lesions [18] or hair waxing [19] have led to discussion of a reactive rather than neoplastic etiology in some cases. Multiple clear cell syringomas have been reported in patients with diabetes mellitus [20].

Histologically, syringomas are characterized by multiple small epithelial collections with central ducts surrounded by a bilayer of cuboidal cells in the superficial dermis (picture 6). Frequently, a tapering, comma-shaped edge is present at one edge of the epithelial collections with an encompassing fibrotic stroma [15-20].

Poroma — Poroid tumors, including hidroacanthoma simplex, classic poroma, dermal duct tumor, and poroid hidradenoma, are benign adnexal tumors characterized by small round, monomorphous cells with small amounts of cytoplasm (poroid cells) that exhibit ductal differentiation. Originally regarded as a purely eccrine tumor, it is now clear that both eccrine and apocrine poromas occur. HRAS mutations have been reported in a small percentage of poromas [21]. RNA sequencing has identified recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in approximately 90 percent of poromas and approximately 65 percent of porocarcinomas [22].

The classic variant of poroma presents as a skin-colored or erythematous papule with a predilection for the palms and soles (picture 7A-B). The other variants are found on the trunk and limbs (picture 1A). The average age at diagnosis for poroid tumors is the fifth and sixth decade of life with no sex predilection [23,24]. Multiple poromas (poromatosis) can occur sporadically but have also been associated with pregnancy, hidrotic ectodermal dysplasia, bone marrow transplant, radiation exposure, chemotherapy, or radiation therapy [25-29].

Histologically, the intraepidermal variant of poroma (hidroacanthoma simplex) resembles a seborrheic keratosis, but is distinguished by duct formation (picture 8). Classic poroma consists of a superficial dermal proliferation of poroid cells with multiple epidermal connections and a highly vascular stroma (picture 9). A purely dermal variant of poroma (dermal duct tumor) is composed of multiple small nodular aggregations (picture 10). Poroid hidradenoma consists of one or a few large aggregations of poroid cells in the dermis, often extending into the subcutaneous fat (picture 11).

Cytologic atypia is typically minimal. Tumor necrosis and mitotic activity are often present in benign poroid neoplasms and should not be mistaken for an indication of malignancy. Porocarcinoma is distinguished by nuclear atypia, infiltrative growth pattern, and rapid growth. (See 'Porocarcinoma' below.)

Cylindroma and spiradenoma — Cylindromas and spiradenomas are sweat duct tumors centered in the dermis that often show overlapping features in the same tumor (spiradenocylindroma). They occur sporadically in the older adult population, typically as a solitary papule or nodule on the head or neck or, less commonly, on the trunk and extremities (picture 1B, 1D). Detection of multiple cylindromas (picture 12) or spiradenomas should raise the suspicion of Brooke-Spiegler syndrome or familial cylindromatosis caused by mutation of CYLD. (See 'Syndromes associated with cutaneous adnexal tumors' below.)

Sporadic cylindromas and spiradenomas also have frequent CYLD mutations. In addition to CYLD mutations, some cylindromas harbor t(6;9) MYB-NFIB gene fusions and mutations in DNMT3A [30,31]. Spiradenomas frequently have ALPK1 mutations, which are mutually exclusive from CYLD mutations [31].

Histologically, cylindroma consists of small, irregularly shaped aggregations of basaloid keratinocytes closely opposed to one another in a pattern resembling interconnecting pieces of a jigsaw puzzle (picture 13). Scattered lymphocytes and small ducts are present within the neoplastic clusters of cells. Hyalinized basement membrane material surrounds the individual clusters and forms small circular collections between cells within the clusters.

Spiradenomas have a similar appearance, with basaloid keratinocytes, interspersed lymphocytes, ductal differentiation, and hyalinized basement membrane material, but form one or a few large nodules in the dermis with a trabecular pattern (picture 14), as opposed to the many small clusters in cylindroma.

Cutaneous mixed tumor — Mixed tumors of the skin, also called chondroid syringoma, are rare apocrine or eccrine tumors with mixed epithelial and stromal components. Myoepithelioma represents a closely related tumor of myoepithelial cells that lacks ductal differentiation.

Mixed tumors usually present in older adults as asymptomatic, slow-growing, firm nodules, most frequently located in the head and neck region (picture 15) [5]. Cutaneous mixed tumors and myoepitheliomas frequently have PLAG1 or EWSR1 gene rearrangements similar to pleomorphic adenomas of the salivary gland [32,33]. PHF1-TFE3 fusion has been reported in a malignant mixed tumor [34].

Histologically, mixed tumors of the skin resemble mixed tumors of the salivary gland (pleomorphic adenoma). Follicular and sebaceous elements may also be observed. Mixed tumors form large, well-circumscribed, nodular aggregations of epithelial cells with focal ductal differentiation in the dermis and upper subcutis. A prominent myxoid, chondroid, or fibrous stroma surrounds the epithelial cells and distinguishes this variant of sweat gland tumor (picture 16). Prominent myoepithelial differentiation is frequently present and can be demonstrated with myoepithelial markers such as smooth muscle actin or calponin. When myoepithelial differentiation is the dominant pattern, a diagnosis of myoepithelioma is rendered. The presence of decapitation secretion or concurrent folliculosebaceous differentiation confirms apocrine lineage.

Syringofibroadenoma — Typically regarded as an eccrine tumor, syringofibroadenoma is a superficial dermal tumor presenting as a hyperkeratotic or verrucous plaque usually found on the extremities and, less commonly, on the eyelid [35] or in a nevus sebaceus [36]. An association with ectodermal dysplasia syndromes has also been reported [37].

Histologically, syringofibroadenoma is composed of thin, interconnecting strands of keratinocytes in a lattice pattern that connects with the undersurface of the epidermis (picture 17). Small ducts are present in variable numbers in the thin strands [35-37]. Syringofibroadenomatosis is a reactive hyperplasia of eccrine ducts seen in areas of trauma or inflammation that histopathologically resembles syringofibroadenoma [38].

Syringocystadenoma papilliferum — Syringocystadenoma papilliferum is an adnexal tumor affecting a much younger patient population than most adnexal tumors, with an average age of 15 at diagnosis [6]. Syringocystadenoma papilliferum presents as a warty plaque most often located on the scalp. Less commonly, lesions can be found on the face, chest, arms, or thighs. Syringocystadenoma papilliferum may occur sporadically, but approximately one-third of cases are associated with a nevus sebaceus [39]. (See "Nevus sebaceus and nevus sebaceus syndromes".)

Histologically, syringocystadenoma papilliferum is a tumor of apocrine derivation characterized by cuboidal and columnar epithelial cells lining ducts that invaginate from the epidermis into the superficial dermis. Dilated, cystic ducts are frequently present, some of which have papillary projections into their lumens. An inflammatory infiltrate with many plasma cells surrounds the tumor (picture 18). Frequently, apocrine (decapitation) secretion is visible in some parts of the tumor. Most syringocystadenoma papilliferum harbor RAS or BRAF mutations [40].

Hidradenoma papilliferum — Hidradenoma papilliferum usually occurs on the vulvar region of middle-aged women (picture 19) [41]. It displays some histopathologic overlap with syringocystadenoma papilliferum but resides in the deeper dermis and subcutis with a more nodular configuration, lacks a plasmacytic infiltrate, and is found almost exclusively in the anogenital region. It has been suggested that hidradenoma papilliferum may derive from anogenital mammary-like glands [42-44]. Mutations in PIK3CA and AKT1 have been detected [45,46]. Rare cases occurring outside the anogenital region have been reported [47-49]. (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers".)

Hidradenoma — Hidradenoma is a benign adnexal tumor related to poroma that presents as a solitary nodule, typically ranging from 1 to 3 cm in size. It occurs in all areas of the body, usually in adults. Hidradenoma can be either apocrine or eccrine, with variants including solid-cystic, clear (pale) cell, nodular, and poroid types. The term "acrospiroma" has also been used for the spectrum of hidradenoma and poroma. Approximately 50 percent of hidradenomas harbor a t(11;19) translocation causing a CRTC1-MAML2 gene fusion [50]. CRTC3-MAML2 and EWSR1-POU5F1 fusions have also been reported.

Histopathologic features include a circumscribed dermal tumor with variable extension into the subcutis, composed of one or more large nodules of epithelial cells with areas of ductal differentiation (picture 20). Epidermal connection is present in 25 percent of cases.

Tubular/papillary adenoma, including papillary cystadenoma — Numerous reports have described benign apocrine or eccrine tumors with a papillary, tubular, and/or cystic pattern under various names, including papillary eccrine adenoma, tubular apocrine adenoma, and papillary apocrine fibroadenoma. These tumors have no sex predilection and are most frequently seen on the head and extremities [6].

BRAF V600E mutations have been identified in >50 percent of these tumors, and KRAS mutations occur in a small percent [51].

Histologically, tubular/papillary adenomas are well-circumscribed proliferations of small epithelial aggregations exhibiting ductal differentiation. They form round, cystic, or tubular structures in the dermis (picture 21). Papillary projections into cystically-dilated ducts are sometimes prominent.

Malignant — Malignant adnexal tumors are rare and typically affect older adults or individuals with familial tumor syndromes. For nearly all of the benign apocrine and eccrine tumors listed above, there is a malignant counterpart (eg, poroma and porocarcinoma) which is differentiated from the benign form by clinicopathologic features including larger size, infiltrative growth pattern (poor circumscription), nuclear enlargement and pleomorphism, increased mitotic activity, necrosis, and ulceration.

Porocarcinoma — Porocarcinoma or malignant eccrine poroma is a rare tumor that occurs most often on the head and neck or lower extremities of older individuals (mean age 68) and sometimes arises in a pre-existent poroma [52,53]. A meta-analysis of 453 cases showed equal sex distribution and progression to metastasis in 31 percent of cases, with lymph node being the most common site of metastasis [53].

Deoxyribonucleic acid (DNA) sequencing data have shown mutations in EGFR, HRAS, TP53, RB1, ATM, ARID1A, PIK3CA, and CDKN2A [21]. RNA sequencing has identified recurrent YAP1 gene fusions in approximately 65 percent of porocarcinomas [22]. Retrospective analysis of the National Cancer Database found 5- and 10-year survival rates of 69 and 54 percent, respectively, for porocarcinoma [54].

Histologically, porocarcinoma is characterized by infiltrative growth pattern, nuclear atypia, increased mitotic activity, and necrosis (picture 22). The presence of an adjacent, benign, poroid component is helpful in establishing the diagnosis.

Wide local excision is the mainstay of treatment. Mohs micrographic surgery has also been utilized for removal of porocarcinoma. Data are lacking to support sentinel lymph node biopsy, though lymph node dissection is typically utilized when lymph node involvement is detected [53].

Large tumor size (particularly >4 cm) is associated with a poor prognosis. Metastasis is detected in 20 to 30 percent of patients at presentation, with most metastases occurring in the lymph nodes (most common site) or lungs [55]. Chemotherapy and/or radiation therapy have been reported for the treatment of advanced stages of porocarcinoma.

Adenoid cystic carcinoma — Adenoid cystic carcinoma is a variant of adenocarcinoma that can arise in multiple organ types. Salivary gland adenoid cystic carcinoma is the most frequent type, but primary adenoid cystic carcinoma has been reported in skin, breast, lung, prostate, lacrimal gland, female genital tract, and gastrointestinal tract.

A characteristic t(6;9) MYB-NFIB gene fusion is present in cutaneous as well as noncutaneous adenoid cystic carcinoma [56]. MYBL1 rearrangements occur in a small minority of cases [57]. Primary cutaneous adenoid cystic carcinoma has a more favorable prognosis than its salivary counterpart [58].

The average age of onset for primary cutaneous adenoid cystic carcinoma is approximately 60 years [58]. The tumor can occur on the scalp, trunk, and extremities, and typically presents as a slow-growing, nondescript nodule on the skin. Diagnosis of adenoid cystic carcinoma on the lower half of the face should prompt evaluation for local spread of salivary gland adenoid cystic carcinoma.

Adenoid cystic carcinoma exhibits three primary histopathologic growth patterns (ie, cribriform, solid, tubular). The cribriform pattern is the most unique of the three, with clusters of epithelial cells with both true ducts and duct-like collections of mucin interspersed in a sieve-like pattern (picture 23). Solid and tubular patterns are also observed, with multiple patterns frequently present in the same tumor. Perineural invasion is frequently present.

Wide local excision is the most common treatment. In a case series of 13 cutaneous adenoid cystic carcinomas, local recurrence occurred in three cases, and distant metastasis occurred in two cases [59]. Perineural invasion, high grade transformation, and ≥1 cm tumor size were associated with aggressive disease. Other studies have reported increasing age, stage, and size ≥ 2.5 cm as risk factors for metastasis [60].

Compared with adenoid cystic carcinoma of the lung, lacrimal gland, genital tract, and salivary gland, adenoid cystic carcinoma of the skin and breast have an excellent prognosis, with an 87 to 96 percent five-year survival rate [61,62]. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)

Mucinous carcinoma and endocrine mucin-producing sweat gland carcinoma — Mucinous carcinoma is a type of adenocarcinoma that occurs in multiple organ systems including breast, skin, ovary, lung, and gastrointestinal tract. Cutaneous mucinous carcinoma presents as a slow-growing, blue or reddish nodule ranging from 0.5 to 8 cm with a predilection for the scalp, eyelids, and axilla. The mean age of onset is approximately 60 years [63]. Endocrine mucin-producing sweat gland carcinoma (EMPSGC) represents a low-grade adnexal carcinoma that can be a precursor to mucinous carcinoma and typically occurs on or near the eyelid [64].

Genetic analysis of these two types of cutaneous carcinomas has yielded minimal results, with many studies detecting no molecular driver mutations or gene fusions. One next-generation sequencing study found mutations in DNA damage response/repair genes (BRD4, PPP4R2, RTEL1) and tumor suppressor pathways (TP53, TSC1, LATS2) [65].

Histologically, mucinous carcinoma consists of islands of epithelial cells seemingly floating within large pools of mucin in the dermis and/or subcutis. Sometimes apocrine decapitation secretion and ductal differentiation is apparent. Biopsy findings in EMPSGC include rounded aggregations of epithelial cells with mild to moderate cytologic atypia in the dermis that express neuroendocrine markers and estrogen and progesterone hormone receptors. Mucin deposition is present but to a lesser degree than mucinous carcinoma. INSM1 and MUC2 immunostaining can assist in the diagnosis.

Recurrence rates range from 20 to 30 percent for EMPSGC and mucinous carcinoma, and no metastases were reported in a large meta-analysis in 2020 [66]. Single cases of metastatic EMPSGC have been reported [67].

Microcystic adnexal carcinoma — Microcystic adnexal carcinoma, also known as sclerosing sweat duct carcinoma, is a locally aggressive malignancy that typically occurs on the central face, although extrafacial cases have been reported [68,69]. Microcystic adnexal carcinoma presents as a slowly expanding, scar-like plaque or firm nodule (picture 24A-D) [69]. The mean age of diagnosis is 64, with a slight female predominance [70].

Recurrent TP53 and JAK1 mutations have been identified with next-generation sequencing [71].

Histologically, microcystic adnexal carcinoma shows divergent differentiation, with follicular elements of keratin cysts in the upper dermis and infiltrating strands of epithelial cells with sweat ductal differentiation that often extends into the subcutis, and an associated fibrotic stroma (picture 25).

Surgical excision (wide local excision or Mohs micrographic surgery) and/or radiation therapy is the most common treatment. Use of radiation treatment has been associated with improved survival in one study [70]. The clinical presentation, diagnosis, and treatment of microcystic adnexal carcinoma are discussed in greater detail separately. (See "Microcystic adnexal carcinoma".)

(Aggressive) digital papillary adenocarcinoma — Digital papillary adenocarcinoma, also called aggressive digital papillary adnexal carcinoma or aggressive digital papillary tumor, is a malignant adnexal tumor presenting as a nodule on the volar surface of the digits of the hands and, less often, of the feet [72,73]. Digital papillary adenocarcinoma is a rare tumor, with an estimated incidence of 0.08 per million person-years [74]. It usually occurs in adult individuals, with a male predominance [73]. Rarely, patients present with metastatic disease to the lymph nodes and lungs.

Sequencing analysis from one study showed BRAF V600E mutations in one out of nine tumors [75]. Gene expression profiling of eight cases showed overexpression of FGFR2, indicating that pathway as a potentially treatment-targetable genetic alteration [76].

Histopathologically, the tumor displays a multinodular, sometimes infiltrative configuration of epithelial cells with glandular and ductal differentiation. Frequently, papillary projections within cystic ductal spaces are present (picture 26). Cytologic atypia is variable, ranging from mild to severe, and does not appear to correlate with prognosis [73].

Wide local excision or digital amputation is the treatment of choice for digital papillary adenocarcinoma [72,73]. Local recurrence rates range from 16 to 50 percent. In one study, local recurrence was reported in 1 of 21 patients treated with re-excision or amputation after the initial excision and in 11 of 22 patients who did not undergo additional procedures after the initial excision, after an average follow-up time of six years [72]. Metastasis occurs in approximately 15 to 30 percent of cases [72-74].

Extramammary Paget disease — Extramammary Paget disease can be either a primary cutaneous adenocarcinoma or a tumor with secondary cutaneous involvement via extension from a lower gastrointestinal or urinary tract carcinoma. The cell of origin for primary cutaneous extramammary Paget disease is controversial. While some cases of extramammary Paget disease represent epidermal extension of an adenocarcinoma arising from underlying apocrine or eccrine glands, extramammary Paget disease may also arise from pluripotent stem cells or Toker cells [77,78]. PIK3CA, AKT1, ERBB2, and RAS/RAF pathway mutations have been reported in extramammary Paget disease [46,79].

Extramammary Paget disease usually presents with well-demarcated, eczematous plaques predominantly located in the anogenital region and, less commonly, in the axillae. Multifocal and bilateral tumors have been reported.

Histopathologically, extramammary Paget disease mimics Paget disease of the breast with a poorly circumscribed proliferation of large epithelial cells distributed singly and in small clusters between normal keratinocytes in the epidermis (ie, pagetoid scatter) with variable ductal differentiation (picture 27). HER2 overexpression in some cases may indicate potential therapeutic response to trastuzumab [80].

The diagnosis, differential diagnosis, and treatment of extramammary Paget disease are discussed separately. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Paget disease of the vulva'.)

Cutaneous cribriform carcinoma — Cutaneous cribriform carcinoma (cutaneous apocrine cribriform carcinoma) is a rare, low-grade sweat gland carcinoma with frequent apocrine differentiation that occurs in adults of all ages and has a predilection for the upper and lower extremities [81]. It presents as a solitary, slow-growing, skin-colored nodule ranging from 1 to 3 cm in size. Surgical excision is the primary treatment, and no metastases have been reported.

Biopsy findings for cutaneous cribriform carcinoma include a relatively well-circumscribed, nodular growth pattern centered in the dermis with peripheral lymphoid aggregates (picture 28). Subcutaneous extension can be seen. The tumor is composed of interconnecting aggregations of epithelial cells with irregular, dilated ductal spaces forming a cribriform pattern (picture 29). The thin, thread-like strands seen in cribriform areas are characteristic. Mitotic figures are frequently present but typically low in number.

Cutaneous secretory carcinoma — Cutaneous secretory carcinoma, also known as cutaneous mammary analogue secretory carcinoma, is a low-grade sweat duct carcinoma caused by a t(12;15) translocation resulting in ETV6-NTRK3 fusion [82]. NFIX-PKN1 gene fusion has been reported in a single case [83].

Cutaneous secretory carcinoma is a rare tumor, analogous by histopathology and molecular origins to secretory carcinoma of the breast and salivary glands. Twenty-five cases have been reported with no metastatic cases [83,84]. Histopathologically, they have a nodular, relatively well-circumscribed pattern with characteristic eosinophilic secretions in ducts.

FOLLICULAR TUMORS

Benign

Trichoblastoma and trichoepithelioma — Trichoblastoma and trichoepithelioma are benign epithelial tumors composed of follicular germinative cells resembling those seen in the embryologic buds of primitive folliculosebaceous units. They present as smooth, nonulcerated, skin-colored papules, sometimes with associated telangiectasias usually located on the head and neck (picture 1C, 1E). The majority of cases occur in adults after the age of 40. The presence of multiple trichoepitheliomas should raise the suspicion of Brooke-Spiegler syndrome or multiple familial trichoepithelioma. (See 'Brooke-Spiegler syndrome' below.)

Histologically, trichoblastoma shows large and small aggregations of basaloid keratinocytes surrounded by a fibrous stroma rich in fibroblasts and mesenchymal cells that often form densely cellular aggregations (papillary mesenchymal bodies) closely opposed to the epithelial cells in a pattern recapitulating embryologic hair follicle development (picture 30).

Trichoepithelioma represents a subset of trichoblastoma composed of smaller islands of basaloid cells, sometimes only one to two cells thick, with marked fibrosis (desmoplastic trichoepithelioma). Numerous histopathologic variants of trichoblastoma have been described, including nodular, retiform, cribriform, racemiform, columnar, and adamantinoid (lymphadenoma) [6].

Trichoadenoma — Trichoadenoma presents as a slow-growing, skin-colored papule on the face. Histologically, trichoadenoma is composed of multiple cystic collections of keratinocytes with differentiation toward the follicular infundibulum (picture 31).

Trichofolliculoma — Trichofolliculoma is a rare hamartomatous lesion with follicular differentiation that typically occurs on the face (picture 32A-C). Histologically, trichofolliculoma is composed of a large central follicle from which multiple small (vellus) hair follicles emanate (picture 33). The vellus follicles sometimes produce fully developed hair, resulting in a clinical appearance of multiple hairs growing centrally from a small papule. A sebaceous variant without fully developed hair shafts has also been described [85].

Trichilemmoma — Trichilemmoma (also known as tricholemmoma) is a benign follicular tumor with differentiation toward the outer root sheath of the hair follicle. It has been hypothesized that human papillomavirus (HPV) may have a pathogenetic role. However, polymerase chain reaction studies for HPV detection in trichilemmomas provided conflicting results [86-89]. The discovery of frequent HRAS mutations supports a neoplastic etiology [90].

Solitary trichilemmomas usually occur in older adults without sex predilection [1]. They present as a small skin-colored papule or verrucous lesion, most often located on the central face (picture 34). Trichilemmoma is a frequent secondary tumor found in nevus sebaceous, and multiple facial trichilemmomas are seen in patients with Cowden syndrome (picture 35). (See 'Cowden syndrome (multiple hamartoma syndrome)' below.)

Histopathologically, trichilemmoma exhibits a papillated, well-circumscribed, exo-endophytic growth pattern (picture 36). Lobules of keratinocytes with pale cytoplasm predominate centrally, with smaller basaloid keratinocytes with peripheral palisading forming a peripheral rim around the tumor. Focal hypergranulosis resembling koilocytic changes of HPV is frequently present at the periphery.

Trichodiscoma and fibrofolliculoma — Although originally described as distinct entities, evidence suggests that trichodiscomas and fibrofolliculomas represent a spectrum of the same neoplastic process [91]. There is also overlap with perifollicular fibroma (angiofibroma). Both fibrofolliculoma and trichodiscoma present as small, 2 to 4 mm, dome-shaped, skin-colored papules on the face, scalp, ears, or upper trunk. They occur sporadically in adults and are seen in multiplicity in patients with Birt-Hogg-Dubé syndrome caused by FLCN mutations (picture 37). (See 'Birt-Hogg-Dubé syndrome' below.)

Histologically, trichodiscomas and fibrofolliculomas are tumors of the follicular mantle with both stromal and epithelial components. In trichodiscoma, a central zone of fibromucinous stroma predominates, with surrounding sebaceous glands in a "mitt-like" configuration (picture 38). In fibrofolliculoma, thin interconnecting strands of keratinocytes punctuated by small collections of mature sebocytes radiate from a dilated follicular infundibulum and are accompanied by a variably fibrotic and mucinous stroma (picture 39).

Tumor of the follicular infundibulum — Tumors of the follicular infundibulum are rare adnexal tumors that usually present as solitary, keratotic papules resembling basal cell carcinoma or actinic keratosis. They usually occur in older adults and are located on the head and neck in the majority of cases [92]. Multiple or eruptive tumors of the follicular infundibulum may present as hypopigmented, scar-like macules or flat papules [93,94]. Microscopic tumors of the follicular infundibulum are often discovered as incidental findings in skin biopsies and excisions.

Despite its name, tumors of the follicular infundibulum is a follicular tumor with predominantly follicular isthmic differentiation and a superficial, plate-like growth pattern running parallel to the overlying epidermis. Keratinocytes with bright pink cytoplasm that contrast sharply with the darker pink epidermal keratinocytes descend from and reconnect with the undersurface of the epidermis (picture 40). Peripheral palisading, small keratin cysts, and ducts are sometimes present.

Panfolliculoma — Panfolliculoma is a very rare adnexal neoplasm that occurs predominantly on the head and neck of older individuals with a male predilection [95]. Panfolliculoma exhibits follicular upper and lower segment (infundibular, isthmic, germinative, and matrical) differentiation within the same tumor (picture 41). Intraepidermal and cystic variants have been described.

Pilomatricoma — Pilomatricoma, also called pilomatrixoma or calcifying epithelioma of Malherbe exhibits differentiation toward the hair matrix portion of the lower segment (stem) of hair follicles. Activating mutations in beta-catenin in the WNT-signaling pathway appear to be involved in the pathogenesis of these tumors [96,97]. Mutation in the PLCD1 gene has been detected in familial pilomatricomas [98].

Pilomatricomas occur at any age without sex predilection and exhibit a bimodal distribution with the highest incidence in children and adults over 50. Fifty percent occur on the head and neck [99]. They present as firm, skin-colored to bluish papules or nodules (picture 42A-B). Transepidermal elimination (perforation) sometimes occurs with extrusion of calcified/ossified portions of the neoplasm. Most lesions are <3 cm, but giant lesions up to 15 cm have been reported [100].

Multiple pilomatricomas are associated with myotonic dystrophy (Steinert's disease) [101], Gardner's syndrome [102], Turner syndrome [103], trisomy 9 [104], Kabuki syndrome [105], Rubinstein-Taybi Syndrome [106], and glioblastoma [107]. The presence of at least six pilomatricomas is highly suggestive of an underlying syndrome (sensitivity 46 percent, specificity 95 percent) [108].

Histologically, pilomatricomas appear as well-circumscribed nodular collections of basaloid epithelial cells that transition centrally into pink keratinized cells without nuclei (ghost/shadow cells). Early tumors have a larger proportion of basaloid matrical cells with abundant mitotic activity. Late-stage pilomatricomas may be composed almost exclusively of shadow cells with areas of calcification and ossification (picture 43).

Proliferating trichilemmal tumor — Proliferating trichilemmal tumor (also called proliferating pilar tumor, proliferating trichilemmal cyst, or proliferating follicular-cystic neoplasm) encompasses a spectrum of rare tumors with follicular isthmic differentiation and varying degree of atypia. The extreme end of the spectrum has been considered a variant of squamous cell carcinoma, but is better classified as a form of follicular adnexal carcinoma (the designation "proliferating follicular-cystic carcinoma" has been proposed) [109].

Most proliferating pilar tumors present as solitary, asymptomatic nodules ranging from 2 to 5 cm with a broad age range and slight female predilection [6,110]. Over 85 percent are found on the scalp.

On histology, these neoplasms have a multinodular configuration that fills the dermis, with frequent extension into the subcutis. Brightly eosinophilic keratinocytes are present in the outer portion of tumor aggregates and cornify abruptly into compact keratin-filled cystic spaces with frequent calcification (picture 44). The degree of cytologic atypia and mitotic activity, as well as the presence of a more infiltrative growth pattern, are indicators of potential malignancy.

Malignant — Basal cell carcinoma is the most common cutaneous malignancy that exhibits follicular differentiation. The remainder of malignant tumors with hair follicle differentiation includes rare tumors seen more frequently in patients with germline mutations that predispose to adnexal tumors. (See "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma" and 'Syndromes associated with cutaneous adnexal tumors' below.)

Trichoblastic carcinoma — Malignant transformation of trichoblastoma is rare. The diagnosis is based upon the histopathologic finding of atypical basaloid keratinocytes with crowded, hyperchromatic nuclei and increased mitotic activity adjacent to a benign trichoblastoma.

Outside this setting, the diagnosis of trichoblastic carcinoma is controversial, with some experts arguing that it represents a variant of basal cell carcinoma [111]. However, the presence of hypercellular stroma that can also exhibit malignant changes (so-called trichoblastic carcinosarcoma) distinguishes trichoblastic carcinoma from basal cell carcinoma.

Trichilemmal carcinoma — Trichilemmal carcinoma is a rare malignant counterpart of trichilemmoma with approximately 100 cases reported [112]. However, the number of cases of trichilemmal carcinoma may be overestimated, due to significant histopathologic overlap with clear cell squamous cell carcinoma [113,114]. FGFR3 and ROS1 gene fusions, along with TP53, NF1, and NRAS mutations, TOP1 amplification, and PTEN deletion, were found in molecular analysis of four trichilemmal carcinomas [115].

Trichilemmal carcinomas are usually found on sun-exposed surfaces of older adult patients, suggesting that ultraviolet radiation plays a pathogenic role. The tumor is composed of infiltrative aggregations of pale keratinocytes with outer root sheath differentiation, cytologic atypia, and brisk mitotic activity (picture 45).

Surgical excision, with or without the Mohs micrographic technique, provides high cure rates and should be considered first-line treatment [112,116]. In a review of 35 cases with follow-up data, local recurrence occurred in 3 cases and metastatic disease in 1 after an average follow-up of 33 months [112].

Pilomatrix (matrical) carcinoma — Pilomatrix carcinoma is an extremely rare tumor derived from follicular matrix cells with a high rate of local recurrence. It usually occurs on the head and neck of middle-aged and older men [117]. Pilomatrix carcinoma shares the same activating mutations in beta-catenin seen in pilomatricoma [97]. However, a component of benign pilomatricoma is not found in the majority of cases, suggesting that most pilomatrix carcinomas arise de novo.

Histologically, both pilomatricoma and pilomatrix carcinoma consist of nodular aggregations of basaloid keratinocytes that transition to shadow (ghost) cells. Poor circumscription, tumor necrosis, cellular pleomorphism, and asymmetry help distinguish pilomatrix carcinoma from its benign counterpart. Mitotic activity can be high in both benign and malignant tumors.

Wide local excision (≥2 cm margins) or Mohs micrographic surgery are the treatments of choice for pilomatrix carcinoma [97,118]. There are isolated reports of therapeutic response of metastatic pilomatrix carcinoma to cyclophosphamide and etoposide (complete response) and radiation therapy (partial response) [119,120].

TUMORS WITH SEBACEOUS DIFFERENTIATION — Tumors with sebaceous differentiation may occur sporadically or in association with Muir-Torre syndrome. Inactivating mutations in lymphoid enhancer factor 1 (LEF1) and mismatch repair genes (MSH2, MLH1, and MSH6) have been implicated in this family of tumors [121-123]. Germline mutations in MUTYH cause MUTYH-associated polyposis syndrome and show similar features to Muir-Torre syndrome. (See "Sebaceous carcinoma" and "Muir-Torre syndrome".)

Sebaceous hyperplasia — Sebaceous hyperplasia is a relatively common lesion resulting from the enlargement of normal sebaceous glands. Sebaceous hyperplasia is not a true tumor but shares clinical and histopathologic features with sebaceous adenoma. It typically presents as 2 to 6 mm umbilicated, skin-colored to yellowish or brownish papules on the forehead, nose, and cheeks of older individuals (picture 46A-B). Rarely, lesions can occur on the areola, genitalia, and anterior chest, sometimes in a linear configuration ("juxtaclavicular beaded lines") [124-127].

Sebaceous hyperplasia has been reported in 15 to 30 percent of transplant patients treated with cyclosporine [128,129]. The so-called premature sebaceous hyperplasia presents with multiple discrete or plaque-like lesions in children and adolescents and is considered a hamartomatous lesion related to nevus sebaceous [130-132].

Visualization with a dermatoscope reveals individual whitish-yellow aggregations with a rim of dilated blood vessels in "crown" configuration (picture 47). Biopsy shows a dome-shaped lesion with numerous mature sebaceous lobules composed of mature sebocytes, frequently radiating from a central dilated hair follicle (picture 48).

Treatment is for cosmetic reasons and includes electrosurgery, cryosurgery, shave removal, dermabrasion, laser therapy, and oral isotretinoin [133-138].

Sebaceous adenoma and sebaceoma — Sebaceous adenomas are benign, well-differentiated sebaceous tumors typically located in the upper dermis. They are often connected directly with the overlying epidermis instead of a central follicle, as in sebaceous hyperplasia. Sebaceoma is a variant of sebaceous adenoma that is typically located deeper in the dermis [139].

Sebaceous adenomas and sebaceomas share similar clinical characteristics with sebaceous hyperplasia but are typically solitary and larger than sebaceous hyperplasia. They present as yellowish or brownish papules, usually <1 cm in diameter, almost exclusively located on the head and neck (picture 49).

Sebaceous adenomas are the most common sebaceous neoplasm associated with Muir-Torre syndrome [140]. In contrast with sporadic cases, sebaceous adenomas in Muir-Torre syndrome occur frequently on the trunk, as well as the head and neck, and can have a cystic pattern [141]. (See "Muir-Torre syndrome".)

Histologically, sebaceous adenoma is composed of well-circumscribed, round aggregations of predominantly mature, lipid-filled sebocytes with a rim of basaloid, germinative cells at the periphery (picture 50). Maturation of the central sebocytes is less orderly than in sebaceous hyperplasia. In sebaceoma, the basaloid germinative sebocytes predominate (>50 percent) and tend to be centered deeper in the dermis. Sometimes, mature sebocytes are few in number and easily overlooked (picture 51). Limited mitotic activity is often present in both sebaceous adenoma and sebaceoma.

Both the genetic and histopathologic findings in sebaceous adenomas and sebaceous carcinomas show overlapping features, which lead to diagnostic uncertainty/discrepancies in pathologic assessment of these tumors [142].

Sebaceous carcinoma — Sebaceous carcinoma is a rare malignant tumor most commonly occurring in the head and neck region, particularly in the periocular area (picture 52) [143]. It is distinguished from sebaceous adenoma and sebaceoma by an infiltrative growth pattern, cytologic atypia, high mitotic rate, and necrosis (picture 53).

Sebaceous carcinomas are genetically heterogenous with three main genetic types: tumors with a microsatellite instability pattern (mutations in MLH1, MSH2, MSH6), tumors with an ultraviolet signature pattern (mutations in NOTCH1/2, FAT3, TP53, RREB1, KMT2D), and paucimutational tumors that include ocular sebaceous carcinomas (mutations in ZNF750) [144].

The clinical presentation, diagnosis, and treatment of sebaceous carcinoma are discussed separately. (See "Sebaceous carcinoma".)

TREATMENT

Benign adnexal tumors — The treatment of choice for benign adnexal tumors is simple surgical excision. Some experts advocate full excision after partial biopsies of benign adnexal tumors to prevent local persistence and to eliminate the chance of future malignant transformation. However, given the excellent prognosis of these benign tumors and extremely low rate of malignant transformation, clinical follow-up may be preferable for patients not desiring additional surgery.

In patients with syndromes causing multiple adnexal tumors, the tumors can be disfiguring and cause significant psychosocial effects. Although surgical excision of large tumors is often used, excision of all tumors is impractical and other measures can be used to help these patients. Such treatment modalities include superficial shave removal, electrocautery, and laser ablation using erbium-doped yttrium aluminum garnet (Er:YAG) or fractional carbon dioxide (CO₂) lasers [145].

Malignant adnexal tumors — General treatment recommendations are discussed in this section.

Patient evaluation and staging — Patients diagnosed with a malignant cutaneous adnexal tumor should receive a complete skin examination that includes palpation of regional lymph nodes to evaluate for clinical signs of regional metastasis. If enlarged lymph nodes are detected, lymph node biopsy via fine needle aspiration or surgical removal of the enlarged lymph node is indicated.

In patients with large tumors (eg, ≥2 cm) in the head and neck region and particularly in the periorbital area, imaging studies with computerized tomography (CT) or magnetic resonance imaging (MRI) are useful to evaluate for invasion of bone, other deep structures, or the orbit.

The staging for malignant cutaneous adnexal tumors is consolidated with the staging system for cutaneous squamous cell carcinoma in the 2017 eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (table 2) [146].

Local disease

Surgery — Wide local excision with negative surgical margins or Mohs micrographic surgery is the recommended treatment for the majority of malignant adnexal tumors. Mohs micrographic surgery, a surgical technique that offers complete circumferential intraoperative margin monitoring, is the preferred treatment for malignant adnexal tumors located on the head and neck and has also been recommended as an appropriate treatment for tumors at all anatomic sites by the American Academy of Dermatology guidelines for Mohs micrographic surgery [147]. (See "Mohs surgery".)

However, wide local excision is a reasonable alternative for tumors on the trunk and extremities. Because of the rarity of these tumors, the width of safety margins has not been evaluated in clinical trials or large observational studies. In general, 1 to 2 cm clinical margins are used [148]. Partial amputation may be necessary in malignant adnexal tumors on the digits.

Radiation therapy — Retrospective reviews and single case reports have reported successful treatment of sebaceous carcinoma with radiation therapy [149,150]. A retrospective review of 1045 patients with a histologic diagnosis of cutaneous adnexal carcinoma with eccrine differentiation showed no survival benefit in patients receiving adjuvant radiation therapy versus surgery alone [151]. Radiation therapy should be reserved for patients in which surgery is not an option or as a postsurgical adjuvant treatment when surgical margins cannot be cleared.

Sentinel lymph node biopsy — Because of the rarity of these tumors and the relatively low rate of nodal involvement [9,152], the role of sentinel lymph node biopsy in patients without clinical lymph node involvement has not been established and cannot be recommended in routine practice.

Metastatic disease — There is very limited evidence on the treatment of metastatic adnexal tumors from single case reports [120,153]. The choice of treatment is made on a case-by-case basis:

●An increasing number of reports detailing mutations in the MAP kinase pathway (eg, BRAF, RAS) and PIK3CA/AKT1 pathway indicate targeted therapies may be of use in selected aggressive adnexal carcinomas. Some apocrine and eccrine carcinomas express estrogen and progesterone receptors.

●Case reports detailing response to hormone-directed therapies (eg, tamoxifen) indicate another potential path of treatment in these tumors [154].

●Reports of HER2 amplification and response to trastuzumab have been reported as well [155]. A few cases have been successfully treated with adjuvant chemoradiation [156,157].

●Cases of malignant adnexal carcinomas successfully treated with immunotherapy (eg, anti-programmed cell death protein 1 [PD1]) have been reported [158,159].

PROGNOSIS — Malignant cutaneous adnexal tumors are primarily locally aggressive tumors. Tumor recurrence resulting from incomplete removal of the tumor is a major prognostic concern. Local recurrence rates range from 10 to 50 percent among patients treated with wide local excision or Mohs micrographic surgery [72,112,160]. Routine postsurgical follow-up visits are advisable to monitor for recurrence.

In a large, retrospective study of malignant cutaneous adnexal tumors using the Surveillance, Epidemiology, and End Results (SEER) database, distant metastases occurred in 12 percent of patients [9]. This may overestimate the actual incidence of metastasis, due to underreporting of early-stage malignant cutaneous adnexal tumors to the SEER database. The overall five-year survival and the five-year disease-specific survival were 73 and 98 percent, respectively. Increasing age, T3 tumors, presence of nodal or distant metastases, and nonsurgical treatment are unfavorable prognostic factors.

SYNDROMES ASSOCIATED WITH CUTANEOUS ADNEXAL TUMORS

Brooke-Spiegler syndrome — Brooke-Spiegler syndrome (MIM #605041) is a rare autosomal dominant syndrome characterized by the development of multiple cylindromas, trichoepitheliomas, and spiradenomas. Brooke-Spiegler syndrome is caused by germline mutations in the CYLD gene on chromosome 16q12-q13, encoding a highly conserved deubiquitinating enzyme involved in the regulation of cell proliferation through multiple cell signaling pathways, including NF-kB and c-Jun N-terminal kinase (JNK) [161]. Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma-1 are allelic and, therefore, may be considered phenotypic variants or a spectrum of the same disease [162,163]. (See "Brooke-Spiegler syndrome (CYLD cutaneous syndrome)".)

Patients with Brooke-Spiegler syndrome present with numerous pink, translucent papules and nodules with telangiectasias ranging from 0.5 to 3 cm located on the face, scalp, and neck (picture 54). Tumors appear in late childhood to early adulthood and gradually increase in size and number throughout life. There is wide variation in the number of tumors, with some patients developing less than 30 and some in the hundreds.

Malignant transformation of these adnexal tumors occurs in 5 to 10 percent of patients [6]. Rapid growth in a lesion should raise concern for malignant change.

Multiple familial trichoepithelioma 1 — Multiple familial trichoepithelioma 1 (MIM #601606) is an autosomal dominant syndrome caused by mutations in the CYLD gene and allelic to Brooke-Spiegler syndrome [163]. Patients develop multiple trichoepitheliomas concentrated on the face and scalp.

Familial cylindromatosis — Familial cylindromatosis (MIM #132700) is an autosomal dominant syndrome allelic to Brooke-Spiegler syndrome and multiple familial trichoepithelioma 1, caused by mutations in the CYLD gene. Familial cylindromatosis is characterized by the occurrence of multiple cylindromas in the head and neck region. Some patients may develop large, confluent tumors on the scalp known as turban tumors (picture 55).

Cowden syndrome (multiple hamartoma syndrome) — Cowden syndrome (MIM #158350) is an autosomal dominant syndrome associated with multiple cutaneous trichilemmomas (picture 35), oral fibromas, sclerotic fibromas, lipomas, acral verrucous hyperkeratosis, intestinal polyps, penile freckling, macrocephaly, and benign and malignant breast, uterine, and thyroid tumors [164]. Cowden syndrome is discussed in detail elsewhere. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)

Birt-Hogg-Dubé syndrome — Birt-Hogg-Dubé syndrome (MIM #135150) is an autosomal dominant syndrome caused by mutations in the FLCN (folliculin) gene and characterized by cutaneous fibrofolliculomas, trichodiscomas, and acrochordons; multiple lung cysts, which can lead to spontaneous pneumothorax; and renal tumors [145]. Over 90 percent of patients with Birt-Hogg-Dubé syndrome present in the third to fourth decade of life with multiple facial fibrofolliculomas or trichodiscomas (picture 37) [6]. The presence of at least five adult-onset fibrofolliculomas, with at least one histologically confirmed, and the detection of pathogenic FLCN germline mutations are major diagnostic criteria for Birt-Hogg-Dubé syndrome [145]. (See "Hereditary kidney cancer syndromes".)

Muir-Torre syndrome — Muir-Torre syndrome (MIM #158320) is an autosomal dominant variant of hereditary nonpolyposis colorectal carcinoma syndrome (Lynch syndrome), characterized by the association with both benign and malignant sebaceous tumors (sebaceous adenoma, sebaceoma, and sebaceous carcinoma), as well as keratoacanthomas [165]. Muir-Torre syndrome is discussed separately. (See "Muir-Torre syndrome".)

SUMMARY AND RECOMMENDATIONS

●Definition and classification – Cutaneous adnexal tumors are a large group of benign and malignant neoplasms that exhibit morphologic differentiation towards one of the four primary adnexal structures present in normal skin: hair follicles, sebaceous glands, apocrine glands, and eccrine glands (table 1). (See 'Classification' above.)

●Clinical presentation – Adnexal tumors typically present as pink, skin-colored, or slightly bluish papules or nodules ranging in size from a few millimeters to several centimeters, most often located on the head and neck (picture 1A-C). Lesions are typically asymptomatic and slow growing over several years. Malignant adnexal tumors have a similar clinical appearance but exhibit rapid growth and can ulcerate. (See 'Clinical features' above.)

●Diagnosis – Because of the extensive overlap in clinical features of cutaneous adnexal tumors, biopsy is essential for diagnosis. Immunohistochemical stains may be useful for the diagnosis of tumors with ambiguous histopathologic features. (See 'Diagnosis' above.)

●Management of benign adnexal tumors – The treatment of choice for benign adnexal tumors is simple excision. In patients with genetic syndromes associated with multiple adnexal tumors, excision of all lesions may not be feasible. For these patients, alternative treatment modalities include superficial shave removal, electrocautery, and laser ablation. (See 'Benign adnexal tumors' above.)

●Management of malignant adnexal tumors – For patients with malignant adnexal tumors, we suggest treatment with Mohs micrographic surgery rather than wide local excision (Grade 2C). Wide local excision with pathologic margin assessment is a reasonable alternative if Mohs surgery is not available. Because of the rarity of these tumors, the width of safety margins has not been evaluated in high-quality studies. In general, 1 to 2 cm clinical margins are used. (See 'Malignant adnexal tumors' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Timothy H McCalmont, MD, who contributed to earlier versions of this topic review.