Chapter 119. Appendage Tumors and Hamartomas of the Skin

Appendageal tumors of the skin comprise a wide spectrum of benign and malignant neoplasms that exhibit morphological differentiation toward one or more adnexal structures in normal skin. The classification and diagnosis of appendageal tumors is challenging due to the wide variety of tumor types, complicated nomenclature, and numerous classification systems that categorize these neoplasms.1–8 Traditionally, cutaneous adnexal tumors are classified into four groups according to differentiation toward follicular, sebaceous, apocrine, and eccrine structures. These adnexal tumors can be further classified by a gradient of decreasing differentiation into three groups: hyperplasias and hamartomas, benign neoplasms, and malignant neoplasms (Table 119-1). This classification is similar to the approach of the World Health Organization International Histological Classification of tumor monographs.4 The hyperplasias are characterized by an increased number of normal cells in a normal arrangement. Hamartomas are described as an abnormal arrangement of normal tissue. Benign neoplasms lack the potential to metastasize, whereas malignant tumors have the ability to cause local destruction and to metastasize to lymph nodes and viscera.

While adnexal tumors are classified based on differentiation, often a tumor is not easily classified into one group because the lesion exhibits histologic features of two or more adnexal cell lines. Since adnexal tumors originate from pluripotent stem cells in the epidermis and its appendages, neoplastic cells may aberrantly express one or more lines of appendageal differentiation. The ultimate histologic characteristics of a tumor are related to the activation of molecular pathways responsible for forming the normal mature adnexal structure, in conjunction with tumor genetics, local vascularity, and microenvironment.4

During embryogenesis, the eccrine apparatus develops separately from the folliculosebaceous-apocrine apparatus. Eccrine glands develop directly from the embryonic epidermis during the third to fifth months of fetal development. Hair follicles also arise directly from the epidermis during the third to fourth months of fetal life. Follicular development differs from eccrine development because mesenchymal cells, which serve as precursors of the follicular papilla, descend into the dermis with the developing epidermal elements. Sebaceous and apocrine glands and ducts begin as secondary structures from the bulges along the hair follicle. Clinically, as predicted by embryogenesis, follicular, sebaceous, and apocrine tumors coincide in the same individuals, whereas eccrine tumors are unrelated.8

Cytogenetics and molecular studies have further elucidated the pathogenesis of certain adnexal tumors. Mutations in p53 have been detected in some adnexal tumors, suggesting an etiologic role for ultraviolet light.9 Germ-line mutations have been reported in various genodermatoses, suggesting a role for these genes in the pathogenesis of certain adnexal tumors. For instance, mutations in the patched (PTCH) genes have been demonstrated in follicular tumors in patients with the basal cell nevus syndrome.10 Mutations in the tumor suppressor gene PTEN have been identified in patients with Cowden's syndrome.11 Microsatellite instability and mutations in MSH2, MLH1, and MSH6 mismatch repair genes have been detected in patients with Muir–Torre syndrome.12 Technologies such as cDNA microarrays, microRNA microarrays, and proteomic studies may lead to the elucidation of additional molecular markers useful in classifying these neoplasms.

Clinically, appendageal tumors are indistinctive, and often present as flesh-colored papules or nodules. Lesions may be solitary or multiple. The anatomic distribution of these lesions corresponds to the normal location of the adnexal structure from which the neoplasms originates. When patients present with multiple lesions, a characteristic anatomic distribution, autosomal dominant inheritance pattern, and association with visceral abnormalities may be observed. Often, appendageal tumors serve as a marker for genetic syndromes. While most lesions are benign, a malignant counterpart exists for most tumors, and it is often associated with a poor outcome.

The most important tool for diagnosing and classifying appendageal tumors is histopathology. The histopathology of the adnexal tumor can be interpreted by comparing its microscopic features to the histology of normal cutaneous appendages. Follicular tumors show a range of morphologic features that recapitulate specific portions of normal hair and the hair follicle such as the infundibulum, isthmus, stem, and bulb. The finding of matrical cells reflects differentiation toward follicular bulbs. Trichohyalin granules and blue–gray corneocytes indicate differentiation toward the inner root sheath. Differentiation toward the outer root sheath is manifested by the presence of either clear columnar cells aligned in a palisade at the bulb, subtly cornified cells with pink cytoplasm at the stem, or fully cornified cells with red cytoplasm, which corresponds to trichilemmal keratinization at the level of the isthmus. Sebaceous tumors reveal areas with sebocytes distinguished by a vacuolated cytoplasm, scalloped nuclei, and tubular structures. Ductal differentiation characterizes apocrine and eccrine tumors. Features of apocrine glands such as decapitation secretion are seen in ductal structures of apocrine neoplasms, whereas a flattened ductal epithelium distinguishes eccrine neoplasms.4

Immunohistochemical analysis has traditionally been of little value in definitively diagnosing adnexal tumors given the significant overlap of immunohistochemical features between apocrine tumors with ductal differentiation and certain visceral malignancies.

Determination of whether an appendageal neoplasm is benign or malignant requires assessment of architectural and cytomorphologic characteristics. Great care is necessary when applying traditional morphologic criteria of malignancy such as asymmetry, poor circumscription, and presence of epithelial aggregations with prominent atypia and mitotic activity. Some malignant aggressive adnexal neoplasms have deceptively bland microscopic appearance. Furthermore, there are certain neoplasms whose malignant potential is not always predictable on histologic grounds alone.

A diagnostic biopsy of a suspicious lesion yielding a correct diagnosis is the initial step in appropriate management of patients with appendageal skin tumors. A number of tumor-related and patient-related factors influence the choice of treatment. Tumor-related factors include the type, size, and anatomic location. Patient-related factors include life expectancy, comorbid conditions, and cosmetic concerns.

Specific treatment of benign appendageal tumors is sometimes unnecessary. In some cases, removal of the tumor is indicated for cosmetic reasons only. The treatment of choice for the majority of benign appendageal tumors is surgical excision. A variety of superficial ablative techniques such as electrodessication and curettage and cryotherapy have proven to be effective in selected patients. A number of other alternative treatment options, including the use of systemic retinoids, lasers, and photodynamic therapy have also been advocated for use in some cases; however, most do not have sufficient data for universal application.

Treatment of malignant appendageal tumors aims mainly at eradication of the cancer, preservation or restoration of normal function, and cosmesis. High-risk patients with tumors known to recur or metastasize most frequently require wide local excision, Mohs micrographic surgery, and/or radiotherapy. Notably, sentinel lymph node biopsy is sometimes valuable in staging of patients with eccrine and apocrine carcinomas.

Sebaceous tumors consist of a wide spectrum of neoplasms from hamartomas, hyperplasias, and benign lesions to highly aggressive malignant tumors. Sebaceous neoplasms, with the exception of sebaceous hyperplasia, are relatively rare compared to the other appendageal tumors. Sebaceous lesions are associated with two systemic syndromes: Muir–Torre syndrome and the epidermal nevus syndrome.

Sebaceous glands develop from the hair sheath, and are located near hair follicles, apocrine ducts, and arrector pili muscles. Sebaceous glands are located in all hair bearing regions of the body, and are most abundant in the head and neck region.13 Ectopic sebaceous glands are common and considered a normal variant. Fordyce spots are located on the vermilion border of the lip and labia minora, Tysons glands on the prepuce and mucosa of the penis, and Montgomery tubercles on the female areola.14

Terminology regarding sebaceous neoplasms remains controversial. The term sebaceous adenoma has been applied to superficial benign sebaceous neoplasms with predominantly mature sebocytes, whereas sebaceous epithelioma and sebaceoma have been used to describe lesions consisting of primarily germinative seboblasts. Others have used the term sebaceoma to describe benign sebaceous proliferations deep in the dermis as opposed to the more superficial sebaceous adenoma.15 In this chapter, the term sebaceous adenoma is used to encompass superficial and deep sebaceous proliferations with varying degrees of sebocyte maturity.

Hamartomas and Hyperplasias

Nevus Sebaceus of Jadassohn

Epidemiology

Nevus sebaceous of Jadassohn, described in 1895, is a benign hamartoma with epidermal, follicular, and apocrine elements.16 It occurs in 3/1,000 neonates.14

Etiology and Pathogenesis

Nevus sebaceous is postulated to develop due to genetic mosaicism in stem cells that expand in the lines of Blaschko. The human papilloma virus (HPV) has been detected in nevus sebaceous tissue, with evidence of viral integration of HPV DNA into genomic DNA.17 These results suggest that maternal transmission of HPV DNA to fetal ectodermal cells could result in epigenomic mosaicism and subsequent cutaneous changes. In familial cases, a paradominant mode of transmission has been suggested.18 Loss of heterozygosity of the patched gene has also been demonstrated in some nevus sebaceous lesions.19

Clinical Findings

Nevus sebaceous presents as a well-demarcated, yellow–orange, alopecic, verrucous plaque that ranges in size from a few millimeters to several centimeters. It most commonly occurs on the scalp (59.3%), but can also occur on the face (32.6%), preauricular area (3.8%), and neck (3.2%).20 It is usually solitary and linear or crescentic, and is distributed in the lines of Blaschko.21

Mehregan and Pinkus described three stages in the clinical and histological evolution of a nevus sebaceous.22 The lesion is slightly raised and barely discernible at birth. The initial stage is characterized by papillomatous epithelial hyperplasia and underdeveloped hair follicles. The second stage commences at puberty and is associated with remarkable sebaceous gland development, epidermal verrucous hyperplasia, and the maturation of apocrine glands. Clinically, this correlates with progressive thickening and development of a pebbly verrucous surface. The final stage involves the development of benign and malignant neoplasms within the nevus sebaceous.

Several neoplasms have been described arising within a nevus sebaceous.20,23 The most common benign neoplasm to occur in nevus sebaceous is trichoblastoma, followed by syringocystadenoma papilliferum. Trichoblastomas, seen in about 5% of nevus sebaceous, presents with new pigmented papules or nodules. The development of basal cell carcinoma is seen in less than 1% of lesions. Other tumors reported to develop in nevus sebaceous include nodular hidradenoma, syringoma, trichilemmoma, proliferating trichilemmal cyst, squamous cell carcinoma, sebaceous carcinoma, apocrine carcinoma, and eccrine poroma.24

Histopathology

In early nevus sebaceous, the epidermis is acanthotic and papillomatous. The sebaceous gland is underdeveloped and decreased in number, leading to difficult diagnosis. The presence of immature hair follicles that resemble the embryonic stage of hair follicles can aid diagnosis in early lesions. At puberty, the epidermis is papillomatous, verrucous, and hyperplastic. Abundant sebaceous glands and vellus hairs are noted in the superficial dermis. Apocrine glands are seen in two-thirds of patients at puberty.22,25

Prognosis

The risk of malignancy in nevus sebaceous is quite low, with the incidence of basal cell carcinoma at 1%. The risk of malignancy increases with age with the majority of studies indicating that children are unlikely to develop malignant tumors.23

Nevus sebaceous is associated with the linear nevus sebaceous syndrome, a subset of the epidermal nevus syndrome. Also known as Schimmelpenning Syndrome, this syndrome is characterized by linear nevus sebaceous, mental retardation, seizures, ophthalmic, skeletal, cardiovascular, and urologic defects. Appropriate work-up in these patients includes electroencephalogram, cerebral computed tomography or magnetic resonance imaging, skeletal survey, analysis of renal and liver function, and calcium and phosphate levels.26

Treatment

Treatment is primarily cosmetic, and surgical excision to adipose or galea is the treatment of choice. Given the low risk of malignancy, many advocate that observation until adolescence is warranted as opposed to early excision. For facial lesions, consideration should be given to excision during childhood when scarring is minimal. Other treatment modalities including photodynamic therapy, carbon dioxide laser resurfacing, and dermabrasion have been advocated. However, since they fail to completely eradicate the lesion, there is a risk of recurrence or development of new tumors.27–29

Sebaceous Hyperplasia

Epidemiology

Sebaceous hyperplasia, a benign enlargement of the sebaceous lobule around a follicular infundibulum, is a common lesion especially in patients with significant sun exposure. The age of onset is 40, with males more commonly affected than females. Prevalence increases with time.21

Etiology and Pathogenesis

The cause of sebaceous hyperplasia is unknown. Although it is seen in individuals with extensive sun exposure, studies do not show an association with solar elastosis or skin type.30 Sebaceous hyperplasia is associated with renal transplantation and chronic immunosuppression with cyclosporine.31,32 Ten percent to 15% of patients on cyclosporine develop sebaceous hyperplasia, which can occur several years after starting the medication, and may affect ectopic locations such as the oral mucosa. Other associations include chronic renal failure, hemodialysis, corticosteroids, Muir–Torre syndrome, pachydermoperiostosis, and X-chromosomal ectodermal dysplasia.33

Clinical Findings

Sebaceous hyperplasia presents as solitary or multiple small ∼3 mm yellow or flesh-colored telangiectatic papules with a central dell on the central face (Fig. 119-1A).21 Nonfacial locations such as the neck, chest, areola, vulva, and penis have also been described.34–36 Atypical presentations include giant or linear lesions, diffuse growths, and juxtaclavicular beaded lines.21,36 Some reports have described sebaceous hyperplasia developing over neurofibromas, melanocytic nevi, verruca vulgaris, and acrochordons.37 Premature or functional familial sebaceous hyperplasia occurs in adolescence and is typified by thick diffuse plaque-like lesions on the face, chest, and upper back.38 Clinically, sebaceous hyperplasia can resemble basal cell carcinoma, and biopsy is performed to rule out malignancy. Dermoscopy can facilitate diagnosis of sebaceous hyperplasia, and reveals a yellow papule with telangiectasias and a central crater.39

Histopathology

Sebaceous hyperplasia reveals large mature sebaceous lobules clustered around discrete, often dilated, infundibula located in the upper dermis.

Prognosis and Clinical Course

The most common variant, the senile variant, is associated with an increased risk of nonmelanoma skin cancer in renal transplant patients.31 Sebaceous hyperplasia may be associated with Muir–Torre syndrome, although it does not serve as a marker for the syndrome, given its high prevalence in the population.40

Treatment

Treatment of sebaceous hyperplasia is for cosmetic purposes. The following destructive modalities have been shown to be effective: excision, cryotherapy, electrodessication and curettage, electrocautery, photodynamic therapy with aminolevulinic acid, and laser therapy with the argon, carbon dioxide, pulse dye, and 1,450 nm diode lasers. These can be associated with scarring, hypopigmention, bleeding, and recurrence.21,33 Isotretinoin has been shown to be effective, but lesions recur rapidly after the medication is continued.33

Benign Neoplasms

Sebaceous Adenoma

Epidemiology

Sebaceous adenomas are rare benign tumors that typically present on the head and neck of elderly individuals.41 These tumors serve as a marker for Muir–Torre syndrome.40

Etiology and Pathogenesis

As a marker of the Muir–Torre syndrome, these lesions demonstrate microsatellite instability and mutations in DNA mismatch repair genes MSH2, MLH1, and MSH6.12

Clinical Findings

A sebaceous adenoma usually presents as a smooth, well-circumscribed, slow-growing pink, flesh-colored, or yellow papule or nodule measuring less than 0.5 cm (Fig. 119-2A). The most common location is the head (70%), followed by the neck, trunk, and legs (30%). Lesions may bleed, ulcerate, and cause pain.42

Histopathology

Sebaceous adenomas reveal multiple well-circumscribed sebaceous lobules. Each lobule has two cell populations: peripheral basaloid germinative cells and mature lipid-filled vacuolated sebocytes in the center of the lobule. Usually, mature sebocytes outnumber the undifferentiated germinative cells (Fig. 119-2B). These lesions lack atypia, necrosis, and invasive growth, which differentiate them from sebaceous carcinoma. Mitoses can be seen in the germinative layers, and is not necessarily indicative of malignancy.4

Prognosis and Clinical Course

Sebaceous adenomas are the most common neoplasm associated with Muir–Torre syndrome, occurring in 68% of patients. In these patients, lesions tend to occur on the trunk. There are no reports of metastases from these neoplasms.26

Treatment

The treatment of choice is complete surgical excision. Persistence or recurrences are common. Mohs micrographic surgery may be beneficial for conservation of the nipple.21 Cryosurgery may be useful in the treatment of some patients.

Excision

Work-up for Muir–Torre syndrome should be initiated in patients with a sebaceous adenoma.

Malignant Neoplasms

Sebaceous Carcinoma

Epidemiology

Sebaceous carcinoma is a rare aggressive neoplasm that typically presents on the eyelids of elderly individuals. It represents 1%–5.5% of all eyelid malignancies.43 The mean age of onset is 63 years, although it has been reported in children.44 While women and Asians were previously thought to have a higher incidence, an analysis of 1,349 cases in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database revealed a slight male predisposition and no Asian predominance.45 Other risk factors include previous irradiation, genetic predisposition for the Muir–Torre syndrome, and immunosuppression with renal transplantation or HIV.45

Etiology and Pathogenesis

Most sebaceous carcinomas develop de novo, although they can also originate from benign sebaceous neoplasms. These tumors are also associated with the Muir–Torre syndrome and may demonstrate microsatellite instability in DNA mismatch repair genes.26

Clinical Findings

The most common clinical presentation is a painless, slowly enlarging, subcutaneous nodule.45 Other clinical presentations mimic chalazion, blepharoconjunctivitis, and basal cell carcinoma, leading to delays in diagnosis.

The most common location is the eyelid, with upper eyelid involvement more frequent than lower eyelid involvement.46 These tumors develop from the meibomian glands and glands of Zeis. Extraocular lesions present as firm, yellow, ulcerated, or bleeding nodules on the head and neck, and less commonly, on the trunk, feet, external genitals, and oral mucosa.

Histopathology

Sebaceous carcinoma is characterized by asymmetric, irregular sebaceous lobules centered in the dermis. Lesions are classified as well, moderately, or poorly differentiated, based on varying degrees of differentiation. Four patterns are recognized: lobular, comedocarcinoma, papillary, and mixed. Tumor cells show remarkable variation in nuclear shape and size, pleomorphism, hyperchromatism, and mitotic activity. Tumors may extend into the subcutaneous fat or muscle.21

Prognosis and Clinical Course

Sebaceous carcinoma is highly aggressive, with a potential for nodal and distant metastases. Recurrence after excision is common. Ocular lesions have a recurrence rate of 11%–30% with distant metastases occurring in up to 25% of patients. Extraocular sebaceous carcinoma is associated with a 29% recurrence rate, and 21% metastatic rate.45 It was previously believed that ocular tumors were more aggressive than extraocular tumors, but this has been challenged, with many reports of metastatic extraocular disease.47,48 The most common site of metastasis is regional lymph nodes, but there are reports of metastases extending to the liver, small bowel, urinary tract, lung, and brain.49

Mortality rates range from 9% to 50%.21 Overall 5-year survival rates for ocular versus extraocular disease is 75.2% and 68%, respectively.45 Negative prognostic signs include upper and lower lid involvement, lymphovascular invasion, multicentric disease, size larger than 1 cm, poorly differentiated tumors, and pagetoid spread.45

Treatment

The standard treatment has been wide local excision with 5–6 mm margins. However, this has been associated with high recurrence rates of 36% and a 5-year mortality rate of 18%.21 Studies have shown that Mohs micrographic surgery may be more effective with recurrence rates of 12%.46 Sentinel lymph node biopsy has been advocated by some authors, although there are minimal studies in this area.23 Orbital exenteration is recommended for extensive orbital or bulbar conjunctival disease. Radiation has not been shown to be effective.

Muir–Torre Syndrome

Epidemiology

In 1967, Muir and Torre independently described a syndrome of sebaceous cutaneous neoplasms, keratoacanthomas, and internal malignancy.50,51 The occurrence of Muir–Torre syndrome in patients with an identified sebaceous neoplasm has been reported as high as 42%, and patients present with sebaceous neoplasm at a mean age of 63.26

Etiology and Pathogenesis

Muir–Torre syndrome is inherited in an autosomal dominant fashion. It occurs due to inactivating germ-line mutations in the DNA mismatch repair genes MSH2, MLH1, and MSH6, leading to microsatellite instability.12 MSH2 is the most commonly mutated gene.52 Muir–Torre syndrome is considered a phenotypic variant of the Lynch Syndrome, or hereditary nonpolyposis coli cancer family syndrome, which is also associated with defects in the DNA mismatch repair system.

Clinical Findings

Muir–Torre syndrome is characterized by sebaceous neoplasms, keratoacanthomas, internal malignancies, and personal or family history of Muir–Torre syndrome. Internal malignancy usually precedes cutaneous lesions in 59% of patients. However, up to 32% of cases report the development of a sebaceous neoplasm occurring prior to visceral malignancy.26 The sebaceous adenoma is the most specific marker for Muir–Torre syndrome, occurring in 68% of cases, but sebaceous hyperplasia, cystic sebaceous neoplasms, and sebaceous carcinoma can also be seen.26 Extrafacial sites are more common in Muir–Torre syndrome than the typical central facial location for sebaceous neoplasms.40

The most common visceral malignancy is colon cancer, followed by genitourinary cancers, breast cancer, and hematologic disorders. MSH2 mutations are associated with a higher risk of colon cancer, whereas MSH6 mutations are associated with increased endometrial cancer.53

Histopathology

Histopathology is consistent with that of the sebaceous neoplasm present in the individual. Other diagnostic methods include immunohistochemical staining for mismatch repair genes, which has been supported as a sensitive, rapid, inexpensive, convenient method for screening patients with suspected Muir–Torre syndrome.54 Gene sequencing confirms the diagnosis. Sebaceous neoplasms and keratoacanthomas in Muir–Torre syndrome are now included in the tumors to be tested for microsatellite instability via genotyping.12

Prognosis and Clinical Course

Visceral tumors tend to behave less aggressively in Muir–Torre syndrome than in sporadic tumors, with a longer median survival in patients with Muir–Torre syndrome for the same tumor types.12 Aggressive cancer surveillance with colonoscopy and urinary cytology should be performed in these patients. Genetic counseling should also be provided.

Treatment

Surgical excision is the treatment of choice for cutaneous lesions. Clinically involved nodes should also be removed. Low dose isotretinoin has been effective.26

Sweat gland neoplasms have traditionally been divided into apocrine tumors and eccrine tumors. However, the distinction between these can be quite difficult due to numerous terms applied to the same histological entity, overlap between classic apocrine and pure eccrine features, and the coexistence of both tissue types in hamartomas or mixed tumors.

The anatomic distribution of apocrine tumors reflects that of the normal location of glands producing apocrine secretion. Therefore, these lesions are generally confined to the head and neck, axilla, genitals, and perianal skin. Additional sites include the umbilicus, eyelid (Moll's glands), areola, and external auditory meatus.6

Apocrine tumors are generally benign, although they possess the ability to degenerate into malignant lesions. An adnexal carcinoma developing from its benign counterpart generally has a history of explosive enlargement of a stable longstanding plaque or nodule. Adnexal carcinomas that develop de novo are more difficult to diagnose clinically, and require histopathologic evaluation. Features such as asymmetry, lack of circumscription, and infiltrative growth pattern support a malignant diagnosis. Histologically, these must be differentiated from cutaneous metastases from breast and gastrointestinal adenocarcinomas. Malignant adnexal tumors rarely metastasize, and treatment of choice is often Mohs micrographic surgery or local excision.

Histopathologically, apocrine lesions are characterized by cells with abundant eosinophilic cytoplasm, eccentric basally located nuclei, and decapitation secretion in the luminal cells. Cells contain periodic acid Schiff (PAS) positive diastase resistant granules. The luminal cells are also reactive to Carcino-embryonic antigen (CEA) and epithelial membrane antigen (EMA), while the secretory cells are positive for low molecular weight cytokeratin and gross cystic disease fluid protein-15 (GCDFP-15).6

Hyperplasias and Hamartomas

Apocrine Hidrocystoma

Epidemiology

Apocrine hidrocystomas are relatively common cystic lesions that present in middle-aged or elderly individuals. There is a slight female predilection.55,56

Etiology and Pathogenesis

Apocrine hidrocystomas arise from a benign proliferation of apocrine glands.

Clinical Findings

The cystic lesions typically present as solitary, smooth, translucent, flesh-colored or bluish, 1–3 mm papules on the head or neck, particularly in the periorbital region (Fig. 119-3A). Rare presentations include multiple lesions, giant tumors, and childhood onset.57 Apocrine hidrocystomas have been reported to appear within nevus sebaceus.23,55

Multiple lesions on the bilateral upper and lower eyelid margins are seen in Schopf–Schulz–Passarge syndrome, an ectodermal dysplasia characterized chiefly by multiple eyelid apocrine hidrocystomas, palmoplantar keratoderma, hypodontia, hypotrichosis, and nail dystrophy. While an autosomal recessive inheritance has been suggested, it can also be sporadic.58,59

Histopathology

On histologic examination, there is a unilocular or multilocular cyst located in the dermis. The epithelial lining consists of a single or double layer of cuboidal–columnar epithelium lying adjacent to an outer myoepithelial layer. Decapitation secretion is notable. Prominent papillations protruding into the lumen are seen in some cases (Fig. 119-3B).55

Prognosis and Clinical Course

Lesions tend to be asyptomatic, and enlarge until a certain size is attained.

Treatment

The treatment of choice for solitary lesions is surgical excision. Multiple lesions can be treated with electrodessication and curettage, carbon dioxide or pulsed dye lasers, local application of trichloroacetic acid, topical atropine, or botulinum toxin.60–63

Apocrine Nevus

Epidemiology

Apocrine nevus is a rare hamartoma consisting of a proliferation of normal appearing apocrine glands in the dermis.

Clinical Findings

There are two clinical variants of apocrine nevus. A pure apocrine nevus is quite rare, and presents as a unilateral or bilateral, soft, lobulated, dermal mass in the axilla or scalp.1 A more common variant occurs as a part of a nevus sebaceus. Cases of apocrine nevus occurring as multiple papules on the chest have been reported.64

Histopathology

There are numerous, discrete, closely spaced tubular structures in the dermis and/or subcutaneous fat. The tubules are lined with typical apocrine glandular epithelium and contain a homogenous vacuolated pink secretion. An apocrine nevus that develops within a nevus sebaceous is usually deeper in the dermis and can coexist with syringocystadenoma papilliferum or trichoblastoma.23

Treatment

The treatment of choice is surgical excision.

Apocrine Fibroadenoma

Epidemiology

Apocrine fibroadenoma is a rare cutaneous apocrine neoplasm that occurs primarily in women younger than 25 years of age.1,65

Etiology and Pathogenesis

Apocrine fibroadenoma is considered analogous to fibroadenoma of the breast.65 The etiology is unclear. Some feel that it most likely results from a proliferation of ectopic mammary tissue in response to excessive circulating estradiol over progesterone, whereas others believe it is derived from apocrine tissue.

Clinical Findings

Apocrine fibroadenoma typically presents as single or multiple firm, rubbery, smooth, mobile, painless nodules up to 2 cm in diameter. It most commonly occurs in the axilla, vulva, and perianal region.65

Histopathology

Histopathology reveals a variably hyalinized stroma surrounding a proliferation of ductal structures with decapitation secretion.

Treatment

The treatment of choice is complete surgical excision.

Erosive Adenomatosis of the Nipple

Epidemiology

Erosive adenomatosis, also known as adenoma of the nipple or florid papillomatosis, is a rare benign neoplasm of breast lactiferous ducts. The peak incidence is in women in the fifth decade, although it has been reported in males and children.66

Etiology and Pathogenesis

The tumor derives from terminal lactiferous ducts and subareolar breast tissue.

Clinical Findings

The classic presentation of erosive adenomatosis is with a unilateral erythematous, eroded, crusted papule on the nipple of middle-aged females. Ulceration and serosanguinous discharge may also occur. The lesion is usually asymptomatic, but patients may complain of irritation, burning, pain, and pruritus. Secretion may vary during the menstrual cycle.67 Clinically, the lesion is often indistinguishable from Paget's disease. Other entities in the differential diagnosis include allergic contact dermatitis, psoriasis, and infection.

Histopathology

Microscopically, erosive adenomatosis reveals a nonencapsulated endophytic proliferation of tubular structures in the dermis with a verrucous or ulcerated surface. Some of the tubular structures exhibit cystic dilations with discrete papillations. The tubules are lined by an inner apocrine secretory epithelium and an outer myoepithelial layer. Differentiating the histologic pattern from intraductal carcinoma of the breast is important. A lack of atypia and necrosis support the diagnosis of erosive adenomatosis.

Prognosis and Clinical Course

Studies have not supported a strong association with breast adenocarcinoma or fibrocystic disease of the breast.66

Treatment

Surgical excision and Mohs micrographic surgery are effective treatment choices. Traditionally, complete excision involved removal of the entire nipple and underlying tissue. However, this treatment is associated with recurrence and significant deformation of the cosmetically and functionally sensitive nipple requiring reconstruction.68,69 More recently, Mohs micrographic surgery has been an effective treatment, with a lower recurrence rate, and minimal deformation. Unique reconstructive techniques, including closure with a purse-string suture, have been employed after Mohs micrographic surgery.70

Hidradenoma Papilliferum

Epidemiology

Hidradenoma papilliferum, also known as papillary hidradenoma, is a relatively uncommon benign neoplasm most commonly presenting in females between the ages of 30 and 49 years.1,71

Etiology and Pathogenesis

This benign neoplasm develops from the anogenital apocrine glands.

Clinical Findings

The lesion typically presents as a small, unilateral, asymptomatic, flesh-colored nodule on the female vulva. There are reports of ectopic or nonanogenital lesions on the head and neck, where it presents as a subcutaneous nodule, tumor, or cyst. Lesions have been reported on the eyelid, external auditory canal, lip, and nasal ala.72 Hidradenoma papilliferum has also been reported to develop within a nevus sebaceous.23

Histopathology

On histopathology, there is a well-circumscribed dermal nodule that is partly solid or solid-cystic. It lacks an epidermal connection. The nodule consists of an anastomosing pattern of numerous glandular structures and papillary folds. The lumina are made of a double layer of cells: an inner layer of secretory cells demonstrating decapitation secretion, and an outer layer of cuboidal myoepithelial cells (Fig. 119-4). Hidradenocarcinoma papilliferum is notable for high cellularity and asymmetry.

Prognosis and Clinical Course

Hidradenoma papilliferum usually follows a benign course. Malignant transformation into hidradenocarcinoma papilliferum has been reported. It presents as a small, solitary, ulcerated nodule in the anogenital region, and rarely in the axilla. Patients may complain of slight pain or brown watery discharge. Fatal metastases, initially involving regional lymph nodes, have been described. Lesions have been seen in association with extramammary Paget's disease.1,73

A fatal metastasizing squamous cell carcinoma arising in a hidradenoma papilliferum has also been reported.74 There are also rare cases of ductal carcinoma in situ arising in hidradenoma papilliferum.75

Treatment

The treatment of choice is surgical excision. In the case of perianal tumors, consultation with colorectal surgery is recommended to preserve anal sphincter function. Sentinel lymph node biopsy may be of value in patients with hidradenocarcinoma papilliferum.

Syringocystadenoma Papilliferum

Epidemiology

Syringocystadenoma papilliferum is a rare benign adnexal neoplasm that presents in young adults. Fifty percent are present at birth or early childhood, and an additional 15%–20% develop before puberty.76,77

Etiology and Pathogenesis

The derivation of syringocystadenoma papilliferum is unclear, with evidence supporting both apocrine and eccrine origin. Forty percent of lesions develop within a nevus sebaceous.78 Some studies show that mutations in the tumor suppressors, PTCH and p16, may play a role in the evolution of syringocystadenoma papilliferum.79

Clinical Findings

Syringocystadenoma papilliferum presents as an asymptomatic, solitary, firm, pink papule or plaque measuring 1–3 cm. A small fistula draining clear, bloody, or malodorous fluid may develop (Fig. 119-5A). At puberty, the lesion often grows and becomes increasingly papillated and hyperkeratotic. The most common location is the scalp.80 Rare presentations include unusual locations such as the trunk, arms, or vulva, and multiple or linearly arranged cutaneous nodules.

The lesion has been seen in conjunction with a wide variety of other adnexal tumors including nevus sebaceous, apocrine nevus, tubular apocrine adenoma, apocrine hidrocystoma, clear cell syringoma, eccrine nevus, verrucous carcinoma, and adenocarcinoma.80 This tumor has also been noted in a patient with focal dermal hypoplasia due to a novel PORCN mutation. Additional apocrine neoplasms seen in this genetic condition include apocrine nevi and apocrine hidrocystomas.81

Histopathology

Syringocystadenoma papilliferum presents with papillomatous epidermal invaginations lined with a double layer epithelium composed of basilar cuboidal cells and an inner columnar layer of secretory cells (Fig. 119-5B). A plasma cell rich infiltrate is also characteristic. There is typically a connection between the epithelial invagination and adjacent glands in the dermis.

The malignant counterpart, syringocystadenocarcinoma papilliferum, is characterized by asymmetry, poor circumscription, extension to the deep subcutaneous tissue, and increases in cellularity, cellular atypia, and mitoses.

Prognosis and Clinical Course

Basal cell carcinoma has been reported to occur in as high as 9% of cases, although this has not been corroborated by others.76,78 Malignant degeneration into syringocystadenocarcinoma papilliferum has been reported, with signs of malignant behavior including rapid growth, ulceration, pain, and pruritus.82,83 There is a low risk of regional lymph node metastases, while distant metastases have not been reported.

Treatment

Complete surgical excision is recommended given the malignant potential of syringocystadenoma papilliferum, although the benefit of prophylactic excision is unclear. In anatomic areas unfavorable for excision or grafting, carbon dioxide laser may be an alternative option.84 For syringocystadenocarcinoma papilliferum, excision and Mohs micrographic surgery have been effective treatment options.82

Cylindroma

Epidemiology

Cylindromas are benign neoplasms that are more common in females and typically present in the third decade.1,85

Etiology and Pathogenesis

Cylindromas are thought to originate from apocrine glands although some support an eccrine or follicular origin.86 Multiple cylindromas are seen in Brooke–Spiegler syndrome, an autosomal dominant condition with variable penetrance and expressivity, that presents with multiple cylindromas, eccrine spiradenomas, and trichoepitheliomas. Inactivating germ-line mutations or loss of heterozygosity in the tumor suppressor gene CYLD result in this disfiguring condition.87 CYLD encodes a ubiquitin hydrolase implicated in the negative regulation of cell proliferation through the nuclear factor κB (NF-κB) pathway. Mutations in CYLD cause an increased expression of NF-κB, and lead to apoptotic resistance and development of tumors seen in Brooke–Spiegler syndrome.88 Some also believe that ultraviolet radiation may play a role given that the most common presentation is on sun-exposed areas such as the face and scalp.

Clinical Findings

Cylindromas most commonly present as slow growing, pink, firm, smooth, alopecic, painful nodules ranging in size from 0.5 cm to 6 cm on the scalp. When multiple lesions coalesce on the scalp forming a confluent mass, the term “turban tumors” has been applied (Fig. 119-6A). While they can present as solitary lesions, the familial variant typically manifests with numerous tumors. Aside from pain, conductive deafness and sexual dysfunction have been reported in periauricular and pubic lesions.86

Patients with Brooke–Spiegler syndrome present with cylindromas, trichoepitheliomas, spiradenomas, sebaceous nevi, basal cell carcinoma and milia.89 Incidental associations with cylindroma include polycystosis of the lungs and kidneys, cervical, breast, and parotid carcinomas, and multiple fibromas.89

Histopathology

Cylindromas are characterized by dermal aggregates of large epithelial cells with abundant cytoplasm in the center and small basaloid cells in the periphery. The nodules are lined by thick basement membrane-like material, and arranged in a classic jigsaw puzzle pattern (Fig. 119-6B).90

Prognosis and Clinical Course

Patients with Brooke–Spiegler syndrome are at risk for basal cell carcinomas, tumors of the salivary glands, and parotid adenomas.91 Malignant degeneration of cylindromas into cylindrocarcinoma has been reported. Malignant transformation more commonly occurs in cases of multiple tumors, females, and in middle-aged to elderly patients.92 Clinical signs include pink to blue discoloration, ulceration, rapid growth, and bleeding. These are highly aggressive tumors with potential for local destructive growth, metastases, and recurrence.92,93 Metastases to the lymph nodes, stomach, thyroid, liver, lung, and bones have been reported.

Treatment

The treatment of choice for a cylindroma is surgical excision. In the case of multiple confluent tumors on the scalp, this can pose a challenge. Entire scalp excision carries the risk of significant blood loss requiring a blood transfusion and skin graft failure.85 Alternative treatments include electrosurgery, dermabrasion, carbon dioxide laser, cryotherapy, and radiotherapy.85,94 New insights into the role of CYLD in the NF-κB pathway has lead to the use of topical salicylic acid in cylindromatosis, with some reports showing complete remission after 6 months.95

Malignant Lesions

Apocrine Adenocarcinoma

Epidemiology

Apocrine adenocarcinoma comprises a rare group of cutaneous adenocarcinomas that show apocrine differentiation. It most commonly presents in middle-aged to elderly males.96

Etiology and Pathogenesis

The lesion usually arises de novo; however, there are reports of it developing in association with apocrine adenoma, cylindroma, nevus sebaceus, extramammary Paget's disease, and accessory nipple.96,97

Clinical Findings

There is significant variation in the clinicopathologic presentation of apocrine adenocarcinoma. It generally presents as an indolent, slow-growing, rubbery, solid to cystic nodule or tumor ranging in size from 1.5 to 8 cm. The color varies from red to purple, and ulceration may be present.98 There are rare presentations that can mimic cellulitis.99 The most common location is the axilla followed by the anogenital skin, regions of high apocrine gland density.98 Less frequent locations include the scalp, forehead, eyelid, upper lip, chest, nipple, and finger.96 Patients may complain of pain, restricted range of motion, ulceration, and purulence.96 Clinically, cutaneous metastases from breast and gastrointestinal cancers must be considered.

Histopathology

Histopathologically, apocrine adenocarcinoma presents with a dermal and/or subcutaneous non encapsulated tumor with infiltrative margins. The carcinoma is composed of large cells with eosinophilic cytoplasm, hyperchromatic nuclei, mitotic figures, and decapitation secretion. The epithelial component shows variable papillary, cribiform or trabecular, and solid patterns.100–102 Signet ring cells and pagetoid spread have been reported.100

Prognosis and Clinical Course

Apocrine adenocarcinoma is a locally invasive neoplasm with potential for regional lymph node metastases. Despite its aggressive behavior, mortality is relatively low.98,100 Local recurrence after wide local excision has been reported at 27.5%.96 Over 40% of reported cases presented with nodal metastases at initial diagnosis. Distant metastases to the lungs, bones, brain, and parotid gland have been reported.96

Treatment

The treatment of choice is wide local excision with clear margins. Some believe that there is a role for sentinel lymph node biopsy and nodal dissection given the high rate of regional nodal metastases.96 Adjunctive chemotherapy and radiation have been used. In some cases, the presence of steroid receptors in the tumor has lead to the use of tamoxifen.100

Eccrine glands are widely distributed in the skin. Therefore, eccrine tumors have a wider anatomic distribution than apocrine tumors. Histologically, eccrine tumors comprise a large spectrum of lesions with differentiation toward various portions of the normal eccrine apparatus, including intraepidermal (acrosyringium), dermal, and secretory ducts. The distinguishing feature is the tendency to form lumina with flattened epithelium. Distinction from apocrine tumors is not always straightforward, as decapitation secretion can be observed in certain tumors traditionally classified as “eccrine.” Similar to apocrine tumors, eccrine tumors are typically benign, but possess the ability to degenerate into malignant lesions.

Hyperplasias and Hamartomas

Eccrine Hidrocystoma

Epidemiology

Eccrine hidrocystomas are common lesions found in middle-aged to elderly patients, predominantly in females.103

Etiology and Pathogenesis

Eccrine hidrocystoma is a benign proliferation of eccrine glands.

Clinical Findings

There are two clinical variants of eccrine hidrocystoma. Robinson first described multiple eccrine hidrocystomas in 1893.104 The solitary type was first reported by Chernosky and Smith in 1973.105 The lesions are typically translucent, skin-colored or blue, dome-shaped, cystic papules on the head and neck. Multiple lesions clustered in the periorbital region may be a sign of ectodermal dysplasia.103 Multiple lesions have also been associated with warm climates, hyperhidrosis, and Graves disease.106

Histopathology

The cyst lining is a double layer of flattened epithelium lacking decapitation secretion. Eosinophilic contents may be seen.

Prognosis and Clinical Course

Eccrine hidrocystoma follows a benign course.

Treatment

Solitary lesions can be surgically excised. Destructive methods such as electrodessication, curettage, laser ablation, and pulsed dye laser therapy have been employed but are often associated with scarring. Botulinum toxin injections have been used with success.103

Eccrine Nevus

Epidemiology

Eccrine nevi, first described in 1976, encompass a variety of rare benign eccrine hamartomas that appear in childhood and adolescence.107 Some lesions may be congenital, whereas others present at advanced ages.108

Etiology and Pathogenesis

Eccrine nevi originate from eccrine glands. Several distinct forms exist. The two main subtypes are the rare pure eccrine nevus and the common eccrine angiomatous hamartoma. Other presentations include the mucinous eccrine nevus and porokeratotic eccrine ostial and dermal duct nevus (PEODDN).109

Clinical Findings

The clinical presentation of eccrine hamartomas is variable depending on the subtype. Pure eccrine nevi classically present with a solitary, well-circumscribed, hyperhidrotic plaque with little to no epidermal change. Hyperhidrotic episodes are triggered by temperature, stress, and exercise. The most common location is the forearm (50%) followed by the back and trunk.109,110 Rare presentations include hyperpigmented patches, linear lesions, centrally depressed plaques, and scaly borders.110

Eccrine angiomatous hamartomas (EAH) are more common and are often present at birth. They present with a solitary or multiple flesh-colored, red, or blue–brown nodules or plaques on the extremities, especially the legs. EAH can be painful.109

Mucinous eccrine nevi are extremely rare lesions that present with nodules or plaques with hyperhidrosis.109,111 Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare disorder of keratinization involving the intraepidermal eccrine duct or acrosyringium.112 PEODDN presents with congenital punctuate keratoses on the hands and feet, and has been associated with deafness, developmental delay, seizures, scoliosis, anhidrosis, alopecia, onychodysplasia, and palmoplantar involvement.113 Lesions are typically linear and follow the lines of Blaschko.

There are rare reports of coexistence with other cutaneous lesions such as clear cell syringoma and neurofibromatosis I.114

Histopathology

There is an increase in the number or size of normal eccrine glands. EAH also shows an increase in the number of capillaries. Mucinous eccrine nevi are characterized by large mucin deposits surrounding eccrine glands. PEODDN demonstrates parakeratotic coronoid lamellae over the eccrine ostia.109

Prognosis and Clinical Course

These lesions are benign. Indications for treatment include pain and excessive hyperhidrosis.

Treatment

The treatment of choice is surgical excision. Often, the lesions are quite large and surgery is not feasible. Alternative therapies include aluminum chloride, systemic and topical anticholinergic agents, clonazepam, antidepressants, and botulinum toxin injections.108 PEODDN has been treated with the carbon dioxide laser and topical retinoids.115

Syringoma

Epidemiology

Syringomas are common benign neoplasms most frequently seen in adult females. There is an increased frequency in Down's syndrome, with 18% of patients exhibiting this cutaneous sign. An increased frequency has also been observed in Marfan's syndrome, Ehlers Danlos, and Nicolas balus syndrome. An eruptive form most commonly presents in adolescent females. The clear cell variant has been linked to diabetes.116

Etiology and Pathogenesis

Syringomas derive from the intradermal eccrine duct or acrosyringium. Local factors, including ductal obstruction by keratin plugs leading to ductal proliferation, may play a role in pathogenesis.117,118 The etiology of eruptive syringomas is unclear. It has been hypothesized that these eruptive lesions demonstrate reactive eccrine gland proliferation following an inflammatory condition.119

Clinical Findings

Syringomas present with numerous, small, firm, smooth, flesh-colored or yellowish papules on the face, especially the lower eyelids, of adult females (Fig. 119-7A). Other sites, such as the scalp, axillae, abdomen, forehead, penis, and vulva can be affected. Four clinical variants have been described: a localized form, lesions associated with Down's syndrome, a generalized eruptive form, and a rare autosomal dominant familial form.120,121

The localized form traditionally occurs in the periorbital region, and can also present with scalp alopecia, a unilateral nevoid appearance, large lesions, and genital lesions.122 Genital syringomas can be remarkably pruritic, and are often mistaken for genital warts.123

Eruptive syringomas, first described by Jacquet and Darier in 1987, present as a sudden onset of successive crops of numerous disseminated syringomas on the upper trunk, especially the anterior neck, chest, trunk, axilla, upper medial arms, and periumbilical region of adolescent females.124

Histopathology

Syringomas are well-circumscribed, symmetric collections of small tadpole-shaped tubular structures in the superficial dermis. These tubules are lined by a single or double layer of bland, monomorphic, cuboidal epithelial cells (Fig. 119-7B). Clear cell syringomas are notable for abundant cytoplasm. The tubular structures are surrounded by thickened collagen bundles. If the biopsy specimen is very superficial, microcystic adnexal carcinoma should be considered in the differential diagnosis.

Treatment

Numerous destructive methods have been described for the treatment of syringomas, including excision, dermabrasion, laser resurfacing, trichloroacetic acid, cryotherapy, and electrosurgery.125,126 Unfortunately, these are often associated with significant scarring and recurrence. Topical and oral retinoids, and topical atropine have also been utilized with suboptimal results.117 The Q-switched Nd:Yag laser has been used after temporary tattooing and shows promising results.126

Poroma

Epidemiology

Poromas were first reported by Pinkus in 1956, and represent 10% of all sweat gland tumors.127,128 Poromas can occur in all age groups, but onset is usually over the age of 40.129

Etiology and Pathogenesis

Poromas represent a group of benign eccrine tumors composed of cuticular and poroid cells similar to those seen in the eccrine acrosyringium. Poromas are classified based on the location relative to the epidermis. Intraepidermal lesions are referred to as hidroacanthoma simplex. Poromas comprise lesions that span the epidermis and dermis, whereas dermal duct tumors exist entirely in the dermis. The etiology is unclear, but occurrence after trauma and radiation has been reported.128–130

Clinical Findings

Hidroacanthoma simplex presents as a solitary hyperkeratotic plaque on the extremities of middle-aged and elderly females. Eccrine poromas classically present as a solitary, slow growing, flesh-colored or bright red, pruritic, painful, pedunculated papule or nodule on the palms and soles of adults. There is a predilection for the sole and sides of the feet, followed by the hands, fingers, head, neck, and trunk.131 A distinct feature is a cup-shaped shallow depression from which the tumor protrudes.14 While poromas tend to be solitary, multiple lesions can exist. When hundreds of poromas are present, the condition is denoted “poromatosis” and is observed in patients with hidrotic ectodermal dysplasia.132 Dermal duct tumors present with deep nodules on any part of the body.

Histopathology

Hidroacanthoma simplex displays sharply demarcated aggregations of cuboidal to ovoid cells in the epidermis. Eccrine poromas reveal aggregations of uniform basaloid cells that radiate from the basal layer of the epidermis into the dermis (Fig. 119-8). Dermal duct tumors consist of several sharply circumscribed dermal nodules consisting of poroid cells with frequent ductal structures

Prognosis and Clinical Course

Eccrine poromas rarely progress to porocarcinoma, although porocarcinoma is the most common form of sweat gland carcinoma.14 Clinically, porocarcinoma presents as a blue–black nodule or infiltrated plaque on the legs, feet, face, thighs, and arm. Interestingly, there is rare involvement of the palms and soles. The average age of onset is 75 years old, although there are reports as early as 12 years of age.7 Porocarcinoma evolving from a poroma is characterized by rapid growth up to 10 cm, bleeding, and ulceration. There is a propensity to form multiple cutaneous metastases. Regional nodal metastases can occur in 20% of cases, but distant metastases are extremely rare. Porocarcinoma has a tendency to recur locally with a 20% recurrence rate after excision. Mortality is 65% if there are positive nodal metastases. Survival with distant metastases ranges from 5 to 24 months.133

Treatment

Mohs micrographic surgery is evolving as the treatment of choice for localized disease with a lower recurrence rate than local excision.134,135

Eccrine Syringofibroadenoma

Epidemiology

Eccrine syringofibroadenoma was first described by Mascaro in 1963.136 It presents in older adults particularly in the seventh to eighth decades.136–138

Etiology and Pathogenesis

Eccrine syringofibroadenoma originates from or is differentiating toward the acrosyringium or eccrine dermal duct.138 There is controversy as to whether the lesion is a hamartoma, reactive hyperplasia, or a true neoplasm. The lesion has been classified into five distinct subtypes: multiple lesions associated with an ectodermal dysplasia, multiple lesions with no additional cutaneous pathology, unilateral linear lesions, solitary lesions, and reactive lesions.139 Reactive lesions have been reported in association with erosive lichen planus, trauma due to diabetic neuropathy, elephantiasis, bullous pemphigoid, burn scars, and peristomal skin.138,140 Human papillomavirus 10 may also play a role in the development of eccrine syringofibroadenomas.141

Clinical Findings

The clinical presentation is nonspecific and variable. Eccrine syringofibroadenomas can range from solitary lesions to multiple papules, plaques, and nodules in a symmetrical and linear or nevoid pattern. The most common site is the limb.137 Additional locations include the face, torso, buttocks, and nail.138

Eccrine syringofibroadenomas are observed in ectodermal dysplasia, and specifically, Clouston’ syndrome. Clouston's syndrome is an autosomal dominant condition with progressive hyperkeratosis of the palms and soles, patchy alopecia, nail dystrophy, normal teeth, and normal sweating. It results from mutations in the connexin 30 or GJB6 gene.141

Histopathology

Unlike the variety of clinical presentations, the histologic picture is quite consistent. There are multiple anastomosing cords of benign epithelial cells surrounded by a loose fibrovascular stroma. The epithelial cords demonstrate ductal differentiation. Occasional luminal eccrine ducts are noted within the anastomosing cords.

Prognosis and Clinical Course

The course of eccrine syringofibroadenomas is typically benign, although malignant transformation into squamous cell carcinoma or eccrine syringofibroadenocarcinoma has been reported.137,138 This occurrence is extremely rare and generally arises in elderly male patients. Signs of malignancy include ulceration, rapid growth, and crusting.

Treatment

Given the malignant potential, complete surgical excision is recommended. If the lesions are too numerous or large for excision, the pulse dye laser has shown promising results.138

Eccrine Spiradenoma

Epidemiology

Eccrine spiradenoma is a benign adnexal tumor first described by Kersting and Helwig in 1956.142 It is relatively common, and presents in young and middle-aged adults between age 15 and 35. Rare familial cases have been reported.7

Etiology and Pathogenesis

Eccrine spiradenoma derives from the intradermal straight eccrine duct.

Clinical Findings

Eccrine spiradenoma typically appears as a solitary, slow growing, 1–2 cm, red–brown deep-seated nodule (Fig. 119-9A). There may be a slightly bluish hue, and paroxysmal pain is a distinct trait. Rare atypical variants include large lesions, vascular lesions, and multiple lesions arranged in a linear or zosteriform configuration.143–145 There is a predilection for the ventral upper trunk.7 Eccrine spiradenoma has been observed growing within a nevus sebaceus.146 These tumors are also seen in the setting of Brooke–Spiegler syndrome, an autosomal dominant condition with numerous cylindromas, eccrine spiradenomas, and trichoepitheliomas due to an inactivating mutation in the CYLD gene.

Histopathology

Biopsy reveals one or several well-circumscribed basophilic nodules in the dermis and/or subcutaneous tissue. Epithelial aggregates are arranged in sheets and cords or in a trabecular pattern. There are two distinct cell populations: small darkly staining basaloid cells rimming the periphery and larger cells with a pale nucleus in the center of the lesion. Tubular or cystic structures are noted within the epithelial aggregations. The basaloid cells are often arranged in rosettes. PAS-positive hyaline material is noted within the tumor (Fig. 119-9B).

Prognosis and Clinical Course

Malignant transformation to eccrine spiradenocarcinoma is extremely rare.147 Long-standing lesions that rapidly enlarge, bleed, ulcerate, or change color should raise the suspicion of malignancy. The average age of presentation is 62. Lesions tend to present on the trunk and extremities and achieve an average size of 7.5 cm. Metastatic disease is most frequently seen in the regional lymph node basin, but can also be seen in the lung, liver, brain, spinal cord, bone, and parotid gland. Metastases can be fatal, and overall mortality has been reported between 20% and 40%.148

Treatment

The treatment of choice for eccrine spiradenoma is surgical excision with clear margins. There is no satisfactory treatment for pain. For spiradenocarcinoma, wide local excision is recommended. The role of sentinel lymph node biopsy, radiation, and tamoxifen for estrogen-receptor positive tumors is unclear.149

Papillary Eccrine Adenoma

Epidemiology

Papillary eccrine adenoma is a rare benign adnexal tumor. While it can present from childhood to advanced age, the mean age is in the fifth decade. It is more common in women.150 An African-American predilection has been noted.151

Etiology and Pathogenesis

Papillary eccrine adenomas exhibit eccrine differentiation. There are architectural similarities to the tubular apocrine adenoma.4 Some classify these two entities under the heading of papillary tubular adenoma.152

Clinical Findings

It most commonly presents as a solitary, firm, flesh-colored nodule on the distal extremity. The size varies from 0.5 to 4 cm in diameter.152

Histopathology

Microscopic examination reveals a well-circumscribed, nonencapsulated dermal nodule comprised of numerous dilated tubules surrounded by a fibrous stroma. The tubules are lined with an outer layer of flattened epithelial cells and an inner layer of cuboidal or columnar cells with intraluminal papillary projections. The lack of atypia and mitoses differentiates this benign entity from aggressive digital papillary adenomas and adenocarcinomas.

Prognosis and Clinical Course

Papillary eccrine adenoma typically follows a benign clinical course with rare recurrence and no reports of metastatic disease.

Treatment

The treatment of choice is surgical excision with clear margins. Mohs micrographic surgery is an effective therapeutic option, given the potential ability to preserve sensory and motor function of the hand.152

Nodular Hidradenoma

Epidemiology

Nodular hidradenoma, also known as eccrine acrospiroma, is a benign adnexal tumor that presents most commonly in middle-aged and elderly females.7,153

Etiology and Pathogenesis

Nodular hidradenoma shows features of eccrine and apocrine differentiation, although it is typically classified as an eccrine tumor. It is also closely related to poroma, and both entities are often regarded together as acrospiromas.

Clinical Findings

Nodular hidradenoma usually presents as a slow-growing, solitary, firm, flesh-colored or red to blue, mobile, solid or cystic nodule that measures 1–2 cm in diameter. The most common locations are the scalp, face, and trunk (Fig. 119-10A).7 Atypical presentations include childhood onset, large lesions, painful tumors, or rapidly growing lesions.

Histopathology

Nodular hidradenoma presents as a well-circumscribed, nonencapsulated nodular, solid, or solid-cystic lesion in the dermis and occasionally extends to the subcutaneous fat. Ductal differentiation is present. The closely packed tumor cells have a biphasic population with small dark polygonal cells and larger clear cells (Fig. 119-10B). Features such as poor circumscription, large size, solid sheet-like growth pattern, necrosis, and vascular and lymphatic invasion, pleomorphism, and high mitotic rate are suggestive of malignant nodular hidradenoma or hidradenocarcinoma.154

Prognosis and Clinical Course

Despite local excision, nodular hidradenoma has a recurrence rate of 12% if not fully excised.6 Rarely, nodular hidradenoma can degenerate into hidradenocarcinoma (Fig. 119-11). Most hidradenocarcinomas arise de novo. The prognosis for hidradenocarcinoma is poor, with a 50% recurrence rate and a 60% metastatic rate. The prognosis for a 5-year disease free survival is only 30%. The most common site of metastases is the regional lymph nodes. Hematogenous spread to distant lymph nodes, bones, viscera, and pleura has been reported.155

Treatment

The treatment of choice for nodular hidradenoma is surgical excision with clear margins. Hidradenocarcinoma should be treated aggressively with wide local excision of 3–5 cm. Moh micrographic surgery has also been employed for margin control in irregular tumors.156,157 Sentinel lymph node biopsy has been advocated by some authors, but there is no known benefit.

Chondroid Syringoma

Epidemiology

Chondroid syringoma, or mixed tumor of the skin, is an uncommon benign appendageal tumor of mixed differentiation that was first described by Hirsch and Helwig in 1961.158 It is generally observed in middle-aged and elderly males.159

Etiology and Pathogenesis

Chondroid syringoma comprises a group of adnexal neoplasms with ductal differentiation and a fibromyxochondroid stroma. The etiology of chondroid syringoma is unclear. It displays features of both folliculosebaceous-apocrine and eccrine differentiation. It is analogous to mixed tumor of the salivary gland.

Clinical Findings

Clinically, chondroid syringoma presents with slow-growing, painless, nonspecific, firm nodules on the head and neck, especially the nose, cheeks, and upper lip (Fig. 119-12A).6 It can also be seen on the upper trunk, axilla, and genital regions. Lesions range in size from 5 to 30 mm, although lesions as large as 7 cm have been reported.160

Histopathology

Chondroid syringoma presents with a circumscribed dermal nodule with bland epithelial cells arranged in cords, ducts and tubules, embedded in a myxoid-cartilaginous stroma (Fig. 119-12B). Eccrine variants exhibit tubules with a small lumen lined with a single row of cuboidal cells. The apocrine variant is lined with two layers of epithelial cells and displays decapitation secretion.

Prognosis and Clinical Course

Chondroid syringomas very rarely transform into malignant chondroid syringomas. The malignant variant tends to present on the extremities and trunks of females, unlike its benign counterpart that predominates on the head and neck of males. The average age of onset is 48 years old. Malignant chondroid syringoma is associated with a nearly 50% metastatic rate to the lymph nodes, bone, and lung.161

Treatment

The treatment of choice for chondroid syringoma is complete surgical excision. Electrodessication, dermabrasion, and vaporization with argon or carbon dioxide laser have been tried with variable results.162 Malignant chondroid syringoma requires a wide local excision with at least a 1 cm margin and possible adjuvant radiation.162

Malignant Neoplasms

Aggressive Digital Papillary Adenoma and Adenocarcinoma

Epidemiology

Aggressive digital papillary adenoma (ADPA) and adenocarcinoma (ADPAca) are rare eccrine gland tumors that present primarily in Caucasian males in their fifties. There are three case reports of this condition occurring in children.163

Etiology and Pathogenesis

The origination of ADPA and ADPAca is controversial. While these entities have traditionally been classified as eccrine neoplasms, decapitation secretion and sebaceous differentiation have been noted in some cases of ADPAca. However, since most lesions present acrally, an anatomic site rich in eccrine units and devoid of apocrine glands, the most likely derivation is eccrine. ADPA and ADPAca exist on a spectrum, where ADPAca represents a more aggressive disease with metastatic potential, although ADPA can also behave in a destructive manner. This entity is not associated with the benign papillary eccrine adenoma.163–165

Clinical Findings

These tumors present as a solitary, firm, tan or pink, rubbery nodule on the acral extremities. Specifically, the most common location is the volar surface of the skin between the nail bed and distal interphalangeal joint.164 While the lesions are generally asymptomatic, patients may experience pain, bleeding, ulceration, and rarely, limited range of motion.

Histopathology

Histologically, these lesions are multinodular dermal and/or subcutaneous proliferations of ductal and glandular structures with focal solid and cribriform zones. Ductal structures exhibit cystic dilatations, in which several papillary projections are present. A fibrocollagenous stroma surrounds the epithelial components. Atypia, necrosis, and invasion of bone and vasculature are signs of an aggressive tumor.

Prognosis and Clinical Course

ADPA and ADPAca are highly aggressive tumors with frequent local recurrence and metastases. The local recurrence rate is nearly 50% after surgical excision, with recurrence occurring as early as two months to 9 years.163–165 Metastases occur in approximately 15% of cases, with the most common site being the lung.164 Other sites of metastases include lymph nodes, brain, kidney, bone, or retroperitoneum.165

Treatment

ADPA and ADPAca should be treated aggressively with excision or digital amputation. Metastatic disease has been treated with chemotherapy with variable results. Annual monitoring for metastatic disease, including physical examination and chest X-ray, is recommended for 10 years after diagnosis.165

Mucinous Eccrine Carcinoma

Epidemiology

Mucinous eccrine carcinoma is a rare low-grade eccrine tumor that presents in elderly males. It is most commonly seen in Caucasian and African-American males.6,166

Etiology and Pathogenesis

Mucinous eccrine carcinoma originates from the deepest portion of the eccrine duct.167 It is analogous to mucinous carcinoma of the breast, and may express estrogen and progesterone receptors.

Clinical Findings

Mucinous eccrine carcinoma typically presents with an asymptomatic, round, elevated, reddish, ulcerated mass. It most commonly occurs on the head and neck in 75% of cases, with 40% of cases on the eyelid. There is a propensity for sudden enlargement.168 Metastatic mucinous gastrointestinal cancers must be excluded.

Histopathology

Histopathologically, mucinous eccrine carcinoma is a well-demarcated, lobular, dermal tumor with frequent extension into the subcutaneous tissue. It consists of PAS-positive, diastase-resistant multilocular pools of mucin, in which nests of bland polygonal cells are embedded. There are rare mitoses.

Prognosis and Clinical Course

This tumor has a favorable prognosis with low metastatic potential. While regional metastases are 15% and distant metastases are 7%, the local recurrence rate is much higher at 36%.167,169

Treatment

The treatment of choice is surgical excision. Wide local excision is associated with high recurrence rates, even with 1–2 cm margins.169 Mohs micrographic surgery has been attempted with good results.166,168,170

Microcystic Adnexal Carcinoma

Epidemiology

Microcystic adnexal carcinoma (MAC), also known as sclerosing sweat duct carcinoma or syringomatous carcinoma, is a rare adnexal tumor first described by Goldstein in 1982.171 It is typically seen in middle-aged to elderly patients, with an average age in the seventh decade. Some reports reveal a slight female predilection.172 While there is a Caucasian predominance, there are reports in African-American individuals.173

Etiology and Pathogenesis

MAC shows features of eccrine, apocrine, and follicular differentiation. Risk factors include immunosuppression and a prior history of therapeutic radiation.6

Clinical Findings

MAC presents as a slow-growing, firm, indurated plaque or nodule with indistinct borders on the face, especially the upper lip. The tumor is generally asymptomatic, but numbness, burning, anesthesia, and paresthesia have been noted.7 The most common location is the head and neck with nearly 75% of lesions occurring in that region.172 There is an increased prevalence on the left side versus the right side of the face.174 The upper lip is nine times more common than the lower lip, unlike squamous cell carcinoma.175 MAC has also been reported to occur on the nipple, axilla, vulva, external auditory canal, extremities, and perianal skin.173,176 The average tumor size in 15 mm.

Histopathology

MAC is a poorly circumscribed dermal tumor embedded in a desmoplastic stroma that can extend into the subcutaneous tissue and muscle. Superficially, the tumor is composed of ducts, keratin horn cysts, and small cords of basaloid cells, resembling syringoma. The deeper component exhibits smaller strands and cystically dilated tubules and ductal structures. There is a lack of cytologic atypia. Perineural invasion is common and extensive. The histologic differential diagnosis includes syringoma, morpheaform basal cell carcinoma, and desmoplastic trichoepithelioma.

Prognosis and Clinical Course

MAC is a deeply infiltrative and locally aggressive tumor with significant morbidity. Local recurrence is common, with a recurrence rate in 50% of cases. Recurrence has been reported to occur several years after initial diagnosis. Local recurrence is attributed to the high rate of perineural invasion, seen in 17%–60% of cases. While recurrence is common, metastases are rare at a rate of 2.2%. Mortality is 0.4%.177

Treatment

The treatment of choice is Mohs micrographic surgery with a recurrence rate between 0% and 12%.174,177–179 Wide local excision is associated with recurrence rates of 50%. Radiation does not have an effect on survival, and may even lead to conversion into a more histologically and clinically aggressive tumor.179

Follicular tumors demonstrate histopathologic features that resemble different portions of a normal hair follicle, including the hair germ, matrix, and outer root or trichilemmal sheath. Unlike apocrine and eccrine tumors that generally have a malignant counterpart, follicular tumors are generally benign with a rare chance of degeneration into a malignant lesion. Pilomatricoma and trichoblastoma have well-documented transformation into carcinomas. Malignant proliferating trichilemmal cysts and trichilemmal carcinoma are thought to be variants of squamous cell carcinoma, as opposed to true adnexal carcinomas.

Hamartomas and Hyperplasias

Hair Follicle Nevus

Epidemiology

The hair follicle nevus, also known as congenital vellus hamartoma, is a rare lesion present in all age groups. Often it is apparent at birth.180

Etiology and Pathogenesis

Some believe that the hair follicle nevus is a variant of trichofolliculoma or accessory tragus.181

Clinical Findings

Hair follicle nevus presents as a dome-shaped, skin-colored papule or nodule from which hair protrudes. It is most common on the hair-bearing surfaces, including the face and periauricular region.180,182 Linear arrangement of multiple papules has been observed. Some authors also advocate that the faun tail, palmoplantar follicles, and Becker's nevus are variants of the hair follicle nevus.183 Rare associations include ipsilateral alopecia, leptomeningeal angiomatosis, multiple epidermal nevi, and frontonasal dysplasia.180

Histopathology

Numerous closely packed mature vellus follicles confines to a focal well circumscribed area in the upper dermis. Follicles are surrounded by a prominent sheath of perifollicular connective tissue, which in turn are surrounded by clefts. Sebaceous lobules may be present.

Prognosis and Clinical Course

The relative size of the lesion decreases with time as the child grows. Therefore, excision may be deferred as it becomes a less prominent cosmetic issue over time.

Treatment

Treatment is not necessary. Surgical excision is effective for cosmetic purposes.

Basaloid Follicular Hamartoma

Epidemiology

Basaloid follicular hamartoma (BFH), also known as benign follicular hamartoma, is a rare follicular neoplasm that can be congenital or develop during adulthood.

Etiology and Pathogenesis

BFH may be related to dysregulation of the PTCH signaling pathway, similar to basal cell carcinomas.184

Clinical Findings

Clinically, there are five variants of BFH: a solitary 2–3 mm papule, a localized plaque with alopecia, linear or blaschkoid, generalized dominantly inherited familial type, and generalized papules associated with myasthenia gravis and diffuse alopecia.184 The familial form presents early in childhood, and can also be associated with milia, comedones, hyperpigmented papules, hypotrichosis, hypohidrosis, and palmar pits. Other systemic associations include systemic lupus erythematosus and cystic fibrosis.185,186 There are reports of circulating autoantibodies, namely antinuclear and antiacetylcholine receptor antibodies.

Histopathology

Histopathologically, there are anastomosing strands of basaloid cells with numerous epidermal connections. Central areas of epithelial aggregations occasionally reveal cells with a squamoid appearance. Features of follicular differentiation, including horn cysts, rudimentary germs, and follicular papillae, are variably present.

Prognosis and Clinical Course

BFH are benign lesions. Patients may have an increased risk of basal cell carcinoma, although it does not arise within the hamartoma. This association may be related to dysregulation of the patched (PTCH) signaling pathway.

Treatment

The treatment of choice is surgical excision.

Benign Neoplasms

Dilated Pore of Winer and Pilar Sheath Acanthoma

Epidemiology

Dilated pore of Winer and pilar sheath acanthoma share the commonality of a central pore, and histologically, exhibit a large cystic space with squamous epithelium that is continuous with the surface epidermis, and filled with keratinaceous material. The dilated pore was described by Winer in 1954, and presents on the face of elderly males.187 In 1978, the pilar sheath acanthoma was described as a separate entity observed on the upper lip of middle aged and elderly individuals.188

Etiology and Pathogenesis

There is a debate as to whether these entities are follicular cysts versus benign neoplasms.3

Clinical Findings

The dilated pore of Winer presents as a solitary, open comedo on the head and neck of elderly males.189 It may arise in a background of cystic acne or actinic damage. It lacks palpable induration. The pilar sheath acanthoma is a solitary, open comedo filled with keratin on the upper lip.188

Histopathology

Histologically, the dilated pore reveals a single or several contiguous, markedly, dilated infundibula in upper dermis. The epithelial lining reveals focal acanthosis and finger-like projections into the surrounding dermis. Dilated infundibula contain cornified cells arranged in basket-weave and laminated patterns. Heavy pigmentation of the epithelium can be observed. The pilar sheath acanthoma differs by exhibiting a larger more irregular branching cystic cavity. Rather than the thin projections seen in dilated pore, there are multiple lobulated masses of cells radiating from the central cavity into the dermis.

Prognosis and Clinical Course

These are benign entities.

Treatment

Treatment is not necessary. Surgical excision can be performed for cosmetic purposes.

Trichofolliculoma

Epidemiology

Trichofolliculoma is a benign follicular neoplasm that presents at any age, but is most commonly seen in adults.

Etiology and Pathogenesis

Trichofolliculoma displays differentiation toward the hair follicle with intermediate differentiation between a hair follicle nevus and a trichoepithelioma.

Clinical Findings

Trichofolliculoma classically presents as a small dome-shaped nodule measuring 5 mm on the face, especially the nose or scalp. A fine tuft of hairs protrudes from a central pore (Fig. 119-13). Trichofolliculoma has been reported in association as a collision tumor with basal cell carcinoma.190

Histopathology

Trichofolliculoma has a characteristic histopathologic appearance with one or more central large dilated follicles with radiating secondary follicles. The secondary follicles display varying degrees of differentiation ranging from immature rudimentary matrix to well-formed follicles with papillae, matrix, trichohyalin granules, and fine hairs. If prominent sebaceous lobules are observed, the lesion is denoted a sebaceous trichofolliculoma.191

Prognosis and Clinical Course

Trichofolliculomas are benign. However, a single case of perineural invasion has been documented in the literature.192

Treatment

The treatment of choice is surgical excision.

Fibrofolliculoma, Trichodiscoma, and Fibrous Papule

Epidemiology

Fibrofolliculoma, trichodiscoma, and fibrous papule or perifollicular fibroma are clinically indistinct from one another, and likely are on the same spectrum of follicular proliferations with differentiation toward the mantle. They also possess a specialized periadventitial dermis that surrounds the upper hair follicle.3 These lesions are rare, appear in adulthood, and are seen in multiplicity together in the Birt–Hogg–Dube syndrome.

Etiology and Pathogenesis

These three lesions represent different stages of differentiation toward the follicular mantle.193 The folliculin gene, a tumor suppressor, is mutated in Birt–Hogg–Dube syndrome and may play a role in the pathogenesis of these follicular tumors.

Clinical Findings

Fibrofolliculomas and trichodiscomas present as multiple small whitish papules measuring 2–4 mm on the head and neck, upper trunk, and arms. They are rarely solitary. Fibrous papules are solitary papules or multiple dome-shaped, skin-colored, pigmented or reddish lesions on the face, especially the perinasal area.3 Multiple fibrous papules are seen in tuberous sclerosis, known as adenoma sebaceum, or Birt–Hogg–Dube syndrome.194

Multiple familial lesions are seen in Birt–Hogg–Dube syndrome, an autosomal dominant condition due to a mutation in folliculin. Although the function of folliculin is not entirely clear, it has been linked to the mammalian target of rapamycin (mTOR) pathway.195 Cutaneous lesions include fibrofolliculomas, trichodiscomas, fibrous papules, and acrochordons. Patients have a predisposition to colonic polyposis, spontaneous pneumothorax, and renal cell carcinoma. Renal cancer risk is higher in males. The overall incidence of renal cell carcinoma, specifically renal oncocytomas and chromophobe renal carcinomas, is 12% in adults over the age of 40. Eighty percent of patients have pulmonary cysts, and nearly 25% are at risk of spontaneous pneumothorax, which typically presents at a younger age.195

Histopathology

Fibrofolliculomas present with a dome shaped lesion with a central relatively well-differentiated hair follicle displaying a single or several contiguous, dilated, keratin-filled infundibula. The infundibula are connected to several thin, focally anastomosing epithelial strands that extend in a radial fashion into the stroma. The infundibula are surrounded by a distinct fibrillary collagenous or mucinous stroma with scant elastic tissue.

Histologically, trichodiscomas reveal the fine fibrillary collagenous stroma containing ectatic blood vessels. A hair follicle may be found at the margin of the lesion, although the primary distinguishing characteristic of trichodiscoma is the stromal component.

Fibrous papule presents as a dome-shaped or polypoid lesion consisting of one or more poorly formed hair follicles surrounded by a cellular stroma with numerous proliferative small blood vessels in the dermis.

Prognosis and Clinical Course

While the cutaneous tumors themselves are benign, these patients should be screened for Birt–Hogg–Dube syndrome. In the case of multiple fibrous papules, a suspicion of tuberous sclerosis should be raised. Genetic counseling should be provided if a diagnosis is confirmed.

Treatment

Solitary lesions can be excised, although this is difficult for multiple lesions. Laser resurfacing with the erbium:Yag or carbon dioxide laser, electrodessication, cryotherapy, and dermabrasion have been tried with variable results.195

Trichoblastoma

Epidemiology

Trichoblastoma is a rare benign follicular neoplasm that presents in adults between the fourth and sixth decades. Childhood presentation outside the context of a nevus sebaceous is highly rare.196

Etiology and Pathogenesis

Trichoblastoma comprises a group of tumors with follicular germinative differentiation.

Clinical Findings

Trichoblastoma presents with a solitary, well-defined, slow-growing, brown or blue–black nodule on the head or neck, especially the scalp (Fig. 119-14A). It can reach up to 3 cm in diameter, although cases up to 10 cm have been reported.197 Multiple lesions are seen in Brooke's disease, which is not associated with other anomalies. Trichoblastomas are the most common neoplasm to arise within a nevus sebaceous. They can also coexist with basal cell carcinoma.23

Histopathology

Histologically, there are several dermal and subcutaneous smooth-bordered collections of basaloid cells arranged in nodular, cribriform, retiform, and racemiform patterns.198 The stroma is characteristically sclerotic or hyalinized. Peripheral palisading and rudimentary follicular papillae are also observed (Fig. 119-14B). Heavy melanin pigmentation and horn cysts can also be seen. The differential diagnosis includes trichoepithelioma and basal cell carcinoma. Cutaneous lymphadenoma is a variant with extensive infiltration of tumors nests with lymphocytes and histiocytes.

Prognosis and Clinical Course

Transformation to trichoblastic carcinoma or trichoblastic sarcoma is extremely rare. Trichoblastic carcinoma has been associated with fatal metastases.199,200

Treatment

Complete surgical excision is recommended given the potential for malignancy and difficult distinction from basal cell carcinoma.

Trichoepithelioma

Epidemiology

The solitary trichoepithelioma presents in elderly patients. Multiple trichoepitheliomas, as seen in the autosomally dominant inherited Brooke–Spiegler syndrome, present in childhood or puberty.

Etiology and Pathogenesis

Trichoepithelioma shows follicular germinative differentiation. Some consider it a variant of trichoblastoma.

Clinical Findings

There are three clinical variants of trichoepithelioma: solitary, multiple, and desmoplastic. Solitary trichoepithelioma is a small 5–8 mm, skin-colored papule on the nose, upper lips, and cheeks.3 It can also develop on the trunk, neck, or scalp. It is often mistaken for basal cell carcinoma. Occasionally, they can grow quite large to several centimeters. This giant solitary trichoepithelioma is most commonly seen on the thigh or perianal region of the elderly.3

Multiple trichoepitheliomas are seen in adolescents in the setting of Brooke–Spiegler syndrome, an autosomal, dominant condition characterized by multiple cylindromas, eccrine spiradenomas, and milia. It is due to germ-line mutations in the CYLD gene, which encodes an inhibitor of NF-κB.201 Patients present with numerous small, shiny, firm papules on the face with a predilection for the upper lip, nasolabial folds, and eyelids (Fig. 119-15A).

Multiple trichoepitheliomas are also seen in Rombo syndrome, which is characterized by atrophoderma, milia, hypotrichosis, basal cell carcinomas, and peripheral vasodilatation.202 Multiple trichoepitheliomas also have an association with systemic lupus erythematosus and myasthenia gravis.

Histopathology

Trichoepitheliomas present with sharply circumscribed, symmetric, dome shaped lesions composed of aggregates of relatively monomorphic basaloid cells in the upper dermis surrounded by abundant fibrous stroma with stromal–stromal retraction. The most common pattern is cribriform, but nodular, racemiform, and retiform patterns have also been observed (Fig. 119-15B). Trichoepitheliomas also exhibit peripheral palisading and papillary mesenchymal bodies.

Prognosis and Clinical Course

There are very few case reports that describe malignant degeneration into malignant trichoepithelioma or trichoblastic carcinoma.203

Treatment

The treatment of solitary trichoepithelioma is surgical excision. This is not feasible for multiple lesions. Cryotherapy, electrodessication, and carbon dioxide laser resurfacing can be employed as destructive methods.201

Desmoplastic Trichoepithelioma

Epidemiology

Desmoplastic trichoepithelioma, also known as sclerosing epithelial hamartoma, is a rare benign adnexal neoplasm initially described by Brownstein and Shapiro in 1977.204 While it most frequently appears in young women, there are reports of congenital lesions.205,206

Etiology and Pathogenesis

Desmoplastic trichoepithelioma may be a variant of trichoblastoma or trichoepithelioma with extensive stromal sclerosis.

Clinical Findings

Desmoplastic trichoepithelioma presents as a solitary, firm, skin-colored to white–gray, sclerotic annular plaque with a central depression on the upper cheek or angle of the lip of a young female (Fig. 119-16). The lesion typically measures 1 cm and is asymptomatic. It is extremely rare to have multiple lesions. It is often mistaken for basal cell carcinoma.205

Histopathology

Histopathologically, there is a well-circumscribed lesion consisting of cords of basaloid cells that are 1–3 cells thick in the upper two-third of the dermis. There are small keratinous cysts and a characteristic desmoplastic stroma that exhibits stromal–stromal retraction. Histologic differential diagnosis includes morpheaform basal cell carcinoma and microcystic adnexal carcinoma.

Prognosis and Clinical Course

Desmoplastic trichoepithelioma behaves in a benign fashion. However, uncertainty regarding the histologic diagnosis often leads to excision.

Treatment

The treatment of choice is Mohs micrographic surgery or excision.205,207 Alternatives include dermabrasion and laser surgery, although these are associated with a higher recurrence rate.

Trichoadenoma

Epidemiology

Trichoadenoma is a rare follicular tumor, described by Nikolowski in 1958, most commonly seen in adults.208 It has also been reported in children, as well as in a congenital case.209

Etiology and Pathogenesis

Trichoadenoma is a follicular tumor with differentiation toward the infundibular portion of the folliculosebaceous canal. It lies on a differentiation spectrum between trichofolliculoma and trichoepithelioma.3,210

Clinical Findings

Trichoadenoma presents as a solitary slow-growing, grayish nodule measuring up to 1.5 cm. The most common location is the face, followed by the buttocks.4,211 It can be vegetative or verrucous.

Histopathology

Microscopic examination reveals a dome-shaped, sharply defined nodule composed of numerous round infundibulocystic structures in the dermis. The infundibulocystic structures are lined by squamous epithelium. Conspicuous collagenous stroma surrounds the tumor nests.

Prognosis and Clinical Course

This is a benign tumor.

Treatment

While treatment is not necessary, excision can be performed for cosmetic purposes.

Pilomatricoma

Epidemiology

Pilomatricoma, also known as calcifying epithelioma of Malherbe and pilomatrixoma, is most frequently seen in children. However, a bimodal onset is observed with the majority occurring in the first and sixth decades. There is an increased prevalence in girls.3

Etiology and Pathogenesis

Pilomatricoma is derived from hair matrix cells.212 It is associated with activating mutations in β-catenin, a mediator in the Wnt signaling pathway.

Clinical Findings

Pilomatricoma presents as a solitary, skin-colored or bluish, firm, cystic nodule on the head, neck, or proximal upper extremities (Fig. 119-17A). It displays a “tent-sign” with many angles and surfaces apparent on skin stretch. Overlying epidermal atrophy is common and designated “anetodermic” variant. Additional variants include multiple lesions, bullous, or giant tumors.213 Giant pilomatricoma has been associated with hypercalcemia and elevated parathyroid hormone-related protein (PTH-rp).214

Multiple lesions are seen in Gardner's syndrome, myotonic dystrophy, Rubinstein–Taybi, and Turner syndrome.215 More recent associations have been made with trisomy 9, sarcoidosis, HIV, and Sotos syndrome.215

Histopathology

Pilomatricoma reveals a fairly characteristic encapsulated mass of basophilic cells with minimal cytoplasm that evolve into eosinophilic shadow or ghost cells toward the center of the lesion. Calcification can be prominent (Fig. 119-17B). Pilomatrical carcinoma demonstrates irregularly sized and variably sized islands of basaloid cells. Atypia, mitoses, and necrosis are notable (Fig. 119-18).

Prognosis and Clinical Course

Pilomatricomas rarely recur locally after excision. Rare malignant transformation to pilomatrical carcinoma has also been reported. Lesions tend to be on the head, neck, upper limbs, and buttocks. It tends to occur in older male patients with sun-damaged skin, as opposed to its benign counterpart pilomatricoma, which is more commonly seen in young females. Metastases to regional lymph nodes and distant sites can occur in 10% of patients.216 Fifty percent of pilomatrical carcinoma recur with local excision. Pilomatrical carcinoma can rarely arise de novo.

Treatment

The treatment of choice for pilomatricoma is excision, and it is associated with a low recurrence rate. Pilomatrical carcinomas should be excised with a wide margin. Mohs micrographic surgery has been employed with good results.216

Trichilemmoma

Epidemiology

Trichilemmoma is a benign follicular neoplasm first described by Headington and French in 1962.217 It typically presents in adulthood.

Etiology and Pathogenesis

Trichilemmoma exhibits differentiation toward the outer root sheath or trichilemmal sheath at the level of the bulb. Some feel that trichilemmoma represents a viral wart, although DNA sequencing has not revealed papillomavirus in these lesions, making it less likely.3

Mutations in the PTEN gene have been implicated as multiple trichilemmomas have been observed in Cowden's syndrome, an autosomal dominant condition with germ-line mutations in the tumor suppressor PTEN gene. PTEN encodes phosphatase and tensin homolog, a phosphatase in the phosphoinositol-3-kinase (PI3K) pathway, which normally inactivates signals in the antiapoptotic PI3K/AKT kinase pathway. When PTEN is absent, decreased, or dysfunctional, there is uninhibited phosphorylation of AKT leading to the inability to undergo apoptosis.218

Clinical Findings

Trichilemmoma can present as a solitary, small 3–8 mm, flesh-colored, asymptomatic, keratotic papule on the face with a predilection for the nose and upper lip. It can be seen arising within a nevus sebaceous.219

Multiple lesions are a maker for Cowden's syndrome (multiple hamartoma syndrome), an autosomal dominant condition due to mutations in the tumor suppressor PTEN gene.218 Additional cutaneous manifestations include oral papillomas and acral palmoplantar keratoses. There is an increased risk for breast, thyroid, and endometrial cancer. The most common cancer is breast cancer with a lifetime risk of 25%–50%, with two-thirds presenting in females between the age of 38 and 46. Trichilemmomas often precede the diagnosis of breast cancer, and therefore appropriate dermatologic diagnosis is critical.218,220 The second most common neoplasm is thyroid cancer, specifically follicular and papillary subtypes. Endometrial cancer is seen in 10% of cases.218 Other manifestations include colonic polyps, breast adenomas, thyroid adenomas, fibrocystic breast disease, and Lhermite–Duclos disease or dysplastic gangliocytoma of the cerebellum.

Histopathology

On histologic examination, there is an exo-endophytic, lobular proliferation of polygonal, pale staining, glycogen containing squamoid cells extending from the epidermis. There is peripheral palisading of columnar cells, and a conspicuous PAS-positive basement membrane surrounding the lesion. The desmoplastic trichilemmoma variant displays tumor cells embedded in a sclerotic stroma.

Prognosis and Clinical Course

There are rare reports of trichilemmal carcinoma, although many feel that this is a variant of squamous cell carcinoma. There is a low metastatic potential associated with this entity.221

Treatment

The treatment of choice is excision. Mohs micrographic surgery has been used for desmoplastic trichilemmomas in cosmetically sensitive areas.221 Alternatives for multiple lesions include cryotherapy, electrodessication and curettage, and laser ablation.

Tumor of the Follicular Infundibulum

Epidemiology

Tumor of the follicular infundibulum (TFI), also known as isthmicoma, was first described by Mehregan and Butler in 1961.222 It presents in middle-aged and elderly adults. It is unclear whether there is a male or female predominance as conflicting reports exist.223,224

Etiology and Pathogenesis

TFI is a neoplasm that demonstrates differentiation toward the follicular isthmus, not the infundibulum as the name would suggest.

Clinical Findings

TFI presents as a solitary, small, asymptomatic, thin, keratotic papule on the head or neck.223 It is often misdiagnosed as a seborrheic keratosis or basal cell carcinoma. There are rare cases of numerous eruptive lesions, which typically appear as atrophic or hypopigmented macules and papules.223,224 TFI has been shown to be associated with basal cell carcinoma and nevus sebaceous.224

Histopathology

Histopathologically, TFI reveals a horizontally oriented, plate-like tumor in the upper dermis with the epithelial component showing multiple connections to the epidermis or hair follicles. The epithelium exhibits a fenestrated pattern with interconnecting cords and columns. There is a surrounding collagenous stroma. Clear glycogenated cells, sebaceous differentiation, ductal structures, and papillary mesenchymal bodies are observed.

Prognosis and Clinical Course

TFI is generally considered a benign lesion. Two cases of degeneration to basal cell carcinoma have been reported.225

Treatment

Various destructive methods including excision, electrodessication, cryotherapy, and laser ablation have been attempted but are associated with potential scarring.226 Topical corticosteroids, keratolytics, retinoic acid, and imiquimod have also been employed as less destructive treatments.223,226

Proliferating Trichilemmal Cyst

Epidemiology

Proliferating trichilemmal cyst (PTC), also known as proliferating trichilemmal tumor or proliferating pilar tumor, presents on the scalp of elderly individuals. There is a female predominance.

Etiology and Pathogenesis

PTCs derive from the outer root or trichilemmal sheath.227 It is felt that there is an evolution, histologically and clinically, from a pilar cyst to proliferating trichilemmal cyst to malignant proliferating trichilemmal cyst. PTC may evolve from a pilar cyst as a result of inflammation or trauma.228 It is felt that PTC degenerates into malignant PTC with the loss of p53.228,229

Clinical Findings

PTC classically presents on the scalp or posterior neck of elderly patients. Other sites include the trunk, groin, vulva, and gluteal region.227 PTC usually starts as a nodule and develops into a large, elevated, rubbery, lobulated mass that can enlarge to 10 cm (Fig. 119-19).7 Lesions often ulcerate. PTC can be associated with nevus sebaceus and basaloid follicular hamartoma.

Histopathology

Histopathologic examination reveals a sharply circumscribed cystic neoplasm occupying the lower dermis and subcutaneous tissue. There is a proliferation of bland squamous cells lining nearly the whole lesion and extending within it in a radial fashion. A characteristic feature is the presence, in the center of lobules, of trichilemmal cornification, i.e., abrupt formation of compact eosinophilic keratin without granular layer interposition. Foci with keratohyaline granules, small horn pearls and squamous eddies, and calcification is noted.

Prognosis and Clinical Course

PTCs have a variable clinical course. While some lesions are well circumscribed, others recur locally, and still others display invasive growth patterns with infiltration into nerves and lymphovasculature.230 Nearly 4% of PTCs recur after excision. There are thirty reported cases of degeneration of PTC into malignant PTC. The malignant tumor is associated with metastatic spread in 35% of cases. Many believe that malignant PTC is actually a variant of squamous cell carcinoma.231

Treatment

The treatment of choice is complete excision or Mohs micrographic surgery.222 Malignant PTC should be treated like a squamous cell carcinoma with excision with clear margins.