Nodular Hidradenoma

BACKGROUND. Nodular hidradenoma is a rare adnexal tumor most likely arising from the eccrine gland. OBJECTIVE. We describe three cases of a nodular hidradenoma presenting as an expanding nodule on the forehead (case l), left lower extremity (case 2), and lefi neck (case 3). W e discuss the clinical and histologic features of this tumor and present a review of the literature. CONCLUSIONS. This report highlights the salient histologicfindings that distinguish nodular hidradenomas from other adnexal tumors and emphasizes the benefit of complete local excision to prevent recurrence of these tumors.

Although regarded as benign tumor, NH may recur after inadequate surgical excision and can be clinically mistaken for other benign or malignant cutaneous tumors. In order to increase awareness of this entity, we describe three typical cases of NH and review the histopathologic and immunohistochemical features of this tumor.

Case 1
An 87-year-old woman presented with an asymptomatic erythematous nodule on the central forehead that had been present for approximately 3 years and was slowly enlarging in size. Spontaneous drainage of a yellowish odorless fluid was occasionally noted. There was no history of trauma preceding the onset of the lesion. Physical examination of the central forehead revealed a 7 X 5-mm freely movable, erythematous nodule with ill-defined borders and a gelatinous texture. Small amounts of serous fluid were expressed from the lesion. The surrounding normal-appearing skin was indurated at a diameter of 0.5 cm. There was no regional lymphadenopathy. The lesion is shown in Figure 1.
A lesional skin biopsy specimen showed a well-circumscribed nodule located in the dermis with extension into the subcutaneous tissue (Figure 2). A crusted ulceration was seen at the center where the tumor cells replaced the overlying epidermis. The tumor was composed of multiple lobules of epithelial cells containing ducts and cystic spaces (Figure 3). The epithelial cells were of two types: polygonal cells with abundant variably pale or eosinophilic cytoplasm and round nuclei, and fusiform cells with scant basophilic cytoplasm and round nuclei (Figure 4) plasma cells. No cytologic atypia or mitotic activity was observed. Surgical excision of the tumor was performed with a resection margin of 5 mm. Because the tumor involved the underlying fascia by gross inspection, the excision included the galea aponeurotica. The wound was closed by primary closure. One year after the procedure there was no evidence of recurrence.

Case 2
A 52-year-old woman presented with a lesion on the left lower extremity that had been noticed for more than a year. She stated that it had slowly increased in size and drained a clear watery fluid spontaneously or upon inadvertent trauma. Her past medical history was significant for breast cancer and bilateral fibrocystic breast disease, for which she had underwent bilateral mastec-  Higher magnification (X20) shows a dense tomy. On physical examination there was a 2.5-cm nodule on the left lateral calf ( Figure 5).
Examination of a biopsy specimen revealed a dermal proliferation of basaloid cells with an edematous and focally mucinous stroma. Within the tumor there were small ductal structures as well as areas of keratinization and necrosis. A focal cystic space lined by a double layer of cuboidal cells was also noted. There were no clear cells, mitotic activity, or cellular pleiomorphism.
The lesion was surgically excised with 4-mm lateral margins and the wound was repaired by primary closure. 'The patient has been followed for 3 months without any recurrence of the lesion.

Case 3
A 57-year-old man was referred for evaluation of an asymptomatic nodule on the left neck that had been present for more than 5 years and had been gradually  Examination of a biopsy specimen showed a multilobulated dermal proliferation of basaloid and clear cells within a mucin-rich stroma. The tumor was connected to the epidermis and contained small cystic spaces and ductal structures. There were focal areas of hyalinized collagen within the tumor. No cellular atypia or mitoses were seen.
The lesion was excised deep to the subcutaneous fat with 4-mm lateral margins. Repair was easily accomplished with primary layered closure. The patient has been followed for 3 months and has had no signs of recurrence on the surgical site.

Discussion
Nodular hidradenomas are rare appendageal tumors occurring mainly in adults (average age of 37.2 years) with a male-to-female ratio of 1:1.7.6 They usually present as solitary slowly enlarging, firm, freely movable tumors and may have a pedunculated or cystic appearance. Their average size is 0.5-2 cm, but larger tumors have been reported with a diameter of 9.5 ~m .~ The overlying skin may be smooth, thickened, atrophic, or ulcerated: and has a skin-colored, red, or brown color.3 Some tumors may spontaneously drain serous or hemorrhagic material, which may serve as a useful diagnostic sign.' Occasionally, multiple lesions can oc-cu1.l' Although any cutaneous site can be affected, the most common sites of involvement are the head and neck (in 30% of patients) and anterior t r~n k .~,~ The histopathology of nodular hidradenoma reveals a well-circumscribed dermal nodule, surrounded by a collagenous pseudocapsule and often extending deep into the subcutaneous tissue." Usually there is no epidermal attachment and the overlying epidermis appears normal; however, in some cases the tumor merges at the surface surrounded by a hyperplastic epidermis. The tumor is composed of multiple lobulated masses of epithelial cells and tubular lumina of variable size and number (Table 1). Larger cystic spaces filled with a homogeneous eosinophilic material are often present within the tumor and are usually bordered by degenerated tumor cells. ' The epithelial cells form the solid portion of the tumor and may be of two types. One type of cells are fusiform cells with elongated, vesicular nuclei and basophilic cytoplasm, usually located on the periphery of the tumor. The other type consists of large polygonal cells with round, often eccentrically located nuclei and pale eosinophilic cytoplasm. In certain cases these cells exhibit a striking cytoplasmic clearing, hence the designation clear cell hidradenoma for the histologic variant where these cells predominate. Their pale or "clear" appearance is explained by the large amount of cytoplasmic glycogen, which is a Periodic acid-Schiff (PAS)positive, diastase-labile material, and which washes off during fixation and embedding procedures. In addition, a PAS-positive, diastase-resistant material can be found at the periphery of the cells.' Transitional cells of both types may also be present within the tumor. The tubular lumina often exhibits branching and is lined by four types of cells: columnar epithelial cells that may show active secretion resembling decapitation secretion, cuboidal cells, squamous cells with a well-formed eosinophilic cuticle, and intermediate cells." The luminar structures contain PAS-positive, diastase-resistant material that also stains with colloidal iron. Mitotic activity may be present (average of 0.3-2.7 mitoses per 10 HPF).7 Occasionally extensive keratinization and horn pearls may be present (epidermoid hidraden~ma).'~ NH shares similar histologic features with eccrine poroma (arising from the intra-epidermal ductal epithelium), and eccrine spiradenoma (ductal and secretory epithelium). A recently described variant of NH, namely poroid hidradenoma, shows architectural features of hidradenoma (tumor with solid and cystic components) and cytologic findings of poroid neoplasm (poroid and cuticular cells with ductal differentiation).14 The differential diagnosis of NH also includes trichilemmoma (usually unilobulated, associated with papillary epidermal hyperplasia, hypergranulosis, and peripheral palisading of tumor cells with no cystic spaces), glomus tumor, inverted follicular keratosis, and metastatic renal cell carcinoma, which is usually not connected with the epidermis and has prominent cytologic atypia and a highly vascularized stroma. The be-  nign epidermoid type of NH shows squamous metaplasia and, thus, may be confused with squamous cell carcinoma.
The histologic distinction between benign and malignant hidradenomas or hidradenocarcinomas may be difficult. Malignant hidradenomas frequently exhibit typical findings of malignancy such as overt nuclear atypia, high index of mitotic activity, areas of necrosis, infiltrative patterns, and perineural or vascular invasion.15 However, in some cases these findings may be ~u b t l e .~ Reported cases of clinically benign hidradenomas with high mitotic activity and cellular pleiomorp h i~m '~,~~ suggest that histology is not always an accurate predictor of the clinical behavior of hidradenomas.
The immunohistochemical profile of hidradenomas has been demonstrated in recent studies ( Table 2)." On electron microscopy the epithelial cells are loosely connected with desmosomes and exhibit numerous pseudovilli that project from their border into the intercellular spaces."^' The fusiform basophilic cells contain numerous tonofilaments and little glycogen, whereas the paler or clear cells contain abundant glycogen and resemble the cells of an eccrine poroma. As previously mentioned the luminal structures are composed of four types of cells: columnar, cuboidal, squamous, and intermediate cells.
The origin of hidradenomas has been a longstanding subject of dispute. Because of the presence of polyhedral and fusiform cells around tubular lumina, N H were originally regarded as tumors differentiating toward myoepithelial cells.'~~ However, the absence of alkaline phosphatase and myofilaments ultrastructurally does not support this histogenesis.'' Although decapitation secretion has been observed in the luminar structures of the tumor,' none of the NH has been shown to have enzymes that would indicate an apocrine differentiation. In contrast, the presence of eccrine-type enzymes, ie, amylophosphorylase, branching enzyme, succinic dehydrogenase, diphosphopyridine nucleotide diaphorase, and leukine aminopeptidase suggests a tumor of eccrine differentiation." This has been supported by the finding of eccrine-specific ultrastructural features such as an inter-cellular canalicular system and intracellular organelles that closely resemble those of eccrine secretory cells?' Thus, nodular hidradenoma is reasonably considered as an eccrine tumor differentiating from the intraepidermal ductal portion (based on the presence of intracellular tonofilaments), or the secretory segment of the eccrine gland @ugh glycogen content, intercellular canalidar system). Similarly, it is regarded as an intermediate neoplasm between eccrine poroma, which has an intraepidermal ductal differentiation, and eccrine spiradenoma with its dermal-ductal and secretory differentiation." In a recent study, short-term cultures of a clear cell hidradenoma were obtained and cytogenetically analyzed?l The tumor displayed a multiclonal pattern with a single abnormal clonal population arising from the tumor and six additional clones found in the adjacent skin. These findings reflect an increase in genomic complexity (cytogenetic divergence) and a reduction of karyotypic diversity (covergence) of the tumor and may indicate a multicellular origin. Interestingly, these karyotypic changes were not seen in similar cytogenetic studies of other eccrine skin tumors (ie, eccrine spiradenoma). 22 Most cases of NH have a benign c o~r s e .~ Recurrences may occur in inadequately excised tumors and are usually located in the deeper dermis or subcutaneous tissue. They do not exhibit more atypia or aggressiveness compared with the primary tumors. According to a large series of patients with clear cell hidradenomas the rate of recurrence is estimated to be approximately 10% of surgically excised tumor^.^ Malignant clear cell hidradenomas usually arise de novo but may develop from benign clear cell hidradenomas in extremely rare case^.'^ Given this remote possibility and the aggressive nature and occasionally bland histology of their malignant counterpart, total surgical excision of nodular hidradenomas is recommended.' Mohs micrographic surgery has been successfully performed in isolated cases of hidradenomas and may be particularly helpful in large or recurrent tumors where wider subclinical spread is possible. 24