Comment
The distinction between primary adnexal and metastatic adenocarcinomas of the skin is challenging both clinically and histologically. Some pathologists have argued that metastatic breast carcinomas and primary cutaneous apocrine carcinomas are essentially indistinguishable.3 Patients with cutaneous metastases, which occur in approximately 5.3% of all malignancies,4 typically can expect survival of no more than 12 months from the time of detection.1 In contrast, primary apocrine carcinomas of the skin, though much less common, carry a remarkably better prognosis, with 5-year relative survival rates of 95.5% and 85.5% reported for patients with localized disease and spread to regional lymph nodes, respectively.2
Fewer than 100 cases of primary cutaneous adnexal (apocrine) carcinomas have been reported overall, with the earliest known report dating back to 1944.5 According to the literature, primary apocrine carcinomas were diagnosed at a median age of 66 years and were slightly more common in females than males.2,6 Apocrine carcinomas were seen most frequently on the head, neck, and trunk,2 generally presenting in the form of asymptomatic nodules or plaques of 2 to 3 cm in size, with gradual progression occurring over months to years.6 Approximately 40% of patients have been reported with positive regional lymph nodes at diagnosis. Treatment of apocrine carcinoma typically has involved local excision with clear margins with or without lymph node dissection. Chemotherapy and radiation therapy have shown no proven benefit.7
Currently, there is no standardized approach to evaluating patients with possible cutaneous metastasis versus primary cutaneous adnexal carcinomas. Imaging studies such as mammography and abdominal CT typically reveal an internal primary cancer in one-third of patients. However, additional studies such as gastrointestinal radiography, chest and pelvic CT, barium enema, and intravenous pyelogram have shown to be of limited value.8 Although specificity and sensitivity of immunohistochemistry is limited, a number of immunomarkers, including CK7 and CK20, are routinely studied to narrow the differential diagnosis of a cutaneous neoplasm of unclear origin. Urothelial, gastric, colorectal, and pancreatic carcinomas generally are positive for CK20; CK7-positive adenocarcinomas include salivary, non-small cell lung, breast, ovarian, pancreatic, endometrial, and transitional cell adenocarcinomas. Carcinomas negative for both CK7 and CK20 include colorectal, hepatocellular, renal cell, prostate, and squamous cell carcinoma of the lung.
The presence of positive staining for estrogen and progesterone receptors as well as GCDFP-15 and mammaglobin raised the possibility of primary breast adenocarcinoma in our patient, but given that these markers can be positive in primary cutaneous adnexal tumors, immunohistochemistry results were not able to provide a definitive primary site. The overall staining pattern was nearly identical to 26 cases of primary cutaneous cribriform apocrine carcinoma, which was found to be positive for CK7 and carcinoembryonic antigen, and negative for CK20 and S-100. The only difference was in GCDFP-15 staining, which was positive in our case and negative in the cases of cribriform apocrine carcinoma.9 Histologic features favoring a primary apocrine origin include normal apocrine glands in the vicinity, glandular structures with decapitation secretion high in the dermis, and intracytoplasmic iron granules.10 Additionally, positive estrogen receptor staining appears to be much more common in apocrine carcinomas (5/10) than in eccrine carcinomas (1/7).11
A number of other markers have been investigated for possible diagnostic utility for distinction between primary adnexal carcinomas and metastatic adenocarcinomas. The nuclear transcription factor p63, which plays a role in keratinocyte differentiation, is preferentially expressed in a number of primary adnexal carcinomas and is purported to be the most sensitive marker overall, with a sensitivity of 78% to 91%.12-14 However, p63 has shown incomplete specificity for primary adnexal neoplasms, having been reported as positive in 11% to 22% of adenocarcinomas metastatic to skin.15-18 Nestin and CK15, which are expressed in hair follicle progenitor cells, also are potential specific markers for some primary adnexal lesions, specifically eccrine carcinoma, porocarcinoma, hidradenocarcinoma, and microcystic adnexal carcinoma; however, in one report, none of the apocrine carcinomas were positive for p63, cytokeratin 15, or D2-40.19 Thus, while markers for some primary adnexal neoplasms are emerging, specific tests at the immunohistochemical level for the apocrine carcinoma subgroup are still lacking.
Conclusion
In summary, a conclusive distinction between primary cutaneous apocrine carcinoma and metastatic adenocarcinoma to the skin remains challenging. Although new markers provide more specificity and sensitivity for neoplasms of eccrine origin, these markers do not appear to differentiate between primary apocrine carcinoma and metastatic breast carcinoma. In this case, as in other recent reports, diagnosis remained dependent on the clinical course of the patient. Although considerable progress has been made regarding immunohistochemical analysis of these cases, additional markers, especially ones more specific for primary skin cancers with apocrine differentiation, are still needed.