Expression of Structurally Unaltered Androgen Receptor in Extramammary Paget's Disease

Abstract

SUMMARY: Extramammary Paget's disease (EMPD) is an uncommon neoplasm of the skin that shows differentiation to an apocrine sweat gland. Although we previously showed that erbB-2 overexpression may play a part in the progression of EMPD, molecular genetic defects underlying the development of EMPD are poorly understood. In the study described here, we examined androgen receptor expression and gene alterations in 30 cases of EMPD without internal malignancy. Immunohistochemistry revealed that 24 of 30 (80%) cases of EMPD variably expressed nuclear androgen receptor. Semi-quantitation of receptor content by scoring immunostained sections showed no difference between in situ (n ϭ 17) and invasive (n ϭ 13) EMPD tumors. Androgen receptor expression was also observed in four of six lymph node metastases. In these lymph nodes, expression of androgen receptor mRNA was confirmed by reverse transcriptase-polymerase chain reaction. Direct sequencing of exon 2 through exon 8, which encodes DNA-and hormone-binding domains of the androgen receptor gene, revealed no mutation in any of the 10 advanced stage tumors. Neither amplification nor deletion of the androgen receptor gene locus was detected by dual color fluorescence in situ hybridization analysis in 14 tumors. The present findings showing frequent expression of structurally unaltered androgen receptor in an advanced stage of EMPD may provide a rational basis for hormone therapy, which is widely used in the treatment of metastatic prostate cancer and androgen receptor-positive breast cancer recurrence. (Lab Invest 2000, 80:1465-1471.E xtramammary Paget's disease (EMPD) is an uncommon neoplasm of apocrine gland-bearing skin, that most commonly involves the vulvar, perianal, perineal, scrotal, and penile regions (Heymann, 1993). Although it is rarely associated with underlying adenocarcinoma, it mostly begins as an intraepidermal adenocarcinoma that can invade the dermis and may metastasize via the lymphatic system (Feuer et al, 1990;Hart and Millman, 1977;Jones et al, 1979;Murata et al, 1999). The histogenesis of EMPD has long been disputed. Emerging information, however, supports the concepts that Paget's cells in EMPD are of glandular origin, usually showing apocrine differentiation and that the disease may arise from a pluripotential epidermal precursor (Guarner et al, 1989;Mazoujian et al, 1984;Roth et al, 1977).The molecular genetic defects underlying EMPD are poorly understood. We previously showed that erbB-2 overexpression by either gene amplification or transcriptional activation may play a part in the progression of EMPD (Takata et al, 1999). However, other molecular genetic defects, including p53 mutations, allelic loss of several selected chromosome arms as well as abnormal activation of the ␤-catenin gene, which are commonly seen in other epithelial malignancies, were not detected in EMPD (Takata et al, 1999;Takata et al, 1997). To explore further the molecular pathogenesis of EMPD, we aimed at examining androgen receptor expression in Paget's cells of EMPD f...

Sex Steroid Hormone Receptors in Human Skin Appendage and its Neoplasms

“…AR immunoreactivity was detected in 71% of the cases of extramammary Paget's disease. Previous studies also demonstrated that AR was detected in 54% [14] and 80% [15] of extramammary Paget's disease. ERa was detected in 29% of extramammary Paget's disease in our series.…”

“…Both ER and PR have been reported to be detected in some of the sweat gland neoplasms [13][14][15][16][17][18][19], but their isoforms have not been examined. ERb, which is widely distributed throughout the body [28], was detected in some sweat gland neoplasms.…”

“…Sex steroids have been implicated in the development of acne in puberty [5][6][7][8], moisturizing of skin or epidermis in women [9][10][11][12] and others. In addition, previous studies demonstrated that some skin appendage tumors were positive for sex steroid hormone receptors [13][14][15][16][17][18][19][20][21][22]. The studies of Thornton et al and Shin et al both demonstrated that immunoreactivity of some sex steroid hormone receptors in human scalp skin [23,24].…”

Malignant adnexal neoplasms

“…[330][331][332][333] Extramammary Paget's disease does not express estrogen or progesterone receptor antigenicity, but has been shown to express androgen receptor proteins as discussed above. 334,335 Differential expression of claudins, proteins involved in tight junction assembly in epithelial and endothelial cells, may differentiate cells of Paget's disease from adjacent squamous epithelia, but not from breast carcinoma cells. 336 Another form of Pagetoid intraepidermal carcinoma with vacuolated cells is sebaceous carcinoma, but in this entity the cells appear vacuolated, with a clear cytoplasmic morphology as opposed to basophilic mucin.…”

Estrogen-Receptor-Alpha-Positive Extramammary Paget’s Disease Treated with Hormonal Therapy

“…It was reported that normal apocrine glands of the skin and mammary apocrine lesions contained no detectable estrogen receptors or progesterone receptors, but did express androgen receptors [1,2,3]. Recent studies demonstrated expression of androgen receptors in extramammary Paget’s disease [4, 5]. In contrast, lack of estrogen and progesterone receptors has been reported in extramammary Paget’s disease [5,6,7,8].…”