Androgen receptors are nuclear proteins that are functionally critical to several organs and tissues [15
]. They are expressed at variable levels in a number of tissues [16
]. Intense staining has been reported in glandular epithelia of male accessory organs (including prostrate, seminal vesicles and epididymis), breast, and sebaceous and sweat glands of skin [17
]. In the testes, sertoli cells, peritubular myoid cells and interstitial cells were immunoreactive with AR [17
]. Stratified squamous epithelia of vagina and cervix showed selective immunostaining of the basal layer whereas in the preputial epithelia, the intensity of immunoreactivity decreased gradually with maturation [17
AR expression has been noted in some benign and malignant tumors. As noted earlier, majority of breast carcinomas evaluated express AR as determined by IHC and biochemical studies [9
]. In adenocarcinoma of the prostate, AR has been demonstrated by IHC with considerable heterogeneity in staining [18
]. A significant number of ovarian carcinomas are also positive for AR [22
]. Malignant cells in some endometrial adenocarcinomas were found to be immunoreactive [24
]. AR has also been detected by IHC in 90% of salivary duct carcinomas [25
]. Amongst the benign tumors, AR expression has been demonstrated in nasopharyngeal angiofibromas [27
], hepatic adenomas [28
], and meningiomas [29
]. Recently, AR expression has been evaluated with reference to clinical and prognostic significance in estrogen receptor-negative breast cancers [30
In our study there was a clear dominance of AR expression in mammary carcinoma compared to other adenocarcinomas. AR expression in 56% (19/34) of the mammary carcinomas is in concordance with previous studies. Whilst 48% (14/29) of the IDC's were immunoreactive for AR, ILC cases demonstrated consistent AR positivity at 100%. The higher frequency could be attributed to lower grade of the ILC's as compared to the poorly differentiated IDC's chosen in our study. It is noteworthy that 20% of ovarian carcinomas were positive with immunoreactivity for AR in more than 10% nuclei.
As specifically evaluated in this study, the nuclear immunostaining pattern is important during interpretation. Only nuclear immunostaining pattern was observed in mammary carcinoma and in a few cases of ovarian carcinoma. All other adenocarcinomas are negative for nuclear immunoreactivity. However, cytoplasmic immunoreactivity was not uncommon in many of these non-mammary/non-ovarian carcinomas.
Two cases (1 female and 1 male) showed positive immunoreactivity for AR in nuclei in the tumors initially selected in the non-mammary adenocarcinoma group. After further evaluation with additional immunomarkers and clinical correlation, these tumors were consistent with metastatic adenocarcinomas. The primary sites respectively were breast in a female and prostate in a male.
Addition of AR in the immunopanel for immunohistochemical evaluation of unknown primary in women is strongly recommended. Silanized slides are recommended to avoid floating and washing away of the tissue sections during alkaline epitope retrieval step. Depending on the clinical correlation, including the status of ovaries and breast, AR positivity favors primary from mammary carcinoma and sometimes ovarian carcinoma.
In summary, AR immunoreactivity in 10% or more nuclei is consistent with AR positive tumor, which is strongly suggestive of breast and in some cases ovarian primary. This study suggests that AR is a potentially useful immunomarker in evaluating metastatic adenocarcinoma of unknown primary in females. It is important to assess the true nuclear immunoreactivity in tumor cells. Cytoplasmic immunostaining alone is non-specific for differential diagnosis of these primary sites.