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    • From a clinical utility standpoint

    2023-05-26

    From a clinical utility standpoint, this study showed that AR can be useful in the GATA3-positive tumor of unknown origin setting. Epidemiologically, in this setting, the top 2 diagnoses in the differential diagnosis are metastatic carcinoma of breast origin or urothelial origin [18]. Seven out of 13 (54%) metastatic GATA3+ breast origin carcinomas stained here showed strong AR expression, whereas none of 10 metastatic GATA3+ urothelial origin carcinomas showed strong AR expression. Thus, the sensitivity of strong AR expression for distinguishing metastatic GATA3+ breast cancer from metastatic GATA3+ urothelial cancer in this study is 54%, whereas the specificity of this test is 100%. If the primary tumor results for lobular carcinomas can be extrapolated to metastases, this study predicts that the sensitivity will be far higher for lobular carcinomas or ductal carcinomas with lobular features. Additionally, this study suggests that testing GATA3+ metastases for AR would yield a significantly higher sensitivity than testing them for ER, PR, GCDFP15, or mammaglobin expression, which all showed lower associations with GATA3 in primary breast cancers studied here. The weak urothelial carcinoma staining for AR documented here has been previously reported. In the literature, of 7 cases of metastatic urothelial origin carcinoma, only 2 showed AR expression, and in both cases, expression was weak (mean number of nuclei staining was 10%) [16]. In another study, of 9 urothelial carcinomas sampled, not one showed strong nuclear AR expression [23]. The main diagnostic confusion using this proposed test in the GATA3+ tumor of unknown origin setting is that between 2% and 26% of endometrial carcinomas express GATA3, and of those, 22% show strong AR expression in >40% of caudatin [24], [25], [26]. Whether strong AR expression can be seen in GATA3+ endometrial carcinoma metastases is unknown. Using the absence of AR expression as a marker of urothelial carcinoma in GATA3-positive tumors of unknown origin could be potentially helpful as well according to this study. A total of 50% (5 of 10) of metastatic GATA3+ urothelial origin carcinomas studied showed no AR expression. However, only 1 of 13 (8%) metastatic GATA3+ breast origin cancers showed less than 1% AR expression. This means that testing absence of GATA3 staining in distinguishing metastatic GATA3+ urothelial origin carcinoma from metastatic GATA3+ breast origin cancer has a sensitivity of 50% and a specificity of 92%. A previous urothelial carcinoma study showed that 5 of 7 (72%) metastatic urothelial carcinomas showed no AR expression [16]. However, this test is not likely as useful as the strong AR test because it requires the distinction of cases with less than 10% staining (6 of 13 metastatic GATA3+ breast origin cancer cases) from cases with complete absence of staining. Thus, complete absence of AR staining in a GATA3+ tumor of unknown origin can also be used as a test for urothelial origin but is likely inferior to testing for strong AR expression, which is more easily interpretable. One proviso to this study is the use of very old formalin-fixed material in the 259-patient TMA from which the correlation of GATA3 with AR was first derived. Immunohistochemistry on ancient samples is prone to epitope loss, and thus, care has to be taken when interpreting results derived from these tissues. A recent article showed that many proteins undergo no degradation in signal over up to 5 decades of formalin fixation. However, a few primarily nuclear proteins did undergo some signal degradation over several decades [27]. Most of the proteins studied here are nuclear. However, epitope degradation only strengthens the main conclusion that there is a strong correlation between GATA3 expression and AR expression. Because this correlation was very strong even using old formalin-fixed blocks, it is possible that the correlation will be even stronger than that reported here with recent material that lacks epitope degradation. Furthermore, the main conclusion—that AR can be used to distinguish metastatic GATA3+ mammary origin versus urothelial origin carcinoma—was derived from results using recent blocks only (2014-2016). The only main conclusion of this article that could be weakened by the use of old tissue is the conclusion that the correlation between GATA3 and AR is stronger than that between GATA3 and ER or PR. This would be the case if the androgen receptor experienced minimal epitope degradation, but ER and PR experienced significant epitope degradation over time. A recent study showed that ER and PR staining on blocks up to 60years old does not show significant trends in either of these markers over time, supporting our conclusions [28].