Invasive high-grade UC can be difficult to differentiate from other high-grade carcinomas as the morphology of high-grade UC is not always specific. Most commonly, high-grade prostatic adenocarcinoma must be excluded. This scenario is frequently encountered in transurethral resections of large tumors involving the bladder neck, where clinically it is virtually impossible to distinguish between a prostate or bladder primary. Certain morphologic features are diagnostically helpful. High-grade prostate adenocarcinoma is composed of atypical but uniform cells with prominent nucleoli typically growing in sheets, cords, and/or as individual cells. UC is composed of atypical pleomorphic cells that tend to form nests. Cribriform architecture is characteristic of prostate adenocarcinoma and not a feature of UC. Subtle ill-defined cribriform architecture may be a clue to the prostatic origin of the tumor. Confounding factors include gland-like lumina and true glandular differentiation in UC mimicking cribriform architecture. A minority of high-grade prostatic adenocarcinomas may have nest formation similar to UC. Additionally, prostate adenocarcinoma may uncommonly demonstrate prominent pleomorphism that at the extreme has been termed “pleomorphic giant cell adenocarcinoma of the prostate.”(16
High-grade UC may also demonstrate a squamoid appearance and thus morphologically overlap with invasive SCC. Therefore, excluding spread from an anal primary or a uterine cervical primary in female patients is necessary. While clinical history in these situations is of great value, that information is not always readily accessible or may be inaccurate. Additionally, the possibility of UC arising in the setting of an anal or cervical SCC must be considered. Given the morphologic overlap of high-grade UC with high-grade prostatic adenocarcinoma and SCC, IHC should routinely be performed in the assessment of a high-grade carcinoma in genitourinary tract when the primary site is not certain.
When excluding a high-grade prostatic adenocarcinoma, our routine immunohistochemical panel includes the following prostatic markers: prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), P501S (Prostein), and NKX3.1. We have previously compared PSA staining in a group of poorly differentiated prostatic adenocarcinomas with “poor” PSA staining to PSMA and P501S and NKX 3.1.(3
) Completely negative staining was seen in 15% (PSA), 12% (PSMA), 17% (P501S) and 5% (NKX 3.1) of the cases. Five per cent of the cases were negative for all four markers combined. Therefore, the lack of immunoreactivity to prostate specific markers in a poorly differentiated tumor within the prostate or bladder, especially if present in limited amount, does not exclude the diagnosis of a poorly differentiated prostatic adenocarcinoma.
Prior to the current study, our panel of immunohistochemical markers for UC was THROMBO, p63, and high molecular weight cytokeratin (HMWCK). The reported sensitivities of THROMBO, p63, and HMWCK for UC are 61%–91%, 83%–87%, and 90%, respectively.(3
) These stains are variably reliable when excluding a high-grade prostatic adenocarcinoma, however, there is significant immunohistochemical overlap between UCs and SCCs. Positive THROMBO IHC has been observed in 5% of high-grade prostatic adenocarcinomas and is a common finding in SCCs from various organ systems including the uterine cervix. (3
) While positive p63 IHC has not been reported in high-grade prostatic adenocarcinoma, p63 is positive in SCCs from a variety of sites including the uterine cervix and anus.(7
) When differentiating UC and high-grade prostate adenocarcinoma, HMWCK is the least specific marker as it is expressed in a small percentage of cells in almost 10% of high-grade prostatic adenocarcinomas.(3
) HMWCK is also present in a large proportion of SCCs.(7
) As a consequence, HMWCK was not included in this study.
Uroplakin III is considered the most specific marker for urothelial differentiation, but it has not received popularity due to lack of uniform expression in UCs. The reported sensitivity is 31%–60% in primary invasive UC and 53% in metastatic UCs.(8
) In a recent paper, Gaisa et al. identified significantly less sensitivity (22%) in invasive high-grade UCs.(5
) Others have also noticed a loss of Uroplakin III expression with increase in grade and stage of UC.(11
We have shown that GATA3 IHC is a sensitive marker for high-grade UC. Eighty percent of the cases of UC examined were GATA3 positive. All positive cases demonstrated non-focal staining and most showed moderate to strong staining intensity. The sensitivity of GATA3 IHC for UC exceeded that of THROMBO and Uroplakin III. GATA3 is also highly specific when differentiating high-grade UC from high-grade prostatic adenocarcinoma. None of the 38 high-grade prostatic adenocarcinomas were GATA3 positive. Sensitivity was maintained in cases of metastatic UC. Eighty percent of pulmonary UC metastases were GATA3 positive, and none of the pulmonary SCCs or non-small cell carcinomas with squamous features were GATA3 positive. We have also shown that in general moderate to strong GATA3 immunohistochemical staining can be used to exclude spread from an anal or uterine cervical SCC. Weak GATA3 IHC can be seen in a minority of cervical and anal SCCs, but tended to be more commonly focal. Focal moderate staining was only seen in 6% and 7% of uterine cervical and anal SCCs, respectively. Therefore, when distinguishing high-grade UC from uterine cervical or anal SCC, weak and focal moderate staining must be interpreted with caution. Typically (71% of cases), high-grade UCs will demonstrate non-focal moderate to strong staining. In difficult cases, in situ hybridization studies for high risk human papilloma viruses may also be of additional value.
Prior to this study, Higgins et al. examined GATA3 IHC in 321 UCs of the bladder and observed that 67% were GATA3 positive with most exhibiting intense non-focal staining.(6
) Two hundred and eight of the UCs were invasive at least into the lamina propria and 113 were noninvasive. Higgins et al. also studied 257 prostate adenocarcinomas from radical prostatectomy specimens [Gleason score 3+3 (n=46); 3+4 (n=136); 4+3 (n=48); 4+4 (n=2); 3+2 (n=1); and 4+ 5 (n=1)]. None of the cases were GATA3 positive. The authors also studied a small group uterine cervical SCCs (n=6) and found no GATA3 staining.
The current study and that of Higgins et al. differ in several respects. Each study obtained a GATA3 antibody from separate sources (Biocare Medical versus Santa Cruz Biotechnology). This difference could account for the higher rate of GATA3 positivity in UC observed in the current study (80% versus 67%). It could also be attributed to the relatively large numbers of low grade and non-invasive UCs studied by Higgins et al. In contrast, the current study only examined high-grade UCs with muscularis propria invasion. The groups of prostate cancers examined in each study also differ. Only 3 of 257 prostate cancers in the Higgins study were Gleason score 8 or 9, and it is not stated whether cases with Gleason pattern 4 featured cribriform architecture. However, all of the cases in the current study were Gleason score 8 or higher, with all but 2 having a Gleason score of 9–10 and none having cribriform architecture. The high-grade cases lacking cribriform architecture in our study more closely reflect the situation where one would apply IHC for the differential diagnosis of UC and prostate cancer. Other differences in assessing GATA3 IHC between the current study and that of Higgins et al. included the examination of anal SCCS, a larger cohort of uterine cervical SCCs, and the evaluation of metastatic UC to the lung, and primary lung SCCs.
In conclusion, GATA3 IHC is a sensitive marker for UC and positive staining in UC is typically non-focal and moderate or strong in intensity. GATA3 is also highly specific in excluding high-grade prostate adenocarcinoma. Although some cervical and anal SCCs can be GATA3 positive, unlike in UC, staining is more commonly focal and weak. GATA3 is also a useful maker when diagnosing metastatic UC to the lung.