Utility of GATA3 Immunohistochemistry in Differentiating Urothelial Carcinoma From Prostate Adenocarcinoma and Squamous Cell Carcinomas of the Uterine Cervix, Anus, and Lung

Abstract

Distinguishing invasive high-grade urothelial carcinoma (UC) from other carcinomas occurring in the genitourinary tract may be difficult. The differential diagnosis includes high-grade prostatic adenocarcinoma, spread from an anal squamous cell carcinoma (SCC), or spread from a uterine cervical SCC. In terms of metastatic UC, the most common problem is differentiating spread of UC to the lung versus a primary pulmonary SCC. Immunohistochemistry (IHC) for GATA binding protein 3 (GATA3), thrombomodulin (THROMBO), and Uroplakin III was performed on a tissue microarray (TMA) containing 35 cases of invasive high-grade UC. GATA3 IHC was also performed on TMAs containing 38 high-grade (Gleason score 8) prostatic adenocarcinomas, representative tissue sections from 15 invasive anal SCCs, representative tissue sections from 19 invasive cervical SCCs, and TMAs with 12 invasive cervical carcinomas of the cervix [SCC (n=10), SCC with neuroendocrine features (n=1), adenosquamous carcinoma (n=1)]. Additionally, GATA3 IHC was performed on representative tissue sections from 15 pulmonary UC metastases and a TMA with 25 SCCs of the lung and 5 pulmonary non-small cell carcinomas with squamous features. GATA3, THROMBO, and Uroplakin III were positive in 28 (80%), 22 (63%), and 21 (60%) cases of high-grade UC, respectively. All GATA3 positive staining was non-focal, 25 (89%) cases demonstrated moderate-strong staining, and 3 (11%) cases demonstrated weak staining. Of the 7 cases that failed to express GATA3, 5 were positive for THROMBO and/or Uroplakin III, while 2 cases were negative for all 3 markers. None of 38 high-grade prostatic adenocarcinomas were positive for GATA3. Weak GATA3 staining was present in occasional basal cells of benign prostate glands, in a few benign atrophic glands, and in urothelial metaplasia. Of the 15 cases of anal SCCs, 2 (7%) cases showed focal weak staining and 1 (3%) case showed focal moderate staining. Weak staining was also rarely observed in the benign anal squamous epithelium. Of the 31 uterine cervical carcinomas, 6 (19%) showed weak GATA3 staining (3 non-focal, 3 focal) and 2 (6%) demonstrated focal moderate staining. Twelve (80%) of the metastatic UC to the lung were positive for GATA3 with 11 cases showing diffuse moderate or strong staining and 1 case showing focal moderate staining. None of the pulmonary SCC or non-small cell carcinomas with squamous features were GATA3 positive. 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.

GATA3 Immunohistochemical Expression in Salivary Gland Neoplasms

“…Initial studies demonstrated that GATA3 immunostaining was seen in a limited number of tumor types: mammary carcinoma, urothelial carcinoma, and a minority of endometrial carcinomas [8,9,16]. Subsequent studies have expanded the list of GATA3-positive tumors to include occasional squamous cell carcinomas of the anus, cervix, and lung [11,12]. By performing immunohistochemistry on a large and diverse collection of salivary gland tumors, we found that approximately half were immunoreactive for GATA3.…”

“…Accordingly, GATA3 immunohistochemical staining is being used as a practical tool for diagnosing breast and urothelial carcinoma, particularly when these tumors present as distant metastases or are so poorly differentiated that they cannot be distinguished from other tumor types [10][11][12]. Various studies across a broad spectrum of diverse tumor types have confirmed the restricted expression of GATA3 staining to breast and urothelial origin, but these studies have curiously not included salivary gland neoplasms [1][2][3][4][5][6][7][8][9][10][11][12]. Mammary glands and salivary glands are both ectodermally-derived exocrine secretory structures that share many embryologic, histologic, and immunohistochemical features.…”

Immunohistochemistry in Undifferentiated Neoplasm/Tumor of Uncertain Origin

“…111 Many markers are useful for identifying HCC, including ARG1, glypican-3, HepPar-1, CD10, and polyclonal carcinoembryonic antigen (CEA). ARG1 is the most sensitive and specific marker for HCC, including poorly differentiated HCC, [77][78][79][80][81][82] whereas HepPar-1 is a sensitive, but not very specific, marker for HCC because its immunoreactivity has been reported in many other carcinomas. The diagnostic sensitivity of both ARG1 and HepPar-1 for identifying liver cell origin is more than 90%.…”

High-grade urothelial carcinoma with squamous differentiation metastasizing to the tongue

“…These can exhibit strong CK5 and CK6 staining, absence of CK20, thrombomodulin and uroplakin III staining, and at times only focal CK7 positivity. 25,26 Staining patterns in metastatic bladder lesions can also vary from the primary lesion. A recent study compared expression of these markers in metastatic UC and suggested that uroplakin expression is lost but that CK7 staining and thrombomodulin staining are seen in 92% and 80% of metastatic UCs, respectively.…”