PAX8-Positive (Gynecologic-Type) Clear Cell Carcinoma Metastatic to the Kidney

A woman in her late 60s presented with a 3.2-cm mass involving both the liver and the right kidney. Histopathologic evaluation showed the presence of a tumor with clear cytoplasm (Figure 1A) that was diffusely positive for the paired box 8 (PAX8) transcription factor, which is frequently used to establish renal histogenesis (Figure 1B). Although the presence of a PAX8-positive tumor with clear cytoplasm suggested a clear cell renal cell carcinoma that was primary to the kidney, this tumor had some unusual morphologic features. This included tubulocystic architecture, with tubular structures lined by a single layer of cuboidal to hobnail cells with minimal nuclear stratification (Figure 1C, D). In addition, the neoplastic cells exhibited large nuclei with prominent nucleoli. These morphologic features raised the possibility of a gynecologic-type clear cell carcinoma. Which of the following immunohistochemistry-based markers would be helpful in confirming this diagnosis?a.Thyroid transcription factor 1b.Synaptophysin and chromograninc.Napsin, hepatocyte nuclear factor 1β (HNF1β), and Wilms tumor 1 (WT1)d.Calretinin and WT1 Answer: c. Napsin, hepatocyte nuclear factor 1β (HNF1β), and Wilms tumor 1 (WT1) Positivity for the PAX8 transcription factor has been described in numerous tumor types, including renal tumors, müllerian origin tumors, thyroid tumors (positive for thyroid transcription factor 1), mesothelioma (positive for calretinin/WT1), and thymoma.1Laury A.R. Perets R. Piao H. et al.A comprehensive analysis of PAX8 expression in human epithelial tumors.Am J Surg Pathol. 2011; 35: 816-826Crossref PubMed Scopus (355) Google Scholar,2Chapel D.B. Husain A.N. Krausz T. McGregor S.M. PAX8 expression in a subset of malignant peritoneal mesotheliomas and benign mesothelium has diagnostic implications in the differential diagnosis of ovarian serous carcinoma.Am J Surg Pathol. 2017; 41: 1675-1682Crossref PubMed Scopus (50) Google Scholar In addition, pancreatic neuroendocrine tumors (positive for synaptophysin/chromogranin) have been reported to label with polyclonal PAX8 antibody clones.3Liau J.Y. Tsai J.H. Jeng Y.M. et al.The diagnostic utility of PAX8 for neuroendocrine tumors: an immunohistochemical reappraisal.Appl Immunohistochem Mol Morphol. 2016; 24: 57-63Crossref Scopus (25) Google Scholar PAX8 positivity coupled with morphologic features (clear cytoplasm) raised the possibility of a clear cell renal cell carcinoma. These tumors typically have alveolar/acinar architectural patterns and show diffuse positivity for markers downstream of VHL gene inactivation, such as carbonic anhydrase 9, and these features were not identified in this case. The tubulocystic morphology (Figure 2A) raised the possibility of a gynecologic-type clear cell carcinoma. Furthermore, this tumor showed absence of staining with estrogen receptor (not shown) and WT1 (Figure 2B) and diffuse positivity for HNF1β (Figure 2C) and napsin (Figure 2D), supporting the diagnosis of a metastatic gynecologic-type clear cell carcinoma rather than a primary kidney tumor.4Kobel M. Kalloger S.E. Carrick J. et al.A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary.Am J Surg Pathol. 2009; 33: 14-21Crossref PubMed Scopus (182) Google Scholar,5Lim D. Ip P.P. Cheung A.N. Kiyokawa T. Oliva E. Immunohistochemical comparison of ovarian and uterine endometrioid carcinoma, endometrioid carcinoma with clear cell change, and clear cell carcinoma.Am J Surg Pathol. 2015; 39: 1061-1069Crossref PubMed Scopus (63) Google Scholar Therefore, a combination of morphologic features and appropriate ancillary immunohistochemical studies is helpful in accurately diagnosing tumors with unusual clinical presentations.