Comprehensive immunohistochemical and molecular characterization of paratesticular clear cell papillary cystadenomas: A multi-institutional study of 14 cases.

Clear cell papillary cystadenomas of the epididymis (CCPCE) are rare epithelial neoplasms originating from the efferent ductules and can be sporadic or associated with von Hippel-Lindau (VHL) syndrome. Herein, in this multi-institutional study we performed a comprehensive morphologic, immunohistochemical, and molecular evaluation of 14 CCPCE, the largest series reported to date. Morphologic features recorded included architecture (cystic, tubular/papillary, nested/solid), cytoplasm (cleared, eosinophilic), World Health Organization (WHO) nuclear grade (including reverse-apical pattern), and presence of "chicken-wire" vascular pattern. The immunohistochemical stains performed included PAX8, CAIX, CD10, KRT7, AMACR, HMWK (34betaE12 or CK5/6), GATA3, and SOX17. Next generation sequencing was performed on 4 CCPCE. Patient ages ranged from 16 to 75 years (mean= 37.4 years) and included 6 epididymectomies (43%) and 8 radical orchiectomies (57%) of nearly equal laterality (right= 8). Tumor sizes ranged from 0.4 to 15 cm (mean= 3.3 cm). All tumors showed positivity for CA9 (including areas of cup-like staining), KRT7, PAX8, & HMWK, while being largely negative for RCC, SOX17 & GATA3. Molecular analysis revealed 1 CCPCE with VHL mutation (in a patient with known VHL syndrome) and no reportable abnormalities in the other 3 CCPCE. While CCPCE can be morphologically indistinguishable from CCPRCT and share PAX8+/KRT7+/CAIX+ immunoreactivity, typically negative staining for RCC/GATA3 coupled with the generally low stage and good outcome for CCPRCT may favor CCPCE in challenging scenarios. Except for VHL mutations in a syndromic setting, CCPCE lacks other molecular alterations of CCRCC (e.g., SETD2, PBRM1, BAP1), although further confirmatory studies are needed.