Original ArticlesContemporary Characterization and Recategorization of Adult Unclassified Renal Cell CarcinomaKwon, Regina MD, MPH*; Argani, Pedram MD*,†; Epstein, Jonathan I. MD*,†,‡; Lombardo, Kara A. BS‡; Wang, Xiaoming PhD§; Pierorazio, Phillip M. MD†,‡; Mehra, Rohit MD§; Matoso, Andres MD*,†,‡Author Information Departments of *Pathology ‡Urology †Oncology, Johns Hopkins University School of Medicine, Baltimore, MD §Department of Pathology and Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI This work was presented as an abstract at the USCAP 2019 Annual Meeting in National Harbor, MD. Conflicts of Interest and Source of Funding: Supported in part by the Joseph C. Eggleston Award in Surgical Pathology to R.K. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Andres Matoso, MD, The Johns Hopkins Hospital, The Weinberg Building, Room 2242, 401 North Broadway, Baltimore, MD 21231 (e-mail: [email protected]). The American Journal of Surgical Pathology: April 2021 - Volume 45 - Issue 4 - p 450-462 doi: 10.1097/PAS.0000000000001629 Buy Metrics Abstract Our recent study of early-onset unclassified eosinophilic renal cell carcinoma (RCC) demonstrated that two third of cases could be reclassified by performing a limited number of immunohistochemistry stains. Following the same approach, we aimed to investigate what proportion of adult unclassified RCC could be reclassified. We identified 79 cases. The mean age at presentation was 58 years (range, 29 to 84 y). Tumors were grouped based on their predominant morphologic features as oncocytic (n=23); papillary (n=22); clear cell (n=22); mucinous tubular and spindle cell (MTSC; n=5); rhabdoid (n=4); or lacking a dominant pattern (n=3). By reviewing the morphologic features and performing ancillary studies, we were able to reclassify 10 cases (13%). Four cases were positive for CK20 and showed morphologic features consistent with eosinophilic solid and cystic RCC. Four cases were reclassified as MTSC based on VSTM2A expression by RNA in situ hybridization. One case was negative for SDHB and reclassified as succinate dehydrogenase–deficient RCC. None of the cases showed loss of expression of fumarate hydratase. One case was diffusely positive for CK7 and negative for CD117 and reclassified as a low-grade oncocytic tumor. Four cases were positive for both cathepsin-K and TFE3 by immunohistochemistry, although fluorescence in situ hybridization failed to identify rearrangement in either TFE3 or TFEB genes. Of the tumors that remained unclassified, those with oncocytic features were less likely to be a high grade (odds ratio [OR]=0.22, P=0.013) or advanced stage (OR=0.19, P=0.039) and were more common in women (OR=3.4, P=0.05) compared with those without oncocytic features. Tumors with rhabdoid morphology were associated with advanced stage (relative risk=3.6, P=0.009), while tumors with clear cell or papillary features had a wide range of grades and stages at presentation. In summary, the most frequent reclassified entity is eosinophilic solid and cystic RCC. Investigation of expression of succinate dehydrogenase or fumarate hydratase in individuals older than 35 years with unclassifiable tumors is low yield in the absence of specific morphologic features. A subset of MTSC without well-developed morphologic features can be reclassified by using RNA-ISH for VSTM2A. Recognition of more-recently described RCC subtypes allows for their distinction from the unclassified subtype and improves the prognostic information provided. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.