Original ArticlesVSTM2A Overexpression Is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the KidneyWang, Lisha MD, PhD*,†; Zhang, Yuping PhD*,†; Chen, Ying-Bei MD, PhD‡; Skala, Stephanie L. MD†; Al-Ahmadie, Hikmat A. MD‡; Wang, Xiaoming PhD*,†; Cao, Xuhong MS*,†; Veeneman, Brendan A. PhD*,†; Chen, Jin MS*,†; Cieślik, Marcin PhD*,†; Qiao, Yuanyuan PhD*,†; Su, Fengyun PhD*,†; Vats, Pankaj MS*,†; Siddiqui, Javed MS*,†; Xiao, Hong PhD†; Sadimin, Evita T. MD§; Epstein, Jonathan I. MD∥; Zhou, Ming MD¶; Sangoi, Ankur R. MD#; Trpkov, Kiril MD**; Osunkoya, Adeboye O. MD††; Giannico, Giovanna A. MD‡‡; McKenney, Jesse K. MD§§; Argani, Pedram MD∥; Tickoo, Satish K. MD‡; Reuter, Victor E. MD‡; Chinnaiyan, Arul M. MD, PhD*,†,∥∥,¶¶,##; Dhanasekaran, Saravana M. PhD*,†; Mehra, Rohit MD*,†,∥∥Author Information *Michigan Center for Translational Pathology Departments of †Pathology ¶¶Urology ∥∥Rogel Cancer Center, University of Michigan ##Howard Hughes Medical Institute, Ann Arbor, MI ‡Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY §Department of Pathology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ ∥Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD ¶Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX #Department of Pathology, EI Camino Hospital, Mountain View, CA **Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada ††Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, GA ‡‡Departments of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN §§Robert J Tomsich Pathology and Laboratory Medicine Institute, Anatomic Pathology, Cleveland Clinic, Cleveland, OH L.W. and Y.Z. contributed equally to this article. S.M.D. and R.M. share senior authorship of this article. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Rohit Mehra, MD, Department of Pathology, Michigan Center for Translational Pathology, 1500 E. Medical Center Drive, Ann Arbor, MI 48109 (e-mail: firstname.lastname@example.org). The American Journal of Surgical Pathology: December 2018 - Volume 42 - Issue 12 - p 1571-1584 doi: 10.1097/PAS.0000000000001150 Buy SDC Metrics Abstract Our recent study revealed recurrent chromosomal losses and somatic mutations of genes in the Hippo pathway in mucinous tubular and spindle cell carcinoma (MTSCC). Here, we performed an integrative analysis of 907 renal cell carcinoma (RCC) samples (combined from The Cancer Genome Atlas and in-house studies) and the Knepper data set of microdissected rat nephrons. We identified VSTM2A and IRX5 as novel cancer-specific and lineage-specific biomarkers in MTSCC. We then assessed their expression by RNA in situ hybridization (ISH) in 113 tumors, including 33 MTSCC, 40 type 1 papillary RCC, 8 type 2 papillary RCC, 2 unclassified RCC, 15 clear cell RCC, and 15 chromophobe RCC. Sensitivity and specificity were calculated as the area under the receiver operating characteristics curve (AUC). All MTSCC tumors demonstrated moderate to high expression of VSTM2A (mean ISH score=255). VSTM2A gene expression assessed by RNA sequencing strongly correlated with VSTM2A ISH score (r2=0.81, P=0.00016). The majority of non-MTSCC tumors demonstrated negative or low expression of VSTM2A. IRX5, nominated as a lineage-specific biomarker, showed moderate to high expression in MTSCC tumors (mean ISH score=140). IRX5 gene expression assessed by RNA sequencing strongly correlated with IRX5 ISH score (r2=0.69, P=0.00291). VSTM2A (AUC: 99.2%) demonstrated better diagnostic efficacy than IRX5 (AUC: 87.5%), and may thus serve as a potential diagnostic marker to distinguish tumors with overlapping histology. Furthermore, our results suggest MTSCC displays an overlapping phenotypic expression pattern with the loop of Henle region of normal nephrons. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.