Case ReportHereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC): A Rapid Autopsy Report of Metastatic Renal Cell CarcinomaUdager, Aaron M. MD, PhD*; Alva, Ajjai MD†,‡; Chen, Ying-Bei MD, PhD§; Siddiqui, Javed MS∥; Lagstein, Amir MD*; Tickoo, Satish K. MD§; Reuter, Victor E. MD§; Chinnaiyian, Arul M. MD, PhD*,‡,∥,¶,#; Mehra, Rohit MD*,‡,∥Author Information Departments of *Pathology #Urology †Internal Medicine, Division of Hematology and Oncology ‡Comprehensive Cancer Center, University of Michigan Health System ∥Michigan Center for Translational Pathology ¶Howard Hughes Medical Institute, Ann Arbor, MI §Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY A.M.U. and A.A. contributed equally. Conflicts of Interest and Source of Funding: Supported in part by the NCI Early Detection Research Network (U01 CA111275) and Prostate Cancer SPORE (P50 CA069568). A.A. is supported by the NIH National Center for Advancing Translational Sciences (KL2 TR000434). R.M. and A.M.C. are supported by the Prostate Cancer Foundation. A.M.C. is also supported by the Alfred A. Taubman Institute, the American Cancer Society, the Howard Hughes Medical Institute, and a Doris Duke Charitable Foundation Clinical Scientist Award. 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, University of Michigan Health System, Room 2G332 UH, 1500 E. Medical Center Drive, Ann Arbor, MI 48109 (e-mail: firstname.lastname@example.org). The American Journal of Surgical Pathology: April 2014 - Volume 38 - Issue 4 - p 567-577 doi: 10.1097/PAS.0000000000000127 Buy Metrics Abstract Rapid (“warm”) autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)—the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, “pseudohypoxic” upregulation of hypoxia-inducible factor 1α (HIF-1α)-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient’s RCC demonstrated extensive sarcomatoid and rhabdoid features—morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules. © 2014 by Lippincott Williams & Wilkins.