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Tuberous Sclerosis–associated Renal Cell Carcinoma: A Clinicopathologic Study of 57 Separate Carcinomas in 18 Patients

Guo, Juan MD, PhD*; Tretiakova, Maria S. MD, PhD; Troxell, Megan L. MD, PhD; Osunkoya, Adeboye O. MD§; Fadare, Oluwole MD; Sangoi, Ankur R. MD; Shen, Steven S. MD, PhD#; Lopez-Beltran, Antonio MD, PhD**; Mehra, Rohit MD††; Heider, Amer MD††; Higgins, John P. MD‡‡; Harik, Lara R. MD§§; Leroy, Xavier MD∥∥; Gill, Anthony J. MD¶¶; Trpkov, Kiril MD##; Campbell, Steven C. MD, PhD***; Przybycin, Christopher MD*,***; Magi-Galluzzi, Cristina MD, PhD*,***; McKenney, Jesse K. MD*,***

The American Journal of Surgical Pathology: November 2014 - Volume 38 - Issue 11 - p 1457–1467
doi: 10.1097/PAS.0000000000000248
Original Articles

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with characteristic tumors involving multiple organ systems. Whereas renal angiomyolipoma (AML) is common in TSC, renal cell carcinoma (RCC) is rarely reported. Fifty-seven RCCs from 13 female and 5 male TSC patients were reviewed. Age at surgery ranged from 7 to 65 years (mean: 42 y). Nine patients (50%) had multiple synchronous and/or metachronous RCCs (range of 2 to 20 RCCs) and 5 had bilateral RCCs (28%). Seventeen patients (94%) had histologically confirmed concurrent renal AMLs, including 15 with multiple AMLs (88%) and 9 (50%) with AMLs with epithelial cysts. None of the 15 patients with available clinical follow-up information had evidence of distant metastatic disease from 6 to 198 months after their initial surgery (mean: 52 mo). The 57 RCCs exhibited 3 major distinct morphologies: (1) 17 RCCs (30%) had features similar to tumors previously described as “renal angiomyoadenomatous tumor” or “RCC with smooth muscle stroma”; (2) 34 RCCs (59%) showed features similar to chromophobe RCC; and (3) 6 RCCs (11%) showed a granular eosinophilic-macrocystic morphology. Distinct histologic changes were also commonly present in the background kidney parenchyma and included cysts or renal tubules lined by epithelial cells with prominent eosinophilic cytoplasm, nucleomegaly, and nucleoli. Immunohistochemically, all RCCs tested showed strong nuclear reactivity for PAX8 and HMB45 negativity. Compared with sporadic RCCs, TSC-associated RCCs have unique clinicopathologic features including female predominance, younger age at diagnosis, multiplicity, association with AMLs, 3 recurring histologic patterns, and an indolent clinical course. Awareness of the morphologic and clinicopathologic spectrum of RCC in this setting will allow surgical pathologists to better recognize clinically unsuspected TSC patients.

*Cleveland Clinic, Robert J. Tomsich Pathology & Laboratory Medicine Institute

***Glickman Urological and Kidney Institute, Cleveland, OH

Department of Pathology, University of Washington, Seattle, WA

Department of Pathology, Oregon Health & Science University, Portland, OR

§Department of Pathology, Emory University, Atlanta, GA

Department of Pathology, Vanderbilt University, Nashville, TN

Department of Pathology, El Camino Hospital, Mountain View

‡‡Department of Pathology, Stanford University, Stanford, CA

#Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX

††Department of Pathology, University of Michigan, Ann Arbor, MI

§§Department of Pathology, Columbia University, New York, NY

**Department of Anatomic Pathology, University of Cordoba, Cordoba, Spain

∥∥Department of Pathology, Lille University Hospitals, Lille, France

¶¶Department of Anatomic Pathology, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, Australia

##Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada

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: Jesse K. McKenney, MD, Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, 9500 Euclid Ave, L25 Cleveland, 44195, OH (e-mail:

© 2014 by Lippincott Williams & Wilkins.