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Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci

A Frequent Morphologic Pattern of Fumarate Hydratase-deficient Renal Cell Carcinoma

Smith, Steven C. MD, PhD; Trpkov, Kiril MD; Chen, Ying-Bei MD, PhD; Mehra, Rohit MD; Sirohi, Deepika MD; Ohe, Chisato MD; Cani, Andi K. MS; Hovelson, Daniel H. MS; Omata, Kei MD; McHugh, Jonathan B. MD; Jochum, Wolfram MD; Colecchia, Maurizio MD; Amin, Mitual MD; Divatia, Mukul K. MD; Hes, Ondřej MD, PhD; Menon, Santosh MD; Werneck da Cunha, Isabela MD, PhD; Tripodi, Sergio MD, PhD; Brimo, Fadi MD; Gill, Anthony J. MD; Osunkoya, Adeboye O. MD; Magi-Galluzzi, Cristina MD, PhD; Sibony, Mathilde MD; Williamson, Sean R. MD; Nesi, Gabriella MD, PhD; Picken, Maria M. MD; Maclean, Fiona MBBS; Agaimy, Abbas MD; Cheng, Liang MD; Epstein, Jonathan I. MD; Reuter, Victor E. MD; Tickoo, Satish K. MD; Tomlins, Scott A. MD, PhD; Amin, Mahul B. MD

The American Journal of Surgical Pathology: November 2016 - Volume 40 - Issue 11 - p 1457–1472
doi: 10.1097/PAS.0000000000000719
Original Articles

An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes—including FH—performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC−. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH−/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC− cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term “FH-deficient RCC” as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.

*Departments of Pathology and Urology, VCU Health, Richmond, VA

Calgary Laboratory Services and University of Calgary, Calgary, AB

¶¶Department of Pathology, McGill University, Montreal, QC, Canada

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY

§Department of Pathology, University of Michigan

∥∥∥∥Michigan Center for Translational Pathology, Department of Urology, Comprehensive Cancer Center, University of Michigan, Ann Arbor

**Department of Pathology, William Beaumont Health System, Royal Oak

∥∥∥Department of Pathology, Henry Ford Health System, Detroit, MI

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA

Institute of Pathology, Kantonsspital St. Gallen, Switzerland

#Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

††Department of Pathology, Charles University and University Hospital, Plzen, Czech Republic

‡‡Department of Pathology and Uro-oncology Disease Management Group, Tata Memorial Hospital, Mumbai, India

§§Department of Anatomic Pathology, A.C. Camargo Cancer Center, Sao Paulo, Brazil

∥∥Department of Pathology, Azienda Ospedaliera Universitaria Senese, Siena, Italy

##Cancer Diagnosis and Pathology Group, Kolling Institue of Medical Research, Royal North Shore Hospital

***Sydney Medical School, University of Sydney, Sydney

****Douglass Hanly Moir Pathology, Macquarie Park, NSW, Australia

†††Department of Pathology, Emory University, Atlanta, GA

‡‡‡Robert J. Tomsich Pathology and Laboratory Medicine Institute Cleveland Clinic, Cleveland, OH

§§§Département d’Anatomie Pathologique, Hôpital Cochin, Université Paris Descartes, Paris, France

¶¶¶Division of Pathological Anatomy, University of Florence, Florence, Italy

###Department of Pathology, Loyola University, Maywood, IL

††††Institute of Pathology, Friedrich-Alexander University, University Hospital, Erlangen, Germany

‡‡‡‡Department of Pathology, Indiana University School of Medicine, Indianapolis, IN

§§§§Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD

A preliminary version of this study was presented as an oral paper at the March 2015 United States and Canadian Academy of Pathology Meeting in Boston, MA.

Conflicts of Interest and Source of Funding: S.A.T. had a prior sponsored research agreement with and has received travel support from Thermo Fisher Scientific. S.A.T. is supported by the A. Alfred Taubman Medical Research Institute. O.H. acknowledges support of the Charles University Research Fund (project number P36) and by the project CZ.1.05/2.1.00/03.0076 from European Regional Development Fund. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Mahul B. Amin, MD, Department of Pathology and Laboratory Medicine, 8700 Beverly Blvd, S. Tower, Rm 8709, Cedars-Sinai Medical Center, Los Angeles, CA 90048 (e-mail:

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