Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome

Trpkov K, Hes O, Agaimy A, Bonert M, Martinek P, Magi-Galluzzi C, Kristiansen G, Lueders C, Nesi G, Comperat E, Sibony M, Berney DM, Mehra R, Brimo F, Hartmann A, Husain A, Frizzell N, Hills K, Maclean F, Srinivasan B, Gill AJ (2016)

Publication Type: Journal article

Publication year: 2016

Journal

American Journal of Surgical Pathology Lippincott, Williams & Wilkins

Book Volume: 40

Pages Range: 865-75

Journal Issue: 7

DOI: 10.1097/PAS.0000000000000617

Abstract

Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas (RCC) are difficult to diagnose prospectively. We used immunohistochemistry (IHC) to identify fumarate hydratase (FH)-deficient tumors (defined as FH negative, 2-succinocysteine [2SC] positive) in cases diagnosed as "unclassified RCC, high grade or with papillary pattern," or "papillary RCC type 2," from multiple institutions. A total of 124 tumors (from 118 patients) were evaluated by IHC for FH and 2SC. An FH deficiency was found in 24/124 (19%) cases. An indeterminate result (only 1 marker abnormal) was found in 27/124 (22%) cases. In a tissue microarray of 776 RCCs of different types, only 2 (0.5%) tumors, initially considered papillary type 2, were FH deficient. FH mutations were found in 19/21 FH-deficient tumors (with confirmed germline mutations in 9 of 9 tumors in which germline status could be assessed) and in 1/26 FH-indeterminate tumors identified by IHC. No FH mutations were found in 2/21 FH-deficient RCCs, 25/26 FH-indeterminate RCCs, and 10/10 RCCs demonstrating FH expression by IHC. Patients with FH-deficient RCC had a median age of 44 years (range, 21 to 65 y). Average tumor size was 8.2 cm (range, 0.9 to 18 cm). FH-deficient RCCs were characterized by at least focal macronucleoli and demonstrated 2 or more growth patterns in 93% cases. Papillary was the most common (74%) and dominant (59%) pattern, whereas other common patterns included: solid (44%), tubulocystic (41%), cribriform (41%), and cystic (33%). At presentation, 57% were stage >=pT3, 52% had positive nodes, and 19% had distant metastases. After a mean follow-up of 27 months (range, 1 to 114 mo), 39% of patients were dead of disease, and 26% had disease progression. We conclude that FH and 2SC are useful IHC ancillary tools, which allow recognition of FH-deficient RCC.

Authors with CRIS profile

Abbas Agaimy Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie

Involved external institutions

Universitätsklinikum Bonn DE Germany (DE) Calgary Laboratory Services (CLS) CA Canada (CA) University of Paris 5 - René Descartes / Université Paris V René Descartes FR France (FR) Mater Health Services AU Australia (AU) Douglass Hanly Moir (DHM) Pathology AU Australia (AU) Sullivan Nicolaides Pathology AU Australia (AU) University of South Carolina US United States (USA) (US) Queen Mary, University of London GB United Kingdom (GB) Assistance Publique-Hôpitaux de Paris (AP-HP) FR France (FR) Università degli Studi di Firenze / University of Florence IT Italy (IT) University of Sydney (USYD) AU Australia (AU) McGill University CA Canada (CA) University of Michigan US United States (USA) (US) Cleveland Clinic US United States (USA) (US) Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ)

How to cite

APA:

Trpkov, K., Hes, O., Agaimy, A., Bonert, M., Martinek, P., Magi-Galluzzi, C.,... Gill, A.J. (2016). Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome. American Journal of Surgical Pathology, 40(7), 865-75. https://doi.org/10.1097/PAS.0000000000000617

MLA:

Trpkov, Kiril, et al. "Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome." American Journal of Surgical Pathology 40.7 (2016): 865-75.

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