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

Am J Surg Pathol

*Calgary Laboratory Services and University of Calgary, Calgary, AB, Canada §§McGill University, Montreal, QC, Canada †Charles University, Pilsen, Czech Republic ‡Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany ∥University Clinic Bonn, Germany §Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH ‡‡University of Michigan, Ann Arbor, MI ∥∥University of South Carolina School of Medicine, Columbia, SC ¶University of Florence, Florence, Italy #Pitié-Salpêtrière Hospital, Paris, France **Hopital Cochin, APHP, Université Paris Descartes, Paris, France ††Barts Cancer Institute, Queen Mary University of London, London, United Kingdom ¶¶Sullivan Nicolaides Pathology, Gold Coast, Qld, Australia ***Mater Hospital, South Brisbane, Qld, Australia ##Douglass Hanly Moir Pathology, North Ryde, NSW, Australia †††Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.

Published: July 2016

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.

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http://dx.doi.org/10.1097/PAS.0000000000000617DOI Listing

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