Fumarate Hydratase–deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome. (July 2016)

• Record Type: Journal Article
• Authors: Trpkov, Kiril; Hes, Ondrej; Agaimy, Abbas; Bonert, Michael; Martinek, Petr; Magi-Galluzzi, Cristina; Kristiansen, Glen; Lüders, Christine; Nesi, Gabriella; Compérat, Eva; Sibony, Mathilde; Berney, Daniel M.; Mehra, Rohit; Brimo, Fadi; Hartmann, Arndt; Husain, Arjumand; Frizzell, Norma; Hills, Kirsten; Maclean, Fiona; Srinivasan, Bhuvana; Gill, Anthony J.
• Is Part Of: American journal of surgical pathology. Volume 40:Number 7(2016)
• Publication Date: 2016-07
• Subjects: renal cancer -- HLRCC -- fumarate hydratase -- FH -- fumarate hydratase–deficient RCC -- succination -- 2SC; Pathology, Surgical -- Periodicals; 617.0705
• DOI: 10.1097/PAS.0000000000000617
• Languages: English
• ISSNs: 0147-5185

Abstract

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.