Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome

Kiril Trpkov*, Ondrej Hes, Abbas Agaimy, Michael Bonert, Petr Martinek, Cristina Magi-Galluzzi, Glen Kristiansen, Christine Lüders, Gabriella Nesi, Eva Compérat, Mathilde Sibony, Daniel M. Berney, Rohit Mehra, Fadi Brimo, Arndt Hartmann, Arjumand Husain, Norma Frizzell, Kirsten Hills, Fiona Maclean, Bhuvana SrinivasanAnthony J. Gill

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)865-875
Number of pages11
JournalAmerican Journal of Surgical Pathology
Volume40
Issue number7
DOIs
Publication statusPublished - Jul 2016
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • 2SC
  • FH
  • fumarate hydratase
  • fumarate hydratase-deficient RCC
  • HLRCC
  • renal cancer
  • succination

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