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Loss of SDHA Expression Identifies SDHA Mutations in Succinate Dehydrogenase–deficient Gastrointestinal Stromal Tumors

Dwight, Trisha PhD*,†; Benn, Diana E. PhD*,†; Clarkson, Adele BSc; Vilain, Ricardo MBBS§; Lipton, Lara PhD; Robinson, Bruce G. MD*,†; Clifton-Bligh, Roderick J. PhD, FRACP*,†; Gill, Anthony J. FRCPA†,‡,¶

The American Journal of Surgical Pathology: February 2013 - Volume 37 - Issue 2 - p 226–233
doi: 10.1097/PAS.0b013e3182671155
Original Articles

Succinate dehydrogenase–deficient gastrointestinal stromal tumors (SDH-deficient GISTs) are a unique class of GIST defined by negative immunohistochemical staining for succinate dehydrogenase B (SDHB). SDH-deficient GISTs show distinctive clinical and pathologic features including absence of KIT and PDGFRA mutations, exclusive gastric location, common lymph node metastasis, a prognosis not predicted by size and mitotic rate, and indolent behavior of metastases. They may be syndromal with some being associated with the Carney Triad or germline SDHA, SDHB, SDHC, or SDHD mutations (Carney-Stratakis syndrome). It is normally recommended that genetic testing for SDHA, SDHB, SDHC, and SDHD be offered whenever an SDH-deficient GIST is encountered. However, testing for all 4 genes is burdensome and beyond the means of most centers. In this study we performed SDHA mutation and immunohistochemical analyses for SDHA on 10 SDH-deficient GISTs. Three showed negative staining for SDHA, and all of these were associated with germline SDHA mutations. In 2 tumors, 3 novel mutations were identified (p.Gln54X, p.Thr267Met, and c.1663+3G>C), none of which have previously been reported in GISTs or other SDH-associated tumors. Seven showed positive staining for SDHA and were not associated with SDHA mutation. In conclusion, 30% of SDH-deficient GISTs in this study were associated with germline SDHA mutation. Negative staining for SDHA can be used to triage formal genetic testing for SDHA when an SDH-deficient GIST is encountered.

*Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research

Department of Anatomical Pathology

Northern Cancer Translational Research Unit, Royal North Shore Hospital

Sydney Medical School, University of Sydney, Sydney

§Hunter Area Pathology Service, Newcastle, NSW

Ludwig Institute for Cancer Research and Royal Melbourne Hospital, Melbourne, Vic., Australia

Conflicts of Interest and Source of Funding: Supported by the Hillcrest Foundation. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Anthony J. Gill, FRCPA, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia (e-mail:

© 2013 Lippincott Williams & Wilkins, Inc.