Identification of Succinate Dehydrogenase-Deficient Bladder Paragangliomas
Emily F Mason, Peter M Sadow, Andrew J Wagner, Stephen P Remillard, Trevor A Flood, Eric C Belanger, Jason L Hornick, Justine A Barletta. Brigham and Women's Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Ottawa Hospital, Ottawa, ON, Canada
Background: A significant number of patients with paragangliomas harbor germline mutations in one of the succinate dehydrogenase (SDH) genes (SDHA, B, C, or D). Tumors with mutations in SDH genes can be identified using immunohistochemistry (IHC). Loss of SDHB staining is seen in tumors with a mutation in any one of the SDH genes, whereas loss of both SDHB and SDHA expression is seen only in the context of an SDHA mutation. Identifying an SDH-deficient tumor can be prognostically significant since tumors with SDHB mutations are more likely to pursue a malignant course. While the rate of SDH deficiency in paragangliomas in general is known to be approximately 30%, there are only rare reports of SDH-deficient bladder paragangliomas. Therefore, the aim of this study was to determine the rate of SDH deficiency in bladder paragangliomas.
Design: Eleven cases of bladder paragangliomas were identified. H&E slides of all tumors were reviewed, and IHC for SDHB and SDHA was performed. For cases with loss of SDHA expression by IHC, mutation analysis of the SDHA gene was performed. Detailed clinical history was recorded from electronic medical records.
Results: Loss of SDHB staining was seen in 3 (27%) cases (2 with loss of SDHB only, one with loss of SDHB and SDHA). While patients with SDH-deficient tumors were younger than those with tumors with intact SDH expression (39 years and 58 years, respectively), this difference did not reach statistical significance (p=0.13). Of the two patients with SDHB-deficient and SDHA-intact tumors, one was found to have a germline SDHB mutation, and the other had a family history of a malignant paraganglioma. Both patients developed metastatic disease. The one patient with a tumor that was deficient for both SDHB and SDHA had no family history of paragangliomas and no evidence of metastatic disease. Sequencing of this tumor revealed a deleterious single base pair substitution in exon 5 of SDHA (R162X) in both the tumor and normal tissue, indicative of a germline SDHA mutation. No patients with intact SDH expression had a family history of paragangliomas; one had a synchronous paraganglioma, but none developed metastatic disease.
Conclusions: A significant subset (27%) of bladder paragangliomas is SDH-deficient. It is essential to identify SDH-deficient tumors since the presence of an SDH mutation has prognostic implications and is important in guiding genetic counseling.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 1:30 PM
Proffered Papers: Section A, Tuesday Afternoon