[657] Loss of SDHB Expression Is Limited to a Distinctive Subset of Gastric Wild-Type Gastrointestinal Stromal Tumors: A Comprehensive Genotype-Phenotype Correlation Study

Leona A Doyle, Michael C Heinrich, Christopher L Corless, Jason L Hornick. Brigham and Women's Hospital & Harvard Medical School, Boston, MA; Oregon Health & Science University, Portland, OR

Background: Gastrointestinal stromal tumors (GISTs) typically harbor activating mutations in KIT or PDGFRA; however, 15% of GISTs in adults and >90% in children lack such mutations ["wild-type" (WT) GISTs]. Pediatric WT GISTs, GISTs in patients with Carney triad and Carney-Stratakis syndrome, and some WT GISTs in adults show similar, distinctive clinical and pathologic features. These "pediatric-type" ("type 2") GISTs occur in the stomach, may be multifocal, show multinodular/plexiform architecture and epithelioid morphology, often spread to lymph nodes, are imatinib resistant, and tend to pursue an indolent clinical course even with metastatic disease. Recent studies have suggested that this distinctive group of tumors can be identified by loss of succinate dehydrogenase subunit B (SDHB) protein expression by immunohistochemistry (IHC). The aim of this study was to validate the predictive value of SDHB IHC for this subset of WT GISTs in a large genotyped cohort.
Design: SDHB protein expression was examined by IHC in whole tissue sections from 261 GISTs with known KIT and PDGFRA genotypes: 179 tumors with KIT mutations (154 in exon 11, 17 in exon 9, 4 in exon 13, and 4 in exon 17), 31 tumors with PDGFRA mutations (24 in exon 18, 4 in exon 12, and 3 in exon 14), and 51 WT tumors. IHC was performed following antigen retrieval using a mouse anti-SDHB monoclonal antibody (1:100; 21A11AE7; Abcam). Cytoplasmic staining was scored as "intact" or "deficient". Histologic features were recorded without knowledge of genotype or SDHB status.
Results: SDHB expression was deficient in 20 (39%) WT GISTs. All other tumors showed intact expression of SDHB, including 100% of KIT and PDGFRA-mutant GISTs and 31 (61%) WT GISTs. All SDHB-deficient GISTs with known primary site (N=19) arose in the stomach and had a multinodular/plexiform growth pattern and epithelioid or mixed morphology. Of the WT GISTs with intact SDHB expression, 10 arose in the small intestine, 7 in the stomach, 5 in the colon, and 1 in the esophagus; primary site was unknown in 8 cases. None showed a multinodular architecture, and only 4 (13%) had epithelioid morphology.
Conclusions: SDHB-deficient GISTs are WT gastric tumors with distinctive features that can be recognized histologically. IHC for SDHB can be used to confirm the diagnosis of this class of tumors, which has prognostic, therapeutic, and syndromic implications. SDHB expression is retained in all GISTs with KIT and PDGFRA mutations.
Category: Gastrointestinal

Monday, March 19, 2012 8:00 AM

Platform Session: Section D, Monday Morning


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