Immunohistochemistry for SDHB Distinguishes Carney Triad and Carney-Stratakis Syndrome Associated GISTs (Type 2 GISTs) from Usual Sporadic GISTs (Type 1 GISTs)
AJ Gill, A Chou, A Clarkson, RP Eckstein, A Shi, C Smith, L Siosson, DE Benn, RJ Clifton-Bligh. Royal North Shore Hospital, Pacific Highway, St Leonards, Australia; Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia
Background: The Carney Triad (CT) is GIST, paraganglioma (PG), and pulmonary chondroma (PC). The Carney Stratakis Syndrome (CSS) is GIST and PG with mutations of succinate dehydrogenase (SDH) B, C or D. No mutations in KIT, PDGFRA or SDH- have been described in CT. Non CT hereditary PGs may be associated with germline SDHB, SDHC or SDHD mutations which form the mitochondrial complex II (MCII). These PGs show negative or weak staining for SDHB regardless of whether the B,C or D subunit is mutated. There is evidence that other yet to be described mutations may cause instability of MCII and also result in negative SDHB staining. We postulated that instability of MCII will occur and thus SDHB IHC will be negative in CT GISTs.
Design: We performed IHC for SDHB on formalin fixed paraffin embedded blocks from 3 GISTs arising in CT and on 104 consecutive apparently sporadic GISTs from 98 subjects.
Results: All 3 CT GISTS showed completely negative staining. Of the sporadic GISTs 99 (95%) were strongly positive, 3 (3%) weakly positive and 2 (2%) negative. Subsequent investigation revealed that 1 of the negative GISTS arose in a young female who had previously had multiple GISTS resected at prior operations over the preceding 17 years. This was unknown to us or the reporting pathologists, but clearly indicates an underlying tumour diathesis (perhaps a forme fruste of CT or CSS). The other negative case was from a young woman who presented with heavy gastric bleeding and hepatic metastases (features seen in CT).
Conclusions: We conclude that negative staining for SDHB occurs commonly in the GISTS of CT and presumably in GISTs of CSS but rarely to never in isolated benign disease. We classify usual SDHB positive GISTS as type 1. The great majority of these GISTS will be driven by KIT and PDGFRA mutations. We classify SDHB negative cases as type 2 GISTs. Type 2 GISTS likely form a heterogeneous group but all are characterized by mitochondrial complex II instability. IHC for SDHB can be used diagnostically to classify GISTS as type1 or type 2. Type 2 GISTs should be offered genetic testing for SDH and if negative follow up as for CT. Provisional data suggests that their natural history and response to treatment may vary from type 1 GISTs.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 55, Tuesday Afternoon