Results from our 12 Pediatric & Wildtype GIST Clinics

The NIH Pediatric and Wildtype (WT) GIST Clinic was established in 2008 as a “model” multidisciplinary clinic that brings together “WT GIST” patients with physicians and researchers to better understand the pathophysiology of WT GIST. Clinical and genetic data have been collected from 115 patients to date.  Tumor samples are being tested for cKIT, PDGFRA, BRAF, NF1, SDH mutations while global methylation analysis is also being performed for every tumor sample. We have found a high incidence (over 80%) of germline SDH mutations in our patient population with SDH deficient tumors, while approximately 88% of them have tumors negative for SDHB  staining. Complete clinical and genetic analysis of 95 patients has revealed 3 distinct patient groups based on methylation status and SDH mutational status. Group A (11 patients) were found to be positive for SDHB IHC staining and we identified NF1, BRAF, CBL, and cryptic cKit-PDGFRA fusion mutations in 9/11 tumors in this group. Group A patients had a median age of 38, were equally divided among men and women, and occurred in both gastric or small bowel locations, and generally included spindle cell morphology. Group B (63 patients) were negative for SDHB IHC staining, contained germline and tumor SDHx mutations. All of these tumors had global genomic hypermethylation, and patients in this group were predominantly female with a median age of 24. Group C (21 patients) were also negative for SDHB IHC protein staining but no SDHx mutations were identified. These tumors were hypermethylated at the SDHC promoter leading to SDH deficiency.  Tumors from Group C patients also had global genomic hypermethylation, and patients were all female with a median age of 15. Both Groups B and C patients more often presented with multifocal gastric GIST of epithelioid morphology. Paragangliomas and/or chondromas were identified in both group B and C patients.  It is important to know that Group B patients have a very high likelihood of germline SDH mutations and thus may require genetic counseling. 

We have also found that in general, these tumors are relatively slow growing, with most patients living for years even when the tumor recurs.  We also observed that while only 1 of 49 patients treated with imatinib (Gleevec) had tumor shrinkage with this treatment, 7 of 38 patients treated with sunitinib (Sutent) had some evidence of tumor shrinkage. 

All of this information has given us ideas on exploring new therapeutic options as well.  For example, tumors with global hypermethylation may be susceptible to drugs that lead to a reversal of this process, and we are actively pursuing such a trial. We hope as we learn more, other therapies will become available based upon the unique findings in these tumors.