A Subset of Gastrointestinal Stromal Tumors Previously Regarded as Wildtype GISTs Carries Sporadic Activating Mutations in the Extracellular Ligand Binding Domain of KIT (Exon 8, p.D419del)
Hans-Ulrich Schildhaus, Sebastian Huss, Sabine Merkelbach-Bruse, Michaela Kleine, Kunstlinger Helen, Reinhard Buttner, Eva Wardelmann. Institute of Pathology, Cologne, Germany
Background: About 15% of GISTs carry wild type sequences in all hot spots of KIT and PDGFRA (wt-GISTs). These tumors are currently defined by having wild type sequences in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of PDGFRA. Until now, the analysis of further exons is not recommended. However, we have previously published a report on a KIT exon 8 germline mutation which was associated with familial GISTs. Thus, we aimed at investigating whether KIT exon 8 mutations might also occur in sporadic GISTs.
Design: We therefore screened a cohort of 145 wt-GISTs for somatic mutations in KIT exon 8. All tumors were immunohistochemically positive for KIT and DOG-1.
Results: Two primary GISTs with an identical exon 8 mutation (p.D419del) were detected, representing 1.4% of all cases investigated. Based on 1338 GISTs from our registry the overall frequency of KIT exon 8 mutations was 0.15%. The first case was found in a 53-year-old male patient. The tumor showed a biphasic spindled-epithelioid pattern with high proliferative activity (13/50HPF). Furthermore, a second low proliferative spindle cell pattern was noted (4/50 HPF). The patient suffered from multiple peritoneal metastases 29 months later. In case 2, the 57-year old female patient followed, however, a benign clinical course under adjuvant treatment. 19 month after removal of the GIST, there is no evidence of recurrence. Skin changes or clinical signs of mastocytosis were not noted in both patients.
Conclusions: We report here for the first time on sporadic mutations in the extracellular ligand binding domain (exon 8) of KIT. The same type of mutation was previously reported in familial GISTs. In this report we could identify a kindred with both GISTs and mastocytosis. We could show, that the mutation results in constitutively activated KIT, which can be successfully inhibited by imatinib. We conclude that a small proportion (about 1%) of GISTs being formerly reported as “wild type” might in fact be KIT exon 8 mutated. Given that (1) this subtype was shown to be activating and imatinib sensitive in vitro and (2) our follow up data, suggesting a favourable outcome for imatinib treated patients, we suppose that the screening for KIT exon 8 mutations should be included in the diagnostic work up of GISTs and that patients with exon 8 mutation and significant risk for tumor progression should be treated with imatinib.
Category: Bone & Soft Tissue
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 27, Tuesday Afternoon