Clinicopathologic profile of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases

Abstract

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms driven by oncogenic, mutational activation of KIT or platelet-derived growth factor receptor a (PDGFRA). GIST-specific KIT or PDGFRA mutations have been linked to tumor location, tumor cell morphology and clinical behavior. The purpose of this study was to evaluate the clinicopathologic profile of GISTs that have KIT exon 13 or exon 17 mutations. Through the collaboration of several GIST research groups, we gathered 54 cases from the pre-imatinib era that had such primary mutations. From our observations and those in the literature, we estimate that the frequency of these mutations is no higher than 1-2%. Almost all (32 of 33, 97%) of the KIT exon 13 mutations were the 1945A4G substitution leading to Lys642Glu. A majority (15 of 21, 71.4%) of the KIT exon 17 mutations were the 2487T4A substitution leading to Asn822Lys. Demographic and clinicopathologic data were available for 26 and 14 KIT exon 13 and exon 17 mutant GISTs, respectively. Median age and male to female ratio were similar to ones reported in other GIST studies. Small intestinal tumors were two times more frequent than gastric ones among KIT exon 17 mutants. Also, intestinal tumors were slightly overrepresented among KIT exon 13 mutants when compared with population-based studies. The majority of KIT exon 13 or exon 17 mutants had a spindlecell morphology and only a few had epithelioid features. Tumor size varied from 1.2 to 25 cm and average mitotic rates were 9.5 and 4.2 for KIT exon 13 and exon 17 mutants, respectively. Gastric KIT exon 13 mutant GISTs tend to be slightly larger and more aggressive than gastric GISTs in average, whereas the behavior of small intestinal GISTs with KIT exon 13 mutations does not differ from other small intestinal GISTs. The latter is also true for all KIT exon 17 mutant GISTs. Modern Pathology (2008) 21, 476-484; doi:10.1038/modpathol.2008 published online 1 February 2008 Keywords: GIST; KIT; tyrosine kinase domain; mutation Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal, mesenchymal neoplasm driven by oncogenic activation of KIT or plateletderived growth factor receptor a (PDGFRA), a tyrosine kinase receptor. GISTs occur in different parts of GI tract and show a histological spectrum. Although spindle-cell morphology predominates, tumors with epithelioid or pleomorphic cell features

The frequencies of c-kit proto-oncogene (KIT) mutations in gastrointestinal stromal tumours: a population based study from Aegean Region of Turkey

“…Exon 9 of KIT gene encodes extracellular subunit of KIT protein, which takes part in receptor dimerization. In literature, the exon 9 mutation frequencies are reported to be between 5% and 18% [19,25,28]. We found exon 9 mutation frequency as 8.3% (5/60) and this result was lower than the other studies in literature [6,24].…”

“…KIT tyrosine kinase subunit mutations have been defined in exon 13, which encodes the "First tyrosine kinase (TK1)-ATP binding" domain of the KIT protein and in exon 17 encoding the "Second tyrosine kinase (TK2)-enzymatic loop" domain in GISTs. In untreated GISTs, KIT exon 13 and exon 17 mutations were only reported sporadically [19,20]. However, at the same time, these domains can be affected by secondary mutations during imatinib mesylate therapy and acquired resistance to this therapy [21].…”

Mutational spectrum and therapy response of metastasized GIST in Central Switzerland – A population-based study

“…In addition the metastasis of patient D harboured a point mutation in exon 13. Previous studies showed, that exon 13 alterations result in poor response to tyrosine kinase inhibitor therapy (16). This could be responsible for the more aggressive course of the disease of this patient, while receiving Imatinib and Sunitinib without any clinical or radiological response.…”

Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis

“…CD34 positivity in GISTs varies between 40 and 82% in the literature (1,(18)(19)(20)25,28,40,41). Positive immunreaction with CD34 was observed in 62% of our cases.…”