Expression of the Receptor for Type I Insulin-like Growth Factor (IGF1R) in Gastrointestinal Stromal Tumors: An Immunohistochemical Study of 1078 Cases With Diagnostic and Therapeutic Implications


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Abstract

A majority of gastrointestinal stromal tumors (GISTs) carry gain-of-function KIT or platelet-derived growth factor receptor α (PDGFRA) mutations. However, no mutational activation of KIT or PDGFRA has been identified in pediatric gastric GISTs, neurofibromatosis-1-associated GISTs, and a small subset of sporadic GISTs in adults [so-called wild-type (WT) GISTs]. Recently, pediatric gastric GISTs and some adult WT gastric GISTs have been found to have losses of the succinate dehydrogenase (SDH) complex, a Krebs cycle/electron transport chain interface protein, as seen by immunohistochemical loss of SDH subunit B (SDHB) expression. Moreover, recently, expression of the receptor for type I insulin-like growth factor (IGF1R) has been detected in pediatric and WT GISTs, although only a small number of cases have been analyzed. In this study, IGF1R expression was examined immunohistochemically in 1078 well-characterized GISTs representing different clinicogenetic categories and in 103 non-GIST gastrointestinal tumors. IGF1R expression was detected in 71/80 of SDH-deficient GISTs (SDHB-negative GISTs) but only in 9/625 (1%) of the SDHB-positive gastric GISTs. The latter often carried KIT or PDGFRA mutations and generally occurred in older patients. None of the 373 intestinal GISTs was IGF1R positive, whereas many primary intestinal sarcomas, including clear cell sarcomas, leiomyosarcomas, and undifferentiated sarcomas, were IGF1R positive. The consistent lack of IGF1R expression in intestinal GISTs should be considered an additional immunohistochemical marker in the differential diagnosis between GISTs and non-GIST sarcomas. Because inhibition of IGF1R signaling might become a therapeutic target in GISTs, screening for IGF1R expression may become important in the near future.

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