title: Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival.
abstract: In gastrointestinal stromal tumors (GISTs), the occurrence of an epithelioid/mixed phenotype has been correlated to PDGFRA mutations, gastric localization and favorable outcome. On the other hand, the prognostic significance of an epithelioid/mixed growth pattern occasionally observed in GISTs with KIT mutation is unclear. The aim of this study was to evaluate the prognostic significance of an epithelioid/mixed phenotype in correlation to anatomical localization, genotype, and expression of cell-cycle markers in a series of 116 primary GISTs with KIT mutation on a tissue microarray. Independent of their anatomical localization, the majority of KIT-mutated GISTs displayed a pure spindled phenotype (72%), with the remaining tumors showing an epithelioid/mixed growth pattern. In KIT-mutated GISTs from the stomach, the occurrence of an epithelioid/mixed growth pattern was significantly correlated with larger tumor diameters (P=0.005), higher mitotic counts (P=0.0001), high-risk category (P=0.001), higher expression of the G2-phase cell-cycle marker cyclin B1 (P=0.04), higher expression of the G1 to M-phase proliferation marker Ki67 (P=0.02) and a significantly shorter disease-free survival (P=0.003) compared with tumors with pure spindled morphology. In contrast, there were no significant differences between pure spindled and epithelioid/mixed GISTs from the small/large bowel. Our findings indicate that the epithelioid/mixed phenotype in KIT-mutant gastric GISTs represents a secondary tumor growth pattern associated with tumor progression and adverse outcome, probably through accelerated G1/S-phase restriction point passage.
authors.affiliation: Department of Pathology, Georg August University, Göttingen, Germany. florian.haller@uniklinik-freiburg.de
authors.forename: Florian
authors.initials: F
authors.lastname: Haller
authors.forename: Judith
authors.initials: J
authors.lastname: Cortis
authors.forename: Joel
authors.initials: J
authors.lastname: Helfrich
authors.forename: Silke
authors.initials: S
authors.lastname: Cameron
authors.forename: Philipp
authors.initials: P
authors.lastname: Schüler
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schwager
authors.forename: Bastian
authors.initials: B
authors.lastname: Gunawan
authors.forename: László
authors.initials: L
authors.lastname: Füzesi
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D018572:Disease-Free Survival; D015622:Epithelioid Cells / Q000378:metabolism / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit