title: Molecular and clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size.
abstract: Although Gastrointestinal stromal tumors (GISTs) affect about 0.0014% of the population, GISTs smaller than 1 cm (microGISTs) are detectable in about 20% to 30% of elderly individuals. This suggests that microGISTs likely represent premalignant precursors that evolve only in a minute fraction of cases toward overt GISTs. We sought histopathologic and molecular explanations for the infrequent clinical progression in small GISTs. To investigate the mechanisms of GIST progression and identify subsets with differential malignant potential, we carried out a thorough characterization of 170 GISTs <2 cm and compared their KIT/PDGFRA status with overt GISTs. The proliferation was lower in microGISTs compared with GISTs from 1 to 2 cm (milliGISTs). In addition, microGISTs were more frequently incidental, gastric, spindle, showed an infiltrative growth pattern, a lower degree of cellularity, and abundant sclerosis. The progression was limited to 1 ileal and 1 rectal milliGISTs. KIT/PDGFRA mutations were detected in 74% of the cases. The overall frequency of KIT/PDGFRA mutation and, particularly, the frequency of KIT exon 11 mutations was significantly lower in small GISTs compared with overt GISTs. Five novel mutations, 3 in KIT (p.Phe506Leu, p.Ser692Leu, p.Glu695Lys) 2 in PDGFRA (p.Ser847X, p.Ser667Pro), plus 4 double mutations were identified. Small GISTs share with overt GIST KIT/PDGFRA mutation. Nevertheless, microGISTs display an overall lower frequency of mutations, particularly canonical KIT mutations, and also carry rare and novel mutations. These molecular features, together with the peculiar pathologic characteristics, suggest that the proliferation of these lesions is likely sustained by weakly pathogenic molecular events, supporting the epidemiologic evidence that microGISTs are self-limiting lesions.
authors.affiliation: Department of Pathology and Molecular Genetics, Treviso General Hospital, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rossi
authors.forename: Daniela
authors.initials: D
authors.lastname: Gasparotto
authors.forename: Luisa
authors.initials: L
authors.lastname: Toffolatti
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastrello
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gallina
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marzotto
authors.forename: Chiara
authors.initials: C
authors.lastname: Sartor
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.forename: Chiara
authors.initials: C
authors.lastname: Cantaloni
authors.forename: Luca
authors.initials: L
authors.lastname: Messerini
authors.forename: Italo
authors.initials: I
authors.lastname: Bearzi
authors.forename: Giannantonio
authors.initials: G
authors.lastname: Arrigoni
authors.forename: Guido
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.forename: Renato
authors.initials: R
authors.lastname: Talamini
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestra
authors.forename: Angelo Paolo
authors.initials: AP
authors.lastname: Dei Tos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D033162:Incidental Findings; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha