Molecular and clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size.
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.
Rossi
Sabrina
S
Department of Pathology and Molecular Genetics, Treviso General Hospital, Italy.
Gasparotto
Daniela
D
Toffolatti
Luisa
L
Pastrello
Chiara
C
Gallina
Giovanna
G
Marzotto
Alessandra
A
Sartor
Chiara
C
Barbareschi
Mattia
M
Cantaloni
Chiara
C
Messerini
Luca
L
Bearzi
Italo
I
Arrigoni
Giannantonio
G
Mazzoleni
Guido
G
Fletcher
Jonathan A
JA
Casali
Paolo G
PG
Talamini
Renato
R
Maestro
Roberta
R
Maestra
Roberta
R
Dei Tos
Angelo Paolo
AP
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
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha