Prognostic stratification of high-risk gastrointestinal stromal tumors in the era of targeted therapy.
BACKGROUND
Recently, a trial of adjuvant imatinib for primary R0-resected intermediate and high-risk gastrointestinal stromal tumors (GISTs) significantly improved recurrence-free survival. But identifying patients having higher chances of recurrence will reduce economic losses and prevent adverse side effects caused by adjuvant treatment.


METHODS
Tissue samples from 93 patients with high-risk GISTs were studied for p16, CD34, and CD44 protein expression and mutations of KIT and PDGFRA gene. Clinicopathologic, immunohistochemical, and mutation results were compared with clinical outcome by univariate and multivariate analyses.


RESULTS
KIT mutations were observed in 75 cases (81%) including 46 exon 11 deletion mutations and 31 deletions affecting codons 557-558. A novel 12 bp deletion mutation (KHNG484-488) on KIT exon 9 was detected in a small intestinal GIST. For recurrence-free survival, R0 resection, organ-confined disease stage, and female sex are better prognostic factors in univariate analysis and disease stage was the only factor predicting recurrence (P = 0.02) in multivariate analysis. In overall survival, mutation types, presence of mutation, location of GISTs, and mitosis were significant by univariate analysis. After multivariate analysis, mitotic counts and presence of KIT mutation corresponded to independent prognostic factors. Moreover, mitosis, KIT exon 11 deletion mutation, and deletions affecting exon 557-558 predict recurrence in R0-resected high-risk GISTs (P < 0.05).


CONCLUSIONS
Prognostic stratification in high-risk GISTs will help identify patients with high-risk GIST who may benefit from adjuvant therapy.
Departments of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Cheol
C
Keun Park
Eui Jin
EJ
Lee
Minji
M
Kim
Ho-Yeong
HY
Lim
Dong Il
DI
Choi
Jae Hyung
JH
Noh
Tae Sung
TS
Sohn
Sung
S
Kim
Mi Jung
MJ
Kim
Hun Kyung
HK
Lee
Kyoung-Mee
KM
Kim
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D003062:Codon; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D016016:Proportional Hazards Models; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012044:Regression Analysis; D012189:Retrospective Studies; D015996:Survival Rate
D018952:Antigens, CD34; D003062:Codon; D018960:Hyaluronan Receptors; D019009:Proto-Oncogene Proteins c-kit