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Prognostic Value of KIT Mutation Type, Mitotic Activity, and Histologic Subtype in Gastrointestinal Stromal Tumors

From the Departments of Pathology and Surgery, Brigham and Women’s Hospital; the Departments of Adult Oncology and Pediatric Oncology, Dana-Farber Cancer Institute, and the Departments of Pathology, Surgery, Pediatrics, and Medicine, Harvard Medical School, Boston, MA.

Address reprint requests to Samuel Singer, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, M607, 1275 York Ave, New York, NY 10021; email: singers{at}mskcc.org

PURPOSE: Previous studies have reported clinical correlates for KIT mutations in GISTs, but in most of those studies the KIT mutations were found in less than 50% of the GISTs. The aim of this study was to evaluate the prognostic relevance for KIT mutations in a series of GISTs in which the mutations were evaluated intensively by genomic and cDNA sequencing.

PATIENTS AND METHODS: A comprehensive clinical and pathologic analysis of 48 patients with GISTs who had snap-frozen tissue was performed. The median tumor size was 10 cm (range, 2 to 30 cm). Median follow-up for disease-free patients was 48 months. KIT genomic and cDNA was sequenced by using nucleic acid templates isolated from frozen tumors.

RESULTS: The overall 5-year recurrence-free survival was 41% ± 6%. Five-year recurrence-free survival for patients with tumors that had mitotic counts of three mitoses or fewer per 30 high-power fields (HPF), more than three to 15 mitoses per 30 HPF, and more than 15 mitoses per 30 HPF were 89% ± 7%, 49% ± 12%, and 16% ± 6%, respectively (P = .0001). The 32 patients with spindle-cell histology had a 49% ± 7% 5-year recurrence-free survival; in contrast, the 16 patients with epithelioid or mixed histology had a 23% ± 11% 5-year recurrence-free survival (P = .01). Five-year recurrence-free survival for patients with tumors less than 5 cm, 5 to 10 cm, and more than 10 cm were 82% ± 12%, 45% ± 9%, and 27% ± 8%, respectively (P = .03). Prognostic associations were found with particular KIT mutation types, and patients with missense exon 11 mutations had a 5-year recurrence-free survival of 89% ± 11% compared with 40% ± 8% for GISTs with other mutation types (P = .03). The independent predictors for disease-free survival were the presence of deletion/insertion exon 11 mutations (hazard ratio [HR] = 4; P = .006), more than 15 mitoses per 30 HPF (HR = 18; P = .0001), mixed histology (HR = 21; P = .0001), and male sex (HR = 3; P = .05).

CONCLUSION: In this series of KIT-expressing GISTs, tumor mitotic activity and histologic subtype were the most important prognostic features. The majority of GISTs contain KIT-activating mutations with the type/location of mutation serving as an independent predictor for disease-free survival. These results suggest that KIT mutation and activation are important in GIST pathogenesis and also may provide important prognostic information.

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