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

• Published in: Journal of clinical oncology Vol. 20; no. 18; pp. 3898 - 3905
• Main Authors: SINGER, Samuel, RUBIN, Brian P, LUX, Marcia L, CHEN, Chang-Jie, DEMETRI, George D, FLETCHER, Christopher D. M, FLETCHER, Jonathan A
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 15.09.2002; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Disease-Free Survival; DNA Mutational Analysis; DNA, Complementary - metabolism; DNA, Neoplasm; Exons; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Humans; Male; Medical sciences; Middle Aged; Mitotic Index; Mutation; Neoplasm Recurrence, Local; Prognosis; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Sequence Deletion; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Stromal Cells - metabolism; Stromal Cells - pathology; Survival Rate; Tumors; Human; Prognosis; Mitosis; Malignant tumor; Gastrointestinal; Pathology; Histopathology; C-Onc gene; Histological type; Digestive diseases; Genetics; Intestinal disease; Mutation; Stromal tumor; Protooncogene; Gastric disease
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2002.03.095

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. 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. 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 <or= 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). 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.