Why We Still Need the Better Risk Classification for GIST

Abstract

The fundamental treatment for primary, localized, resectable gastrointestinal stromal tumors (GIST) is radical resection with negative margins. Nonetheless, virtually all GISTs are associated with some risk of recurrence. The identification of the risk factors for relapse after primary surgery is essential to establish a reliable prognosis and follow-up schedule, and the most importantly, to select the patients who may potentially benefit from the adjuvant therapy, aiming for a decrease in disease recurrences. Currently, the main criteria for aggressiveness in GIST are based on primary tumor site, size and mitotic index (localized tumors) as well as the presence of metastases (overtly malignant cases). The staging system of the American Joint Committee on Cancer (AJCC) combines three crucial features (i.e., size, site, and mitotic index) and reflects the data showing that gastric GISTs demonstrate a much lower rate of aggressive behavior than jejunal and ileal GISTs of comparable size, mitotic rate, or both. More recently, tumor rupture (spontaneous or iatrogenic) was established as an additional important risk factor strongly associated with the increased rates of relapses and was included in the modified National Institutes of Health criteria by Joensuu in 2008. Moreover, prognostic contour maps developed on non-linear modeling may be more appropriate for estimation of individualized outcomes. In addition to these aforementioned clinicopathologic factors, accumulating data show that KIT and PDGFRA mutational status also may have a prognostic importance in primary GIST. However, the kinase mutation status still is not incorporated into the risk stratification of primary tumors. Several studies have implied more favorable behavior after resection of primary tumors harboring exon 11 KIT point mutations or insertions and PDGFRA exon 18 mutations compared with tumors carrying exon 9 KIT duplications and exon 11 KIT deletions, especially those involving codons 557 and/or 558 or those in homozygous state. Recent extended analysis of clinicopathologic and molecular data from 1844 patients with localized GIST who underwent surgery with curative-intent (R0/R1) and were registered in the European ConticaGIST database confirmed that specific tumor genotype (KIT exon 11 deletions involving Trp557/Lys558, including p.Trp557_Lys558del and KIT exon 9 duplications) is an independent molecular prognostic variable associated with GIST of gastric origin and should be included in prognostic classification to optimize adjuvant imatinib treatment of primary GIST patients. Population-based series of patients after resection of primary GIST have confirmed a more favorable prognosis for PDGFRA mutations and KIT exon 11 duplication mutation or deletion of one codon. In the current Annals of Surgical Oncology, Hølmebakk et al. reports a retrospective study that analyzed a population-based cohort of 295 patients with primary gastric GIST and found a correlation of mutational status with anatomic distribution of tumor in the stomach. Specifically, the authors detected that PDGFRA-mutated tumors were located mainly in the lower two thirds of the stomach, in contrast to KIT-mutated GIST located in the upper part. Moreover, deletions 557 and 558 in the KIT gene are located in high prevalence in the upper part. This has clinical relevance because in this study, more than 90 % of the tumors located in the upper third of the stomach carried imatinib-sensitive mutations. On the other hand, they were related to a higher risk or recurrence than tumors in the Society of Surgical Oncology 2021