Furthermore, mutational analysis probably has more clinical significance in therapeutic aspect as it has predictive value for sensitivity to molecular-targeted therapy (including dosage) and prognostic value. It is strongly recommended that it should be included in the diagnostic work-up of all GISTs (135). The correlation between KIT and PDGFRA mutational status and the response to tyrosine Inhibitors,research,lifescience,medical kinase inhibitors and their

role in primary and secondary resistance has been widely investigated (31,136). Tumors harboring KIT exon 11 mutations have a better outcome under imatinib treatment than tumors harboring different mutation, whereas tumors with PDGFRA exon 18 mutations (D842V) have primary resistance to imatinib both in vivo and in vitro (27,71,137). Therefore, GIST mutational analysis is strongly recommended in current NCCN (National Comprehensive Cancer Network) clinical practice guidelines (Figure 6) and in ESMO (European Society for Medical Oncology) clinical recommendations (138,139). Inhibitors,research,lifescience,medical Table 2 Molecular classification of GISTs (134)* Figure 6 NCCN Guidelines Version 1.2012, Gastrointestinal

Stromal Tumors (GIST) (Abbreviations: H&P, history & physical Inhibitors,research,lifescience,medical examination; Mets, metastatic disease; IM, imatinib; Preop, preoperative; DX, diagnosis; SU; sunitinib; mo, month; y, year) Prognostic factors, grade and stage The risk of relapse of GISTs is Inhibitors,research,lifescience,medical estimated based on mitotic rate, tumor size, tumor site, surgical margins and the status of tumor rupture. Tumor size and mitotic count are considered to be the most useful and best studied prognostic factors by the 2002 Consensus risk classification (Table 3) (99). It is believed that indicating a risk level of GIST (low, intermediate, or high) is more appropriate than definitively labeling the tumor as Tubacin manufacturer benign or malignant. This risk classification was based on the cumulative experience of

the authors in the committee. The most important cut-offs Inhibitors,research,lifescience,medical as indicators of aggressive clinical behavior were tumor size of 5 cm and 5 mitoses/50 HPF. This consensus guideline indicated that all GISTs may have malignant potential (99). Based on long-term selleck follow-up of more than 1,600 GISTs (1,055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal), Miettinen Batimastat and colleagues proposed risk classification incorporates primary tumor site in addition to the mitotic count and tumor size (Table 4) (140). It demonstrates the fact that gastric GISTs have a better prognosis than small intestine or rectal GISTs. The more recently updated consensus NCCN guidelines from 2007 (141) includes anatomic site as an additional parameter in risk assessment for GIST. Based on those guidelines, GISTs that are smaller than 2 cm are considered to be essentially benign.