Abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Significant prognostic heterogeneity has been described with GISTs, which can range from clinically benign to frankly malignant tumors. Although several GISTs classification systems have been established to identify tumors with high risk of relapse, there is a sample of patients who still do not receive an appropriate treatment. The classification scores by Fletcher et al and Miettinen and Lasota are the most widely clinically accepted, while the Memorial Sloan Kettering Cancer Center prognostic nomogram is considered the most feasible. There are several studies about new prognostic factors in radiological, biological, and surgical fields. Tumors with mixed growth pattern, enlarged vessels feeding, or draining the mass on computed tomography or with high standardized uptake values on positron emission tomography/computed tomography should be considered as high-grade GISTs. Among biological markers, the most relevant are programmed cell death ligand 1, Pfetin, SETD2, SLITRK3, mir-215-5p, and monoglyceride lipase. These factors need to be further investigated in order to validate their use in risk stratification. Laparoscopy and open surgery can have the same oncological outcomes even for larger gastric tumors, up to 10 cm. Laparoscopy should be considered the best surgical approach when executed by skilled surgeons and for tumor localized in reachable sites. Adjuvant chemotherapy with imatinib is recommended for high-grade GIST, but the optimal duration of this therapy is still debated. Some authors advocated that imatinib treatment should last for 5 years. A subgroup of GIST is represented by small GISTs, lesions <2 cm in diameter, which need a radical surgical treatment in the presence of symptoms or when high-risk factors such as irregular borders, cystic spaces, ulceration, echogenic foci, internal heterogeneity, tumor progression during follow-up, small intestinal or colorectal localization are present.
Keywords: GIST, classification, prognostic factors, treatment, imatinib, small GIST
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract (80%), but they represent only 1% of all gastrointestinal tumors. Their incidence is around 1/1,00,000/year.1 The neoplastic GIST cells arise from a common precursor of the interstitial cells of Cajal in the normal myenteric plexus.2 The transformation of these cells is caused by activating mutations of KIT gene (about 75%) and less commonly PDGFRA (10%–15%). These genes encode receptor tyrosin kinases (TK), and their constitutive activation brings uncontrolled cell replication. Imatinib is a low-molecular weight TK inhibitor (TKI) that blocks the kinase activity of both KIT and PDGFRA.3 There is a small fraction of GIST, about 10%–15%, which does not bear any mutation in these genes, so-called wild-type GIST. This group is heterogeneous and includes two main subgroups: GIST characterized by inactivation of any of the components of the mitochondrial succinate dehydrogenase (SDH) complex which are essentially all gastric and NF1-inactivated GIST, mostly nongastric. Notably, SDH-inactivated GIST and NF1-inactivated GIST are typically associated with syndromic conditions, that is, Carney Stratakis syndrome and neurofibromatosis type 1, respectively, but may also occur in an apparently sporadic context.4–7 Also belonging to the “wild-type” group are very rare GIST cases bearing activating mutations in BRAF, and GIST carrying gene fusions, for example, ETV6-NTRK3.8–10 In general, “wild-type” GISTs are poorly responsive to imatinib and may require alternative strategies, for example, sunitinib and regorafenib for SDH-inactivated GIST, dabrafenib for BRAF-mutated GIST, and inhibitors of TRK for GIST bearing ETV6-NTRK3.11,12 GISTs most commonly arise from the stomach (50%–60%) and small bowel (30%–35%) and less frequently arise from the colon–rectum (5%) and the esophagus (<1%).13 They may also arise at extra gastrointestinal sites such as the omentum or mesentery.14 Significant prognostic heterogeneity has been described with GISTs, which can range from clinically benign to frankly malignant tumors.15,16The standard treatment for localized primary GIST is complete surgical resection with clear margins. Nonetheless, the risk of recurrence remains even after complete resection.17 Imatinib is now recommended as adjuvant or supportive therapy in patients with high risk and advanced/unresectable disease by the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guidelines. They recommend the adjuvant use of TKI for patients with “a significant risk of relapse”, particularly those with high-risk tumors, and also for tumors with intermediate risk up to 3 years.18,19 Therefore, there is a clinical need for a more reliable risk classification system that is simple to apply and able to stratify more precisely high-risk, low-risk, and very-low-risk patients for progression of disease. We focus on which is the most reliable classification in risk stratification and which could be the new prognostic factors.
Several GISTs classification systems have been established to identify tumors with high grade of relapse, which may benefit from adjuvant chemotherapy. In 2002, Fletcher et al20 proposed the National Institute of Health (NIH) classification for defining the risk of aggressive behavior in GISTs. They divided GISTs into four groups with high, intermediate, low, and very low risk of progression, thereby excluding a benign category (Figure 1).
This classification is based on tumor size and mitotic count in 50 high power fields (HPF).20 In 2006, Miettinen et al15 analyzed 1,756 GISTs of the stomach and 906 GISTs of the small intestine in their work and published a new classification, also termed as the Armed Forces Institute of Pathology (AFIP) classification. Besides tumor size and mitotic count, this classification also takes into account the anatomic site of the primary tumor. Gastric GISTs show a much lower rate of aggressive behavior than comparable intestinal GISTs. Furthermore, they fixed a specific area of 5 mm2 for mitotic counting. Miettinen and Lasota established five risk groups, with eight subgroups, considering a benign class of tumor.15 The main difference between AFIP and NIH classifications is the importance given to the localization of the tumor. In 2007, Huang et al reevaluated NIH consensus criteria in 289 cases. They found no significant differences between the very low and the low risk groups, and they have been merged into a Level I risk group. Therefore, they included only GIST with size >5 cm and >10 mitoses per 50 HPFs into Level IV, because of prognostic heterogeneity in the high-risk category of NIH scheme.16 In 2008, Joensuu et al3 proposed the “modified NIH classification” in which they introduced the tumor rupture as a prognostic factor (Figure 2).
Furthermore, they suggested a new modified high-risk group that would include all patients designated as high risk by the NIH classification and, in addition, patients with nongastric tumors 2–5 cm and >5 mitoses per 50 HPFs, or 5–10 cm and ≤5 mitoses per 50 HPFs, and all patients with tumor rupture into the abdominal cavity regardless of tumor size or mitotic count.3 In 2009, the Memorial Sloan Kettering Cancer Center (MSKCC) developed a prognostic nomogram: it is based on three factors score (size, site, and mitotic index [MI]), and the sum of the three scores corresponds to a prediction of 2- and 5-year recurrence-free survival (RFS) after surgical resection of a localized primary GIST21 (Figure 3).