There are other biological factors that are currently used in the diagnosis of GISTs, whose prognostic role could be investigated, since only initial studies have been published at the moment. Some of them are as follows: phosphorylated form of histone 3 (PHH3), DOG-1, ETV1, and Ki 67. Immunohistochemistry for the PHH3, which is present during early prophase, has been shown to be a reliable mitosis-specific marker. There is a tendency to undergrade GISTs based on H&E compared with PHH3, which alters the stage, risk of disease progression, and treatment recommendations. PHH3 cutoff value of seven mitoses or higher was associated with worse OS.40 DOG1 (discovered on GIST-1) shows a higher sensitivity as a diagnostic marker than KIT. Patients with a strong DOG1 expression, tumor size ≥5 cm, and mutations of KIT or PDGFRA had a worse prognosis. On the contrary, DOG1-negative patients have a more favorable postoperative 2-year RFS rate.41 ETV1, a member of the ETS family, is upregulated in GISTs, and its signaling is integrated into a cellular signaling network for resistance to apoptosis, tumor cell invasion, and survival. ETV1 was strongly expressed in the GISTs, which can aid in the diagnosis of GISTs particularly when KIT is negative in the high-risk group. The prognostic significance is still controversial.42 Ki67 is a good marker of cell proliferation in a variety of tumors. There is a greater rate of Ki67 overexpression in NIH-intermediate and NIH-high GIST risk groups. Ki67 expression may be an effective complement to the NIH criteria for predicting the risk of malignant GIST, especially for intermediate- and high-risk cases.43 Cancer-associated inflammation is shown to promote tumor progression and metastases via suppressing antitumor immunity, and it is closely related to various stages of tumor development. There is a significant association between low hemoglobin (Hb) levels, an elevated white blood cell (WBC) count, neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), and decreased OS. Low hemoglobin level, an elevated WBC, as well as an elevated NLR, dNLR, and platelet/lymphocyte ratio (PLR) are parameters that were significantly associated with poor RFS. Of all the studied variables, only elevated dNLR was associated with a higher risk of local or distant recurrence after adjusting for Miettinen score. The association between NLR and PLR with disease progression was independent of the Miettinen score, but the inclusion of these variables did not improve the clinical risk prediction of 2-year disease progression and death. This finding indicates that NLR and PLR are independent prognostic variables for RFS, but their impact on improving prognostication in surgical-treated GIST patients appears to be limited.44 However, in patients receiving adjuvant imatinib, peripheral blood counts did not show any prognostic significance. Preoperative NLR is a feasible and reproducible peripheral biomarker that helps identify patients for intensive adjuvant therapy and frequent surveillance.45 Molecular stratification may support the clinician in decision-making for adjuvant therapy, particularly for intermediate-risk GIST, where the presence of unfavorable mutations may tip the scales on the side of adjuvant therapy.

Surgery

Surgery is the main treatment for primary GIST with no evidence of metastasis. The standard is complete surgical excision, avoiding tumor rupture, with no dissection of clinically negative lymph nodes.18 Nowadays, laparoscopy is increasingly used in surgery for its well-known advantages: earlier patient recovery, reduction of hospitalization, and better esthetic/cosmetic results. Laparoscopic approach is more often applied to treat GIST, and its feasibility has been demonstrated in several studies. This technique must also respect the principles of oncological radicality, in particular, avoiding the rupture of the tumor mass. For this reason, both NCCN and ESMO guidelines recommend an open approach in case of large GIST (>5 cm) or if the tumor is difficult to access. On the other hand, for gastric GIST, there are several groups that have gone beyond the size limit imposed by the guidelines to verify the consequences also in prognostic terms. For these tumors, a wedge resection should be performed, when it is possible. Hsiao et al showed that the laparoscopic approach is feasible for tumors up to 8 cm in diameter with an acceptable operative and oncological outcome after an intermediate follow-up. However, they emphasize how the gastric location of the tumor is an important factor to be evaluated, considering some gastric sites such as the cardias, the small gastric curve, or prepyloric area could be more challenging for a laparoscopic resection.46 Lin et al analyzed 23 patients with tumor >5 cm in diameter treated by laparoscopic resection and were randomly matched (1:1) by tumor size (±1 cm) to patients with open resection. They demonstrated that laparoscopic resection of gastric GISTs up to 10 cm results in operative durations, morbidity, and outcomes that are similar to those of open resection but is associated with shorter hospital stays, and that tumor location is clearly an important factor in the selection of an operative approach. They suggested a neoadjuvant treatment with imatinib to prevent the risks of rupture or bleeding of the tumor during the resection.47 Piessen et al showed that overall morbidity, surgical morbidity, and medical morbidity were significantly lower in laparoscopic group. Five-year RFS was also significantly better in this group. Patients with gastric GISTs >5 cm had hospital morbidity and 5-year RFS similar to the open group.48

In conclusion, 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 tumors localized in reachable sites. Obviously, radicality must be respected: when the rupture or the bleeding of the mass becomes an issue, an open approach should be advocated to prevent any spillage of the tumor.

Imatinib

Imatinib, a TKI, is now recommended as an adjuvant or supportive therapy in patients with high risk and advanced/unresectable disease. There are many prognostic score systems to evaluate recurrence risk. The NCCN considers prognostic factors as tumor size, mitotic rate, and tumor site. Joensuu et al developed two risk stratification scores to predict GIST recurrence in patients treated with adjuvant imatinib therapy.49 A risk score was generated using five independent factors associated with favorable RFS: low tumor mitotic count (with central assessment), location in the stomach, adjuvant imatinib for 36 months, small tumor size, and absence of rupture. Another risk score included two factors that were most strongly associated with RFS: tumor mitotic count assessed centrally and tumor site. Both scores generated were effective in stratifying the risk of GIST recurrence in patient populations treated with adjuvant imatinib. GISTs with high mitotic count arising at nongastric sites recur frequently despite adjuvant imatinib, and some of such tumors recur even when the patient is on imatinib suggesting that more efficient treatments need to be pursued. Despite guidelines recommendations and the various prognostic scores, there is a sample of patients who still do not receive an appropriate treatment. Bischof et al considered all patients who underwent surgery for primary GIST in USA and Canada between January 2009 and December 2012. They found that following surgery, 23% of patients were undertreated and 2% of patients were overtreated, when compared with NCCN guidelines. They tried to identify the clinicopathologic predictors of treatment with adjuvant imatinib following surgical resection of GIST. Tumor size, mitotic rate, and neoadjuvant imatinib therapy were associated with receipt of adjuvant imatinib therapy. Interestingly, tumor site was not associated with receipt of adjuvant imatinib therapy. The reasons for undertreatment of these patients remain unclear.50 Guérin et al attempted to determine the extent of physician underestimation of risk of recurrence after complete primary GIST resection. Findings suggest that borderline measures were more difficult to categorize, and some physicians might not adequately take into account tumor location. High-risk tumors of intermediate-level tumor size, intermediate-level mitotic count, and nongastric GIST location were frequently underestimated. High-risk patients were more likely to have a planned adjuvant therapy duration of <3 years after resection if their recurrence risk was underestimated compared with patients whose risk was not underestimated. Planned adjuvant therapy duration of <3 years was associated with reduced RFS.51 Another important problem is about duration of adjuvant imatinib therapy. In the ACOSOG Z9001 study, Dematteo et al demonstrated that 400 mg of daily imatinib for 1 year following surgery improved RFS in patients with GIST at least 3 cm in size compared with placebo alone.52 In the SSGXVIII/AIO trial, Joensuu et al found that 3 years of adjuvant imatinib was associated with improved RFS and OS compared with 1 year of adjuvant imatinib in patients with high-risk GIST (tumor size >10 cm, mitotic rate >10 mitoses per 50 HPF, tumor diameter >5 cm, and mitotic rate >5 mitoses/50 HPF, or tumor rupture).53 Currently, ESMO and NCCN guidelines recommend 3 years of adjuvant imatinib for high-risk GIST.18,19 In their review, Trent and Subramanian confirmed that adjuvant imatinib therapy for at least 3 years can be recommended for patients who have an intermediate or high risk of GIST recurrence.54 However, the optimal duration of therapy, and whether high-risk patients should use adjuvant imatinib continuously, remain unknown. Risk of recurrence should be assessed using accepted risk assessment criteria, based on tumor size and MI, to appropriately identify which patients are at greatest risk and are most likely to benefit from adjuvant imatinib therapy following surgical resection. Other factors such as GISTs mutational status, tumor location, and tumor rupture can add prognostic value. Lin et al suggest that patients with high-risk GIST should receive imatinib treatment for at least 5 years following surgical resection. They observed how the recurrence rate increased when imatinib treatment was stopped, arriving almost at the same rate of patients who did not receive any therapy. So, the question is does adjuvant imatinib therapy only delay the patients’ relapse? The result showed that the RFS of patients with high-risk GIST increased significantly due to the prolongation of medication time.55 In their intergroup randomized trial of adjuvant imatinib vs no further therapy after surgery, Casali et al analyzed imatinib failure-free survival (IFFS). They found that the trend of IFFS in the adjuvant arm at least suggested that exposure to imatinib in the adjuvant setting did not induce a selection pressure toward secondary resistance, at least within the time interval that adjuvant imatinib was administered in this study (2 years). A crucial finding is that adjuvant imatinib therapy does not seem to cure minimum residual disease in patients with resected GIST. In fact, they observed how stopping adjuvant therapy is followed by relapse in at least most patients expected to experience relapse in the absence of any adjuvant therapy.56 Of course, the most logical consequence for clinical research is the attempt to prolong treatment duration. Other trials are necessary to rule out a detrimental effect of long-lasting adjuvant treatment in terms of an earlier incidence of secondary resistance. Maybe, new strategies of administering targeted therapies will be more effective possibly guided by molecular biomarkers during treatment. In a recent study, Joensuu found a correlation between the duration of adjuvant imatinib and KIT deletion mutations. The adverse prognostic influence of some frequent mutations, such as deletion mutations that involve KIT exon 11 codons 557 and/or 558, was no longer detectable in patients treated with adjuvant imatinib for 3 years. Tumor mutation analysis aids in the selection of patients for adjuvant imatinib treatment because patients with KIT deletion mutations benefit more from 3 years of adjuvant imatinib than patients with other mutations.57

Small GIST

GISTs <2 cm are defined as small GISTs. Often, they are incidental findings during procedures for other diseases. Based on the AFIP risk criteria, there is a “very low, if any malignant potential” for all gastric tumors <2 cm with an MI <5, while “high malignant potential” is attributed to all rectal GISTs with an MI >5, irrespective of the size. The category of small GIST includes the so-called microGIST, which are lesions with a size ≤1 cm, considered mostly self-limiting and with no malignant potential.58,59 With the exception of microGIST, the natural course of small GIST in general is not well defined. Compared with larger GISTs, GISTs <2 cm have a lower frequency of mutations overall and particularly of KIT exon 11 mutations, while carrying a higher fraction of rare/novel mutations, likely of low pathogenic potential.60 However, most of the data on small GIST are limited to pathological analyses and autopsy studies. Coe et al published the first population-based analysis of malignant GIST <2 cm throughout the gastrointestinal (GI) tract and identified a mortality risk that has been underappreciated by gastroenterologists, surgeons, and oncologists.61 In fact, they found that the 5-year GIST-specific mortality rate was 12.9%. Furthermore, 11% of patients with GIST <2 cm had regional or distant metastases. However, this study does not include undiagnosed or asymptomatic tumors. Therefore, the described rates are specific to small GISTs that are coded as malignant and have been histologically evaluated following biopsy or resection, likely overestimating the GIST-specific mortality of all small GISTs. Furthermore, no information on the molecular characteristics of the cases is provided, and possibly the series includes cases that are pathogenetically heterogeneous. The treatment of these tumors is still debated. Surgery could be an overtreatment, especially in elderly patients with gastric small GISTs. On the other hand, there is a risk of underestimating these tumors. The NCCN recommends resection for all GISTs ≥20 mm; no clear statement is made regarding incidentally encountered small GISTs (<20 mm) due to the insufficient data. Complete surgical resection is suggested for those gastric GISTs having high-risk endoscopic ultrasonography (EUS) features, and endoscopic surveillance at 6–12 months intervals for the lesions without high-risk features.19 ESMO guidelines suggest control at short term (eg, at 3 months) and then to prolong the follow-up intervals in case of no growth for small lesions, if follow-up strategy is the preferred choice.18Japanese guidelines state that lesions <20 mm in size and without ulceration or surface depression can be followed up endoscopically once or twice a year.62 In a recent review, Nishida et al63 proposed an algorithm to guide diagnostic and treatment strategies for patients with small GISTs (Figure 5).

They considered the following as high-risk features: the presence of symptoms, irregular borders, cystic spaces, ulceration, echogenic foci, internal heterogeneity, tumor progression during follow-up, small intestinal or colorectal localization.63 EUS surveillance is recommended to measure the exact dimensions and to provide information on any change to high-risk sonographic features related to the increased likelihood of malignant behavior. These high-risk EUS features suspicious of malignancy for GISTs were defined as larger size, irregular borders, heterogeneous echo patterns, presence of anechoic spaces, and echogenic foci.64,65 In most cases, EUS findings allow only a presumptive diagnosis and determine the need for further explorations such as tissue sampling, surgery, or follow-up. A tissue diagnosis with EUS-guided fine-needle aspiration (EUS-FNA) is generally performed, but it provides inadequate material in up to 33.3% of the cases. Even in the case of a GIST diagnosis accomplished by EUS-FNA, evaluation of the malignant potential of the tumor based on the MI may not be possible due to the lack of sufficient material as required for prompt investigation.66 Therefore, even for the small GIST, the site of origin is an important prognostic factor. Other risk factors are the presence of symptoms, ultrasound features, and growth during follow-up.