Gastric gastrointestinal stromal tumors: therapeutic strategies and long-term prognosis

Abstract Objectives This study aimed to evaluate the clinical and prognostic characteristics of primary gastric gastrointestinal stromal tumors (GIST). Methods Patients who underwent resection for primary gastric GIST between January 2002 and December 2017 were included. Recurrence-free survival (RFS) was calculated by Kaplan–Meier analysis, and Cox proportional hazards model was used to identify independent prognostic factors. Results Altogether, 653 patients were enrolled. The median patient age was 59 years (range 15-86 years). Open, laparoscopic, and endoscopic resections were performed in 394 (60.3%), 105 (16.1%), and 154 (23.6%) patients, respectively. According to the modified NIH consensus classification, 132 (20.2%), 245 (37.5%), 166 (25.4%), and 88 (13.5%) patients were categorized into very low-, low-, intermediate-, and high-risk, respectively. A total of 136 (20.8%) patients received adjuvant imatinib treatment. The median follow-up time was 78 months (range 4–219 months), and the estimated 5-year RFS rate was 93.0%. In all patients, tumor size and rupture, mitotic counts, and adjuvant imatinib treatment were independent prognostic factors. The prognosis of gastric GIST treated with endoscopic resection was not significantly different from that of laparoscopic or open resection after adjusting for covariates using propensity score matching (log-rank p = .558). Adjuvant imatinib treatment (HR = 0.151, 95%CI 0.055–0.417, p < .001) was a favorable prognostic factor for high-risk patients, but was not associated with prognosis in intermediate-risk patients. Conclusion Patients with small gastric GISTs who successfully underwent endoscopic resection may have a favorable prognosis. Adjuvant imatinib treatment improve the prognosis of high-risk gastric GISTs, however, its use in intermediate-risk patients remains controversial.


Introduction
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive system and have varying levels of potential malignancy [1].Approximately 50-60% of GISTs originate from the stomach, and the most common location of GISTs is the body of the stomach (42-75%) [2][3][4].Patients with gastric GISTs may have different symptoms such as gastrointestinal bleeding, satiety, abdominal pain, belching, or fatigue [3][4][5].Gastric GISTs commonly occur in patients aged between 55 and 65 years of age, and there is no difference in the prevalence between men and women [5][6][7].
Surgical resection with negative margins (R0 resection) is the preferred treatment for primary GISTs.Generally, open resection (OR) is the most common treatment for GISTs.Wedge resection without lymph node dissection is appropriate for most cases of gastric GISTs.In recent years, laparoscopic resection (LR) and endoscopic resection (ER) have been used for gastric GISTs with relatively small tumor size and favorable anatomic locations [8].
A population-based cohort study reported that approximately 30% of patients experienced recurrence in the first five years after complete resection of GISTs [2], and the 5-year recurrence-free survival (RFS) rate for gastric GISTs after surgery was 74-92% [9,10].In comparison to GISTs originating from other sites, gastric GISTs with the same pathological features tend to have a lower risk of recurrence after surgery [10].According to current clinical guidelines, adjuvant treatment with imatinib for 1-year is recommended for intermediate-risk GISTs, and for at least 3-year for high-risk GISTs [8,11].However, whether adjuvant imatinib treatment should be recommended for intermediate-risk gastric GISTs is controversial [12].In addition, large scale clinical studies have seldom investigated the prognosis of patients with gastric GISTs.In this study, we analyzed the clinicopathological data of patients who underwent curative-intent resection for gastric GISTs to evaluate their clinical and prognostic features.

Patients
Clinical data of patients who underwent resection for primary gastric GISTs at the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou), China between January 2002 and December 2017 were reviewed retrospectively.Pathological diagnosis of GIST was made based on a combination of histopathological evaluation and immunohistochemistry (IHC) staining for CD117 and/or DOG-1.Data on sex, age, clinical symptoms, tumor size, mitotic count, tumor necrosis, tumor rupture, treatment approach, and adjuvant imatinib treatment were collected.The recurrence risk assessment of gastric GISTs was based on the modified National Institute of Health (NIH) consensus classification [13].
The inclusion criteria were as follows: (1) any age; (2) curative resection (including OR, LR, and ER) for primary gastric GISTs; (3) Eastern Cooperative Oncology Group (ECOG) performance status score 2 or less; (4) survival for > 1 month after surgery.Patients with metastatic disease or other malignant tumors were excluded from the study.Patients with a history of pre-operative targeted therapy or radiotherapy were also excluded.
This study was approved by the Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University, China.All procedures were conducted in accordance with the principles of the Declaration of Helsinki.

Follow-up
All patients were followed up every 3-6 months for 1-2 years, every 6-12 months for 3-5 years, and then annually after 5 years.The follow-up included a combination of laboratory tests, radiographic imaging (computed tomography or magnetic resonance imaging), or gastrointestinal endoscopy if necessary.The median duration of follow-up was 78 months (range 4-219 months), and the latest follow-up was recorded on December 31, 2020.

Statistics
The chi-square test or the Fisher exact test was used to analyze categorical variables.The ANOVA test was used to compare differences in continuous variables.RFS was defined as the time from resection to tumor recurrence or death (regardless of the cause), whichever occurred first.Patients who were alive and free of tumor recurrence in December 2020 were censored from the RFS analysis.Survival curves were analyzed using the Kaplan-Meier method, and compared using the log-rank test.The Cox proportional hazard model was used to determine the independent prognostic factors for RFS.All results were two-sided, and p < .05 was considered as statistically significant.All statistical analyses were performed using SPSS software version 19.0Windows (IBM, Armonk, New York, USA).
One-to-one propensity score matching (PSM) was performed to eliminate unbalanced distributions of covariates between patients who underwent ER and those who underwent LR/OR.Because most patients (152/154, 98.7%) underwent ER between January 2013 and December 2017, a synchronous PSM was conducted.Six covariates (age, sex, tumor size, mitotic count, tumor necrosis, and adjuvant imatinib treatment) were included.PSM was conducted using R software, version 3.6.2based on logistic regression of the propensity score, with a caliper value of 0.02.

Survival analysis
There were 23 (3.5%) patients who were lost to follow-up.Of the 53 patients who experienced the events, 31 were diagnosed with GIST recurrences or metastasis.The most common site of recurrence was the liver (n = 17), followed by the peritoneum (n = 14).
For patients with very low-, low-, intermediate-, and high-risk gastric GIST, the estimated 5-year RFS rates were 96.6%, 95.8%,  96.8%, and 71.1%, respectively.No significant difference was observed very low-, low-or intermediate-risk gastric GIST, whereas the prognosis for high-risk GIST was significantly worse than that for the other risk categories (Figure 3(E)).For very low-, low-and intermediate-risk gastric GIST, survival analysis did not reveal any factors associated with RFS.Additionally, imatinib adjuvant treatment was not an independent prognostic factor for intermediate-risk gastric GISTs (log-rank p = .188,Figure 4(B)).

Discussion
Gastric GIST has a favorable prognosis compared to GISTs in other locations.In this retrospective analysis of 653 patients with primary gastric GISTs, the estimated 5-year RFS was 93.0%, and the independent prognostic factors included tumor rupture, tumor tumor mitotic counts, and adjuvant imatinib treatment.The long-term prognosis of patients with small tumor size who received ER successfully was comparable to those received OR/LR in the present study.A total of 136 (20.8%) patients received adjuvant imatinib treatment, and survival analysis revealed that postoperative imatinib treatment could improve the prognosis of high-risk gastric GISTs.In recent years, the application of laparoscopic or endoscopic resection has expanded to become an acceptable alternative to laparotomy for gastric GISTs originating from favorable anatomical sites, especially the body of the stomach.Some studies concluded that laparoscopic surgery is not inferior to laparotomy for gastric GISTs [3].Moreover, laparoscopic surgery has been proven to have advantages in short-term outcomes, such as blood loss, time to flatus, and postoperative hospitalization [5].The European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend ER as an alternative to LR for intraluminal gastric GIST <3.5 cm in size [14].Another study concluded that endoscopic resection of gastric GISTs up to 5 cm in size by a trained endoscopist may be a safe and feasible option.[15].A Meta-analysis also reported no differences in short-term outcomes between ER and LR [16].However, there is a risk of conversion of minimally invasive treatment to laparotomy due to perforation, bleeding, technical difficulties or other reasons.According to Kim's classification of gastric GIST, type-III (tumor in the middle of the gastric wall) and type-IV (tumor protruding mainly into the serosal side of the gastric wall) tumors have a higher incidence of stomach perforation during ER [17][18][19].The incidence of stomach perforation was higher at the fundus than at any other location [20].The conversion rate from ER to LR/ OR was 6.7%, and from LR to OR was 7.1% in this study, which is comparable to that reported in previous studies [21][22][23].Furthermore, long-term survival analysis revealed no significant difference between the ER and LR/OR groups after PSM in the present study (Figure 2(B)).In consideration of the surgical conversion risk, it is necessary to conduct further research to explore the indications of ER for gastric GIST, though small size with a favorable anatomic location were considered suitable cases by some studies.
Tumor size, mitotic count, location, and tumor rupture are independent prognostic factors for GISTs [7,9].A modified NIH consensus classification system was established using the above parameters, and GISTs were classified as very low-, low-, intermediate, and high-risk postoperatively.In this study, tumor size, mitotic count, and tumor rupture were also associated with the prognosis of gastric GISTs (Table 3).However, subgroup analysis showed that these factors were not associated with the prognosis of very low-, low-, or intermediate-risk gastric GISTs, which may be attributed to the low recurrence rate.In addition to these prognostic factors, other clinicopathological characteristics have also been proven to be associated with prognosis, including tumor necrosis, Ki-67, diffuse moderate atypia, tumor ulceration, and mucosal invasion.Tumor necrosis is defined as a distinct type of cell death associated with abnormal processes, including exposure to toxins, infections, ischemia, and trauma [24,25].Previous studies have demonstrated that tumor necrosis is associated with the prognosis of GISTs.A longterm follow-up study concluded that tumor necrosis was associated with a poor prognosis in the small intestine [24].Another study that included 740 gastric GISTs also found tumor necrosis to be an independent prognostic indicator for high-risk patients [25], which was consistent with the results of our study.
Commonly, at least three years of adjuvant imatinib treatment is recommended for high-risk GISTs.The present study confirms these findings (Figure 4(D)).However, there is controversy regarding the adjuvant treatment of intermediate-risk GISTs, which may be associated with the different risk classifications.Currently, the most frequently used classifications are the Armed Forces Institute of Pathology (AFIP) and modified NIH classifications.The European Society of Medical Oncology (ESMO) guidelines recommend that the low/intermediate-risk patients should be followed up according to the AFIP classification [13].The Chinese consensus recommended 3-year adjuvant imatinib treatment for intermediaterisk non-gastric GISTs, and 1-year for intermediate-risk gastric GIST according to the modified NIH classification.Long-term follow-up of the EORTC-62024 study revealed that 2 years of adjuvant imatinib treatment did not improve the prognosis of low/intermediate-risk patients [26].Another retrospective study in China showed that adjuvant imatinib treatment significantly improved the prognosis of non-gastric GIST, but not of gastric GIST.In our study, approximately half the patients with intermediate-risk gastric GISTs received adjuvant imatinib treatment.However, survival analysis showed no significant difference in RFS for intermediate-risk patients, which was similar to the results of the two studies mentioned above.
This study has some limitations.First, as a retrospective study, it was subject to inevitable information and selection bias.Second, genetic mutations of tumors were not studied for all patients, and the relationship between KIT/PDGFRA genotypes and prognosis could not be investigated.

Conclusions
Patients with small tumor size who successfully underwent endoscopic resection achieved a favorable prognosis, but the indications should be further investigated.Adjuvant imatinib treatment could significantly improve the prognosis of high-risk gastric GISTs, however this remains controversial in intermediate-risk patients.Multicenter randomized controlled studies are warranted to investigate the effectiveness of adjuvant imatinib treatment for intermediate-risk gastric GISTs.

Figure 1 .
Figure 1.Study flow chart of patients diagnosed with primary gastric gastrointestinal stromal tumor (GiSt).

Figure 4 .
Figure 4. Survival analysis of recurrence-free survival for patients received imatinib adjuvant treatment.(a) all of the patients (log-rank test p = .103);(B) intermediate-risk patients (log-rank test p = .188);(c) high-risk patients (log-rank test p = .001);(d) high-risk patients with different durations of imatinib adjuvant treatment (log-rank test p = .005).

Table 1 .
clinical characteristics and pathological outcomes of patients underwent sugery for gastric GiSt.
HPf: high power field; niH: national institution of Health; na: not available.

Table 2 .
the demographic and clinicopathological characteristics after PSM (Jan 2013 to dec 2017).

Table 3 .
univariate and multivariate analysis of disease-free survival for overall patients.

Table 4 .
univariate and multivariate analysis of disease-free survival for high-risk patients.Hr: hazard ratio; ci: confidence interval; HPf: high power field.