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Significance of Primary Malignant Tumors on the Outcome of Patients With Resected Gastrointestinal Stromal Tumors

Aim: This study aimed to clarify the significance of primary malignant tumors for the outcome of resected gastrointestinal stromal tumors (GISTs). Patients and Methods: The medical history, pathological findings and prognosis of 66 patients with GISTs resected at our institute between January 2003 and December 2018 were investigated retrospectively and compared statistically. Results: Among 66 patients with GISTs, 24 (36%) had concomitant malignant tumors. In an average study period of 57 months, one patient died from GIST, seven from other malignant tumors, and one from another disease. Only coexistence of GIST and other malignant tumors was recognized as a prognostic factor. Increasing age was significantly correlated with other malignant tumor in combination with GIST. When comparing patients with GIST alone and GIST with other malignant tumors, the latter showed significantly poorer prognosis. Conclusion: Coexistence of other malignant tumors was commonly observed in patients with GIST, and was associated with poorer prognosis. This association should be carefully considered and monitored in patients with GISTs.

recurrence, one of whom underwent resection of recurrent intra-abdominal tumors twice, administered imatinib mesylate, and survived for 13 years without GIST recurrence. Another patient underwent a hepatectomy for liver metastases at 3 years and 6 months after gastrectomy and died of GIST 3 months after the hepatectomy. The GISTs were located in the stomach in 88%, intestine in 8%, peritoneum in 2%, rectum in 2% and duodenum in 2%. The tumor sizes ranged from 5 to 165 (average=51.4) mm. Among the 66 patients, 24 (36%) were diagnosed as having 29 other malignant tumors, including three patients with two other malignant tumors and one patient with three other malignant tumors. The incidence rates of other malignant tumors were 17% for those located in the stomach, 11% for the colorectum and anus, 5% for the liver (cholangiocellular carcinoma, 3%; hepatocellular carcinoma, 2%), 3% for the bladder, and 2% each for the esophagus, larynx, breast, prostate, ureter, ovary, and lung. Among the patients with both GISTs and other malignant tumor, eight cases had already been detected before the GIST treatment, 11 had been detected simultaneously, and nine had been detected after the GIST treatment. Among the 11 patients with simultaneous detection of GISTs and other malignant tumors, six had gastric cancer and one had esophageal cancer. Among the seven resected GISTs with gastric or esophageal cancer at the same time, three were not diagnosed preoperatively, and the average tumor diameter was small (16 mm). For the seven patients who died of malignant tumor other than GISTs, four died of stomach cancer and three of liver cancer. For the patients with GIST without other malignancies, one died of their disease at 3 years and 9 months postoperatively.
To investigate the prognoses of patients with GIST, patient age, gender, tumor diameter, mitotic rate, Miettinen risk    classification, TNM classification, and coexistence of other malignant tumors were investigated (Table II). In the prognostic evaluation based on survival analysis using prognostic factors for GIST, no significant difference was observed in age, gender, tumor diameter, mitotic rate, and risk classification; only the coexistence of other malignant tumor showed a statistically significant association with poorer survival. Differences between patients with GISTs with and without other malignant tumors are shown in Table III. The average age was significantly higher for the patients with other malignant tumors than those without. The tumor diameter, gender ratio and Miettinen GIST classification did not differ between the groups.
Twenty patients treated with imatinib mesylate after GIST resection had been followed up for an average of 1,425 days, and 46 patients not treated with imatinib mesylate had been followed up for an average of 1,855 days. The average age, gender, and GIST classification stages of both groups did not significantly differ (data not shown). The incidence of other malignant tumors after GIST resection also did not significantly differ between those receiving imatinib mesylate (2/20) and those not (7/46) (p=0.576).
A comparison between survival curves of patients with GIST alone and those with other malignant tumors is shown in Figure 1. Patients with GIST alone appeared to have a significantly superior disease-free survival.

Discussion
This study enrolled 66 patients with GIST who were treated surgically. A high incidence (36%) of coexistence of GISTs with other malignant tumors was observed. On comparing patients with GISTs with and without other malignant tumors, the former were found to be older and have significantly worse prognoses but no differences in GIST staging were observed between the groups.
Many cases of GIST with other malignant tumors have been reported. The incidence rate of additional malignancies ranges from 4.5 to 43% (5)(6)(7)(8)(9)(10)(15)(16)(17). In a recent large-scale study, the occurrence of secondary tumors was reported to be increasing because older patients were expected to develop malignancies; indeed, 25.2% of older adults (aged ≥65 years) newly diagnosed with cancer had a history of prior cancer (18). In the current study, the mean age at the time of GIST surgery was 65.8 years. The frequency of GIST with other malignant tumors (36%) was considered high, although the frequency was different from the evaluation method in the previous study. Moreover, the number of GIST cases coexisting with other malignant tumors was considered to be increased due to the extended follow-up period.
Others have investigated the type and chronology of other malignant tumors in relation to GIST (6,7,9). No clear trends have been established but many GIST cases coexisted with gastric cancer. A report demonstrated that GISTs were present with high frequency (35%) in the resected stomach of patients with gastric cancer (19). The size of GIST malignancies simultaneously resected with other malignancies tended to be small and the grade low (20). Therefore, pathological examination of surgical specimens from gastric cancer surgery may find GIST and increase the number of patients with GIST. Reports on GISTs simultaneous with other gastrointestinal cancer types have revealed worse prognosis than that of GIST alone (21,22).
GISTs commonly activate the mutations of the gene encoding KIT proto-oncogene, receptor tyrosine kinase (KIT). Although hereditary GIST syndrome has been reported (23,24), the frequency of occurrence is low. Some reports also revealed that specific genetic abnormalities occurred when neurofibromatosis type 1 or neuroendocrine tumor merged with GIST (25,26). No mutational correlation was reported between GISTs and the coexistence of tumors of different histogenesis regarding KIT and platelet-derived growth factor receptor alpha genes (27). Thus, further genetic research is expected.
In the current study, the mortality rate of patients with GIST was very low. GIST prognosis is determined by metastasis, tumor size, number of mitoses, and degree of risk (12). According to the therapeutic guidelines, the ratio of low-risk patients increases with the increasing resection of smaller and less malignant GISTs. A good prognosis is observed after surgery for those with low-risk GISTs (28). In the current study, three patients were classified as risk class IV according to the TNM classification, of whom only one died. The other two patients survived for a long period due to multidisciplinary treatment. The proportion of patients in the high-risk group was extremely low; therefore, we consider that the prognostic outcome of GIST itself was not reflected in the prognostic determination and instead was influenced by other factors. In the current study, the prognosis of GIST tended to be determined by the other malignant tumors that coexisted with GIST.
The prognosis of GIST is improved by tumor resection and adjuvant drug therapy (imatinib mesylate administration) (29,30). Improvement of the prognosis in the high-risk patients is likely to have been due to treatment with imatinib mesylate. Guiliani et al. showed an increase in secondary malignancies after treatment of GISTs with imatinib mesylate, which suggested that the prognosis was extended because of imatinib mesylate administration (31). The low occurrence of secondary malignancies after imatinib mesylate administration in the current study may be due to the short follow-up period.
Based on the above considerations, we believe that the coexistence of other malignant tumors negatively influences the prognosis of patients with GIST. Therefore, a stricter follow-up for other malignancies should be conducted in patients with GIST because of their long-term survival and the fact that prognosis seems to be adversely affected by the coexistence of other malignant tumors.

Conclusion
Co-existence of GIST and other malignant tumors is often observed and seems to adversely affect the outcome of GIST.

Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.