Metastatic pattern and prognosis of gastrointestinal stromal tumor (GIST): a SEER-based analysis

The results showed that the rate of metastasis to liver, bone and lung were 9.19, 0.47, and 0.76%, respectively. The rate of liver metastasis in our study was not as high as that of some previous studies, which was 20–25% at diagnosis of GIST [25]. Similarly, the rate of bone metastasis was also lower than 3.2–5.5% of some studies reported [3, 16]. As for lung metastasis, only some sporadic cases of GIST with lung metastasis were reported and Nilsson et al. [26] had reported that only one out of 259 patients (0.39%) with GIST developed lung metastasis. Such differences between our results and previous studies might be related to the sample size and potential bias. However, the rate of liver metastasis was still much higher than the other two sites, in which case some appropriate modalities like MRI to examine the liver lesions should be recommended as a routine [20]. Moreover, although it is conventionally acknowledged that gastrointestinal tumors can metastasize to liver via portal vein most commonly and they can also metastasize to other sites like lung or bone directly or indirectly via blood or lymph system, our results showed that there were not significant differences of risks of bone or lung metastasis between patients with and without liver metastasis, which suggested that liver metastasis and bone or lung metastasis might be the independent events to each other. So, considering such low metastasis rate and irrelativity to liver metastasis, it is unnecessary to regard screening bone or lung metastasis status as a routine.

Our results showed that men had a higher risk of liver metastasis than women, which is in accordance with the previous studies that showed GIST had a mild male predominance [25, 34]. GIST in different sites could have different incidence [10], which might account for the differences of risks in liver and lung metastasis. For the tumor grade, the majority of GIST appeared not to be well differentiated [22, 32], so the percentage of poorly differentiated (13.9%) and undifferentiated (16.2%) GIST patients with liver metastasis in our study were also much higher than that of well (1.8%) and moderately (4.5%) differentiated ones. Besides, T stage was also a significant factor for the risk of metastasis. Several previous studies had reported that tumors with the size of> 5 cm had more possibility to metastasize [6, 13, 23]. So, we compared the tumors of T3 (5–10 cm) and T4 (> 10 cm) with tumors of T0, T1 (< 2 cm), and T2 (2–5 cm) and we found that it was more likely for tumors of> 5 cm than < 5 cm to metastasize only in liver (10.4% vs 2.9%, P < 0.001) but not in bone (0.4% vs 0.2%, P = 0.279) or lung (0.7% vs 0.3%, P = 0.070). Although some researches also recommended the tumor size of 2 cm as a cutoff point for screening the possibility of metastasis [12], our study also proved that only liver metastasis had significant evidence, but not the other two sites. Moreover, it was accessible that patients in N1 stage and patients who did not receive surgery both had a significantly high percentage of metastasis. Therefore, sex, tumor site, tumor grade, tumor size, regional lymph node metastatic condition and surgery were all the risk factors of metastasis.

The median overall survival time of GIST without metastasis was more than 60 months and patients without metastasis survived longer than those with liver, bone, or lung metastasis, which suggested that GIST with metastasis had a poorer prognosis. However, except for liver and lung metastasis, patients with metastasis of liver and bone or with metastasis of all the three sites did not show a significantly worse overall survival than the patients with only liver metastasis. So, the results indicated that liver metastasis might be more significant for the prognosis of GIST than metastasis of the other two sites and the lesions in the liver of GIST patients should be paid more attention.

Since liver metastasis was the most common type of metastasis pattern in GIST patients, we analyzed the relative prognostic factors and our multivariate analysis resulted showed that < 65 years old, female, married patients, and patients who received surgery might have a better prognosis for GIST with liver metastasis. The poorer prognosis in elder patients might be related to combination with other diseases or reception of less treatment due to higher possibilities of drug side-effects [5, 11]. The relationship between sex and prognosis was not clear, but might be correlated with more psychological distress in male patients [14]. Our results showed that married status might be a beneficial prognostic factor, which was in accordance with the studies of Song et al. [30] and Chen et al. [7]. The protective function of married status might be related to less psychological burden, earlier diagnosis, better compliance to prescription and even more financial support, etc.[2, 14, 15, 27] It had also been proved that surgery could improve overall survival in GIST patients with metastasis [4, 9, 28]. Interestingly, T stage (especially T3, T4), namely tumor size, was the significant prognostic factor in the univariate analysis (5-year OS T3 vs T4: 61.8% vs 39.0%, P = 0.011). It had also been reported in previous studies that the tumor size of > 5 cm was the poor prognostic factor and even tumor size of > 10 cm meant worse survival [8, 23, 24]. However, our multivariate analysis results showed that tumor size was not a significant prognostic factor in the GISTs with liver metastasis. We guessed it might be related to the following reasons: (1) the larger the tumor size was, the easier the tumor could be detected and the earlier the patients could receive treatment; (2) the larger tumor had a higher risk of metastasis and patients needed to receive other adjuvant therapy like imatinib, a TKI inhibitor [36]; (3) the larger tumor need more extensive resections [21], in which case the tumor might be resected more thoroughly.

To our best knowledge, it is the first study to excavate the metastatic pattern of GIST based on SEER database. However, there are also some limitations existing in our study. First, the number of patients of bone or lung metastasis was too small, so the insufficient sample size might lead to large bias and unconvincing results. Second, this study is a kind of retrospective study which might have selection bias because not all the GIST patients had routine tests for metastasis, under which circumstance the incidence of metastasis might be underestimated. Finally, although there were studies that reported that KIT mutation-positive and DOG1-negative cases indicated a tendency of higher rate of tumor metastasis [17, 19] and no relationship was found between PDGFRA mutation and metastasis [19], the SEER database did not provide such information about the status of KIT, DOG1, and PDGFRA, which are all the important immunohistochemical markers for GIST diagnosis and prognosis. Anyway, regardless of these limitations, it is the first study to discuss the potential relationship of liver metastasis and bone or lung metastasis and it also provide possible elements to estimate survival from external and macroscopic aspect in the population. We wish our study could be helpful for clinical diagnosis and treatment of GIST.