In the present study, we observed that in addition to the well-established T and N stages, BMI was independent risk factor for the prognosis of resectable gastric cancer. The result showed overweight/obesity was a protective factor for the prognosis of patients with gastric cancer. Subsequently, the adipose tissue distribution analysis showed that VAT was negatively correlated with the prognosis of gastric cancer, while SAT was positively correlated with the prognosis of gastric cancer. Moreover, the VAT/SAT ratio was an independent risk factor for the prognosis of gastric cancer. To the best of our knowledge, this is the first study documenting how different types of body adipose tissue distribution differentially influence the prognosis of patients with gastric cancer.
Meanwhile, our study showed that overweight/obese patients (BMI ≥ 25 kg/m2) had a better prognosis than non-overweight/obese patients (BMI < 25 kg/m2) with gastric cancer. This phenomenon has been reported in some previous studies, although the sample size was small in those retrospective studies . However, a randomized controlled trial from Korea demonstrated that BMI was not associated with the prognosis of gastric cancer . Only 136 patients were included in the trial, including 27 obese cases, and the small sample size may be one of the reasons for the lack of statistically significant difference in the results. Meanwhile, Rodrigues reported that obesity was not associated with gastric cancer prognosis in the Western population, although the obesity threshold was BMI = 30 kg/m2 in the study . It is noteworthy that there are several differences in the study of gastric cancer between Eastern and Western countries. Firstly, compared with Western countries, Asian countries had a high incidence of gastric cancer, especially in China . Secondly, in Rodrigues’ study, obese gastric cancer patients in China accounted for less than 20% of the total number of cases but over 60% accounted for Western obese gastric cancer patients, which may be the reason for the inconsistent results . Although the mechanism by which obesity improves the prognosis of gastric cancer is vague, it has been reported that obesity can be used as a prognostic biomarker for immunotherapy of some cancers [28, 29]. In a small subset of patients, obese patients demonstrated better immunotherapy outcomes than non-obese patients. Obese patients also have better physical and nutritional status than non-obese patients [30, 31]. As a result, obese patients are more likely to receive adjuvant treatment, including chemotherapy, which may improve prognosis.
Obese patients may also have tumors that are sensitive to chemotherapy. Campbell et al. found that overweight and obese patients were more likely to have microsatellite instability-stable and low-microsatellite instability tumors than normal-weight patients in colorectal cancer . Evidence suggests that microsatellite instability-stable and low-microsatellite instability tumors are more susceptible to fluorouracil treatment than high-microsatellite instability tumors . This information may support the protective effect observed in overweight/obese patients. Therefore, the effect of obesity on cancer is complex and seemingly paradoxical. Most studies may use BMI to define overweight/obesity, which does not reflect adipose tissue distribution.
We further investigated the correlation between adipose tissue distribution and the prognosis of gastric cancer. The adipose tissue distribution was still associated with gastric cancer prognosis after adjusting for BMI. Consistent with our results, previous reports have shown the negative effect of visceral fat on the prognosis of cancer patients [11, 19]. Similarly, Dong et al. included over 1000 cases of gastric cancer and showed that low subcutaneous fat was a risk factor for the prognosis of gastric cancer, including overall survival and disease-free survival . However, some studies have suggested that visceral fat is not associated with the prognosis of gastrointestinal tumors. These studies had a sample size of less than 100 and most patients had received neoadjuvant chemotherapy [35–37]. Neoadjuvant chemotherapy may affect the judgment of the influence of adipose tissue on the prognosis of gastric cancer. Similarly, an observational study of 447 gastrointestinal tumors showed that pretreatment of subcutaneous adiposity was not associated with the prognosis of esophageal and gastric cancer . The study was limited in that it included only 65 cases of gastric cancer and did not perform a subgroup analysis of gastric cancer patients. A randomized controlled trial showed that preoperative visceral fat and subcutaneous fat areas were not associated with the prognosis of gastric cancer, although it had a small sample size . Conversely, Feng believed that low visceral fat was an independent risk factor for the prognosis of gastric cancer; however, only 46 cases of metastatic gastric cancer patients without surgery were included in the study . Therefore, these conclusions warrant further investigation.
VAT is an important metabolic tissue that secretes factors that systemically alter the immunologic, metabolic, and endocrine milieu. Excess VAT promotes chronic systemic inflammation with associated insulin resistance and dysmetabolism . Therefore, we further analyzed VAT and inflammatory markers and the results showed that there was an association between the two. However, there was still a correlation between VAT and the prognosis of gastric cancer after adjusting inflammatory markers, suggesting that there could be other mechanisms by which VAT affects the prognosis of gastric cancer.
Furthermore, early studies suggested that patients with differentiated early gastric cancer had higher subcutaneous fat and visceral fat content than those with undifferentiated early gastric cancer and the researchers speculated that lower fat content was conducive to the occurrence and development of undifferentiated gastric cancer . Recently, visceral fat has been implicated in the promotion of carcinogenesis and cancer progression through several pathways, including adipocytokine-related inflammation and insulin resistance. The latter is associated with disturbances in insulin-like growth factor-1 (IGF-1) and hypoxia . Adipocytokines secreted by visceral adiposity attract inflammatory cells, particularly macrophages and T cells, which produce cytokines, such as the tumor necrosis factor-α and interleukin-6, thereby creating a proinflammatory, insulin-resistant, protumorigenic environment. Excess visceral fat decreases adiponectin. Adiponectin inhibits the proliferation, angiogenesis, and inflammatory properties of tumor cells and promotes their apoptosis . It also induces chronic hyperinsulinemia followed by insulin resistance, which reduces the expression of IGF-binding protein, subsequently increasing IGF-1 expression. IGF-1 has protumorigenic properties and is linked to increased malignancy and progression of several gastrointestinal malignancies .
Other studies reported that the VAT/SAT ratio is associated with surgical site infections in patients with gastric cancer . Subcutaneous fat is associated with a postoperative incisional hernia for gastric cancer . Higher visceral fat was associated with higher postoperative complications of gastric cancer . However, there is growing evidence that postoperative complications are associated with the long-term prognosis of gastric cancer. A possible explanation is that cell-mediated immunity is compromised by surgical stress and excessive catecholamine and prostaglandin responses adversely affect the immune system, contributing to metastatic progression and worse survival outcomes .
Finally, we grouped patients with resectable gastric cancer using the VAT/SAT ratio and BMI as stratification factors. The results showed that overweight/obese patients with a low VAT/SAT ratio had the best prognosis, although only six cases were involved. In contrast, non-overweight/obese patients with a high VAT/SAT ratio had the worst prognosis. The latter accounted for the highest percentage of the entire cohort. Therefore, we believe that besides BMI, the adipose tissue distribution should also be considered during preoperative evaluation of gastric cancer patients.
This study comprehensively elaborated on the influence of different adipose tissue distribution on the prognosis of gastric cancer. We believe that BMI is a prognostic factor and VAT and SAT have different effects on the prognosis of gastric cancer. However, this study has some shortcomings. First, we did not subdivide overweight/obese patients into subgroups according to severity of obesity, such as super-obese patients. However, super obesity is rare in patients with gastric cancer, especially in Asian populations. Secondly, because data on changes in adipose tissue distribution after surgery are not available, we did not analyze the changes in adipose tissue distribution after surgery and their association with prognosis, which merit further exploration. Finally, due to the initial stage of relevant research, the threshold value was not uniformly standardized. However, our method to establish an optimal cutoff value is adopted by most of the current studies. Further research is warranted to verify our conclusions.