NENs is a type of digestive system tumor with different clinical symptoms and biological characteristics. It is important to identify patients with different prognoses according to their clinical and pathological conditions to provide individualized treatment to improve the efficacy of g-NENs treatments. However, there are still few studies evaluating the prognostic factors in g-NENs patients[8, 9]. Recently, the influence of preoperative body composition parameters (such as skeletal muscle mass) on postoperative short-term and long-term outcomes has attracted the attention of scholars in the east and the west. Sarcopenia is characterized by a progressive decline in systemic muscle mass, muscle strength, or muscle physiological function associated with aging. At present, several studies have shown that sarcopenia is closely related to the prognosis of various malignant tumors[10–16]. However, the effect of sarcopenia on the prognosis of g-NENs patients undergoing radical gastrectomy has not been reported. Therefore, this study combined the clinicopathological data of 138 patients from two institutions to explore the effect of sarcopenia on the short-term and long-term postoperative outcomes of g-NENs patients.
Based on the definition of sarcopenia of the European Working Group on Sarcopenia (EWGSOP) and the Asian Working Group for Sarcopenia (AWGS), sarcopenia is diagnosed with low skeletal muscle mass, low muscle strength and poor low physical performance. However, in the current research, low skeletal muscle mass is mostly used as the definition of sarcopenia. A meta-analysis to explore the relationship between sarcopenia and the risk of postoperative complications of gastrointestinal tumors included a total of 29 studies related to sarcopenia, of which 26 used low skeletal muscle mass as the definition of sarcopenia. In both eastern[10, 11] and western[15, 21, 29] studies, researchers tend to use low skeletal muscle mass as the definition of sarcopenia. And the data of the patient's muscle mass can be obtained by analyzing the abdominal CT scan. Abdominal CT scan is also a routine follow-up item for patients with g-NENs after radical gastrectomy. Using low skeletal muscle mass as the definition of sarcopenia can help clinicians to make treatment decisions more conveniently and quickly.
At present, the value of the cutoff point of sarcopenia is still controversial. The most commonly used definitions were defined by Prado et al. and Martin et al.. In the past, our center used x-tile software to analyze the 3-year OS rates of 924 patients with gastric adenocarcinoma after R0 resection and defined sarcopenia as a SMI < 32.5 cm2/m2 for males and a SMI < 28.6 cm2/m2 for females. However, when previous definitions were applied, we found that only those of Martin et al. could obtain the prevalence of sarcopenia similar to those in the previous studies (Supplementary Table 3). Therefore, we included the cutoff point defined by Martin et al. in the analysis. The Kaplan-Meier analysis, Cox regression analysis indicated that the cutoff points defined by Martin et al. could not serve as prognostic factors for g-NENs patients in our study (Tables 3, 4, Supplemental Table 2, Supplementary Fig. 3). Therefore, this study used x-tile software to analyze the 3-year OS rates of 138 g-NENs patients from the two institutions and defined a SMI < 44.3 cm2/m2 for males and a SMI < 32.4 cm2/m2 for females as sarcopenia, and the incidence of sarcopenia in our study was 42.8% (59/138). There’s no significance survival difference in female group (Supplementary Fig. 2), maybe it's because the proportion of female patients in this study is relatively small (33/138 cases, 23.9%). But in the previous studies of sarcopenia, different values of the cutoff point of sarcopenia are usually used in male and female groups[14, 15, 29, 31]. This is mainly because there are great differences in the strength and quality of skeletal muscle between male and female groups. And in this study, compared the average SMI in male and female g-NENs cohort, there was a significant difference in the average value of SMI between male and female groups (45.2 cm2/m2 in male, 37.5 cm2/m2 in female, p < 0.05). Therefore, in order to better evaluate the effect of sarcopenia on the prognosis of g-NENs patients, we used different diagnostic criteria for men and women in this study.
The effect of sarcopenia on short-term postoperative outcomes in patients with malignant tumors is still controversial. Previous studies have confirmed that sarcopenia is associated postoperative short-term prognosis in patients with multiple malignant tumors[11, 13, 15, 32]. In a Chinese study, analysis of 937 patients with gastric cancer after radical gastrectomy showed that sarcopenia was related to severe postoperative complications. An American study showed that sarcopenia was associated with the short-term outcomes in patients with pancreatic cancer after pancreatectomy. However, some studies have indicated opposite opinions[31, 33]. Tegels' study showed that although the incidence of sarcopenia was high in patients with gastric cancer, it was not associated with a poor postoperative prognosis. Ouchi's study showed that sarcopenia did not increase the incidence of total and severe postoperative complications in patients with colorectal cancer. In this study, there was no significant difference in the incidence of total postoperative complications, surgical complications and systemic complications between the g-NENs patients with and without sarcopenia. According to the physical location of the complications, the results showed that there was no significant correlation between sarcopenia and specific types of complications in patients with g-NENs.
In recent years, studies have confirmed that sarcopenia is closely related to the long-term prognosis of patients with multiple malignant tumors[10, 12, 14, 16]. Studies by Voron have shown that sarcopenia is an independent prognostic factor for long-term outcomes in patients with hepatocellular carcinoma after hepatectomy. Tan's study suggested that sarcopenia was associated with poor prognosis of pancreatic cancer patients. Similar to previous studies, our study showed that preoperative sarcopenia was an independent risk factor for the long-term prognosis of g-NENs patients. For this result, we have examined the interaction between sarcopenia and the gastrectomy status and tumor aggressiveness. There was no significant difference in surgical methods, laparoscopic gastrectomy extent and pathological stage between the sarcopenia group and the nonsarcopenia group (Table 1). Multivariate analysis showed that pN stage and sarcopenia were independent prognostic factors of 3-year OS and RFS rates in g-NENs patients, while surgical methods, laparoscopic gastrectomy extent and pT stage were not (Table 3). And The HR value of sarcopenia changed little between univariate and multivariate analysis in our study (Table 3). This shows that the prognostic effect of preoperative sarcopenia is less affected by the gastrectomy status and tumor aggressiveness in g-NENs patients. However, g-NENs can be divided into three different pathological types, namely, gNET, gNEC, and gMANEC. The degree of tumor differentiation, grade level, and cell components of three pathological types are not the same, and the treatment strategy and prognosis also show significant differences with different pathological types[34, 35]. In this study, a further stratified analysis showed that sarcopenia was related to the 3-year OS and RFS rates in patients with gMANEC. In view of this result, we think it may be related to the following reasons. First, for the subgroup of the gNET population, gNET is a highly differentiated neuroendocrine tumor, of mostly low or moderate malignancy, presenting as G1 and G2. The lower tumor invasiveness and the lower effect on skeletal muscle mass may be the reason why sarcopenia cannot be used as a prognostic factor for gNET patinets. Second, compared with gNEC and gMANEC, gNEC is a poorly differentiated neuroendocrine carcinoma, which is mostly highly malignant and manifests as G3. GMANEC is defined as a malignant tumor with morphological components of glandular epithelial cells and neuroendocrine cells, both of which account for at least more than 30%. Previous studies have shown that the clinical characteristics of gMANEC largely depend on the proportion of neuroendocrine carcinoma components[36, 37]. Fernandes et al. believe that the prognosis of gMANEC might be related to whether certain tumor components are more invasive. Furthermore, previous studies have confirmed that sarcopenia is associated with the long-term prognosis of gastric adenocarcinoma patients[10, 11]. Therefore, we think that the mechanism may be influenced by the presence of more adenocarcinoma components in gMANEC, then sarcopenia is only related to the long-term prognosis of gMANEC patients and has nothing to do with the prognosis of gNET and gNEC patients in this study. The underlying molecular mechanism needs to be further elucidated.
This study had some limitations. First, because most gNET patients received endoscopic treatment, the number of gNET patinets in this study was limited, which may cause bias. Second, this study is a retrospective case-control study conducted in an Asian population, the results of which need to be confirmed by prospective studies and data from western regions. Third, the proportion of female patients in this study is relatively small (33/138 cases, 23.9%), so the prognostic effect of sarcopenia on female g-NENs patients needs to be further tested by a larger population study, and we will conduct related studies in the future. Fourth, this study did not analyze the effect of postoperative adjuvant chemotherapy and the effect postoperative sarcopenia caused by the gastrectomy status and tumor aggressiveness on long-term outcome, which may also bias the results. Nevertheless, as far as we know, this study is the first to explore the effect of sarcopenia on the short-term and long-term outcomes in patients with g-NENs by using data from two independent large-volume institutions, thus providing a reference for future clinical trials.