Sarcopenia is defined as decreased muscle mass, quality, and strength in elderly people (1) and is closely associated with frailty syndrome in the elderly (2). As early as 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) first advocated the diagnostic criteria of age-related sarcopenia (3), after which sarcopenia has aroused great concern, especially in cancer patients. Current research on the link between cancer and sarcopenia has focused on (1) the prevalence of sarcopenia in different cancers (4); (2) the predictive role of preoperative sarcopenia or postoperative sarcopenia in cancer prognosis (5); (3) radiotherapy-induced sarcopenia (6, 7); (4) the effect of sarcopenia treatment, such as exercise, nutrition, or medication intervention, on the prognosis or complications of cancers (8, 9); (5) the effect of sarcopenia on chemotherapy-related toxicity (10, 11); and (6) the potential mechanism of cancer-associated sarcopenia (12).

Gastric cancer (GC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in China according to the latest epidemiological data (13). Surgical resection has been, without doubt, the most effective therapy for potentially curable GC we have had so far (14). As a previous report, the prevalence of sarcopenia in GC was 32.05%, which is the lowest one in digestive cancers (15–20), but higher than age-related sarcopenia (8.2% for men and 6.8% for women) based on EWGSOP algorithm (21). However, to date, there are no internationally accepted diagnostic criteria for sarcopenia in cancer patients. All the diagnoses concerning cancer-related sarcopenia are based on age-related sarcopenia established by EWGSOP or the Asian Working Group for Sarcopenia (22) or calculated by clinical data using statistical analysis (23, 24). Thus, current studies about the predictive value of sarcopenia in GC are still controversial.

Nowadays, several methods have been proposed for the assessment of muscle mass, including computed tomography (CT) scans, dual-energy X-ray absorptiometry (DXA), and bioelectrical impedance analysis (BIA). Among these, measurement of the cross-sectional muscle area at the level of the third lumbar vertebra (L3) on CT scans is the method that is used most commonly, since CT is a part of the routine staging process in cancer patients (25). In addition, muscle mass index (MMI) (16) which divides the patient’s muscle mass (kg/m²) or muscle area (cm²/m²) by the height squared is also widely used in the prognostic analysis of cancer.

Interestingly, a recent study from Korea suggested that the impact of postoperative muscle mass loss and surgery-induced sarcopenia on survival outcomes is dependent on sex. To be specified, the association between muscle mass and long-term survival was meaningful in men but not in women (26). Moreover, the amount and rate of muscle mass loss during aging also differ between men and women (27, 28), which suggests that we should consider the influence of sex factor when we investigate the relationship between sarcopenia-related factors and prognosis of GC. The reasons why gender influences prognosis may be complex, including gene expression (29), skeletal muscle kinetics, and fiber-type composition (30).

In this study, we present a retrospective investigation of the influence of sarcopenia on the prognoses of GC patients who underwent radical gastrectomy. In addition to the classic indicator L3 skeletal muscle index (L3 SMI), other indexes like visceral fat area (VFA), subcutaneous fat area (SFA), visceral fat index (VFI), subcutaneous fat index (SFI), subcutaneous and visceral ratio (SV), and skeletal muscle radiation attenuation (SM-RA) were also included in our study according to previous studies (31–35). Moreover, we further evaluated potential sex differences in the relationship between sarcopenia and long-term survival.

In the present study, the prevalence of preoperative sarcopenia in patients with GC was 25.20% in men, which is dramatically lower than in women (30.40%). In terms of long-term outcomes, 5-year OS was significantly shorter in patients with sarcopenia. Moreover, in addition to indicators that evaluate the disease progression of cancer (pathological TNM, depth of invasion, lymph node metastasis, poor differentiation), preoperative sarcopenia (for men), decreased SMA (for men), SFA, SFI, SV (for women), and SM-RA (especially for men) were also significantly associated with lower 5-year OS in GC patients. Multivariate analysis revealed that pathological TNM, depth of invasion, poor differentiation, and SM-RA were independent prognostic factors for patients with GC who underwent radical gastrectomy. Notably, the present study demonstrated the predictive effect of sarcopenia on survival outcomes is depended on sex.

Although previous studies came to heterogeneous conclusions, sarcopenia was generally identified as an independent prognostic factor for a poor OS of GC. In a retrospective study, CT-determined sarcopenia was reported to be an independent prognostic factor for patients with advanced GC who underwent palliative chemotherapy in Korea (16). In Japan, scholars also came to a similar conclusion that preoperative sarcopenia was related to poor survival in GC patients and appeared to be a significant negative prognostic factor in patients with GC who underwent curative resection (40). A cohort study from China also drew the similar conclusion that sarcopenia was an independent predictor of severe postoperative complications and long-term survival after radical gastrectomy (41). This conclusion is applicable to Western patients (42). Moreover, preoperative sarcopenia is also independently associated with severe postoperative complications in GC patients undergoing gastrectomy (43–46), and an independent prognostic factor for progression-free survival (PFS) in patients with microsatellite-stable (MSS) GC treated with programmed death-1 (PD-1) inhibitors (47). However, for patients with GC who received neoadjuvant chemotherapy, sarcopenia did not appear to impact the length of stay or survival (48). Similarly, in a study from the Netherlands, sarcopenia was not associated with postoperative morbidity or mortality in GC surgical patients (49).

The diagnostic criteria for sarcopenia remain controversial and the cutoff values used for defining sarcopenia were different between studies. In the studies described above, the Korean study defined sarcopenia as L3 SMI ≤ 49 cm²/m² for men and ≤ 31 cm²/m² for women using Korean-specific cutoff values (16). However, the diagnostic criteria for sarcopenia in the Japan study were defined as a decreased arm muscle area < 38.05 cm² in men and < 27.87 cm² in women combined with a decline in grip strength < 26 kgf in men and < 18 kgf in women (40). The cohort from China calculated the cutoff values of sarcopenia and classified L3 SMI as < 34.9 cm²/m² for women and < 40.8 cm²/m² for men (41). In our present study, we defined sex-specific L3 SMI-related mortality cutoff as 39.73 and 32.97 cm²/m² for men and women, respectively, which is consistent with previous studies, that cutoff values for L3 SMI to define sarcopenia in GC ranged from 32.5 to 54.5 cm²/m² in men and from 28.6 to 41.0 cm²/m² in women (14). More research is needed to obtain good reference values for various ethnic groups and cancer patients.

As we described before, both classic indicator L3 SMI and other indicators like fat area, including both fat area in visceral or subcutaneous, VFI, SFI, SV, and SM-RA, were taken into account in the present study. A recent study attempted to investigate more accurately predictive factors of postoperative complications or prognosis in patients with gastric cancer rather than sarcopenia defined by L3 SMI. The authors found that both psoas muscle mass index (PMI) and VFA were useful predictive factors for postoperative pneumonia and intra-abdominal abscess in patients with gastric cancer, but only PMI was a useful prognostic factor (34). Rinninella et al. assessed body composition changes of GC patients receiving the docetaxel (FLOT) regimen and reported that preoperative FLOT was associated with a further reduction in both SMI and VFI. However, these changes were not associated with short-term outcomes (32). Our study came to a similar conclusion that neither VFA nor VFI was associated with long-term results in patients with GC. Although visceral fat does not seem to affect the prognosis of GC patients, subcutaneous fat plays a role in GC prognosis according to our results. Furthermore, SFA, SFI, and SV in women are prognostic factors for the 5-year OS of GC patients who underwent radical gastrectomy. Similarly, a retrospective from Japan demonstrated that visceral-to-subcutaneous adipose tissue area ratio (VSR) was a prognostic factor for the overall survival of elderly patients with gastric cancer after gastrectomy (33). Moreover, reduced SM-RA is independently associated with postoperative outcomes in cancer patients (35, 50), which is consistent with our findings.

The influence of sex factor on the relationship between sarcopenia and the prognosis of cancer is an emerging field. Women exhibit higher global fat mass and reduced skeletal muscle mass (51). One reason for the sex difference might be the discrepancy in muscle and fat mass between men and women, since testosterone level which has an anabolic effect on the muscle is higher in men (29). Skeletal muscle fiber composition, myosin heavy chain expression, contractile function, and the regulation of these physiological differences by thyroid hormone, estrogen, and testosterone might also play important role in sex differences (30). Moreover, the absolute rate of decline in skeletal muscle mass was reported to be greater in men than women (27). Similarly, accumulating studies demonstrated that male cancer patients lost more body weight, muscle mass, and had higher rates of mortality compared with female patients (52, 53). A recent study demonstrated that surgery-induced sarcopenia was a risk factor for OS and relapse-free survival (RFS) in men only (26). Consistent with previous studies, our result also showed that sarcopenia was a risk factor for 5-year OS only in men. However, SFA, SFI, and SV in women were prognostic factors for the 5-year OS, and SFA was significantly associated with 5-year OS in GC patients after multivariable analysis in women rather than men. As previously mentioned, women are characterized by an increased propensity to store subcutaneous fat (51), which might partly explain why subcutaneous fat is more sensitive in women than men. Moreover, low SMI in men and high visceral-to-SFA ratio in women were good prognosticators for patients with colorectal cancer (54). We speculated that muscle reserves in men are more important than fat reserves for the pathological of cancer, which is different from women. However, the potential mechanism of this sex difference needs to be further studied.

One limitation of this study was that we were unable to collect information about muscle strength and physical performance since our study is a retrospective study. Similarly, no record of the height information of patients was found in the computerized database; thus, we have to use the height 1–5 obtained from CT scans instead. Lastly, the sample size is not large enough due to the high rate of lost follow-up. A prospective large cohort study is needed to verify the results.

Decreased L3 SMI and SM-RA were associated with increased mortality in patients with GC after radical gastrectomy. The impact of indexes investigated in our study on survival outcomes is dependent on sex. The association between sarcopenia, SMA, SM-RA, and long-term survival was meaningful in men but not in women. On the contrary, SFA, SFI, and SV were significantly associated with 5-year OS in GC patients in women rather than men. Further studies are needed to clarify the specific mechanisms of sex difference.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study.

TL, JG, and XY performed the material preparation, data collection, and analysis. MT, HL, and TL wrote the first draft of the manuscript. MT, TL, XY, and JG reviewed and edited the previous versions of the manuscript. JZ, FT, and KS verified the data and amended the manuscript. All authors contributed to the study conception and design, read, and approved the final manuscript.