Abstract
Background/Aim: Although cholesterol is an important indicator of nutritional status, it is also involved in cancer progression. In this study, we investigated the clinical significance of the dynamics of perioperative total cholesterol (T-Cho) levels in patients with gastric cancer (GC). Patients and Methods: A total of 212 patients with pathological stage II/III disease who underwent gastrectomy between 2004 and 2020 were enrolled in this retrospective study. The preoperative and postoperative serum T-Cho levels were measured in these patients. Results: Increased serum T-Cho levels were significantly correlated with low preoperative serum albumin levels (p<0.001). Patients with increased serum T-Cho levels after surgery had significantly lower overall and recurrence-free survival rates (p=0.030 and p=0.013, respectively; log-rank test). Cox proportional hazards model revealed that increased serum T-Cho levels (p=0.040), advanced pathological stage (p<0.001), and the provision of adjuvant chemotherapy (p=0.006) were independent prognostic factors for recurrence-free survival in patients with GC. Conclusion: Increased serum T-Cho levels after gastrectomy may be an independent prognostic factor in patients with GC.
Gastric cancer (GC) is one of the most commonly diagnosed cancers and the third leading cause of cancer-related mortality worldwide (1). Evaluation of nutritional status is essential in patients with GC, and nutrition is greatly involved in the maintenance of immune function and continuity of adjuvant chemotherapy (2, 3). Body mass index (BMI), albumin (Alb) levels, and prognostic nutritional index (PNI), which combines preoperative Alb and lymphocyte (Lym) count as an immune index, are generally used in clinical practice for nutritional evaluation (4-6). Total cholesterol (T-Cho) is an important nutritional indicator, and its usefulness as an immuno-nutritional indicator in the CONUT score, which combines preoperative T-Cho, Alb, and Lym, has also been reported (7, 8). It was previously reported that high preoperative T-Cho levels reflect a favorable prognosis in patients with GC (9).
While T-Cho is an important indicator of nutritional status, it also has other aspects, such as it being a metabolic regulator involved in cancer progression (10). In addition, lipid metabolism is affected by other endocrine diseases, and hypothyroidism caused by malnutrition may cause secondary dyslipidemia (11).
Gastrectomy for patients with GC significantly changes the patient’s bodily functions, including digestion, absorption, and glucose metabolism (12). Patients with GC who have undergone gastrectomy cannot avoid malnutrition, and postoperative weight loss rate reflects their prognosis (13). Postoperative weight loss rate and Alb levels are commonly used as postoperative nutritional indicators (13, 14). However, T-Cho is rarely used as a postoperative nutritional index, and the significance of the changes in perioperative T-Cho levels has not been clarified. We often observe a significant increase in serum T-Cho levels compared with preoperative serum T-Cho levels, despite the patient’s weight loss after gastrectomy. We hypothesized that assessing perioperative changes in serum T-Cho levels may be more than just a nutritional indicator, unlike the preoperative assessment of serum T-Cho levels. In the present study, we investigated the clinical significance of changes in perioperative T-Cho levels by measuring the preoperative and postoperative T-Cho levels in patients with GC who underwent gastrectomy.
Patients and Methods
Patients. This retrospective study enrolled 212 patients with pathological stage II/III GC who underwent gastrectomy at the University of Yamanashi Hospital between January 2004 and February 2020.
Preoperative diagnosis of gastric adenocarcinoma was confirmed by endoscopic biopsy. Gastrectomy and lymph node dissection were performed according to the Japanese Gastric Cancer Treatment Guidelines (15). Tumor stage was determined based on the 8th edition of the International Union Against Cancer (IUAC) tumor, node, metastasis (TNM) classification system (16). Macroscopic and histological types and lymphatic or venous invasions were classified based on the Japanese Classification of Gastric Carcinoma, 3rd edition (17). The patients were subsequently followed up every 3-6 months for the first 2 years after surgery, and follow-up was continued for at least 5 years. The follow-up evaluations consisted of physical examination, blood testing, computed tomography (CT), and gastroscopy. The presence of recurrence was confirmed by imaging, which generally involved CT. Recurrence was confirmed histologically, if possible, by surgical biopsy, needle biopsy, or appropriate fluid cytology. Clinicopathological features of each patient were retrieved from the hospital database. Perioperative serum cholesterol levels were also measured in these patients. Patients who did not undergo gastrectomy, those without their perioperative serum T-Cho levels measured, and those who received cholesterol-lowering medication were excluded. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1964 and its later versions. Informed consent was obtained from all the patients included in the study.
Evaluation of perioperative serum T-Cho levels. To define elevated T-Cho levels, we reviewed the preoperative serum T-Cho just before surgery and postoperative serum T-Cho a month after surgery in patients with GC who underwent gastrectomy. Based on the perioperative serum T-Cho results, we categorized the patients into two groups, the increased and decreased T-Cho groups.
Statistical analysis. Statistical analysis was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). Clinicopathological variables pertaining to the corresponding patients were analyzed using the χ2 test or Fisher’s exact test. Quantitative results are presented as mean±standard deviation (SD) and were evaluated using the Mann–Whitney U-test. For survival analysis, Kaplan–Meier survival curves were constructed for groups based on the predictors determined by univariate analysis, and differences between the groups were tested using the log-rank test. Univariate and multivariate survival analyses were performed using the likelihood ratio test of the stratified Cox proportional hazard model. Differences were assessed using a two-sided test and were considered significant at p<0.05.
Results
Clinicopathological characteristics of patients. The clinicopathological characteristics of the patients involved in the present study are summarized in Table I. The median age was 69 years (range=29-97 years) and the male/female ratio was 1.9:1. The median tumor size of the primary tumor was 55 mm (range=9-190 mm), and the number of patients with pathological stage II and III GC were 107 and 105, respectively.
Clinicopathological characteristics of patients in the present study.
Clinicopathological characteristics of patients with increasing and decreasing serum T-Cho levels. The clinicopathological characteristics of the patients with decreasing and increasing serum T-Cho levels during the perioperative period are summarized in Table II. Of the 212 patients in whom perioperative serum T-Cho levels were measured, 173 (81.6%) were classified into the decreasing group and 39 (18.4%) were classified into the increasing group based on the T-Cho levels about a month after surgery relative to the preoperative values. Patients with increased serum T-Cho levels had significantly lower preoperative serum albumin levels (p<0.001). Regarding the recurrence pattern, no significant difference was found between the increasing and decreasing serum T-Cho levels in patients with GC (p=0.977). Figure 1 shows a scatter plot of the T-Cho levels before and after surgery. The increasing group tended to have low serum T-Cho levels before surgery, suggesting that patients with increased serum T-Cho levels may have a poor nutritional status before surgery.
Clinicopathological characteristics of transition of T-Chol value in patients with gastric cancer.
Scatter plot showing perioperative serum total cholesterol (T-Cho) levels. This scatter plot shows the changes in T-Cho levels before and after surgery. The red circles indicate the group in which serum T-Cho levels increased after gastrectomy (increasing), and the blue circles indicate the group in which serum T-Cho levels decreased after gastrectomy (decreasing).
Prognostic effect of changes in the perioperative serum T-Cho levels. Figure 2 shows the prognostic implications of changes in perioperative serum T-Cho levels in patients with GC. Patients with increased serum T-Cho levels after gastrectomy had significantly lower overall and recurrence-free survival rates than those with decreasing T-Cho levels (increasing vs. decreasing: 5-year overall survival 39.4% vs. 59.4%, p=0.030 and 5-year recurrence-free survival 36.4% vs. 56.3%, p=0.013, respectively; log-rank test) (Figure 2).
Overall and recurrence-free survival in patients with gastric cancer (GC) whose total cholesterol (T-Cho) levels increased after surgery and in those whose levels decreased. Overall survival (A) and recurrence-free survival (B) rates were significantly lower in patients with GC with increasing T-Cho levels than in those with decreasing T-Cho (p=0.030 and p=0.013, respectively; log-rank test).
Table III shows the 10 patients with the highest rate of increase in postoperative serum T-Cho levels. These patients had early recurrence, and as a result, had a poor prognosis. Hematogenous recurrence occurred in 4 four of the 10 patients.
Clinicopathological features of patients with the highest rate of increased serum T-Cho levels after surgery.
Table IV shows the results of the univariate and multivariate analyses used to identify the independent prognostic factors for recurrence-free survival in stage II and III GC. On univariate analysis, older age (p=0.013), low preoperative albumin levels (p=0.004), venous invasion (p=0.010), stage III disease (p<0.001), non-administration of adjuvant chemotherapy (p=0.015), and increased T-Cho (p=0.016) were significantly associated with prognosis. On multivariate analysis, increased T-Cho (p=0.040), pathological stage (p<0.001), and the administration of adjuvant chemotherapy (p=0.006) were independent predictors of recurrence-free survival of patients with GC (Table IV).
Cox proportional hazard model for 5-year recurrence free survival in patients with gastric cancer.
Discussion
Nutrition is one of the important factors for predicting prognosis of cancer. The nutritional and inflammatory status - as assessed by nutrition and inflammation assessment tools - may have some clinical influence on both the short- and long-term oncological outcomes in patients with GC (18). Mimatsu et al. reported that the Glasgow prognostic score (GPS) and neutrophil lymphocyte ratio (NLR) were useful prognostic factors that predicted postoperative survival in patients undergoing non-curative surgical treatment for stage IV GC (19). The present study demonstrated the possibility that increased serum cholesterol levels after gastrectomy are associated with worse prognosis and could be an independent prognostic marker after surgery in patients with GC. Takagi et al. reported that the CONUT score is a potential good estimator of the postoperative complication risk after esophagectomy (20). Moreover, Aoyama et al. reported that the preoperative CONUT score was a significant prognostic factor for patients with GC who underwent gastrectomy and adjuvant treatment (21). A prognostic index using serum T-Cho levels in the perioperative period is simple and could be a useful method that is easy to use in daily clinical practice for patients with GC.
Cholesterol is an essential lipid component of mammalian cell membranes that maintains membrane integrity and fluidity and forms membrane microstructures (22). Previous studies have reported the effects of cholesterol on cancer; however, their findings are diverse and unclear. A recent study indicated that cholesterol and its metabolites play an important role in cancer; for example, high serum cholesterol levels increase the antitumor functions of natural killer cells and reduce the growth of liver tumors in mice (23). Other studies have confirmed that intracellular cholesterol promotes tumor formation and growth. The effects of cholesterol on cancer progression have also been reported in lung cancer, prostate cancer, and bone metastasis (24-26). Some previous studies also demonstrated that high levels of low density lipoprotein (LDL), cholesterol, and triglycerides were associated with worse prognosis in patients with small-cell lung cancer and breast cancer (27, 28). The LDL receptor is over-expressed in certain types of cancer cells. In addition, the LDL receptor has a pro-tumorigenic effect mediated by the enhancement of cell growth or migration (29, 30). Rozeveld et al. reported that excess lipids stored in organelles called lipid droplets (LD) are a key resource for fueling the energy-intensive process of metastasis in pancreatic cancer (31).
Cholesterol has been reported to be an important nutritional index in GC. In general, decreased serum T-Cho levels reflect caloric depletion. Moreover, lower cholesterol levels affect intracellular signaling involved in cancer progression and impair the anti-tumor immune response. Matsubara et al. demonstrated that decreased levels of triglycerides, T-Cho, LDL cholesterol, HDL cholesterol, and remnant cholesterol are associated with poor cancer-specific survival rates in patients with GC (9). In this study, patients with GC with increased serum T-Cho levels after surgery tended to have low Alb levels before surgery, suggesting that many of these patients had a poor nutritional status before surgery.
Kobayashi et al. reported that the mechanism of elevation of LDL cholesterol was associated with thyroid hormone; that is, prolonged fasting leads to low triiodothyronine levels, resulting in reduced LDL receptors on the cell membrane (32). In this study, thyroid function may have been involved in the mechanism of increased postoperative serum T-Cho levels in patients with preoperative malnutrition.
However, no significant correlation was found between increased serum T-Cho levels after gastrectomy and preoperative body weight, BMI, and PNI, suggesting that nutritional status may not be the only mechanism that accounts for the postoperative elevation of serum T-Cho levels.
Previous studies have suggested that increased serum T-Cho levels suppress the anti-tumor immune response by deactivating regulatory T cell-controlled expression of genes such as sterol regulatory element binding proteins (SREBPs). Perry et al. found that interruption of SREBPs resulted in much better anti-tumor immune responses in two forms of cancer transplanted beneath animal skin than in animals that had functional SREBPs (33). Although this is only a hypothesis, it is possible that such an increase in cancer-related cholesterol metabolic factors results in an increase in postoperative serum T-Cho levels.
The present study has several limitations. The small patient population and retrospective nature of the present study do not allow us to draw any concrete conclusions regarding the prognostic implications of changes in perioperative serum T-Cho levels in patients with GC. Furthermore, we also did not indicate a clear mechanism by which patients with GC with increased serum T-Cho levels after surgery have a poor prognosis, although hypothyroidism and cholesterol metabolism related factors involved in tumor progression may be involved.
Conclusion
In the present study, we demonstrated that patients with GC whose serum T-Cho levels increased dramatically after gastrectomy had early recurrence and poor prognosis, suggesting that meticulous surveillance is needed. For these patients, elevated serum T-Cho levels do not indicate an improved nutritional status, and appropriate perioperative nutritional intervention may be required.
Footnotes
Authors’ Contributions
AY and KS designed the research. KS performed the research. AY reviewed the clinical data. AY and KS analyzed the data. AY and KS wrote the paper. All Authors read and approved the final manuscript.
Conflicts of Interest
None of the Authors have any conflicts of interest to disclose in relation to this study.
- Received November 17, 2022.
- Revision received December 20, 2022.
- Accepted January 10, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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