Sarcopenia Is Associated With Aggressive Clinicopathological Outcomes and Is a Poor Prognostic Indicator for Non-metastatic Renal Cell Carcinoma

Abstract

Background/Aim: We aimed to describe the impact of preoperative sarcopenia on the oncological outcome of non-metastatic renal cell carcinoma (RCC) after surgical treatment.

Patients and Methods: Data on 299 Japanese patients with non-metastatic RCC who underwent radical treatment at Kanazawa University Hospital between October 2007 and December 2018 were extracted. Clinicopathological features and survival prognosis of patients stratified by the presence or absence of sarcopenia as indicated by the psoas muscle mass index (PMI) were retrospectively analyzed. PMI <516.8 and <235.1 mm²/m² at the L3 level for male and female were defined as the cutoff values for sarcopenia, respectively.

Results: Of 299 patients, 113 (37.8%) were classified as sarcopenic. The sarcopenia group showed a larger tumor size, worse pathological tumor stage and histological grade, and more frequent lymphovascular invasion than the non-sarcopenia group. According to Kaplan-Meier curves, sarcopenia was associated with a shorter overall survival (OS) and metastasis-free survival (p=0.0174 and 0.0306, respectively). Multivariate analysis identified sarcopenia as a significant and independent prognostic factor for poor OS (hazard ratio, 2.58; 95% confidence interval=1.09-6.08; p=0.030).

Conclusion: Sarcopenia is a significant factor indicating worse pathological outcomes and poor survival prognosis in surgically treated non-metastatic RCC.

Sarcopenia is a progressive and widespread skeletal muscle disease characterized by decreased skeletal muscle mass and muscle function (1). Although the mechanisms and pathophysiology of sarcopenia are not yet clearly understood, a declining trend in hormone levels, number of neuromuscular junctions, activity, and adequate nutrition, as well as inflammation, have been suggested (2,3). Several recent studies have confirmed that the development of sarcopenia is closely related to the treatment and prognosis of many resectable malignancies, such as colorectal, hepatocellular, pancreaticobiliary, and urothelial carcinomas (4,5). However, few studies on the relationship between sarcopenia and renal cell carcinoma (RCC) have been conducted in Japan. Several different muscle strength measures are used to quantify sarcopenia. The psoas muscle mass index (PMI) is one relatively simple way of expressing total body skeletal muscle mass and is often used to quantify sarcopenia.

In this study, we retrospectively investigated the relationship between the clinicopathological features of RCC and preoperative PMI and evaluated the prognosis after curative surgical treatment in a Japanese population.

Patients and Methods

Patients. Patients with non-metastatic RCC (T1-T4, N0, M0) who underwent partial or radical nephrectomy at Kanazawa University Hospital between October 2007 and December 2018 were included in this retrospective study. The inclusion and exclusion criteria were set according to our previous study (6). Also, this study was approved by the Medical Ethics Committee of Kanazawa University (2018-116) (6).

Data collection and variable definitions. Baseline clinical data at the time of surgical treatment, including age, sex, body mass index (BMI), PMI, smoking and alcohol use history, medical conditions such as hypertension and diabetes, method of diagnosing RCC, and preoperative serum C-reactive protein (CRP), were collected. Additionally, baseline oncological data, including pathological tumor stage and size, histological subtype, histological nuclear grade, lymphovascular invasion, and concomitant of sarcomatoid changes were obtained. Pathological stage evaluation was performed according to the tumor–node–metastasis (TNM) classification of malignant tumors (eighth edition) by the Union for International Cancer Control (2017).

Overall survival (OS) and cancer-specific survival (CSS) were determined as the time from the date of the surgical treatment to death from any cause and to death from RCC, respectively. Metastasis-free survival (MFS) was measured as the time from the date of surgical treatment to the first detection of metastasis from RCC.

Assessment of the PMI. Preoperative computed tomography images were manually traced to measure the total psoas muscle cross-sectional area at the L3 level, and PMI (mm²/m²) was calculated by normalizing the total psoas muscle area (mm²) by the square of the patient’s height (m²). The optimal cutoff value for PMI in this study was determined using the point closest to (0,1) on the receiver operating curve (ROC) (7). Sarcopenia was defined as any measurement below each cutoff value for PMI.

Statistical analyses. Differences in the patients’ characteristics were compared using chi-square test, Fisher’s exact test, and Mann-Whitney test, as appropriate. OS, CSS, and MFS were estimated using the Kaplan-Meier method and compared using the log–rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models to evaluate the association of sarcopenia with MFS and OS. Statistical analyses were performed using GraphPad Prism version 6.07 (GraphPad Software Inc., San Diego, CA, USA) and IBM SPSS Statistics version 25 (IBM Corp., Armonk, NY, USA). A p-value <0.05 indicated statistical significance.

Results

Patient background. Data on 299 patients with T1-T4, N0, M0 RCC who underwent partial or radical nephrectomy were extracted. The demographics of overall patients are shown in Table I. The median follow-up period for the study population was 4.43 years (range=0.02-14.71 years). Of the 299 patients, 113 (37.8%) and 186 (62.2%) were identified with sarcopenia and without sarcopenia, respectively. A significant difference in age at diagnosis of RCC was found between the sarcopenia group [67 years, interquartile range (IQR)=62.0-75.0 years] and non-sarcopenia group (60 years, IQR=50.3-67.8 years; p<0.001). A significant difference was also observed in sex between the sarcopenia group [102 (90.3%) for male patients and 11 (9.7%) for female patients] and non-sarcopenia group [114 (61.3%) for male and 72 (38.7%) for female; p<0.001]. In addition, the sarcopenia group showed a lower BMI (p<0.001) and a higher value of preoperative serum CRP (p=0.012) and rate of coexisting hypertension (p=0.006) than the non-sarcopenia group.

Table I. Patient characteristics.

BMI: Body mass index; CRP: C-reactive protein; IQR: interquartile range; PMI: psoas muscle mass index; RCC: renal cell carcinoma. Data presented as n (%), unless otherwise noted.

The optimal thresholds for PMI. Using OS as the end point for PMI, the optimal cutoff value was determined by ROC analysis. The ROC curve showed that the optimal cutoff value of PMI was 516.8 mm²/m² for male [area under the curve (AUC)=0.576; 95% confidence interval (CI)=0.459-0.692; p=0.2893, with sensitivity of 61.1% and specificity of 54.0%] and 235.1 mm²/m² for female patients (AUC=0.684; 95%CI=0.432-0.935; p=0.2175, with sensitivity of 50.0% and specificity of 88.6%).

Correlations of PMI with age and BMI. PMI was correlated with several clinical values. Median PMI was 520.8 mm²/m² (IQR=440.5-618.0 mm²/m²) for male and 300.3 mm²/m² (IQR=249.9-380.5 mm²/m²) for female patients. In linear regression, a weakly negative correlation was observed between PMI and age (all patients: r²=0.1322, p<0.0001; male: r²=0.2015, p<0.0001; female: r²=0.0866, p=0.0060) (Figure 1A-C), whereas a weakly positive correlation was observed with BMI (all patients: r²=0.1677, p<0.0001; male: r²=0.1515, p<0.0001; female: r²=0.1264, p=0.0010) (Figure 1D-F).

Figure 1. Relationship between psoas muscle mass index (PMI), age, and body mass index (BMI) in all (A, D), male (B, E), and female (C, F) patients, respectively.

Oncological parameters. A summary of the oncological parameters was evaluated as shown in Table II. The tumor size tended to be larger in the sarcopenia group (median, 3.0 cm; IQR=2.2-5.5 cm) than that in the non-sarcopenia group (median, 2.8 cm; IQR=1.9-4.8 cm; p=0.063). Pathological T-stage determined according to the TNM classification system and histological grade were significantly worse in the sarcopenia group than those in the non-sarcopenia group (p=0.042 and 0.009, respectively). Otherwise, a trend toward a significant difference in the incidence of lymphovascular invasion between the sarcopenia and non-sarcopenia groups was observed (p=0.072).

Table II. Oncological parameters.

IQR: Interquartile range; ccRCC: clear cell renal cell carcinoma. Data presented as n (%), unless otherwise noted.

Survival rates and prognostic factors. During the observation period, 48 patients developed metastatic recurrence, and 22 patients died, nine of them from RCC. The results of Kaplan-Meier analysis for OS, CSS, and MFS in all patients with or without sarcopenia are shown in Figure 2. A significant difference in OS was found between the sarcopenia and non-sarcopenia groups (p=0.0174, Figure 2A). The 5-year OS values in the sarcopenia and non-sarcopenia groups were 93.0% and 94.5%, respectively. Although no significant difference was seen in CSS between the two groups (p=0.2069, Figure 2B), the MFS varied significantly between the two groups (p=0.0306, Figure 2C). The 5-year MFS values in the sarcopenia and non-sarcopenia groups were 74.3% and 86.9%, respectively. The results of the multivariate analysis of the prognostic factors showed that the presence of sarcopenia was not an independent predictor associated with MFS (Table III) but was the only independent prognostic factor for poor OS (hazard ratio=2.58; 95%CI=1.09-6.08; p=0.030) (Table IV).

Figure 2. Kaplan-Meier analyses for (A) overall survival, (B) cancerspecific survival, and (C) metastasis-free survival in all patients based on the presence or absence of sarcopenia.

Table III. Univariate and multivariate analysis of the association between clinicopathological characteristics and metastasis-free survival.

†Continuous variable. ccRCC: Clear cell renal cell carcinoma; CI: confidential interval; CRP: C-reactive protein; HR: hazard ratio; KPS: Karnofsky performance status.

Table IV. Univariate and multivariate analysis of the association between clinicopathological characteristics and overall survival.

†Continuous variable. ccRCC: Clear cell renal cell carcinoma; CI: confidential interval; CRP: C-reactive protein; HR: hazard ratio; KPS: Karnofsky performance status.

Discussion

The need for improved preoperative prediction in localized RCC has remained significantly unmet. Several previous studies have reported that sarcopenia is associated with an increased risk of death and recurrence after nephrectomy in both localized and metastatic RCC (8-10). In addition, a recent meta-analysis showed that patients with malignant neoplasms, including RCC and sarcopenia, at preimmunotherapy had worse clinical outcomes than those without (11).

The present study examined the relationship between preoperative sarcopenia and oncological outcomes and survival. The results confirmed that the presence of sarcopenia, as indicated by low PMI, was associated not only with significantly worse pathological features, such as tumor stage, histological grade, and lymphovascular invasion incidence, but also with an increased rate of metastasis and decreased survival after radical surgery for non-metastatic RCC, and that sarcopenia was an independent poor prognostic factor for OS.

Although sarcopenia is a consequence of atrophy from disuse, its molecular mechanisms underlying this phenomenon are unknown. Altogether, sarcopenia is considered to be a multifactorial process; malnutrition, alterations in muscle structure, altered muscle signaling, and decreased physical activity (12). Another proposed explanation is sarcopenia as a marker of an increased cancer-related inflammatory response (13). In particular, accumulating evidence demonstrated that serum levels of tumor necrosis factor-α, interleukin-6, and CRP are elevated in sarcopenia, usually up to 2-4-fold higher than those in young controls (14). Additionally, high CRP is also associated with a number of poor prognostic indicators, including tumor size, higher grade and stage, lymphatic involvement, microvascular invasion, and aggressive histopathologic findings such as spindle or sarcomatoid morphology (15). Therefore, these biomechanical backgrounds may support the present study’s findings of worse pathological outcomes and poor survival in the sarcopenia group. On the basis of these findings, a notable advantage of identifying patients with high preoperative sarcopenic status is the opportunity for early intervention to alter the disease trajectory (16). Early intervention with exercise programs designed to build muscle may offset the long-term risk of sarcopenia and thus may improve survival. Several studies have shown the benefit of preoperative exercise regimens in reducing the length of hospital stay, postoperative complications, and costs for patients with cancer undergoing surgery (17,18). Interestingly, a recent study reported that pre- and postoperative sarcopenia dynamics were significant predictors of survival outcomes, indicating that the maintenance of a good pre- and postoperative nutritional status was essential for long-term survival in patients with RCC (19). Therefore, a multimodal approach to body composition at all stages of the disease may benefit those at high risk for developing metastatic disease.

This study has several limitations. Data collected on PMI were determined using manual tracing, but the correlation between PMI and total skeletal muscle mass was not determined. In addition, the cutoff value for PMI depended on race, and the exact cutoff values for different races were not established. However, previous studies have reported a cutoff value of PMI of 545 mm²/m² in men and 385 mm²/m² in women, as defined by an international consensus of experts on cancer cachexia (20), as well as 538 mm²/m² in men and 346 mm²/m² in women in Japanese populations (21). Therefore, the cutoff value for PMI set in this study is considered to be generally similar to those of previous reports. Moreover, no details of systemic treatment for patients with recurrent metastatic RCC after radical surgery were included in this study because of complicated sequential treatment using various agents available presently. In addition, recent significant advances in surgical treatment may have influenced these prognostic analyses. Finally, the sample size and observation period may be insufficient to determine precise statistical significance. However, the present study confirms that the presence of sarcopenia, defined here as low PMI, is an independent predictor of survival in Japanese patients surgically treated for non-metastatic RCC. Further research investigating the dose relationship of sarcopenia and validating optimal criteria would help to accurately define the role of sarcopenia in the oncologic outcome of RCC.

Conclusion

The results of this retrospective analysis showed that Japanese patients with non-metastatic RCC and concurrent sarcopenia tend to have a larger tumor size, worse pathological tumor stage, lymphovascular invasion, higher incidence of metastasis, and poor life expectancy. The PMI can be easily measured as an indicator of patient sarcopenia and may be useful for prognostic risk stratification of patients with non-metastatic RCC undergoing surgical treatment.

Conflicts of Interest

The Authors declare no conflicts of interest in relation to this study.

Authors’ Contributions

Conceptualization, T.M.; methodology, T.M.; validation, T.M.; formal analysis, T.M.; investigation, T.M.; resources, T.M.; data curation, T.M.; writing—original draft preparation, T.M.; writing—review and editing, K.I., H.I., S.K., and Y.K.; visualization, T.M.; supervision, A.M.; project administration, T.M. and K.I. All Authors have read and agreed to the published version of the manuscript.

Acknowledgements

The Authors would like to thank Enago (www.enago.com) for the English language review (accessed on 30 May 2022).