To the best of our knowledge, this is the first study to show that body composition measures are associated with the prognosis of HCC in Indonesian patients. This study showed that both sarcopenia and IMF deposition predicted poor survival of HCC patients independently of demographics, cancer stage, and the degree of liver dysfunction.
In a large-scale retrospective cohort study of 1257 Japanese patients, both quantity (defined by low SMI) and quality (determined by low MA) of muscle were identified as significant predictors of HCC survival [2]. In Japan, where a national surveillance program has been applied to the high-risk population since 1980, 62% of HCC cases are diagnosed at BCLC stage A, and the median survival time for HCC patients is 47.2 months, which is considered the best in the world [6, 11]. In Japan, HCC is mostly caused by hepatitis C virus infection and is more prevalent in the older population (mean age, 68 years); this may affect sarcopenia status, as this term also refers to the age-related decline in muscle mass and function [2]. However, in Indonesia, the prevalent characteristics related to HCC are advanced-stage presentation, early-age onset, and HBV endemicity, which differ from those in Japan [6]. The present findings suggest that sarcopenia and IMF deposition could be used to predict the outcomes of HCC patients regardless of age, the causative virus, and stage at diagnosis.
Sarcopenia, derived from the Greek words “sarcos” for flesh and “penia” for deficiency, was initially used to describe the decline in muscle mass and function related to the aging process [12]. However, later studies examined sarcopenia occurring in association with several types of cancer, such as ovarian cancer, lung cancer, pancreatic cancer, renal cell carcinoma, oesophageal cancer, and lymphoma, as this condition affects the overall survival of patients [9, 13]. Sarcopenia is also correlated with poor quality of life (QOL) and symptoms of depression, cognitive impairment, inflammatory bowel disease, and chronic kidney disease [14–16]. Regarding liver disease, studies show that sarcopenia is associated with poor outcomes in patients with cirrhosis and HCC with reduced tolerance to chemotherapy [2, 17–19]. Recent studies show that sarcopenia is associated with low-grade systemic inflammation, as indicated by increased inflammatory cytokines (IL–1, IL–6, and TNFα) leading to oxidative stress, which together with mitochondrial dysfunction, could be central to the pathogenesis of sarcopenia [2, 10, 20]. Inflammation and stress-related signalling pathways, including nuclear factor-κB and signal transducer and activator of transcription, are critical players in the progression of liver fibrosis and HCC development [21], which could explain the association of sarcopenia with poor prognosis in our study (Figure 1).
In addition to the decline of muscle mass, adipose tissue deposition in skeletal muscle has recently attracted interest in cancer research [2, 10, 13]. Normal skeletal muscles contain a small amount of fat that is used as a source of energy during aerobic activity [22]. An increase in muscle lipid content associated with decreased CT attenuation values within the muscle may represent a marker of myosteatosis or a possible surrogate for muscle function and quality [22, 23]. Low average skeletal muscle attenuation on CT is a more important indicator of a patient’s functional status than the quantification of muscle mass [13]. The degree of adipose infiltration into skeletal muscle, the liver, and other organs is associated with increased triglyceride content and reduced insulin-stimulated glucose uptake, which interferes with insulin signalling and leads to insulin resistance [10, 23, 24]. Low skeletal muscle attenuation is associated with deficits in physical function, altered metabolism, and poor prognosis [23]. A previous study showed that muscle adiposity is strongly correlated with inflammation, which may depend on the secretory profile of adipocyte-derived factors, as shown by increased IL–6 expression and CRP levels in patients with intramuscular fat deposition [10]. In the present study, HCC patients with IMF deposition had significantly higher levels of AST and CRP, indicative of local and systemic inflammation (Table 3). Further basic and clinical research focusing on intramuscular adipocytes and myosteatosis is warranted in the HCC population, particularly given the unique set of metabolic derangements associated with the disease.
The present results suggest that BCLC stage and the JIS score are superior indicators for predicting patient outcomes in HCC (Table 2). The functional impairment caused by the underlying liver disease has a significant impact on outcomes, irrespective of tumour stage [8]. For this reason, systems that include only the anatomical characteristics of the tumour, such as the AJCC and LCSGJ staging systems, which stratify patients using the TNM classification, do not have an excellent predictive capability [8]. Analyses performed in US and Asian patients of any stage demonstrated that the BCLC system has a stronger predictive power than other systems, since it integrates information about tumour extension, liver function, and the presence of constitutional symptoms, providing important information to guide therapeutic choices [8, 25, 26]. The JIS score, which combines TNM and Child–Pugh and is widely used in Japan, showed good predictive value regarding survival in Indonesian HCC patients in our study [27].
In the present study, survival was worse in men than in women (Table 2). The gender disparity of HCC is an essential topic in hepatocarcinogenesis, as the incidence and mortality of HCC are significantly lower in women than in men [28]. Postmenopausal women are at a higher risk of developing HCC, suggesting that oestrogen has protective effects on HCC development and progression [28]. The male predominance of HCC could also be associated with androgen and androgen receptor (AR) signalling [29]. Increased testosterone levels are significantly associated with the risk of HCC. Androgen/AR signalling may promote early-stage hepatocarcinogenesis by increasing cell growth through the transcriptional regulation of transforming growth factor beta 1 and the modulation of cell cycle-related kinase transcription [29]. However, a study of HCC survival conducted in Japan showed no significant difference in survival between men and women [2]. Further investigation of the roles of hormones in HCC progression is warranted, particularly because the efficacy of hormone therapy for liver cancer remains controversial [30].
The present findings support that sarcopenia and IMF deposition are independent predictors of the survival of HCC patients, as shown in several studies in other populations [2, 17–19]. We believe that measurement of skeletal muscle mass and quantity should be added to widely used staging systems for HCC stratification in clinical practice. The present study had some limitations related to the small sample size and limited duration of observation. We attempted to overcome these challenges by performing a prospective cohort study in which patient status was followed-up each month to determine the correlation between skeletal muscle measurement and mortality. However, we were unable to address the question of causality in the present study. Additional basic research and larger clinical studies are necessary to clarify these issues. In addition, we only included patients enrolled in Yogyakarta Province Hospital (RSUP Dr. Sardjito), a tertiary hospital that receives patients referred from several provinces in Indonesia. Furthermore, although the patients included were mostly Javanese, it is the most prevalent ethnic population in Indonesia (40.06%) [5]. Therefore, we believe that our data are representative of the overall Indonesian population.