Transarterial chemoembolization (TACE) is the standard treatment modality for patients with intermediate stage hepatocellular carcinoma (HCC) according to the widely applied Barcelona Clinic of Liver Cancer (BCLC) staging system (Marrero et al., 2018; Villanueva, 2019). However, the response rates and survival are heterogeneous, and the target patients who will benefit particularly well from TACE is still controversial (Forner et al., 2018). In brief, tumor burden, liver function, and etiology have great influence on the prognosis of BCLC B stage HCC patients. Additionally, simple predictive algorithms including 6 to 12, up to 7, HAP, BCLC sub-classifications, which are mainly based on the tumor number and size as well as Child–Pugh class, were suggested for making decisions for those patients with significant degree of disease heterogeneity (Kim et al., 2017; Lee et al., 2019; Wang et al., 2019). Nevertheless, considering that the predictive value of these parameters could not be validated in larger clinical trials, it is crucial that novel pre-treatment stratification strategies are corroborated in order to improve the overall survival (OS) for intermediate stage HCC patients.

In recent years, previous studies demonstrated that the sarcopenia, which is defined as the declination in muscle volume mass and strength was associated with poor outcomes of HCC patients (Fujiwara et al., 2015; Antonelli et al., 2018; Cruz-Jentoft and Sayer, 2019; Hamaguchi et al., 2019; Qayyum et al., 2021). However, the correlation between sarcopenia and outcomes such as tumor response and survival in intermediate stage HCC patients undergoing TACE treatment has not been largely evaluated (Marasco et al., 2020). In addition, the prognostic role of the pre-treatment skeletal muscle remains debated (Loosen et al., 2019). More recently, the increased visceral adiposity tissue (VAT) has been suggested as an independent risk factor for recurrence after resection in HCC patients (Imai et al., 2021). Nevertheless, its predictive value has not been well studied in these patients receiving TACE treatment. Except from the quantitative measurements of body composition, the mean tissue attenuation expressed in Housfield units (HU) can also offer a qualitative information as well as provide perception into the pathophysiology (Larsen et al., 2020). By contrast, although mean tissue attenuation is easily measured on the computed tomography (CT) images, limit data are shown regarding the prognostic impact of tissue density in BCLC B stage HCC patients.

This study aimed to evaluate the association of skeletal muscle and adipose tissue mass and density with prognostic outcomes of intermediate stage HCC patients treated with TACE.

The current study showed the prognostic performance of VAT density for intermediate stage HCC patients treated with TACE. We demonstrated that the VAT density was not only associated with survival such as OS and PFS but also tumor response, suggesting that the influence of VAT HU on BCLC B stage HCC patients’ outcomes could reflect tumor-specific factors.

Hepatocellular carcinoma patients with BCLC B stage are a group of highly heterogenous in terms of variable liver function, tumor burden, and disease etiology, leading to various individual responses (Arizumi et al., 2015). Furthermore, repeated TACE may induce impaired liver function and has an impact on the prognosis of the inter-mediated stage HCC patients (Kudo et al., 2014). To prolong OS of the intermediate-stage HCC patients, it is crucial to identify the target population who may benefit from TACE and make risk stratification. There remains considerable uncertainty, which the existing guidelines do not adequately address criteria for prognostic factors, given the diversity of clinical responses (Vitale et al., 2018). Except the well-knowledged factors such as alpha-fetoprotein, bilirubin, performance status, the other non-invasive and simply applied factors are still on the prowl.

In recent years, previous evidence suggested that there is a correlation between obesity and prognosis of malignancies including HCC (Charette et al., 2019). In addition, non-alcoholic fatty liver disease (NAFLD), which is becoming the first cause of chronic liver disease, is the risk factor of HCC development and prognosis of HCC patients (Seror et al., 2021). Although the body mass index (BMI) is widely applied to characterize the body compositions, limitations persist in its use such as inability to differentiate fat and muscle mass (Strulov Shachar and Williams, 2017). In contrast, analytic morphomics, using semi-automated image-processing platform to evaluate body composition, was considered as offering an accurate approach to quantitate not only the aggressive nature of HCC itself but the underlying HCC patients’ characteristics such as liver status (Singal et al., 2016). Moreover, with its available resolution of adipose tissue, CT scan is the gold standard quantitative assessment of tissue density (Doyle et al., 2013).

Previous studies showed that both SAT and VAT density were negatively correlated with survival, suggesting that an increased adipose tissue attenuation could be used as a novel non-invasive biomarker for predicting prognosis (Murphy et al., 2014; Rosenquist et al., 2015). More recently, Hessen et al. suggested that high SAT density correlates negatively with OS in patients with HCC (von Hessen et al., 2021). Our study showed that VAT density was significantly in correlation with tumor response (CR + PR) (odds ratio: 1.035, 95% CI: 1.014–1.058, p = 0.001). As such, a pre-TACE VAT HU below −89.1 was an independent predictor for favorable outcomes. HCC patients in this cohort below the cutoff value presented a median OS and PFS of 25.1 and 15.4 months compared with 17.6 and 6.6 months in patients with a VAT HU above the cutoff, highlighting the value of VAT in predicting outcomes of inter-mediated stage HCC patients undergoing TACE. Iwase et al. (2020) reported that a high VAT area was correlated with a reduced disease-free survival in breast cancer patients undergoing neoadjuvant chemotherapy. In general, SAT and VAT are two main compartments with different metabolic characteristics of body fat tissue (Shuster et al., 2012). Compared with SAT, previous studies showed the association between VAT and various pathologies such as insulin resistance, impaired glucose, and lipid metabolism could relate to the prognosis of patients with cancers, and VAT was regarded to be more pro-tumorigenic and pro-inflammatory (Neeland et al., 2019; Li et al., 2020). Moreover, hormones and bioactive molecules including interleutin 6 (IL-6), tumor necrosis factor, adiponectin, and resistin are released by the VAT (Shuster et al., 2012). Insulin can irritate the proliferation of HCC cells and accelerate the vascular invasion of HCC (Karagozian et al., 2014). In particular, considering that adiponectin has protective antiangiogenic activity, regulating the vascular endothelial growth factor (VEGF) levels induced by TACE could have an impact on outcomes of HCC patients (Bagchi et al., 2013). The reasons for only high VAT density had a negative impact on outcomes are speculated as follows: First, adipose tissue density might be qualitative biomarker and a high adipose tissue density is in correlation with a depletion of adipose, which could reflect the poor nutritional condition (Charette et al., 2019). In addition, the underlying diseases in HCC patients and chronic inflammation could also lead to a higher VAT density (Batista et al., 2016). Finally, in patients with cancer cachexia, the high CT density of fat tissue, which is determined by fat and lipid could result from the activation of brown adipose tissue (Beijer et al., 2012). Interestingly, a cutoff value of −89.1 HU, which has been demonstrated in the present study, was close to the previous study in HCC patients, with a cutoff value of −88 HU (von Hessen et al., 2021).

Numerous studies showed that sarcopenia, which is defined as a progressive and generalized skeletal disorder, was considered associated with a higher incidence of adverse events and poor prognosis in HCC patients treated with various therapies (Choi et al., 2020; Uojima et al., 2020). Nevertheless, there is little data concerning the prognosis value of sarcopenia in HCC patients receiving TACE (Marasco et al., 2020). This study suggested that patients with a higher muscle density had a PFS gain, whereas the muscle mass and density had no correlation with the OS and tumor response. Kobayashi et al. (2018) and Fujita et al. (2019) showed there was no significance between pre-TACE muscle mass and clinical outcomes. In contrast, two other studies indicated pre-TACE sarcopenia was an independent factor of negative outcomes (Dodson et al., 2013; Loosen et al., 2019). These finding demonstrated that the role of the sarcopenia in predicting prognosis may mainly depend on the general clinical status of HCC patients and not directly on the local response of TACE treatment (Marasco et al., 2020).

Of note, there are some limitations in this study. First, it is a small sample retrospective study and subject to collection and selection bias. HCC patients with unavailable CT scans were excluded in this study. Additionally, the lack of a control group represents limit in the convincing evidence of the analysis. The results also need to be confirmed with external validation. Finally, changes in the body composition parameters after TACE treatment were not analyzed in the study. The impact of changes of these parameters on the outcomes of intermediate stage HCC patients treated with TACE should be further conducted with future large sample size studies.

In conclusion, the VAT density could provide prognostic prediction value and may be helpful to stratify the BCLC B stage patients in order to optimize the selection criteria for undergoing TACE treatment.

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

The current study was reviewed and approved by the Institutional Review Board of the Soochow University and was conducted in accordance with the ethical standards laid down in the Declaration of Helsinki. The requirement for informed consent was waived due to its retrospective nature.

All authors contributed to the review and critical revision of the manuscript and approved the final version of the manuscript. TC, C-FN, QL, and LZ contributed to the study concept and design. QL, LZ, Z-HH, D-XZ, and SZ contributed to the acquisition of data. LZ, Z-HH, D-XZ, and J-BL contributed to the analysis and interpretation of the data. LZ, Z-HH, D-XZ, and YY contributed to the statistical analysis. QL, LZ, Z-HH, and D-XZ contributed to the drafting of the manuscript. The corresponding author had full access to all the data and took full responsibility for the veracity of the data and the statistical analyses.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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