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Table 2. Impact of sarcopenia on post-LT HCC recurrence
Ref. n Surgical procedure Impact on overall ouctome Multivariable impact on post-LT HCC relapse
Itoh et al. [72] 153 LDLT Low SVR was associated with poor RFS (P = Low SVR was identified as an inde-pendent promoter
0.01) and OS (P = 0.03.) of poor post-LDLT outcome
Kim et al. [73] 92 LDLT Cumulative HCC recurrence probability was Sarcopenia was identified as an independent predictor
significantly higher in sarcopenic vs. non- of HCC relapse (HR = 2.25; 95%CI 1.18-76.32; P =
sarcopenic MC Out patients (P = 0.044). 0.034), along with AFP
HCC recurrence rates were 36.1% and 5.0%
in sarcopenic and non-sarcopenic patients.
Sharma et al. [74] 118 DDLT Overall post-LT survival was significantly Low BMD was identified as an independent predictor
lower in patients with low BMD compared of post-LT mortality in HCC LT patients (HR = 0.90;
to those with high BMD (P = 0.018) 95%CI 0.83-0.90; P = 0.03)
BMD: bone mineral density; CI: confidence interval; DDLT: deceased donor LT; HCC: hepatocellular carcinoma; HR: hazard ratio; LDLT: living donor
liver transplantation; MC: Milan criteria: SVR: skeletal muscle-to-visceral fat area ratio

immunocompetence may also increase the oncological risk in LT patients [Table 2]. In a subset of 153 patients
following LDLT for HCC, low skeletal muscle-to-visceral fat area ratio (SVR) was shown to predict poor
recurrence-free survival (RFS) and OS. In addition, low SVR was identified as an independent and significant
[72]
[73]
prognostic factor for post-LT outcome . Kim et al. have specifically studied the impact of sarcopenia in
series of 92 LDLT patients with Milan Out HCC. Tumor recurrence rate was 36.1% in sarcopenic patients and
only 5% in those without muscle depletion. Apart from AFP level and MVI, sarcopenia was identified as an
[74]
independent and significant promoter of HCC relapse. In series of 118 HCC LT patients, Sharma et al. were
able to demonstrate that bone mineral density (BMD), an early predictor of sarcopenia, is an independent
predictor of post-LT mortality, with HCC recurrence to be the most common cause of death. A recent meta-
analysis by Chang et al. including 13 studies and 3111 HCC patients after curative treatments concluded
[75]
that sarcopenia is correlated with both, all-cause mortality (HR = 1.95; 95%CI 1.6-2.37) and tumor recurrence
(HR = 1.76; 95%CI 1.27-2.45).

Implementing clinical features of sarcopenia in pretransplant decision making, such as the ability to walk, may
[63]
significantly improve selection process and outcome . In addition, perioperative interventions like intense
physiotherapeutic rehabilitation and nutritional treatment are able to improve posttransplant OS [76-78] . Whether
this may have a beneficial impact on oncological outcome post-LT needs to be further assessed.

Immunological dysbalance associated to malnutrition should be discovered early before sarcopenia has been
established. In this context, Nagai et al. have identified peritransplant lymphopenia, which is considered a
[78]
surrogate marker of immunosuppression and poor nutritrional status, as an independent predictor of both,
impaired OS and RFS following LT for HCC.

Liver graft injury and marginal liver grafts
Hepatic ischemia reperfusion (I/R) injury
I/R injury to the liver graft is an inevitable process during harvesting, preservation, storage and final
implantation of the organ, triggered by consecutive cold and warm ischemia periods. Severe hepatic I/
R damage increases the risk of posttransplant early allograft failure and immunological complications .
[79]
Currently, there is growing evidence from experimental studies that immune damage and pro-inflammatory
response reaction induced by allograft hypoxia promote the oncological risk [80,81] . Although the precise
molecular mechanisms have not yet been identified, it seems to be evident that I/R damage has cancerogenic
[82]
capabilities via different molecular approaches and levels . Simply put: (1) hepatic I/R produces a pro-
cancer microenvironment via microvascular disturbances, tissue hypoxia and angiogenesis; (2) resulting pro-
inflammatory response reactions render HCC cells to be more aggressive by supporting mechanisms of cell
adhesion, migration and invasion; and (3) hepatic I/R injury stimulates circulatory progenitor and immune
cells to support post-LT HCC relapse.