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Kornberg et al. Hepatoma Res 2018;4:60 I http://dx.doi.org/10.20517/2394-5079.2018.86 Page 3 of 19

systemic immunosuppression through multiple mechanisms and effector cells, such as T-cell exhaustion,
[40]
T-regulatory cells, myeloid-derived suppressor cells and M2 macrophages . In this context, HCC has an
exceptional position, since 90% of the cases develop in underlying cirrhosis and fibrosis, which are promoted
by chronic liver inflammation. Liver damage and necroinflammation induced by alcoholic disease, non-
alcoholic fatty liver disease (NAFLD) and in particular by chronic viral hepatitis comprise a substantial
risk of carcinogenesis [41,42] . Activation of the innate immune system, hepatocyte death with production of
damage-associated molecules (DAMPs), T cell exhaustion, and upregulation of pro-inflammatory cytokines
[interleukin (IL)-2, IL-7, IL-12, IL-15, IFN-g] seem to be major molecular mechanisms. Thereby induced local
and systemic pro-inflammatory reactions and immunosuppression lead to replication stress, DNA damage
and genetic instability, which may result in development of liver cancer and impact cancer treatment [42,43] .

Another important aspect is that liver dysfunction is another important prognostic factor enhancing
tumor progression. The liver plays a key role in maintaining immunocompetence. In addition to numerous
other mechanisms triggered by its unique blood supply, it has an essential capability to remove gut-
derived microbial compounds, and hosts a great variety of innate and adaptive immune cells (sinusoidal
cells, hepatic stellate cells, Kupfer cells, dendritic cells), and is able to preserve immunotolerance to non-
pathogenic and inflammatory triggers. Decrease of these immunological efficacies result in a persistent up-
regulation of inflammatory stimuli which may promote carcinogenesis. For example, increased levels of
circulating T regulatory cells were shown to be associated with increased mortality of HCC patients [42,43] .

Currently, 2 major ways of posttransplant HCC recurrence are postulated: (1) growth of pre-LT undetected
extrahepatic micrometastases; and (2) engraftment of circulating tumor cells (CTC) that have been released
[44]
during transplant procedures . Both ways of metastasis are significantly promoted by immunological
[34]
dysbalance . In particular, patients with advanced HCC stages are at an extraordinary oncological
risk post-LT, since macromorphologic tumor load correlates with unfavorable tumor features, such
as poor grading and vascular invasion, and thereby with numbers of CTC [45,46] . A prevailing state of
immunosuppression and pro-inflammation in the peritransplant period might, therefore, be particularly
dangerous for advanced HCC LT patients. Consequently, recipients’ factors (cirrhosis, sarcopenia), liver graft
quality, surgical procedure and post-LT immunosuppressive treatment as non-cancer features affecting the
immunological state have to be considered in order to safely expand the patient selection criteria.

Recipients’ factors
Background liver cirrhosis
Progressive liver cirrhosis induces complex pro-inflammatory and immunosuppressive mechanisms referred
[47]
to as cirrhosis-associated immune dysfunction (CAID) syndromes . This may impair outcome following
non-surgical treatment and hepatic resection [48,49] . This aspect has not yet been intensively studied in the LT
setting so far, which may be due to the fact that most HCC transplant patients present with less severe Child
A or B cirrhosis and liver dysfunction are cured by liver replacement, probably implying that CAID has
no influence on posttransplant clinical course. However, some interesting recent data have shown that the
extent of background native cirrhosis may affect cancer-specific outcome in the LT setting [Table 1]. Already
[50]
in 2008, Ioannou et al. demonstrated in a large study cohort using the UNOS database, that apart from
increased AFP level, laboratory (lab.)MELD score ≥ 20 was the most important predictor of poor post-LT
[51]
survival. Again by using the UNOS dataset of 3519 liver transplants, Halazun et al. identified pretransplant
rising (lab.)MELD score as an independent predictor of microvascular invasion (MVI) on explant pathology,
which in turn was the most important factor of poor cancer-specific outcome. Others have recently confirmed
the oncological significance of background cirrhosis severity in the liver transplant setting [52-54] . In a series
[55]
of 243 transplant candidates with HCC, Faitot et al. demonstrated that clinically evident portal PH was