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Page 2 of 19 Kornberg et al. Hepatoma Res 2018;4:60 I http://dx.doi.org/10.20517/2394-5079.2018.86

Due to cirrhosis-related portal hypertension (PH) and liver dysfunction, these patients are mostly not eligible
[2]
for hepatic resection, so that only palliative treatment options have frequently been possible in former days .
In particular, the implementation of the so-called Milan criteria (MC) in 1996 for realizing a strict and rigid
selection process based on radiographic tumor size and number (one tumor nodule ≤ 5 cm, or up to 3 HCC
nodules each ≤ 3cm, no macrovascular invasion) established LT as best curative treatment option in early
[3]
stage HCC patients . The pre-MC era was characterized by high posttransplant tumor recurrence rates and
[4,5]
mortality, which was not acceptable in view of donor organ shortage . In contrast, numerous validation trials
have clearly shown that Milan-based LT for HCC produces excellent long-term survival rates above 70% at 5
[6-8]
years, which was absolutely comparable to those of other transplant indications . Therefore, the MC have
been implemented as standard selection features in large public allocation systems, such as the United Network
of Organ Sharing (UNOS) and Eurotransplant [9,10] . Currently, in times of model for end-stage liver disease
(MELD) score based organ allocation, priority is still given to patients with HCC meeting the MC [11,12] .

With increasing experience in rescue LT of marginal donor grafts and living donor liver transplantation (LDLT),
who are both independent from MELD-based allocation rules, it became evident in recent years that the MC
are too rigid and very often unjustifiably preclude patients with beyond MC tumors from potentially curative
treatment [13-15] . In order to increase the pool of eligible transplant patients, several expanded macromorphologic
tumor selection criteria have been proposed, such as the University of California San Francisco (UCSF) and
the registry based Up-to-seven (UTS) criteria [16-18] . However, as shown in the metroticket concept, increasing
[18]
“distance” from the MC burden limits enhances the oncological risk . In addition, differences between
radiologic and pathologic tumor staging additionally hamper the clinical applicability of tumor size based
selection approaches [19,20] . Poor differentiation and vascular (micro/macro) invasion of the tumor were
identified as most important predictors of unfavorable tumor biology in the LT setting [21-23] .

However, both histopathologic features may not adequately be assessed prior to LT by radiographic tools or by
using tumor biopsy [24-26] .

The identification of patients with aggressive tumor behavior is one important clinical practice to safely expand
the pool of eligible liver transplant recipients beyond the MC [27-29] . Different surrogate markers of tumor biology
were shown to improve the selection process beyond the MC, such as alpha-fetoprotein (AFP) [30,31] , protein
induced by Vitamin K absence II (PIVKA-II) [32,33] , serological inflammatory markers [C-reactive protein (CRP);
[34]
neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR)] , 18F-fluorodeoxyglucose (FDG) uptake
on positron emission tomography (PET) [35,36] and tumor downstaging under locoregional treatments [37,38] .
Apart from that, there is increasing evidence that not only tumor-specific characteristics, but also non-cancer
factors may decisively influence cancer-specific outcome. Beneficial modulations of these non-HCC related
factors might probably be another useful approach to improve post-LT prognosis, since HCC recurrence is the
major risk factor for poor overall survival (OS). Therefore, it was the major aim of this manuscript to review
the current available clinical data on the prognostic impact of non-tumor factors on post-LT HCC recurrence
and tumor-specific survival.

The role of immunology and inflammation
Immunocompetence is a major prognostic factor of outcome in cancer patients. However, a specific
characteristic of neoplasia is that it induces a state of inflammation and immunosuppression, which may
[39]
additionally impair prognosis . Since the postulation of the link between inflammation and cancer by
Virchow in 1863, important molecular mechanisms of cancer-induced pro-inflammatory response reactions
have been identified. Malignant cells were shown to release inflammatory and immunosuppressive cytokines
to their local environment, promoting tumor invasiveness and growth. In addition, cancer itself may induce