Patients and Phenotypes

Histopathological specimens were obtained from a total of 210 patients with multifocal HCC transplanted between 2005 and 2014 at transplant centers University Hospital Schleswig-Holstein Campus Kiel, Charité Campus Virchow Klinikum Berlin, University Hospital Regensburg, University Hospital Muenster, and Hannover Medical School. Informed consent was obtained from all patients, and the study was approved by the local ethics committee of the University Hospital Schleswig-Holstein Campus Kiel. For each patient, a formalin fixed paraffin embedded (FFPE) specimen from 2 different tumor locations and from the explanted cirrhotic liver was retrieved from the pathology archives. Clinical data was obtained from the respective routine clinical documentation. Median patient follow up was 1634 [1091-2137] days after transplantation. Assessed parameters were sex, age at time of LTx, type of concurrent liver disease, hepatitis and type of hepatitis, type of bridging therapy, response to bridging therapy, lab-MELD at time of LTx, retransplantation, length of follow-up, type of immunosuppression, Tumor Nodes Metastasis (TNM) status according to the 7^th Edition, tumor grading, number and cumulative size of tumor lesions (≥8 cm), tumor stage related to up to 7, Milan and UCSF criteria, AFP-level before LTx (≥20, ≥200, ≥400 ng/mL), tumor recurrence and localization of the recurrent disease, survival and tumor-free survival. After LTx, tumor staging of the liver explant was carried out using a histopathological examination. Tumor recurrence was diagnosed by positive histology, elevated AFP >400 ng/ml in combination with hyper vascularized lesions detected by MRI or CT or hypervascularized lesions detected by 2 different methods, including MRI or CT according to the guidelines of the federal German Medical Association. Patients and tumor characteristics are shown in Table ​Table1.1. Patients with a survival below 60 days after transplantation were excluded from the analysis to avoid confusion of perioperative mortality with long-term survival determined by tumor biology, which was the focus of this analysis.

Clinical characteristics of the study population