Methods
Aiming at a clinical characterization of patients with HCC in NCL, a retrospective analysis in a large single-center cohort in Germany was performed. Patients with HCC in NCL were compared to patients with HCC in LC with respect to demographic and clinical characteristics. Additionally, factors influencing the survival of patients with HCC in NCL were analyzed.
The medical records of 714 patients diagnosed and treated with HCC at the University Hospital of Magdeburg between February 1994 and January 2013 were analyzed retrospectively. The analysis included patients who were referred to the Department of Gastroenterology, Hepatology and Infectious Diseases, to the Department of Surgery or to the Department of Radiology and Nuclear Medicine. After excluding patients in whom sufficient data was not available for the purpose of this study, 664 patients were included into the final analysis. Of these, 571 were diagnosed with HCC in LC and 93 patients (14.01%) suffered from HCC in a non-cirrhotic liver.
The retrospective analysis was performed following the guidelines of the Declaration of Helsinki and approved by the ethical review committee of the Otto-von-Guericke University Magdeburg, Germany.
Epidemiological Data
Age, gender, height, weight, calculation of body mass index (BMI) and performance status at the time of diagnosis were recorded.
Liver cirrhosis was either diagnosed histologically or by typical clinical signs, i.e. findings consistent with portal hypertension (enlarged spleen, ascites, esophageal or gastric varices or portal hypertensive gastropathy) combined with sonographical findings. The diagnosis of a non-cirrhotic liver was based on reports of the histopathological evaluation of liver tissue obtained by surgery at time of the resection of HCC or obtained by biopsy from the non-tumor-tissue at the time of diagnosis of HCC. Patients without histological sampling were classified as non-cirrhotic if they were completely free of any evidence of cirrhosis based on clinical, laboratory and radiological findings.
Liver cirrhosis was considered to be a consequence of chronic alcohol abuse if the patient had reported a consumption of more than 60 g alcohol/day or if a history of chronic alcohol abuse was documented in the past medical history. Data on the status of hepatitis B viral infection was available for all and on hepatitis C virus infection for 643 patients.
Information on prevalence of diabetes mellitus as a metabolic risk factor was available for 427 patients. NAFLD was diagnosed by criteria for steatosis in transabdominal ultrasound in the absence of other possible causes of liver disease.
Serum Parameters
To diligently characterize underlying chronic liver disease with respect to liver function, inflammatory activity and etiology, a panel of parameters on clinical chemistry were extracted from the medical records. These included levels of bilirubin, albumin, quick, prothrombin time, alkaline phosphatase, gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, creatinine, hemoglobin, platelet count, urea nitrogen and protein. If available, levels of ferritin, transferrin saturation, immunoglobulin (Ig) G, IgA, IgM, coeruloplasmin, antinuclear antibodies, antibodies against soluble liver antigen, anti-liver kidney microsomal antigen and alpha-1-antitrypsin were analyzed, too. Additionally, the level of alpha-fetoprotein (AFP) at the time of diagnosis was evaluated. All serum parameter values were classified according to a specified threshold for explorative analyses on parameters' impact on survival.
Tumor Stage
Radiological reports were used for the assessment of tumor stage. Number and size of HCC nodules as well as the presence of distant metastases including lymph node involvement and information on the patency of the portal vein were recorded. The Barcelona-Clinic Liver Cancer (BCLC) stage was defined respecting tumor stage, liver function as assessed by Child-Pugh-score in patients with LC and clinical performance status of the patient. Additionally, the CLIP score was rated for all patients if possible.
Survival Data
In 397 cases the exact date of death was taken from the medical records. For the remaining patients, data on survival was censored at the time of the last documented contact to the patient. Thus, the length of survival was calculated from the date of HCC diagnosis to the date of death or to the date of the last documented contact, respectively.
Statistical Analysis
All statistical analyses were performed using IBM SPSS Statistics 21.0.0 (IBM Corporation, New York, N.Y., USA). Results for numerical data are given as median together with minimum and maximum of the sample (i.e. range). For categorical data, results are given as absolute numbers with percentage. For comparison of categorical data, Chi-Square-tests were applied. Mann–Whitney U–tests were used for testing homogeneity of independent samples in continuous data. For the analysis of individual factors influencing survival Cox regression analyses were performed. Factors that were shown to have a significant input on patients' survival at univariate analysis were included into a multivariate Cox regression analysis except for the two staging systems (CLIP score and BCLC score) that are influenced by several of the clinical and tumor related factors. Median survival times that were also compared by log-rank tests and Kaplan-Meier curves are given for single influencing factors. All tests were carried out two-sided. The level of significance was set to 0.05 without adjusting for multiplicity. The analysis has to be regarded as explorative.