Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study

Abstract

Background: The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients.

Methods: After we assessed the trend of patients who were first diagnosed with HCC at 53 tertiary care centers in Japan from 1991 to 2010, we collected detailed data of 5326 patients with non-viral etiology. The etiologies were categorized as autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), unclassified, and other. Baseline characteristics at initial diagnosis, the modality of the initial treatment, and survival status were collected via a website. Survival of the patients was assessed by the Kaplan-Meier method and Cox proportional hazard regression.

Results: The proportion of patients with non-viral etiologies increased from 10.0% in 1991 to 24.1% in 2010. Of the patients, 92% were categorized as ALD, NAFLD, or unclassified. Body mass index (BMI) was ≥ 25 kg/m(2) in 39%. Diabetes was most prevalent in NAFLD (63%), followed by unclassified etiology (46%) and ALD (45%). Approximately 80% of patients underwent radical therapy, including resection, ablation, or transarterial chemoembolization. Survival rates at 3, 5, 10, 15, and 20 years were 58.2, 42.6, 21.5, 15.2, and 15.2%, respectively. Multivariate analysis revealed that patients with BMI > 22 and ≤ 25 kg/m(2) showed the best prognosis versus other BMI categories, after adjusting by age, gender, tumor-related factors, and Child-Pugh score.

Conclusions: Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes. Slightly overweight patients showed the best prognosis.

Fig. 1

Trend in background liver disease in hepatocellular carcinoma in Japan. A marked increase in the proportion of patients categorized as non-B, non-C in the participating hospitals was observed (p < 0.001 by Cochran–Armitage test)

Fig. 2

Body mass index according to background liver disease. Median (25th–75th percentiles) BMI values in all categories were 23.8 (21.6–26.3) kg/m² in males and 24.4 (21.8–27.5) kg/m² in females. Box plot ‘whiskers’ show the minimum and maximum values; the horizontal line in each box plot shows the median, and the colored segment shows the interquartile range. AIH autoimmune hepatitis, PBC primary biliary cirrhosis, ALD alcoholic liver disease, NAFLD non-alcoholic fatty liver disease

Fig. 3

Overall survival. A Overall survival of the entire patient cohort. Overall survival rates at 1, 3, 5, 7, 10, 15, and 20 years were 80.1, 58.2, 42.6, 32.2, 21.5, 15.2, and 15.2 %, respectively. B Overall survival according to BCLC stage. Survival rates at 1, 3, 5, 7, 10, 15, and 20 years were 94.5, 76.4, 58.7, 44.7, 30.7, 21.9, and 21.9 % in stage A, 71.1, 44.1, 29.1, 22.2, 13.0, 9.0, and 9.0 % in stage B, 44.6, 18.8, 15.5, 9.3, and 9.3 % in Stage C, and 48.0, 24.4, 12.3, 7.3, 3.1 %, respectively, in Stage D

Fig. 4

Multivariate Cox proportional hazard regression analysis of survival. AFP alpha-fetoprotein, AFP-L3 lens culinaris agglutinin-reactive fraction of AFP, DCP des-gamma-carboxy prothrombin AFP alpha-fetoprotein, AFP-L3 lens culinaris agglutinin-reactive fraction of AFP, ALT alanine aminotransferase, Anti-HBcAb anti-hepatitis B core antibody, DCP des-gamma-carboxy prothrombin, IQR interquartile range