Metastasis in Patients With Hepatocellular Carcinoma

Prevalence, Determinants, Prognostic Impact and Ability to Improve the Barcelona Clinic Liver Cancer System

Chia-Yang Hsu; Po-Hong Liu; Shu-Yein Ho; Yi-Hsiang Huang; Yun-Hsuan Lee; Rheun-Chuan Lee; Teddy S. Nagaria; Ming-Chih Hou; Teh-Ia Huo


Liver International. 2018;38(10):1803-1811. 

In This Article

Abstract and Introduction


Background & Aim: Patients with hepatocellular carcinoma and metastasis are classified as advanced or terminal stage by the Barcelona Clinic Liver Cancer system. This study investigates the prevalence, determinants, and prognostic effect of metastasis and its ability to improve the Barcelona Clinic Liver Cancer system.

Methods: A total of 3414 patients were enrolled. The Kaplan-Meier and Cox regression methods were used to determine survival predictors. Akaike information criterion was used to compare the prognostic performance of staging systems.

Results: There were 357 (10%) patients having extrahepatic metastasis at the time of diagnosis. Metastases were associated with old age, alcoholism, hepatitis B, poorer liver function, higher α-foetoprotein level and larger tumour burden (all P < .05). Vascular invasion was associated with metastasis regardless of total tumour volume, and higher α-foetoprotein level and multiple tumours were associated with metastasis in patients with smaller tumour volume (all P < .05). Patients with both vascular invasion and metastasis had significantly worse outcome compared to patients with either vascular invasion or metastasis (P < .05). In the Cox proportional model, the co-existence of vascular invasion and metastasis was an independent predictor of decreased survival (P < .05). Re-allocating 181 Barcelona Clinic Liver Cancer stage C patients with both vascular invasion and metastasis into stage D was associated with lower Akaike information criterion, indicating enhanced prognostic power of the Barcelona Clinic Liver Cancer.

Conclusions: Metastasis is not uncommon, and is strongly associated with tumoural factors and poor long-term survival in hepatocellular carcinoma. Modification of the Barcelona Clinic Liver Cancer system based on vascular invasion and metastasis may further improve its predictive accuracy in advanced stage patients.


Hepatocellular carcinoma (HCC) is one of the most common malignancy worldwide. The Barcelona Clinic Liver Cancer (BCLC) staging system is the recommended staging model endorsed by major academic societies of liver disease.[1,2] Tumour burden, severity of cirrhosis and performance status (PS) are closely associated with survival and serve as the cornerstones of the BCLC system for prognostic prediction. Tumour burden is typically evaluated with size and number of tumours, vascular invasion and metastasis (including lymphatic involvement) by the BCLC system. However, patients with large tumour volume, vascular invasion and distant metastases may still not be regarded as terminal stage if they have preserved liver function and PS. Our recent study disclosed the significant prognostic effect of tumour burden on BCLC stage D HCC patients,[3] and currently, there is no study supporting that the predictive accuracy of BCLC system might be improved by integrating tumour burden into the criteria of BCLC stage D.

Extrahepatic metastasis has been found in approximately 10% of HCC, which is relatively rare compared to patients with other prominent malignancies.[4,5] Metastasis is often associated with sizable intrahepatic lesions and also vascular invasion,[6] and the most common sites of metastasis are lungs, lymph nodes, bones and adrenal glands.[4] The survey of metastasis at the time of diagnosis has not been standardized, and very little is known about the prognostic effect of metastasis on HCC patients given independent reports showed that the causes of death in HCC patients with metastasis were mainly from intrahepatic tumor(s) or liver failure.[5,7,8] A more recent study showed that the co-existence of vascular invasion and metastasis predicted significantly decreased overall survival compared to patients with vascular invasion alone or metastasis alone among BCLC stage C patients.[9] In this study, we comprehensively investigated the prevalence, associated factors and prognostic impact of metastasis in a large prospective cohort of HCC patients, and proposed a modified BCLC system based on metastasis to further enhance its predictive accuracy.