# Extrahepatic Recurrence After Surgical Resection of Hepatocellular Carcinoma Without Intrahepatic Recurrence: A Multi-Institutional Observational Study

## TL;DR

This study finds that certain tumor features increase the risk of liver cancer spreading outside the liver after surgery, even when no cancer remains in the liver.

## Contribution

The study identifies specific risk factors for extrahepatic recurrence in patients with no detectable intrahepatic recurrence after liver cancer surgery.

## Key findings

- Microvascular invasion, tumor necrosis, and advanced tumor stage significantly increase the likelihood of extrahepatic recurrence.
- Extrahepatic recurrence is strongly linked to decreased survival after liver cancer surgery.
- Patients with EHR experienced earlier initial recurrence compared to those without EHR.

## Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and its recurrence outside the liver, known as extrahepatic recurrence (EHR), is associated with poor prognosis. While EHR typically occurs in patients with high-risk factors, its development without detectable HCC remaining in the liver is not well understood. This study aims to identify the clinical characteristics and risk factors associated with EHR in patients who have undergone curative liver surgery for HCC. By analyzing data from 569 patients, we found that microvascular invasion, tumor necrosis, and advanced tumor stage significantly increased the likelihood of EHR. Furthermore, EHR was linked to shorter survival after surgery. These findings highlight the importance of close monitoring in high-risk patients, as detecting and managing EHR early may improve outcomes.

Background/Objectives: Extrahepatic recurrence (EHR) is a significant negative prognostic factor in hepatocellular carcinoma (HCC). Although EHR is commonly observed in high-risk patients following HCC hepatectomy, its occurrence without concurrent intrahepatic HCC remains poorly understood. Therefore, this study aims to examine the clinical characteristics and risk factors associated with EHR in patients without intrahepatic HCC at diagnosis. Methods: This study included 1066 treatment-naïve patients who underwent curative hepatectomy for HCC at four tertiary academic centers between January 2004 and December 2019. After excluding those with intrahepatic recurrence (IHR), concurrent EHR, or incomplete clinical records, 569 patients were included in the final analysis. Risk factors for EHR were assessed using multivariate Cox regression over a median follow-up period of 3.91 years. Results: Among the cohort, 38 patients developed EHR post-surgery without residual intrahepatic HCC, with a median follow-up of 1.04 years. These patients experienced earlier initial HCC recurrence than those without EHR (1.73 vs. 4.43 years). Multivariate analysis revealed significant associations between EHR and microvascular invasion (hazard ratio [HR]: 2.418, p = 0.020), tumor necrosis (HR: 2.592, p = 0.009), and initial tumor staging beyond the Milan criteria (HR: 3.008, p = 0.001). Moreover, Cox regression analysis revealed that EHR strongly correlated with decreased post-hepatectomy survival (HR: 14.044, p < 0.001). Cumulative EHR and survival rates were closely linked to the number of risk factors present. Conclusions: EHR without detectable IHR is significant and warrants close monitoring in high-risk patients.