Distinct patterns of late recurrence in long-term hepatocellular carcinoma survivors

Among patients with hepatocellular carcinoma (HCC), late recurrence - defined as recurrence occurring ≥2 years after treatment - has often been treated as a singular, uniform event, despite being inherently heterogeneous and driven by diverse biologic mechanisms. This study aimed to identify prognostic factors associated with recurrence among long-term survivors of HCC after treatment, with particular emphasis on the role of underlying liver fibrosis and intrinsic tumor aggressiveness.

Patients who underwent hepatectomy for HCC between 2000 and 2021 were identified from an international database. The prognostic factors for recurrence-free survival (RFS) were evaluated using multivariate Cox regression. The recurrence timing patterns were assessed using kernel density plots.

Among 769 patients, 166 (21.6%) developed late recurrence. Compared with patients who did not experience late recurrence, individuals who experienced late recurrence had a higher fibrosis-4 (FIB-4) index (median: 2.09 vs 2.31, respectively; P =.002) and tended to have more frequent microvascular invasion (13.6% vs 19.3%, respectively; P =.089). A high FIB-4 index (hazard ratio [HR], 1.090 [95% CI, 1.011-1.174]; P =.024) and the presence of microvascular invasion (HR, 2.064 [95% CI, 1.260-3.383]; P =.004) were independently associated with worse RFS. Patients were stratified into low-, intermediate-, and high-risk groups based on these factors relative to RFS (P =.027). The hazards of recurrence at 5 years were 2-fold higher among high-risk patients (HR, 2.07 [95% CI, 1.20-3.59]) and 34% higher among intermediate-risk patients (HR, 1.34 [95% CI, 0.93-1.95]) (both P <.05). Kernel density plots demonstrated that microvascular invasion was associated with a peak in recurrence risk at approximately 3 years and that a high FIB-4 index was associated with a more gradual and sustained risk, peaking at approximately 4 years that persisted beyond 5 years.

A high FIB-4 index and microvascular invasion were independent predictors of late recurrence. Distinct temporal risk patterns emphasize the need for tailored, risk-based postoperative surveillance to enhance detection and early intervention of HCC recurrence.