How Should We Assign Large Infiltrative Hepatocellular Carcinomas for Staging?

Infiltrative gross morphology of hepatocellular carcinoma (HCC) is known to be associated with poor prognosis, but this is not considered for staging. A total of 774 HCC patients who underwent curative liver resection were retrospectively reviewed and the prognostic significance of infiltrative type HCC was assessed using the American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) staging systems. Seventy-four patients (9.6%) had infiltrative HCCs with a higher proportion of multifocal tumors, larger tumors, vessel invasion, increased tumor marker levels, and advanced T-stages than those with nodular HCC (all, p < 0.01). Infiltrative morphology was independently associated with lower overall survival (OS), but its impact was significant when the tumor size was ≥ 4 cm (p < 0.001). Under current AJCC and BCLC staging criteria, these large infiltrative HCCs were associated with significantly worse OS in early AJCC T-stages (T1b/T2, p < 0.001) and BCLC stage A/B (both, p < 0.01) but not in late AJCC (T3/T4) and BCLC C. The reassignment of this subtype to T3 and T4 increased the discriminatory ability of AJCC T-staging with lower AIC values (3090 and 3088 vs. 3109) and higher c-index (0.69 and 0.69 vs. 0.67), respectively (both, p < 0.001). Similarly, the reassignment of large infiltrative HCC to BCLC stages B and C also improved the prognostic performance. Large infiltrative HCCs should be assigned to more advanced stages in current staging systems for their prognostic impact.