Macrotrabecular HCC- Hepatology 26

Hepatocellular carcinoma (HCC) displays marked histologic heterogeneity that reflects distinct biological behaviors and treatment responses. Among recognized variants, macrotrabecular–massive HCC (MT-HCC) represents a particularly aggressive subtype characterized by thick tumor trabeculae wrapped by endothelial cells. A related vascular phenotype, vessels encapsulating tumor clusters (VETC), shares a similar “inverted” tumor–vessel architecture. Both patterns are strongly associated with early recurrence, metastasis, and poor prognosis.

This commentary highlights emerging insights into the immunovascular biology underlying MT and VETC patterns. These tumors exhibit high expression of angiogenic factors such as VEGF-A and angiopoietin-2 and are frequently linked to oncogenic drivers including TP53 mutation, MYC activation, and Wnt/β-catenin signaling. The abnormal vasculature not only facilitates hematogenous spread but also contributes to an immunosuppressive microenvironment, marked by reduced T-cell infiltration and diminished interferon-γ–related signaling.

Recent experimental work demonstrates that additional mediators, notably angiopoietin-like protein 2 (ANGPTL2) and IL-11, play key roles in shaping the macrotrabecular vascular pattern and suppressing antitumor immunity. Importantly, inhibiting angiogenic signaling—either genetically or pharmacologically—restores immune infiltration and enhances responsiveness to immune checkpoint blockade in preclinical models.

Clinically, MT and VETC patterns can increasingly be inferred through imaging features, such as heterogeneous arterial enhancement, enabling noninvasive risk stratification. These findings support combined anti-angiogenic and immunotherapeutic strategies and underscore the need for integrated pathologic, radiologic, and immune profiling to guide personalised treatment in HCC.