Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths
worldwide, with poor clinical outcomes due to challenges in early detection and
limited efficacy of current treatments such as receptor tyrosine kinase
inhibitors and immunotherapy. HCC exhibits significant heterogeneity at both
histopathological and molecular levels, complicating its management but offering
potential for personalized therapeutic approaches. This review outlines the
morpho-molecular heterogeneity of HCC and summarizes various histological
subtypes, including steatohepatitic, clear cell, macrotrabecular-massive,
scirrhous, lymphocyte-rich, and fibrolamellar HCCs. Each subtype possesses
distinct clinical, histological, and molecular features; for instance,
steatohepatitic HCC is associated with metabolic dysfunction and shows
IL-6/JAK/STAT activation, while clear cell HCCs often have IDH1
mutations and favorable prognosis. The macrotrabecular-massive subtype is linked
to poor outcomes and TP53 mutations, whereas scirrhous HCCs
express stemness markers and have TSC1/TSC2 mutations.
Lymphocyte-rich HCCs are characterized by immune cell infiltration and better
prognosis. CTNNB1-mutated HCCs show specific morphological
features and may benefit from targeted therapies. Understanding these subtypes
and associated molecular alterations is crucial for developing effective
diagnostic and therapeutic strategies, including potential predictive biomarkers
and personalized treatments. Additionally, the identification of patterns like
vessels-encapsulating-tumor-clusters offers prognostic implications and may
guide therapeutic decisions. Recent molecular studies have enhanced our
comprehension of HCC heterogeneity, laying the groundwork for more personalized
approaches. Pathologists play a vital role in recognizing these subtypes, aiding
in prognosis prediction and treatment planning. Advances in digital pathology
and artificial intelligence may further facilitate biomarker research,
ultimately improving patient outcomes in HCC management.