Ewha Med J.  2024 Oct;47(4):e58. 10.12771/emj.2024.e58.

The histopathological and molecular heterogeneity of hepatocellular carcinoma: a narrative review

• Chung W
• Kim H

• KMID: 2561406
• DOI: http://doi.org/10.12771/emj.2024.e58

Abstract

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-encapsulatingtumor-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.

Keyword

Carcinoma, hepatocellular; Liver; Pathology

Figure

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  Fig. 1. Microscopic features of a typical hepatocellular carcinoma (HCC). (A) Non-neoplastic hepatocytes (lower half) and HCC tumor cells (upper half) are separated by a fibrous capsule. (B) Trabecular pattern HCC with steatosis. (C) Pseudoglandular pattern HCC with cholestasis (Hematoxylin-Eosin stain, original magnification ×100 [A,B], ×200 [C]).

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  Fig. 2. Steatohepatitic hepatocellular carcinoma (HCC). (A) The tumor demonstrates a yellow hue on macroscopy reflecting the lipid component. (B) High power magnification showing the diffuse steatosis of tumor cells, tumor cell ballooning (arrow), some inflammatory cells, and pericellular fibrosis (Hematoxylin-Eosin stain, original magnification ×400).

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  Fig. 3. Clear cell hepatocellular carcinoma (HCC). Most of the tumor cells demonstrate clear cytoplasm due to glycogen accumulation (Hematoxylin-Eosin stain, original magnification ×200).

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  Fig. 4. Macrotrabecular-massive hepatocellular carcinoma (HCC; A) and vessels-encapsulating-tumor clusters (VETC) pattern (B). (A) Macrotrabecular-massive HCC demonstrating thick tumor cell trabeculae, of more than 10-cell thickness (Hematoxylin-Eosin stain, original magnification ×100). (B) CD34 immunostain highlighting the VETC pattern, where the CD34-positive endothelial cells completely surround tumor cell clusters.

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  Fig. 5. Scirrhous hepatocellular carcinoma (HCC). (A) The tumor appears as a firm, yellowish-white and lobulated mass on gross examination, mimicking an intrahepatic cholangiocarcinoma. (B) Dense intratumoral fibrosis is evident at low power magnification (Hematoxylin-Eosin stain, original magnification ×40). (C) Immunohistochemical expression of cytokeratin 19 is seen in a few tumor cells.

Reference

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