Types of Hepatocellular Carcinoma
Hepatocellular carcinoma is classified into "not otherwise specified" (NOS-HCC) and eight distinct morphological subtypes, with additional molecular and developmental classifications that carry significant prognostic implications. 1
Morphological Subtypes
The 2025 EASL guidelines recognize the following eight morphological subtypes beyond NOS-HCC 1:
- Fibrolamellar HCC - occurs typically in younger patients without cirrhosis 1
- Scirrhous HCC - characterized by abundant desmoplastic stroma 1
- Clear cell HCC - contains cells with clear cytoplasm 1
- Steatohepatitic HCC - displays histological features of steatohepatitis including ballooning, steatosis, fibrosis, inflammatory infiltrates, and Mallory-Denk bodies 1
- Macrotrabecular/massive HCC - associated with poor prognosis and aggressive behavior 1
- Chromophobe HCC - rare variant with specific cytoplasmic characteristics 1
- Neutrophil-rich HCC - characterized by prominent neutrophilic infiltration 1
- Lymphocytic-rich HCC - associated with better prognosis 1
Developmental/Size-Based Classification
For nodules <2 cm, two distinct subtypes exist based on growth pattern and differentiation 1:
- Early HCC - vaguely nodular growth pattern with well-differentiated histology; fatty change present in approximately 40% of cases 1
- Progressed HCC - distinctly nodular with moderate to poor differentiation; associated with vascular invasion and intrahepatic metastasis 1
Pathomolecular Classification
The integration of genomic, transcriptomic, and epigenomic data has enabled a pathomolecular classification that correlates morphology with biological behavior and prognosis 1:
Poor Prognosis Subtypes
- Macrotrabecular/massive phenotype - aggressive behavior with high recurrence risk 1
- Progenitor phenotype - expresses stem cell markers (cytokeratin 19, EpCAM, NCAM, CD133, SALL4, nestin) and carries poor prognosis 1
Better Prognosis Subtypes
- Lymphocyte-rich subtype - favorable outcomes compared to other variants 1
Histological Grading
Beyond subtyping, differentiation grading remains clinically important 1:
- Well-differentiated HCC 1
- Moderately differentiated HCC 1
- Poorly differentiated HCC - associated with worse outcomes in surgical and transplantation series 1
Combined Tumors
Combined hepatocellular-cholangiocarcinoma represents a distinct entity showing both hepatocellular and cholangiocellular components within the same nodule 1:
- Classical type 1
- Stem cell type with subtypes: typical, intermediate cell, and cholangiocellular 1
- Accounts for 1-15% of all cholangiocarcinomas 1
Clinical Implications
The 2025 EASL guidelines strongly recommend reporting tumor differentiation and HCC subtyping per WHO classification when biopsy is obtained, as these features have proven prognostic value 1. The macrotrabecular/massive and progenitor phenotypes warrant particular attention due to their association with poor outcomes, potentially influencing treatment decisions including transplant eligibility 1.
The steatohepatitic variant deserves special mention as it occurs in patients with MASLD/MASH and may present diagnostic challenges on imaging, with increased odds of absent washout and capsule appearance correlating with hepatic fat content 1.