The histology of a tumor still matters in the era of molecular medicine because almost all solid cancers are managed according to their stage, which is defined for specific histological types [1]. Tumor stage is a combination of the T (tumor), N (nodal), and M (metastatic) categories, and the criteria for choosing specific categories depend on the histological type of the tumor. Determining the histological type of a tumor is mainly based on the World Health Organization (WHO) classification of tumors. Recently, updated versions of this classification system introduced a new section, termed ‘Subtype(s)’ in each major chapter. Thus, in the 2019 WHO classification of digestive system tumors (fifth edition), the ‘Subtype(s)’ of hepatocellular carcinoma (HCC) are modified and summarized as fibrolamellar, scirrhous, clear cell type, steatohepatitic, macrotrabecular massive (MTM), chromophobe, neutrophil-rich, and lymphocyte-rich [2]. In the fourth edition, these subtypes were described as “variants” which were explained under the section, ‘Histopathology’; thus, ‘Subtype(s)’ in the new edition is an upgraded and refined version of ‘variants’. The term, ‘variants’, was discarded because of its association with the concept of genetic alteration.

HCC is a morphologically heterogeneous tumor with varied features that are often observable by the naked eye. HCC is the most common histological type of the primary liver cancer and the second cause of cancer-related death in male patients worldwide [3], [4]. Although HCCs are relatively well-differentiated tumors, occasionally, mass-forming intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma, as well as metastatic tumor, should be ruled out in diagnosing HCC, when the tumor is poorly differentiated and/or has conspicuous sclerotic stroma. Assigning an HCC to an appropriate subtype is increasingly important because this guarantees the diagnosis and treatment and allows decisions regarding the prognosis of the patient.

In the fourth edition of the WHO classification of digestive system tumors, ‘Architectural patterns’ and ‘Cytological variants’ were described under the section ‘Histopathology’ of HCC. Combinations of various architectural patterns (trabecular [plate-like], pseudoglandular or acinar, and compact) and cytological variants (pleomorphic, clear, spindle, fatty change, bile production, hyaline bodies, pale bodies, and ground glass inclusions) can be identified in HCC. These combined appearances were integrated into ‘Special types of carcinoma’ as follows: fibrolamellar carcinoma, scirrhous HCC, undifferentiated carcinoma, lymphoepithelioma-like carcinoma, and sarcomatoid hepatocellular carcinoma. Among these special types, fibrolamellar carcinoma and scirrhous HCC were retained as subtypes in the fifth edition of the classification. ‘Lymphoepithelioma-like carcinoma’ was renamed as ‘lymphocyte-rich’ and a new inflammatory subtype, ‘neutrophil-rich’, was added. Clear cell and steatohepatitic types were included in the fifth edition, with adjustment of the former cytological variants–clear cells, fatty change, and hyaline bodies. In addition, MTM and chromophobe type were newly defined.

However, HCC subtypes have not been fully explained and have limited clinical relevance [2]. For example, there are doubts concerning whether the steatohepatitic type represents a true subtype. Moreover, the minimum percentage of clear cells for distinguishing the clear cell subtype has not been defined. Depending on the researcher, the cut off of 30 %, 50 % or 80 % may be applied [2], [5], [6], [7], [8]. Therefore, although the classification system has evolved over the last decades, assigning a non-classical HCC to an appropriate subtype remains challenging in practice. Some HCCs fit into more than one or none of the subtype classifications. This may be partly because carcinogenesis of HCC is complex and heterogeneous [9]. HCC is caused by viral infection (mainly due to hepatitis B and C viruses [HBV and HCV, respectively]), metabolic abnormalities (obesity or diabetes), alcohol consumption, or many other etiologies. Each etiology contributes to HCC through its own pathways and might affect the morphology of HCC.

We adopted the 2019 WHO HCC classification system and reclassified archived cases. The aim of this study was to evaluate the clinical relevance of HCC subtyping based on the 2019 WHO classification system and to reappraise some of the major subtypes.