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Hepatocellular carcinomas are heterogeneous tumours with many levels of heterogeneity. This heterogeneity has been explored for many years in order to individualize patient care, and it has resulted in the identification of various hepatocellular carcinoma subtypes identified by morphological and/or genetic approaches. This study examines both gross and histological degrees of heterogeneity within hepatocellular carcinoma, with a focus on histological results, and discusses how various levels of histological heterogeneity are employed as building blocks to form morphological hepatocellular carcinoma subtypes. Three techniques are offered for better research on hepatocellular carcinoma subtypes:

• Use a systemic, rigorous approach to defining hepatocellular carcinoma subtypes (four point model)

• Once a definition for a subtype is established, it should be followed in research studies, as this common denominator improves the ability to compare results between studies

• Subtype studies will be more effective when morphological and molecular results are used in synergistic and study designs, where the results of one approach are used to refine the results of another.

Historically, hepatocellular carcinomas were thought to be a single homogeneous tumour, but many different layers of heterogeneity have been recognized over time, including aetiology, clinical presentation, and the degree of fibrosis in the background liver, radiology findings, H&E morphology, molecular studies, and outcomes.

This heterogeneity is crucial to comprehend because it has the potential to influence all critical elements of patient care, including as diagnosis, therapy, and prognosis, as well as provide insight into the aetiology of hepatocellular carcinoma, which may lead to even better therapies. Despite decades of progress in many areas, especially in identifying the most common etiologies of hepatocellular carcinoma and improving diagnostic tools (laboratory testing, radiology, histology), the complexities within these layers of heterogeneity have been difficult to sort out in order to maximize individual patient care.

This study focuses on histological heterogeneity, summarizing current state-of-the-art understandings and describing how histological heterogeneity is employed as building blocks to construct more significant hepatocellular carcinoma subtypes.

Macroscopic heterogeneity

A small hepatocellular cellular carcinoma has a diameter of less than 2 cm. They are divided into two primary subgroups based on whether the hepatocellular carcinoma is well confined and distinguishes itself from the surrounding liver (distinctly nodular) or not (vaguely nodular). The vaguely nodular appearance is assumed to be the result of dysplastic nodules, and it typically has a few remnant portal tracts. Vaguely nodular hepatocellular carcinomas are nearly typically seen in livers with severe fibrosis/cirrhosis (>90%) and are highly differentiated (>90%). They often lack a well-developed pseudocapsule, are hypovascular on imaging, and show vascular penetration relatively infrequently (5%). The distinctively nodular type of small hepatocellular carcinoma, on the other hand, is more likely to have a pseudocapsule (50%), to be moderately differentiated (60%), to be hypervascular on imaging, and to have vascular penetration (40%). Hepatocellular carcinomas have shown several macroscopic growth patterns. The nodular and large types develop as separate nodules, with or without smaller satellite nodules. The nodular kind can be any size, but the large type replaces nearly an entire liver lobe. Pedunculated hepatocellular carcinomas protrude from the capsule surface as mass lesions. Diffuse hepatocellular carcinoma develops as a proliferation of tiny tumour nodules that resemble cirrhotic nodules in size and form (synonym is cirrhotomimetic).

Histological heterogeneity

Pathologists must detect when various morphologies are consistent with hepatocellular carcinoma even when they're not. Histological heterogeneity is crucial at the diagnostic level. Pathologists detected and documented a wide range of histological changes in the morphology of hepatocellular carcinoma as a result of this critical diagnostic necessity. They have established strong immunostain techniques to confirm hepatocellular carcinoma diagnosis across a wide range of shapes. Many of the various findings that comprise histological heterogeneity have been employed as building blocks to create unique hepatocellular carcinoma subtypes throughout time; this latter use will be highlighted in this study. These fundamental building components are broadly characterized as (1) cytological discoveries of individual tumour cells, (2) architectural development patterns, or (3) alterations within the tumour matrix, such as fibrosis or inflammation.

Cytological heterogeneity

Clear cell change, fatty change, bile production, pale bodies, Mallory Denk bodies, and hyaline bodies are the most prevalent cytoplasmic findings. Lipofuscin pigmentation and large cell transformation are uncommon alterations. Clear cell and fatty changes are distinguishing characteristics of the clear cell and steatohepatitic types of hepatocellular carcinoma, respectively. Bile production is not mutation-specific, however it is more prevalent in CTNNB1-mutated hepatocellular carcinomas. Similarly, pale bodies are more prevalent in fibrolamellar carcinoma than in typical hepatocellular carcinoma but are not distinctive to the disease. Hyaline bodies have been associated to a adverse prognosis, but not Mallory Denk bodies.