Table 1.

Various difficult cases and the points of differentiation

Various difficult cases	Points of differentiation
1. Dysplastic nodules	Difficult to diagnose definitively by biopsy If resected or autopsied specimen shows parenchymal atypia as intermediate features between benign liver tissue and well differentiated HCC and no stromal invasion, a definitive diagnosis is made
2. Very well differentiated HCCs	Difficult to diagnose definitively by biopsy If resected or autopsied specimen shows stromal invasion, a definitive diagnosis is made
3. Large regenerative nodules with high cellularity	Difficult to diagnose definitively by biopsy However, comparison with extra-nodular control tissue is sometimes useful. In such cases, control tissue also shows high cellularity to some extent
4. Mixture of HCC cells and benign cells	Difficult to diagnose definitively by biopsy Careful examination is necessary in resected or autopsied specimens
5. Well differentiated HCCs with marked fatty change	Tumor tissue without fatty change should be searched If this tissue shows the features of well differentiated HCC (hypercellularity double of that in control tissue), a definitive diagnosis is made
6. Benign large regenerative nodules with marked fatty change	Nodule tissue without fatty change should be searched If this tissue shows the same features as control tissue, the diagnosis is benign liver tissue (a large regenerative nodule or sampling error)
7. Thick sliced specimens with high cellularity and strong stainability of cytoplasm	Specimens must be processed carefully. Nodule tissue and control tissue must be sliced at the same thickness and stained with the same conditions
8. Focal nodular hyperplasia (FNH) with high cellularity and microacinar formation	Difficult to diagnose definitively only by biopsy However, a comprehensive evaluation of biopsy specimens and imaging findings is very usefula

HCC: hepatocellular carcinoma, FNH: focal nodular hyperplasia

^aWhen the biopsy specimen shows histology of well differentiated HCC or FNH, silver staining for reticulin fibers is recommended. If the lesion shows loss of reticulin fibers, it is diagnosed as an HCC. If the lesion shows intact reticulin fibers, vascularity of the lesion in imaging findings should be evaluated. If it is a hypo-vascular (hypo-arterial) lesion, it is very likely to be a well differentiated HCC. If it is a hyper-vascular lesion, it is very likely to be an FNH. A (very) well differentiated HCC with intact reticulin fibers is usually hypo-vascular in imaging findings, while an FNH and a moderately differentiated HCC are usually hyper-vascular