Cirrhosis is defined as a diffuse fibrosing disease secondary to liver injury, usually low-grade chronic injury. However, unlike the scar fibrosis that accompanies injury elsewhere, this fibrotic process is dynamic and has a nodular pattern due, in part, to the pressure of the regenerating liver cells. If hepatocyte injury to the entire liver is uniform, as seen in alcohol abuse, and every acinus is uniformly damaged, the fibrosis splits the acini into small fragments, which on regeneration form tiny nodules less than 3 mm in size, that is, micronodular cirrhosis [1
]. If the injury to the liver is less uniform, as in hepatitis B, then the fibrosis is irregular, and both preserved and destroyed acini are seen within the larger areas bound by the fibrous bands, that is, macronodular cirrhosis. However, as regeneration, pressure ischaemia, fibrosis, ischaemic cell death, etc. are ongoing processes, the nodules keep remodelling and micronodular cirrhosis can become macronodular cirrhosis over time, and vice versa [2
The proliferation of reparative capillaries within the fibrous tissue and increase in hepatic arterial branches lead to arterialization. Arterialization leads to fast flow, avoiding the usual percolation of portal blood around the hepatocytes. This results in virtual shunting of blood through the liver depriving the lobules of hepatocytes of their usual share of portal blood, leading to further cellular atrophy and loss.
Hepatocytes that normally have a low turnover rate begin to regenerate rapidly in cirrhotic livers. Frequently multiplying cells are prone to errors in nuclear DNA, and thus cells may be created, which if ‘blessed’ by activated proliferative advantages can form clonal clusters. These hyperactive clones multiply, eventually occupying the whole regenerating nodule. As these are rapidly multiplying, closely packed and hypercellular, these nodules tend to bulge on the cut surface. As they represent a distinct clone, they may also be distinct by way of colour and texture when compared with the surrounding regenerative nodules. Mild dysplasia, with lesser proliferative advantages, would be slow growing, and have time to mature. Cells would have near-normal amount of cytoplasm, less atypia, and would be difficult to distinguish from the surrounding regenerating cells. Without tests of monoclonality, and other molecular markers, many so-called large cell dysplasias actually represent regenerating nodules [3
]. Therefore, the incidence of large cell dysplasia showing progression to hepatocellular cancer (HCC) is low and clinically insignificant [4
]. In contrast, small cell dysplasia represents fast multiplying cells, more uniform nuclear shape, greater chance of being clonal and is, therefore, much more frequently associated with progression to HCC [5
]. These represent clonal clusters of rapidly dividing cells, with less time to develop cytoplasm and mature. Histologically, small cell dysplasia is identified by fairly uniform small cell proliferation and cords that are more often ‘twinned’ and disoriented than single corded. On gross examination, these nodule bulge on the cut surface with a distinctive physical appearance. A small area of high-grade dysplasia when identified within a macroregenerative nodule is a ‘nodule within a nodule’. The rate of transformation of small cell dysplasia into HCC is not a known, nor are the exact genetic mutations that separate a carcinoma from a dysplasia [6
]. Therefore to differentiate between small cell dysplasia and small HCC remains a hair splitting academic exercise, currently based on educated guesswork.
As the clonal cells within a high-grade dysplastic nodule continue to multiply they acquire more carcinogenic mutations. They start showing greater architectural,and nuclear atypia, thicker trabecular or adenoid arrangements. They obtain infiltrative ability and invade into the fibrous bands that surround them as well as adjacent vessels. These are features of a full-blown HCC.
The problems in the histological diagnosis of HCC occur at both ends of the spectrum. Tumours that are very well differentiated are difficult to differentiate,on biopsy, from benign lesions such as adenoma, focal nodular hyperplasia and macroregenerative nodules. Focal nodular hyperplasia is identified by its scattered bile ducts and thick vessels, and a large core or a wedge biopsy would have greater chances of including these structures within it, as compared with a thin core [7
]. Adenoma, except for its characteristic clinical setting, is near impossible to differentiate from a well-differentiated HCC on biopsy [8
On the other end of the spectrum are the poorly differentiated tumours whose malignant nature is clearly evident, but showing no clue of their cell of origin. The diagnostic difficulty in these cases is compounded by the problem that serum alpha-fetoprotein is elevated in only 60–70% of HCCs, and may also show elevation in some gastric carcinomas, germ cell tumours and cirrhosis itself. Poorly differentiated tumours would need ancillary studies, such as immunohistochemistry.
When intraoperative biopsies are contemplated, the surgeon should remember that it is advisable to obtain the biopsy sample at the beginning of the surgical procedure to avoid artifacts such as neutrophilic infiltration [9
]. Subcapsular regions are usually more fibrosed; hence, a deep-needle biopsy is more representative of the true state of fibrosis within the liver parenchyma [10
]. When scattered liver involvement is a possibility, as in granulomatous disease, more than one core is advisable.