Fig. 8.16 Early hepatocellular carcinoma showing well differentiated histological features.

abundant eosinophilic cytoplasm and round nuclei with distinct nucleoli. A pseudoglandular pattern is also frequent, and pseudoglands frequently contain bile or proteinaceous fluid. Poorly differentiated HCC. This proliferates in a solid pattern without distinct sinusoid-like blood spaces, and only slitlike blood vessels are observed in large tumour nests. Neoplastic cells show an increased nuclear/cytoplasmic ratio and frequent pleomorphism, including bizarre giant cells. Poorly differentiated HCC is extremely rare in small early-stage tumours.

Malignant progression of HCC. HCC is known to vary histologically even within a single nodule. From the viewpoint of his-tological grade, most cancer nodules less than 1 cm in diameter have a uniform distribution of well differentiated cancerous tissues, whereas approximately 40% of cancer nodules 1.0-3.0 cm in diameter consist of more than 2 types of tissue of different histological grades {900}. Less differentiated tissues are always located inside, surrounded by well differentiated tumour on the outside. The area of well differentiated neoplasm diminishes as the tumour size increases, and they are completely replaced by less-well-differentiated cancerous tissues when the tumour size reaches a diameter of around 3 cm. When less-well-differentiated areas within a well differentiated tumour nodule are growing expansively, the nodule often has a 'nodule-in-nodule' appearance {1275}.

Multicentric development of HCC

HCCs frequently occur as multiple intrahepatic nodules. Genetic analysis of

HBV Integration pattern, chromosomal allele loss, and mutational inactivation of tumour suppressor genes has indicated multicentric independent development of these nodules {1647, 1392}. These studies have shown that nodules apparently growing from portal vein tumour thrombi or satellite nodules surrounding a large main tumour represent intrahepatic metastases, whereas other nodules can be considered multicentric HCCs if they satisfy any of the following three criteria: (1) multiple, small early-stage HCCs or concurrent small early-stage HCCs and classical HCCs; (2) presence of peripheral areas of well differentiated HCC in both lesions or in the smaller ones; and (3) multiple HCCs of obviously different histology.

Multicentric HCCs are associated with a high rate of tumour recurrence, even after curative resection, making treatment difficult and the prognosis poor. The presence of hyperplastic foci, small-cell dysplasia, an increase in the prolifer-ative activity of non-tumourous liver tissue, or the progression of background liver disease are risk factors for multicen-tric HCC development {1902, 1859}.

Fig. 8.17 Adenomatous hyperplasia with minimal nuclear atypia and without features of malignancy.

Precursor and benign lesions

Early stage HCC and precancerous lesions

Because of remarkable advances In Imaging techniques and their widespread availability, increased numbers of small HCCs are detected clinically. Liver transplantation has become common treatment for liver cirrhosis and HCC in highly selected cases. Studies of resected and explant livers have revealed new information about the morphological characteristics of small early-stage HCC and equivocal nodular lesions. The most striking information is that HCC associated with cirrhosis probably evolves from precancerous lesions, and well differentiated HCC further progresses to a less differentiated form {952, 1646, 1882, 1645, 81}.

Histological features of small early-stage HCC

Although some small HCCs show features of classical HCCs, most less than 1.5 cm in diameter are vaguely nodular with indistinct margins macroscopically and have a uniform distribution of well differentiated cancerous tissues. They are characterized by increased cell density with increased nuclear/cytoplasmic ratio, increased staining intensity (eosinophilic or basophilic), irregular thin trabecular pattern with a frequent acinar or pseudoglandular pattern, and fatty change {959, 1324}. Diffuse fatty change of tumour cells is present in approximately 40% of tumours less than 2 cm in diameter. Many portal tracts are present within the tumour nodule, and tumour cell invasion into some portal tracts can be seen. At the tumour boundary, neoplastic cells proliferate as though they are replacing normal hepatocytes ('replacing growth'), and there is no capsule formation. These small tumours may correspond to 'carcinoma in-situ' or 'microinvasive carcinoma' of the liver. They tend to preserve the underlying liver structures, including portal tracts, receive portal blood supply, and do not show tumour blushing in angiographic examinations. In contrast, classical HCCs, even if small and well differentiated, show tumour blushing without portal flow {1883}. Invasion into the stromal tissue can be sometimes identified, but vascular invasion and intrahepatic metastases are exceptional {1942}. Moreover, these lesions are locally curable, have a favorable long-term outcome, and can be defined clinically as 'early HCC'.

Adenomatous hyperplasia (dysplastic nodules)

This lesion is characterized by marked enlargement of individual cirrhotic nodules that show thick liver cell plates. Small nodular lesions, most of which are below 1.5 cm in size, have been noticed in the livers of patients with HCCs that have been resected surgically and in explant cirrhotic livers. The nodules show variable atypia but lack features of definite malignancy. Macroscopically, most lesions are vaguely nodular and are not much different from small, well differentiated HCC with indistinct margins; it is almost impossible to distinguish them from cancer on the one hand or from large regenerative nodules on the other hand. Microscopically, they are characterized by a moderate increase in cell density with a slightly irregular trabecular

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