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Fig. 8.11 Hepatocellular carcinoma in a 17-year old patient with Fanconi anaemia. A Green bile staining and extensive necrosis and haemorrhage. B Trabecular and pseudoglandular pattern with bile plugs.

Tumour spread

Invasion into the blood vessels, in particular into the portal vein, is a characteristic of HCC. Tumour thrombi in the portal veins are present in more than 70% of autopsies of advanced HCCs. Intra-hepatic metastases is caused mostly by tumour spread through the portal vein branches. Tumour invasion into the major bile ducts is infrequent clinically, but found in about 6% of autopsy cases. Extrahepatic metastasis is mostly haematogenous, the lungs being the most common target. Regional lymphatic metastasis is frequent though distant lymph nodes are rarely involved.

Histopathology

HCCs consist of tumour cells that resemble hepatocytes. The stroma is composed of sinusoid-like blood spaces lined by a single layer of endothelial cells. Unlike the sinusoidal endothelial cells in normal liver tissue, those of HCC are immunohistochemically positive for CD34 and factor-VIII-related antigen. Ultrastructural observation shows a basement-membrane-like structure between the endothelial cells and tumour cell tra-beculae, and basement-membrane-like materials are immunohistochemically positive with antibodies for laminin and type IV collagen. Thus, the sinusoid-like blood spaces resemble capillary vessels. This phenotypic change of sinusoids is called 'capillarization' {472, 919, 917}. In the sinusoidal blood spaces, varying numbers of macrophages, which show immunohistochemical positivity with anti-lysozyme and CD68, are also present and resemble Kupffer cells in well differ entiated tumours {1894}. HCCs vary architecturally and cytologically. The different architectural patterns and cytolog-ical variants frequently occur in combination. Immunohistochemical features of HCC are summarized in Table 8.01.

Architectural patterns Trabecular (plate-like). This pattern is the most common in well and moderately differentiated HCCs. Tumour cells grow in cords of variable thickness that are separated by sinusoid-like blood spaces. Well-differentiated tumours have a thin trabecular pattern and trabeculae become thicker with de-differentiation. Sinusoid-like blood spaces often show varying degrees of dilatation, and pelio-sis hepatis-like change are occasionally observed in advanced HCCs. Pseudoglandular and acinar. HCC frequently has a glandular pattern, usually admixed with the trabecular pattern. The glandular structure is formed mostly by a single layer of tumour cells, and some glandular or acinar structures are formed by dilatation of the bile canaliculus-like structure between cancer cells. Pseudoglands frequently contain proteinaceous fluids, which often stain with PAS but do not stain with mucicarmine or Alcian blue. Bile may be present. Cystic dilatation of the pseudoglands sometimes occurs, such dilated glands are occasionally formed by degeneration of thick trabecu-lae. Generally, the glandular structure is smaller in well differentiated tumours than in moderately differentiated tumours. Compact. Sinusoid-like blood spaces are inconspicuous and slit-like, giving the tumour a solid appearance.

Scirrhous. This uncommon type is characterised by marked fibrosis along the sinusoid-like blood spaces with varying degrees of atrophy of tumour trabeculae. It is observed even in small tumours. The scirrhous type should not be confused with cholangiocarcinoma or fibrolamellar carcinoma. Similar fibrotic changes occur following chemotherapy, radiation, and transchemo arterial embolization. Such post-therapeutic fibrosis should be distinguished from the scirrhous variant. The term 'sclerosing hepatic carcinoma'

Fig. 8.12 Immunostaining for polyclonal CEA demonstrates canaliculi in a hepatocellular carci-
Fig. 8.13 Bile production in a hepatocellular carcinoma.

{1424}, which has been used to designate a variety of tumours arising in non-cirrhotic livers and associated with hypercalcemia, does not constitute a distinct histopathological entity {806}, some of these tumours appear to be hepato-cellular, but others are intrahepatic (peripheral) cholangiocarcinomas.

Cytological variants

Pleomorphic cell. Tumour cells show marked variation in cellular and nuclear size, shape, and staining. Bizarre multinucleated or mononuclear giant cells are often present, and osteoclast-like giant cells may be seen rarely. Generally, pleomorphic tumour cells lack cohesiveness and do not show a distinct trabecular pattern. Pleomorphic cells are common in poorly differentiated tumours. Clear cell. The tumour consists predominantly of cells with clear cytoplasm due to the presence of abundant glycogen. This type is sometimes difficult to distinguish from metastatic renal cell carcinoma of clear cell type. Sarcomatous change. HCC occasionally appears sarcomatous, characterised by the proliferation of spindle cells or bizarre giant cells. When the tumour consists solely of sarcomatous cells, it is difficult to distinguish from sarcomas such as fibrosarcoma and myogenic sarcoma. When sarcomatous features are predominant, the tumour is called sarcomatoid HCC or sarcomatous HCC. In many cases, however, the sarcomatous change is present in a part of the tumour, and transitional features between trabecular HCC and sarcomatous components are frequent. Sarcomatous change is more frequent in cases with repeated chemo-therapy or transchemo arterial embolization {953}, but it is also seen in small tumours. Most sarcoma-tous cells are positive for vimentin or desmin but negative for albumin and alpha-fetoprotein. Some are also positive for cytokeratin.

Fatty change. Diffuse fatty change is most frequent in small, early-stage tumours less than 2 cm in diameter. Its frequency declines as tumour size increases, and fatty changes are rather infrequent in advanced tumours. Metabolic disorders related to hepatocarcino-genesis and insufficient blood supply in the early neoplastic stage have been suggested as a possible mechanism for the development of fatty change in small tumours, but a definite mechanism has not yet been determined. Bile production. Bile is occasionally observed, usually as plugs in dilated canaliculi or pseudoglands. When bile production is prominent, the tumour is yellowish in color and turns green after formalin fixation.

Mallory hyaline bodies are intracytoplas-mic, irregular in shape, eosinophilic and PAS-negative. They consist of aggregated intermediate filaments and show immunohistochemical positivity with anti-ubiquitin antibodies.

Globular hyaline bodies are small, round, homogeneous, and strongly acidophilic intracytoplasmic bodies. They are PAS-positive and stain orange to red with Masson trichrome stain. Immunohisto-chemically, they are often positive for alpha-1-antitrypsin.

Pale bodies are intracytoplasmic, round to ovoid, amorphous and lightly eosino-philic. They represent an accumulation of amorphous materials in cystically dilated endoplasmic reticulum, and show distinct immunohistochemical pos-itivity with anti-fibrinogen {1846}. They are commonly seen in the fibrolamellar variant of HCC but are also found in the common types of HCC, especially in scirrhous HCC.

Ground glass inclusions are rarely observed in tumours of HBsAg-positive patients. They stain with modified orcein, Victoria blue, or aldehyde fuchsin, and show immunohistochemical positivity with anti-HBsAg antibody. They are not seen in tumour casts in the portal vein or in extrahepatic metastases, and most are thought to be HBsAg-positive hepato-cytes entrapped in a tumour.

Fibrolamellar HCC

This variant usually arises in non-cirrhotic livers of adolescents or young adults {353}. It is rare in Asian and African countries but not so rare in Western countries. The tumour cells grow in sheets or small trabeculae that are separated by hyalin-ized collagen bundles with a characteristic lamellar pattern. They are large and polygonal and have a deeply eosino-philic and coarsely granular cytoplasm and distinct nucleoli. The eosinophilic granularity is due to the presence of a large number of mitochondria. Pale bodies are frequently present, and stainable copper, usually in association with bile, can occasionally be shown.

Undifferentiated carcinoma

Undifferentiated carcinoma is rare, accounting for less than 2% of epithelial liver tumours. There is male preponderance but data on geographical distribution are not available. Localization, clinical features, symptoms and signs, and diagnostic procedures display no difference as compared to hepatocellular carcinoma. Undifferentiated carcinomas are postulated to have a worse prognosis (compared to HCC), although greater case numbers to support this are not available {351, 806}.

Grading

According to histological grade, HCC is classified into well differentiated, moderately differentiated, poorly differentiated, and undifferentiated types.

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Fig. 8.14 Nodule-in-nodule type of hepatocellular carcinoma. The border between early and advanced components is shown in C.

Fig. 8.15 A, B Fibrolamellär type of hepatocellular carcinoma.

Well differentiated HCC. This is most commonly seen in small, early-stage tumours less than 2 cm in diameter and is rare in advanced tumours. The lesions are composed of cells with minimal atyp-ia and increased nuclear/cytoplasmic ratio in a thin trabecular pattern, with frequent pseudoglandular or acinar structures and frequent fatty change. In most tumours larger than 3 cm in diameter, well-differentiated carcinoma is observed only in the periphery if at all. Moderately differentiated HCC. The moderately differentiated type is the commonest in tumours larger than 3 cm in diameter and is characterized by tumour cells arranged in trabeculae of three or more cells in thickness. Tumour cells have

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