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Fig. 8.19 A-C Atypical adenomatous hyperplasia with mild atypia and extensive fatty change.

pattern. There are many portal tracts within the nodules but no invasion into the portal tracts. These nodules sometimes contain distinct, well differentiated cancer foci. Many of them gave rise to distinct HCC in clinical follow-up studies {1882, 1645} and are, therefore, considered precancerous lesions. Some of

Fig. 8.18 Adenoma. A Extensive central haemorrhage. B Benign appearing hepatocytes arranged in plates, one or two cells thick.

component.

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Fig. 8.20 Focal nodular hyperplasia. A Solitary lobulated nodule with typical central stellate scar. B Masson trichrome stain shows extensive blue connective tissue component.

these nodules contain areas with a marked increase in cell density, a more irregular trabecular pattern, and frequent fatty change, characteristic of well differentiated HCC but insufficient in extent to warrant such a diagnosis. These foci have been designated adeno-matous hyperplasia {1080, 806} or dys-plastic nodule {64}. Additional terms used for these lesions include macrore-generative nodule, hyperplastic nodule and borderline lesions. Morphological criteria for the differential diagnosis of adenomatous hyperplasia (dysplastic nodule, low grade), atypical adenomatous hyperplasia (dysplastic

Fig. 8.21 Nodular regenerative hyperplasia. A Multiple pale nodules of varying size. B Reticulin stain showing mild distortion of liver architecture.

nodule, high grade) and early-stage HCC are still under discussion, mainly due to the lack of objective phenotypic or genotypic markers {1080, 64, 805}.

Focal liver cell dysplasia (LCD) Large cell dysplasia. The term liver cell dysplasia (LCD) was first coined by Anthony et al. {73} to describe a change characterized by cellular enlargement, nuclear pleomorphism and multinucle-ation of liver cells occurring in groups or occupying whole cirrhotic nodules. The change was found in only 1% of patients with normal livers, in 7% of patients with cirrhosis and in 65% of patients with cirrhosis and HCC. There was a strong relationship between LCD and HBsAg seropositivity {73}. They concluded that the presence of LCD identified a group of patients at high risk for development of HCC, and that such patients should be followed by serial alpha-fetoprotein determinations.

Small cell dysplasia. Watanabe et al. {2068} have expanded the original definition of LCD to include a 'small cell' variant. The nuclear/cytoplasmic ratio is increased in small cell dysplasia, the ratio being between that of liver cancer and normal hepatocytes. This is in contrast to large cell dysplasia that has normal nuclear/cytoplasmic ratio. Also, multinucleation and large nucleoli are characteristic of large cell dysplasia but not small cell dysplasia. The small dys-plastic cells have more of a tendency to form small round foci than large dysplas-tic cells. On the basis of their morphological and morphometric studies Watanabe et al. {2068} proposed the hypothesis that small cell dysplasia, rather than large cell dysplasia, is the precancerous lesion in man.

Hepatocellular adenoma

A benign tumour composed of cells closely resembling normal hepatocytes, which are arranged in plates separated by sinusoids. On gross examination, adenomas are soft, rounded, yellow or tan masses, often with areas of necrosis, haemorrhage, and fibrosis. A fibrous capsule is uncommon. Lesions are solitary in two-thirds of cases {511}. When more than 10 lesions are encountered, a diagnosis of 'adenomatosis' has been recommended {511}. Adenoma is histologically composed of benign-appearing hepatocytes arranged in plates one or two cells in thickness {64, 803, 351, 71}. Portal tracts are absent; the lesion is supplied by arteries and veins. In most cases, the tumour cells are uniform in size and shape, but occasionally, mild to moderate cytologi-cal variation may be seen. Mitotic activity is almost never found. Lipofuscin, fat and clear cell change (due to water or glycogen accumulation) are often present in the cytoplasm. Haemorrhage, infarction, fibrosis, and peliosis hepatis may be seen.

The differential diagnosis may be difficult with small biopsies. Features suggesting hepatocellular carcinoma include mitoses, high nuclear/cytoplasmic ratio, and plates more than 2 cells in thickness. Loss of a normal reticulin pattern is common in HCC whereas it is preserved in hepatocellular adenoma. HCC typically also shows diffuse capillarization using

CD34 immunostain in comparison with hepatocellular adenoma, which is either negative or shows only focal staining. Any evidence of ductular differentiation suggests a regenerative lesion such as focal nodular hyperplasia (FNH). Portal tracts within the peripheral portion of an adenoma may cause confusion. The clinical setting is an important consideration in differential diagnosis. Most patients have a known risk factor, especially the use of contraceptive or anabolic steroids. Glycogen storage disease has also been associated. A diagnosis of adenoma should be made with caution in the absence of a known cause or in the presence of cirrhosis, where dysplastic nodules, carcinoma, and large regenerative nodules are far more frequent.

Focal nodular hyperplasia (FNH)

A lesion composed of hyperplastic hepatic parenchyma, subdivided into nodules by fibrous septa which may form stellate scars. The majority of FNH lesions are asymptomatic. Infarction may lead to abdominal pain but rupture is rare. When more than one FNH lesion is present the patient often has other features suggesting a systemic abnormality of angiogen-esis, including hepatic haemangioma, intra-cranial lesions (vascular malformations, meningeoma, astrocytoma), and dysplasia of large muscular arteries {2054, 2055}.

Most FNH lesions are solitary, firm, and lobulated nodules (Fig. 8.20). Lesions on the surface of the liver may protrude above the capsule. On cut section, they are circumscribed but not encapsulated, and paler than the surrounding liver. They typically consist of a central stellate scar surrounded by parenchymal nodules. Although most lesions are paler than the surrounding liver, a less common telangiectatic type has prominent blood-filled vascular spaces {64, 2055}.

Histologically, FNH has a regular hierarchical structure defined by the arterial supply, which is usually a single artery with several orders of branching. Each terminal branch is located in the center of a 1 mm nodule. The large arteries often have degenerative changes in the media and eccentric intimal fibrosis. The arteries are found in a fibrous stroma without portal veins and usually without ducts. Proliferating ductules are usually present and may be prominent, com

Fig. 8.22 Multicentric, independent development of two HCC (T1 and T2), indicated by differences in their HBV DNA integration pattern. (N, normal tissue)

monly with visible features of chronic cholestasis (cholate stasis, copper accumulation) and neutrophil infiltration. Nascent FNH is a small region of hyper-plasia or dilated sinusoids, recognised in the context of more definite FNH lesions. The rare telangiectatic type of FNH has a similar arterial supply but with markedly dilated sinusoids comprising at least a quarter of the lesion. The histological differential diagnosis of FNH includes cirrhosis, in which septa contain portal areas, and hepatocellular adenoma. If the ductular component is not sampled, an unequivocal diagnosis may not be possible.

Nodular regenerative hyperplasia (NRH)

This condition is characterized by small regenerative nodules dispersed throughout the liver, associated with acinar atrophy with occlusive portal vascular lesions.

The liver has a normal weight and shape with a fine granularity of the capsular surface. The cut surface demonstrates a diffuse nodularity with most nodules measuring 1-2 mm. Occasionally, there are clusters of nodules up to several cm in diameter {64, 2056, 2053}. The nodules are paler than the atrophic hepatic parenchyma which surrounds them. Microscopically, the normal architecture is mildly distorted by widespread atrophy admixed with numerous monoacinar regenerative nodules. The nodules are composed of normal-appearing hepato-cytes in plates 1-2 cells wide centered on portal tracts. The atrophic regions have small hepatocytes in thin trabecu-lae with dilated sinusoids. No significant paren-chymal fibrosis is present but numerous small portal veins are obliterated.

Histological diagnosis of NRH depends on the recognition of a nodular architecture in the absence of parenchymal fibrosis. Nodularity may be suspected when there are two adjacent populations of hepatocytes that are normal and atrophic, respectively. This pattern is best appreciated on a reticulin stain. Macro-nodular, incomplete septal, or regressed cirrhosis commonly have regions with this configuration, especially in livers with healed portal vein thrombosis {1742}. These forms of cirrhosis are difficult to exclude in a small biopsy.

Genetic susceptibility

Several rare inherited disorders of metabolism are associated with an increased risk of developing HCC.

Carbohydrate metabolism disorders

In glycogen storage disease (GSD), especially type 1 {323}, HCC can develop within preexisting adenomatous lesions {137}. Distinction between benign and malignant tumours is difficult, since GSD-associated HCCs are well differentiated, and atypical lesions ('nodule within nodule' pattern and Mallory bodies) are found commonly in GSD-related adenomas {137, 1527}. Cirrhosis is never present.

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