Give a critical appraisal of pre-neoplastic foci in liver.

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Give a critical appraisal of pre-neoplastic foci in liver.

It has been demonstrated on numerous occasions that the administration of hepatocarcinogens to rats gives rise to an increased frequency in the appearance of certain lesions [1]. Such lesions appear sequentially and seem to be representative of the different stages in the carcinogenic process. In this essay I aim to describe one of these lesions, the focus and to discuss its significance with respect to neoplasia.

The process of hepatic carcinogenesis is multi-stage and involves atypical phenotypic and genotypic alterations to cells. The first step in carcinogenesis is usually called initiation and is characterised by an irreversible alteration of one or more hepatocytes, [1]. The initiation of carcinogenesis is thought to occur spontaneously or following the administration of a carcinogenic substance and results in the formation of an early lesion [1]. Following this are one or more stages of cell proliferation which are said to “fix” the lesion prior to further changes. The first recognisable hepatocellular lesion is the focus, which is then thought to transform into the neoplastic nodule, composed of cells phenotypically similar to those of the foci, yet larger in size. Later still is the development of hepatocellular carcinomas.

Foci of altered hepatocytes.

        Foci are microscopic lesions, distinguishable from healthy liver by various phenotypic characteristics. They are typically located in the periphery or intermediate region of the liver lobule, but may later progress to the centrilobular region [2]. Foci have been observed following the treatment of rats and mice with various carcinogens and hence have been used as markers in the identification of potential carcinogenic substances, [3]. Foci have also occurred in rats following x-irradiation [3] and in woodchucks infected by the woodchuck hepatitis virus [3].

        An age-dependent increase in the occurrence of foci has been observed in control rats of several strains, particularly in aged rats [2]. An extremely high spontaneous incidence is observed in Fischer 344 rats, which may reach up to 90% at two years, however such spontaneous foci do not necessarily possess all of the abnormal phenotypic characteristics of chemically-induced lesions [2]. These findings have been attributed to genetic factors, food contamination and other environmental elements [2].

Identification and classification of foci.

The gross appearance of foci is of small white spots on the liver surface, although they are not usually visible with the naked eye. Microscopically they can be identified by standard hematoxylin and eosin (H&E) staining or by various special staining procedures [4]. Staining reveals the basophilic, eosinophilic, vacuolated or clear appearance of the cytoplasm of the cells. The foci exhibit a gradual and progressive change in staining intensity with respect to the normal surrounding parenchyma [4]. It is important to consider that different stains may actually identify different lesions owing to enzymatic heterogenicity [4].

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Staining also reveals the typically circular shape of the lesion in histologic section, representing a cross section of a three-dimensional spherical entity of several hundred microns diameter [4]. No upper limits are placed upon the size of the foci, however smaller foci are far more common than those extending to a diameter greater than that of a normal hepatic lobule [4].

Foci are typically associated with a variety of abnormalities such as aberrations in metabolic pathways such as carbohydrate and drug metabolism. This has been observed in rats and in other species including humans [3]. Such perturbations may be due ...

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