Abstract
Part I - For harmonization of liver diagnostic nomenclature, the establishment of an international nomenclature is essential. In Chapters 2 to 5, such system is presented in the first part of this thesis. In this document, all pathological aspects of the rodent liver were investigated with regard to terminology and
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the establishment of differential diagnoses in both non-proliferative as well as proliferative lesions of rodents. In Chapter 6 various aspects of grading of are discussed.
Part II - One of the safety issues after long-term administration of a xenobiotic is carcinogenicity assessment, and both early and late proliferative liver lesions might be indicative of potential hepatocarcinogenesis or carcinogenesis at other sites in humans.
In the comparative review of Chapter 7, histomorphological features of common non-neoplastic and neoplastic hepatocyte lesions of rats and humans are examined using H&E-stained slides. The morphological similarities and differences of both neoplastic (hepatocellular carcinoma and hepatocellular adenoma) and presumptive preneoplastic lesions (large and small cell change in humans and foci of cellular alteration in rats) are presented and discussed. There are major similarities in the diagnostic features, growth patterns and behaviour of both rat and human hepatocellular proliferative lesions. Further study of presumptive preneoplastic lesions in humans and rats should help to further define their role in progression to hepatocellular neoplasia in both species.
The purpose of the pilot study as presented in Chapter 8 was to identify homologies and differences in immunohistochemical (IHC) protein expression between human and rat HCC. We investigated the comparative features of 6 immunohistochemical markers (b-catenin, glutamine synthetase, Ki-67 and CD34, C-myc and TGF-a) previously shown to be positive or altered in rodent and human HCC. Glutamine synthetase was strongly positive in 5 human and 4 rats HCCs. CD34 and Ki-67 were consistently positive in 5 human HCCs but weakly positive in only 2 or 3 rat HCCs, respectively. Our findings suggest that glutamine synthetase, CD34 and Ki-67 are most likely to be useful in studying precursor lesions involved in the pathogenesis of HCC in rats and humans.
In Chapter 9, comparative immunohistochemical (beta catenin, glutamine synthetase and C-myc) results are presented of both rat and human hepatocellular proliferative lesions and their significance in hepatocarcinogenesis is discussed. Apart from the morphological similarities and differences of both neoplastic (hepatocellular carcinomas and adenomas) and presumptive pre-neoplastic lesions (foci of cellular alteration in rat and large and small cell change (liver cell dysplasia) respectively in humans, differences for the expression of GS-staining between human versus rat pre-neoplastic lesions exist. There are great similarities in the glutamine synthetase staining patterns of both rat human hepatocellular neoplastic lesions (hepatocellular carcinoma and hepatocellular adenoma) and their role in the process of hepatocarcinogenesis as revealed by their staining patterns for the immunohistochemical markers. Moreover, human dysplastic lesions (large cell change and small cell change) as well as clear cell foci in the rat also show increased expression of glutamine synthetase suggesting metabolic changes of these hepatocytes predisposing them to gain carcinogenic potential in the process of hepatocarcinogenesis.
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