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Carcinogenesis vol.7 no.5 pp.689-695, 1986

COMMENTARY

Preneoplastic lesions as end points in carcinogenicity testing. I. Hepatic preneoplasia

P.Bannasch
Abteilung filr Cytopathologie, Institut fur Experimentelle Palhologie, Deutsches Krebsforschungszentrum, Im Neuenbcimer FeW 280. D-6900 Heidelberg, FRG

Introduction The evaluation of the carcinogenic risk deriving from chemicalcompounds depends mainly on conventional histopathology up to the present. The accepted end point in carcinogenicity testing is the tumor as defined histologically. A great disadvantage of this approach is the long lag period in the development of tumors induced by chemicals. In order to overcome this drawback, many efforts have been made to detect early biological or morphological lesions which mightbe specific for carcinogens. A great number of short-term tests carried out in vitro provided valuable information about the reactions of cellular constituents and biological macromolecules to the chemicals tested, but they did not allow an unequivocal prediction of the carcinogenic potential of the respective compounds in whole animals, not to mention man. The introduction of modernmicromorphological methods such as electron microscopy and cytochemistry in the evaluation of whole-animal studies also revealed many new aspects on carcinogen-induced cellular and subcellular alterations which appeared to be unreliable as indicators of the carcinogenic risk of chemicals. However, during the past two decades a number of characteristic cellular changes has been detected in various tissues,especially in the liver. These changes regularly precede the development of certain tumor types, and are regarded as preneoplastic lesions (1,2). The altered cell populations usually form well-defined foci. They appear prior to the development of tumors in the target tissue of the carcinogen, and should be duly considered in the evaluation of the carcinogenic risk from chemicals in bioassays.Definition of preneoplasia The definition of preneoplasia has to include prestages of both benign and malignant neoplasms, especially since many observations suggest that benign tumors are often nothing but intermediate stages in the development of malignant neoplasms. Hence, 'preneoplasia' is not identical to 'precancer'. At the histological level, preneoplastic lesions may be defined as phenotypicallyaltered cell populations which have no obvious neoplastic nature, but have a high probability of progressing to a benign or malignant tumor. Theoretically, such a lesion might consist of definitive tumor cells which are only prevented from growing 'autonomously' by superordinate mechanisms residing outside the transformed cells, such as the frequently postulated microenvironmental factors orinfluences of the immune system. On the other hand, preneoplastic lesions might also be composed of cells which are phenotypically altered by the carcinogenic agent but lack important properties of the final tumor cells. Numerous recentfindingssuggest that certain types of focal lesions preceding
•Abbreviations: 7-GT, 7-glutamyltranspeptJdase; NNM, Mnitrosomorpholine. © IRL Press Limited, Oxford,England

the development of tumors do indeed consist of preneoplastic cells which are only fully transformed after additional intracellular changes (2). We have to admit, however, that other types of focal lesions may also contain neoplastic cells which might be mixed with preneoplastic cells or even occupy the whole lesion. Thus, the definition of preneoplastic lesions used in this commentary refersto the histological level and does not necessarily mean that the lesion is made up of preneoplastic cells. The important question as to whether the conception of preneoplasia is only useful at the organizational level of the tissue or can also be applied to single cells will be discussed later on. In human and experimental pathology, 'hyperplasia' has often been regarded as an early stage in...