Changes in Ploidy Distributions in Human Liver Carcinogenesis

Abstract

Cellular and nuclear DNA content was measured by flow cytometry and the fraction of binucleated cells by fluorescence microscopy in normal adult human livers, hepatocellular carcinomas, cirrhotic livers surrounding tumors, and in some benign liver conditions. In five normal livers about one-half of the hepatocytes were polyploid; the majority of these were binucleated tetraploids containing two diploid nuclei. Thus, polyploidization in human liver does not progress as far as, for example, in the rat, where 80%-90% of adult hepatocytes are polyploid, mostly with tetraploid or octoploid nuclei. In five human euploid hepatocellular carcinomas and one investigated case of focal nodular hyperplasia, the percentage of polyploid cells was significantly reduced. Four other carcinomas exhibited a prominent aneuploid (hypotetraploid) peak in addition to the diploid peak. An abnormally low fraction of binucleated cells was also indicated in these tumors. Liver tissue surrounding the tumors had a ploidy distribution similar to that of normal liver. The results suggest that, like in several models of experimental hepatocarcinogenesis, human hepatocellular tumor growth is associated with a decreased polyploidization tendency and a corresponding increase in diploid, divisional growth, which may give the tumors a growth advantage relative to the surrounding liver.

Large cell change (liver cell dysplasia) and hepatocellular carcinoma in cirrhosis: Matched case-control study, pathological analysis, and pathogenetic hypothesis

“…On the other hand, these same proximately 40% to 50% polyploid (primarily tetraploid) he-chronic inflammation-induced effects can operate on populations of prolifpatocytes, some two thirds of which are binucleated. 42,43 The erating diploid hepatocytes in a progressive, multistep fashion to eventually biological role of polyploidization is not entirely clear, but give rise to HCC. polyploid hepatocytes are considered to be fully functional but terminally differentiated end-stage cells with a low proliferative capacity.…”

Prediction of relapse or survival after resection in human hepatomas by DNA flow cytometry.

“…It is well accepted that minimized cell debrils and improved quality of DNA histograms can be obtained by using 50-,um or thicker paraffin-embedded sections (21,22). Besides, the abnormal DNA distributions have been more easily and more reliably identified in histograms from isolated nuclei, since these give better peak resolution than do the analyses of whole cells ( 15). Previous studies have speculated on the pattern of DNA ploidy distribution of human hepatomas into two groups, diploid (euploid) and nondiploid (aneuploid), in the order ofwider distribution (14,15).…”

“…Besides, the abnormal DNA distributions have been more easily and more reliably identified in histograms from isolated nuclei, since these give better peak resolution than do the analyses of whole cells ( 15). Previous studies have speculated on the pattern of DNA ploidy distribution of human hepatomas into two groups, diploid (euploid) and nondiploid (aneuploid), in the order ofwider distribution (14,15). In this study, our new system grouped hepatomas into three different patterns, pattern I, pattern II, and pattern III.…”

“…Previously, using cell cycle analysis, studies on rodent liver carcinogenesis showed a substantial increase in the fraction of diploid hepatocytes, both in preneoplastic liver (9,10) and tumors (11)(12)(13). However, ploidy changes in human hepatomas, which have been grouped into diploid and aneuploid status, have been reported to have no correlation with survival of patients with hepatomas who underwent hepatic resection (14,15).…”

Growth-related alterations during liver carcinogenesis: effect of promoters.

“…We have analyzed hepatocellular carcinomas induced by a variety of carcinogenic regimens, and found a predominantly diploid growth pattern in all cases (39). Even in human liver cancer, a reduced polyploidization tendency is evident, although the moderate degree of polyploidy in the normal human liver tissue makes the difference somewhat less striking than in the rat (51). The emergence of increasing numbers of diploid cells is observable at an early stage of carcinogenesis (23,25) (Table 6).…”