Hepatocellular DNA synthesis in rats given peroxisome proliferating agents: comparison of WY-14,643 to clofibric acid, nafenopin and LY171883.

The mitogenic effects of peroxisome proliferating agents have been implicated in their carcinogenicity. WY-14,643 stimulates an increase in hepatocellular DNA replication that persists with continued administration, but it is unclear if other peroxisome proliferators share this property. In these studies, WY-14,643 was compared to clofibric acid, nafenopin and LY171883 given to rats in the diet for up to 30 days. DNA replication in the rat liver was quantified by immunohistochemical methods after continuous s.c. infusion of bromodeoxyuridine by osmotic minipump. During the first 7 days of treatment, WY-14,643 (0.1% in diet) and nafenopin (0.05%) increased the percentage of bromodeoxyuridine-labeled hepatocytes to greater than 50%, from 3% in controls. Clofibric acid (0.5%) and LY171883 (0.3%) increased the labeling to approximately 33%. The replicative response to each of the compounds was localized primarily to the periportal region of the liver lobule. The time-course of replication induced by clofibric acid and WY-14,64.3 was examined over 3 day intervals. The peak of replication in response to clofibric acid occurred during days 4-6, whereas the effect of WY-14,643 peaked during days 1-3 and was much greater than clofibric acid. The replicative response to WY-14,643 persisted through 30 days at dietary concentrations of 0.1 and 0.005%. Nafenopin, LY171883 and clofibric acid were without effect on DNA replication on days 28-30 even though the hepatomegaly and induction of peroxisomal beta-oxidation persisted. Thus, under the conditions of these experiments, the persistent replicative effect through 30 days was unique to WY-14,643. Although sustained replication in the general population of hepatocytes may be involved in the carcinogenesis of WY-14,643, it does not appear to be a factor in the hepatocarcinogenesis of the other peroxisome proliferators.

The pluripotential nature of the mesenchyme-like component of yolk sac tumor.

Germ cell neoplasms were reviewed for the investigation of a mesenchyme-like component of yolk sac tumor (YST) characterized by spindle cells with few mitoses in a myxoid, vascular background. Nineteen YSTs with this pattern were identified. The mesenchyme-like component of these YSTs appeared to derive from the epithelial elements of YST, since cytokeratin as well as vimentin positivity occurred in the spindle cells of the mesenchyme-like areas and foci of epithelial-spindle cell transition were present. In some cases the mesenchyme-like component showed differentiated mesenchymal elements (usually skeletal muscle). Similar features were identified in 13 chemotherapy-treated cases of YST that consisted only of this mesenchyme-like component. The mesenchyme-like component of YST appears to represent a chemoresistant, pluripotential cell population arising from metaplasia of YST epithelium; it may give rise to sarcomas occurring in some patients with treated germ cell tumors.

Yolk sac differentiation in germ cell tumors. A morphologic study of 50 cases with emphasis on hepatic, enteric, and parietal yolk sac features.

We assessed 50 germ cell tumors with areas of yolk sac tumor (YST) for a variety of features including histologic patterns; hyaline droplets; syncytiotrophoblastic elements; hepatic, enteric, and parietal yolk sac differentiation; and granulomatous reaction. Of prime interest was the fact that many YSTs formed hepatic-like foci (22%), enteric-like glands (34%), and parietal yolk sac structures (92%). Hepatoid areas were characterized by nests and cords of polygonal, acidophilic cells with prominent nucleoli and intense cytoplasmic staining for alpha-fetoprotein. Enteric differentiation occurred as well-defined glands with a sharp, striated border and relatively bland nuclear features. Ultrastructurally these glands had apical microvilli with associated glycocalyx and long anchoring rootlets. The apical cytoplasm and luminal contents stained for carcinoembryonic antigen. Parietal yolk sac differentiation was characterized by the intercellular accumulation of basement membrane substance as generally thick and longitudinally arranged bands of eosinophilic material. Such material, by electron microscopy, was both intra- and extracellular, and had irregular outlines and inhomogeneous electron density. It contrasted with the strictly intracellular, round, homogeneous, hyaline globules that, we believe, represent visceral yolk sac differentiation. This intercellular material stained positively for laminin, a basement membrane component. Assessment of 22 embryonal carcinomas and 24 germinomas failed to show hepatic, enteric, and parietal yolk sac features, with one possible exception. We believe these features, especially parietal yolk sac differentiation, are helpful in differentiating YSTs from embryonal carcinomas and germinomas.