Histopathology of IQ-induced hepatocarcinogenesis in nonhuman primates

This study describes histopathological findings in 26 nonhuman primates (cynomolgus and rhesus monkeys) with liver tumors after dosing with IQ for time periods of 27 to 72 months. In most of the cases 2-5 well-defined tumor nodules were present in the liver at the time of autopsy. In 5 cases there were numerous nodules occupying most of the liver. Intrahepatic vascular invasion was observed in 14 cases, and lung metastases in 6 cases. The histology of 72 nodules from 21 cases with well-defined tumors and the 5 cases with massive involvement was studied. The majority of the tumors represented well to moderately well-differentiated hepatocellular carcinoma (HCC). Trabecular pattern was most common, followed by solid and pseudoglandular patterns. Five nodules displayed poorly differentiated pleomorphic variant of HCC with large, often multinucleated, tumor cells. Spindle cell and clear cell variants of HCC were seen in one nodule each. Two nodules were classified as cholangiocarcinomas. Immunostaining for cytokeratins 7 and 19 did not prove to be reliable markers for tumors of bile duct origin, since they were also expressed in some of the poorly differentiated HCC. The most common microscopic finding of the noncancerous portions of the liver were clear cell foci, composed of large, glycogen rich hepatocytes with small eccentric nuclei. Other lesions commonly found were dysplastic hepatocyte foci around the central veins and proliferating bile ductular-like (oval) cells along the portal areas and portal tracts.