Sequential histopathologic analysis of alpha-hexachlorocyclohexane-induced hepatic megalocytosis and adenoma formation in the HPB mouse

A temporal, gross, and histologic analysis of the livers of male HPB black mice maintained on a diet containing 500 ppm alpha-hexachlorocyclohexane (alpha-HCH) was performed at 1, 3, 4, 8, 14, 21, 30, 33, 44, and 50 weeks. Grossly, progressive liver enlargement was first noticed at 3 weeks, hepatic nodules at 21 weeks, and emaciation at 30 weeks. Histopathologic liver alterations included universal hypertrophy of centrolobular hepatocytes first seen at 1 week and the merging of adjacent megalocytic zones at 3 weeks. At 21 weeks, microadenomata and macroadenomata were seen in 2 of 7 mice. At 30 weeks, adenomata occurred in 7 of 8 mice and at 33, 44, and 50 weeks in 6 of 6, 5 of 5, and 5 of 5 mice, respectively. Individual adenomata were composed of large well-packed cells with basophilic and acidophilic pale-staining or lipid-laden cytoplasm forming disorganized cords of variable thickness. Depending on the stage of development, adenomata were classified into 4 subtypes. Subtype I, the earliest form seen, arose within megalocytic areas and was composed of a small number of megalocytic cells exhibiting loss of polarity. Subtype II was smaller than a liver lobule. Subtype III was larger and at times resulted from the merging of adjacent subtype II nodules. Subtype IV included the largest adenomata, most of which resulted from coalescing smaller sized subtypes. Under the conditions of this experiment, neither hepatocellular carcinoma nor metastases in the lungs were detected. It was concluded that if alpha-HCH-induced hepatocellular adenoma is ever to give rise to hepatocellular carcinoma, this transformation must progress very slowly.