Review Article: Cystic Degeneration/Spongiosis Hepatis in Rats

Abstract

Cystic degeneration /spongiosis hepatis in rats has been proposed to be a preneoplastic and/or neoplastic lesion by some authors, because of its proliferative properties and persistent increased cell turnover rate in stop experiments using hepatocarcinogens , and the assumption that it can develop into a sarcoma. The neoplastic potential of cystic degeneration is questioned in this review article. Cystic degeneration , which appears to derive from altered Ito cells, does not have neoplastic histomorphologi c characteristics, although it may be composed of cells with an increased mitotic index. In this regard, persistent proliferation is also seen with other nonneoplasti c lesions. Argument s are presented to show that the induced, probably extremely rare sarcoma that was associated with cystic degeneration most likely derives from the very rare induced spherical Ito-cell aggregate with an unusually high cellular turnover rate in rats treated with hepatocarcinogens , and not from cystic degeneration . Also, in none of 12 referenced standard oncogenicity studies with chemically induced cystic degeneration was the lesion associated with mesenchymal (Ito-cell) tumors. Consequently, evidence is lacking that cystic degeneratio n in rats should be classi ed as a preneoplastic or neoplastic lesion.The 12 oncogenicity studies in rats with induced cystic degeneratio n showed a marked sex predilection, with males more likely to develop either spontaneous or chemically induced lesions. In these 12 studies, cystic degeneration was more often associated with hepatocellular hypertrophy or hepatotoxicit y, rather than hepatocarcinogenicit y. Thus, it is concluded that hepatocarcinogen s induce cystic degeneration , not because they are carcinogenic , but because they have other effects on the liver, and that cystic degeneration may be a secondary /reparative change. Cystic degeneration in sh parallels the situation in rats in many respects, yet the existence of the lesion in other species, including man, is not as well supported. Based on the data presented in this review, spontaneous and induced cystic degeneratio n in rats and sh is not a preneoplasti c or neoplastic lesion and risk assessment for man can be based on no-effect levels and safety margins, as for other nonneoplasti c adverse effects that have no counterpart in man.

A Review of Nomenclature and Diagnostic Criteria for Proliferative Lesions in the Liver of Rats by a Working Group of the Japanese Society of Toxicologic Pathology.

“…One group has proposed that spongiosis hepatis may be a preneoplastic and/or neoplastic lesion because of its proliferative properties and persistent increased cell turnover rate in stop experiments with hepatocarcinogens, and the assumption that it can develop into a sarcoma 26 . In contrast, the other group has suggested that the lesion may be a secondary/ reparative change but not a preneoplastic or neoplastic lesion, because spongiosis hepatis was more associated with hepatocellular h y p e r t r o p h y o r h e p a t o t o x i c i t y , r a t h e r t h a n hepatocarcinogenicity in 12 oncogenicity studies in rats with induced spongiosis hepatis 27 . In addition, the group has indicated that persistent proliferation is also seen with other nonneoplastic lesions and spongiosis hepatis does not have neoplastic histomorphologic characteristics.…”

Risk assessment of oral exposure to diisononyl phthalate from children’s products

“…Therefore, they concluded that spongiosis hepatis was not a consequence of MCL. Spongiosis hepatis may occur in association with hepatocarcinogens (e.g., Bannasch et al, 1981;Braunbeck et al, 1992;Zerban and Bannasch, 1983), but frequently occurs in the absence of hepatocarcinogenesis and peroxisome proliferation (reviewed in CPSC, 2002;Karbe and Kerlin, 2002). Spongiosis hepatis has not been reported in humans (Karbe and Kerlin, 2002).…”

Unusual Lipomatous Lesion with Extramedullary Hematopoiesis Possibly Derived from Ito (Perisinusoidal) Cells in a CD-1 Mouse

“…Lipomatous lesions in the liver are thought to be tumors originating from Ito cells 1,5 . In addition, neoplasms derived from Ito cells associated with spongiosis hepatis have been previously described in rats 6,7 . Although the mechanism remains unclear, the vacuolated (lipid-laden) and spindle-shaped cells in the present study could be phenotypes of Ito cells as reported previously in rats 7 and mice 3 .…”

“…In addition, neoplasms derived from Ito cells associated with spongiosis hepatis have been previously described in rats 6,7 . Although the mechanism remains unclear, the vacuolated (lipid-laden) and spindle-shaped cells in the present study could be phenotypes of Ito cells as reported previously in rats 7 and mice 3 . Immunohistochemical examination of the present case revealed that vimentin was partially expressed in some of the prolifelative cells.…”

“…This occurs with proliferation of mature lipocytes such as myelolipoma, a kind of hamartomas, in adrenals, spleens, and livers. It is thought that myelolipoma/ myelolipomatous lesions in the liver may originate from Ito cells 7 based on report of a human case 12 . However, the spindle-shaped cells in our case did not correspond to myelolipoma.…”