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Toxicologic Pathology
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Histopathology Of Hemangiosarcomas in Mice and Hamsters and Liposarcomas/Fibrosarcomas in Rats Associated with PPAR Agonists

Jerry F. Hardisty1, Michael R. Elwell2, Heinrich Ernst3, Peter Greaves4, Holly Kolenda-Roberts1, David E. Malarkey5, Peter C. Mann6 and Pierre A. Tellier7

1 Experimental Pathology Laboratories, Inc. (EDL), Research Triangle Park, NC 27709
2 Covance Laboratories, Vienna, VA 22182
3 Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Nikolai-Fuchs-Str. 1, D-30625 Hannover
4 Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Science Building, Leicester Royal Infirmary, Leicester
5 National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC
6 EPL Northwest, Seattle, WA
7 Charles River Laboratories, Senneville, QC H9X 3R3, Canada

Correspondence: Address correspondence to: Jerry Hardisty, P.O. Box 12766, Research Triangle Park, NC 27709; e-mail:jhardisty{at}epl-inc.com

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, and related complications. Consequently, the identification of PPAR subtypes and the potential for their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. In 2005, the Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established by a group of pharmaceutical companies to advance research on and to understand the modes of action and human relevance of this emerging rodent tumor data for PPAR agonists. Since the most commonly observed tumor types reported in rodents are hemangiosarcomas, fibrosarcomas and liposarcomas, the PPAR Agonist Project Committee approved a Pathology Working Group (PWG) to develop consensus of morphologic criteria for tumor diagnoses and consistency of diagnoses across multiple studies for hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats. Therefore, the focus of the PWG review was to establish consistent tumor diagnostic criteria, to assess evidence of potentially preneoplastic changes and to identify distinguishing morphologic differences which may exist between spontaneous changes present in control animals with similar changes from treated animals. Specific diagnostic criteria and nomenclature are recommended for the classification of proliferative vascular lesions which may be present in mice or hamsters and for proliferative mesenchymal changes in rats in studies that are conducted with PPAR agonists.

Key Words: PPAR agonists • hemangiosarcoma • liposarcoma • fibrosarcoma • rodent • carcinogenesis • diagnostic criteria

Toxicologic Pathology, Vol. 35, No. 7, 928-941 (2007)
DOI: 10.1080/01926230701748156
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