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Toxicologic Pathology
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Validation: The New Challenge for Pathology

Robert D. Cardiff

Center for Comparative Medicine, University of California, Davis, Davis, California, USA, Department of Pathology, School of Medicine, University of California, Davis, Davis, California, USA, rdcardiff{at}ucdavis.edu

Andrea Rosner

Center for Comparative Medicine, University of California, Davis, Davis, California, USA, Current Address: Department of Radiotherapy Radiation Oncology, Experimental Center, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Dresden, Germany

Michael A. Hogarth

Department of Pathology, School of Medicine, University of California, Davis, Davis, California, USA

Jose J. Galvez

Center for Comparative Medicine, University of California, Davis, Davis, California, USA, Department of Pathology, School of Medicine, University of California, Davis, Davis, California, USA

Alexander D. Borowsky

Center for Comparative Medicine, University of California, Davis, Davis, California, USA, Department of Pathology, School of Medicine, University of California, Davis, Davis, California, USA

Jeffrey P. Gregg

Department of Pathology, School of Medicine, University of California, Davis, Davis, California, USA

Modern pathologists have been challenged to "validate" mouse models of human cancer. Validation requires matching of morphological attributes of the model to human disease. Computers can assist in the validation process. However, adequate controlled, computer-readable vocabularies that can match terms do not currently exist in mouse pathology. Further, current standard diagnostic terminologies do not include the new concepts discussed here such as pathway pathology and mammary intraepithelial neoplasia. The terminologies must be revised and improved to meet the challenge. Human medicine has traditionally used "guilt-by-association" to validate interpretations of disease. Experimental pathology uses experimental verification exemplified by "test-by-transplantation." Genetically Engineered Mice (GEM) develop unique tumor phenotypes bringing new structural-functional insights and reevaluation of concepts. Novel GEM-related tumors appear in all organ systems but mouse models of human breast cancer are prototypes. For example, mammary tumors induced by Mouse Mammary Tumor Virus (MMTV), chemical, radiation or other carcinogenic stimuli have limited phenotypes. These "spontaneous" or induced mammary tumors have never resembled human breast cancers. GEM tumors created with genes associated with human cancer are strikingly different. GEM tumors have unique histological phenotypes. Depending on the genes, the tumors may: 1) resemble MMTV-induced tumors, 2) display "signature" phenotypes, and 3) mimic human breast cancers. The phenotypes can be placed into structural and functional clusters with shared characteristics leading to the concepts of Pathway Pathology: tumor phenotype reflects the genotype.

Key Words: Pathology • informatics • mouse models • breast cancer • genetically engineered mice • validation • vocabulary.

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Toxicologic Pathology, Vol. 32, No. 1 suppl, 31-39 (2004)
DOI: 10.1080/01926230490424662
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