Cancer Consortium Prostate Pathology Committee the Bar Harbor Meeting of the Mouse Models of Human Definitions and Classification . The Consensus Report from Prostate Pathology of Genetically Engineered Mice :

The Pathological Classification of Prostate Lesions in Genetically Engineered Mice (GEM) is the result of a directive from the National Cancer Institute Mouse Models of Human Cancer Consortium Prostate Steering Committee to provide a hierarchical taxonomy of disorders of the mouse prostate to facilitate classification of existing and newly created mouse models and the translation to human prostate pathology. The proposed Bar Harbor Classification system is the culmination of three meetings and workshops attended by various members of the Prostate Pathology Committee of the Mouse Models of Human Cancer Consortium. A 2-day Pathology Workshop was held at The Jackson Laboratory in Bar Harbor, Maine, in October 2001, in which study sets of 93 slides from 22 GEM models were provided to individual panel members. The comparison of mouse and human prostate anatomy and disease demonstrates significant differences and considerable similarities that bear on the interpretation of the origin and natural history of their diseases. The recommended classification of mouse prostate pathology is hierarchical, and includes developmental, inflammatory, benign proliferative, and neoplastic disorders. Among the neoplastic disorders, preinvasive, microinvasive, and poorly differentiated neoplasms received the most attention. Specific criteria were recommended and will be discussed. Transitions between neoplastic states were of particular concern. Preinvasive neoplasias of the mouse prostate were recognized as focal, atypical, and progressive lesions. These lesions were designated as mouse prostatic intraepithelial neoplasia (mPIN). Some atypical lesions were identified in mouse models without evidence of progression to malignancy. The panel recommended that mPIN lesions not be given histological grades, but that mPIN be further classified as to the absence or presence of documented associated progression to invasive carcinoma. Criteria for recognizing microinvasion, for classification of invasive gland-forming adenocarcinomas, and for characterizing poorly differentiated tumors, including neuroendocrine carcinomas, were developed and are discussed. The uniform application of defined terminology is essential for correlating results between different laboratories and models. It is recommended that investigators use the Bar Harbor Classification system when characterizing new GEM models or when conducting experimental interventions that may alter the phenotype or natural history of lesion progression in existing models. Introduction and Objectives The increased generation of potential models of prostate neoplasia in genetically engineered mice (GEM) and their use in investigations of possible cancer therapies in prostate carcinoma (Pca) mandate the development of a standardized pathology classification scheme. Because mice and other rodents do not spontaneously develop Pca, histological criteria have been developed based on the disorders observed in newly created GEM models and by efforts to translate these lesions to the familiar histopathology of human Pca and its precursor lesions. Because the goal of the Mouse Models of Human Cancer Consortium (MMHCC) is to model human neoplasia, use of criteria and terminology applied to human prostate pathology is logical. However, as detailed herein, there are anatomical and natural history issues that impact on the ability to make straightforward analogies between GEM models of Pca and the human disease being modeled. Furthermore, in addition to pathological criteria, other criteria that can be incorporated into characterization and validation of GEM models include genetic and other molecular alterations and the natural history of the prostate lesions, and the similarity of these aspects to human Pca. GEM models will be useful for delineating novel causative molecular alterations in the development and/or progression of Pca and useful in testing interventions that will translate to treatments in human Pca patients if such models are similar, at least in some regards, to this heterogeneous human neoplasia at initiating or secondary molecular alterations. Because histopathologic features are a phenotypic consequence of these underlying molecular alterations, pathology assessment will be useful for characterizing new models and for detecting potentially meaningful changes as a consequence of genetic crosses or therapeutic interventions. Protocols for proper tissue submission are necessary for characterizing the pathology of the prostate and other organs in new GEM models. Tissue-based analysis of biological parameters including proliferation, apoptosis, and microvessel density can contribute to model characterization and provide mechanistic insight into effects of genetic manipulations and therapeutic interventions. Hence, the specific objectives of the MMHCC Prostate Pathology Committee to facilitate characterization and application of GEM models of prostatic disease were as follows: (a) development of a classification scheme for disorders of the prostate and related organs in GEM; (b) provision of histopathologic definitions for these disorders; (c) collection and annotation of images illustrating these disorders; and (d) collection, organization, and distribution Received 4/9/03; accepted 1/19/04. Grant support: National Cancer Institute Mouse Models of Human Cancer Consortium Grant, U01 CA-98–013, and a Department of Defense Prostate Cancer Center Grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: S. Shappell is currently at the Oppenheimer Urologic Reference Laboratory in Nashville, TN. Requests for reprints: Scott B. Shappell, Oppenheimer Urologic Reference Laboratory (OUR Lab), 1854 Airlane Drive, Suite 17A, Nashville, TN 37210. Phone: (615) 874-0410; Fax: (615) 232-8009; E-mail: scottshappell@ourlab.net.

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