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Pathology of the hereditary colorectal carcinoma

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Abstract

Positive familial history (first or second degree relative) for colorectal carcinoma (CRC) can be found in approximately 30% of all newly diagnosed cases, but less than 5% will be due to a defined genetic category of hereditary CRC. Pathologic examination of the biopsy or resection specimen can help in identification of unsuspected cases of certain forms of hereditary CRC due to the characteristic morphologic findings. Additional immunohistochemical and molecular studies can then provide a definitive diagnosis. The most common form of hereditary CRC is Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) which is characterized by proximally located tumors frequently showing mucinous and medullary type histologic features. The syndrome results from a germline mutation in genes for mismatch repair (MMR) proteins leading to insufficient DNA repair and development of tumors characterized by high levels of instability in short tandem repeat DNA sequences (microsatellites) or “microsatellite instability-high” (MSI-H). The presence of intra-epithelial lymphocytes is single most helpful morphologic feature in identification of CRC caused by deficiency in MMR proteins, for which MSI-H status is a good marker but morphologic features and MSI-H do not differentiate tumors caused by germline mutations in one of the MMR genes (Lynch syndrome) from sporadic CRC due to inactivation of MLH-1 through promoter methylation. Hereditary CRC may also arise in various familial polyposis syndromes which include familial adenomatous polyposis (FAP), attenuated FAP and other multiple adenomas syndromes as well as various hamartomatous polyposis syndromes. All of these rare conditions have characteristic clinical presentation and histopathologic features of polyps and most of them have defined genetic abnormality. Furthermore, due to the germline nature of mutations in these syndromes, various extracolonic manifestations may be the first sign of the disease and knowledge of such associations can greatly improve the quality of care for these patients. The role of pathologist is to recognize these characteristics and initiate appropriate follow up with clinicians and genetic counselors.

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Acknowledgements

Authors thank A. Brian West, MD, Tina Bocker-Edmonston, MD, PhD, and Lehel Somogyi, MD, PhD for critical reading and invaluable comments during the preparation of the manuscript. We also thank Mrs. Carol Jones and Lisa Lee, PhD for help in manuscript preparation. Supported in part by Nebraska Cancer and Smoking Disease Research Program LB595.

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  1. Department of Pathology, Creighton University Medical Center, 601 North 30th Street, Omaha, NE, 68131, USA

    Zoran Gatalica

  2. Department of Pathology, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada

    Emina Torlakovic

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Correspondence to Zoran Gatalica.

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Gatalica, Z., Torlakovic, E. Pathology of the hereditary colorectal carcinoma. Familial Cancer 7, 15–26 (2008). https://doi.org/10.1007/s10689-007-9146-8

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