Pathology of the hereditary colorectal carcinoma

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.

Clinicopathologic and Molecular Profiles of Microsatellite Unstable Barrett Esophagus-associated Adenocarcinoma

“…However, germline mutations in MMR genes also predispose to MSI-H colorectal cancers in patients with hereditary nonpolyposis colorectal cancer (HNPCC). 14,22,39 It has been well documented that MSI-H colorectal cancers, both sporadic and syndromic, have a better overall prognosis compared with microsatellite stable colorectal cancers. 39 Growing evidence suggests that patients with MSI-H colorectal carcinomas do not benefit from adjuvant chemotherapy with fluorouracil (5-FU), which has been commonly used for the treatment of both colorectal cancer and esophageal adenocarcinoma.…”

Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management

“…A more comprehensive discussion on FAP is beyond the scope of this chapter insofar as it is comprehensively addressed by Gatalica and Torlakovic [44] in this special issue.…”

Current status and future potential of somatic mutation testing from circulating free DNA in patients with solid tumours

“…In familial cancer syndromes, germline mutations predispose to malignant transformation and often result in earlier onset disease (Gatalica and Torlakovic 2008;Sluiter and van Rensburg 2011). In contrast, in more common sporadic cancers, the tumour usually originates from clonal expansion of a transformed cell through the accumulation of serial somatic mutations ).…”