Elsevier

The Lancet Oncology

Volume 1, Issue 4, December 2000, Pages 220-226
The Lancet Oncology

Review
Familial colorectal cancer: pathology and molecular characteristics

https://doi.org/10.1016/S1470-2045(00)00152-2Get rights and content

Summary

Appropriate management of familial colorectal cancer revolves around the diagnosis of the underlying genetic syndrome. This necessitates an interdisciplinary approach allowing integration of clinical, morphological, and molecular evidence that may involve several members of the same family. Genetic disorders express themselves over time, whereas clinical investigation of family members is likely to be episodic. Generic features of hereditary colorectal cancer syndromes include a positive family history, early age at onset, multiple neoplasms, and extracolonic lesions of either a developmental or neoplastic nature. Deriving a complete description of a genetic disorder is hampered by the need to trace and obtain tissue samples from many institutions. This review examines the usefulness of tissue-based investigations, both morphological and molecular, in raising the suspicion of familial colorectal cancer, providing a definitive tissue diagnosis and contributing to the larger body of diagnostic evidence. The account focuses on the two most well-studied syndromes – familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) – but consideration is also given to less well-understood syndromes. Some of these, notably hyperplastic polyposis and mixed polyposis, may closely mimic FAP or HNPCC.

Section snippets

A working diagnosis

The principles listed above underlie best-practice guidelines for the clinical management of familial colorectal cancer. Diagnosis depends on the careful collection of evidence in the form of family history and tissue manifestations (clinical, morphological, and molecular). Cancer family clinics, informed by registries that serve as repositories of fully verified data, provide the time-tested means of managing familial bowel cancer in a safe and standard way14. Knowledge of the underlying

Familial adenomatous polyposis

The diagnosis of familial adenomatous polyposis (FAP) is generally straightforward. The main feature is the development of hundreds, if not thousands, of adenomas by the mid-teens (Figure 1). Gardner recognised the extracolonic features (Gardner's syndrome), and other manifestations were documented subsequently (Table 3).16 FAP and Gardner's syndrome are synonymous, but polyp numbers and extracolonic presentations are influenced by the location of the germline mutation within the APC gene and

Hereditary non-polyposis colorectal cancer

The term ‘hereditary non-polyposis colorectal cancer’ (HNPCC) was introduced to highlight a form of autosomal dominant bowel cancer distinct from FAP. More by default than design, this rather imprecise term now equates to a specific syndrome, determined by the inheritance of a mutated DNA-mismatch repair gene (Table 2). No individual clinical feature is pathognomonic for the syndrome (unlike the multiple adenomas in FAP), but combinations of features, recognised mainly by Lynch (Table 4),22, 23

MSI-H colorectal cancer – discrimination of familial and non-familial forms

Familial MSI-H cancers arise through the inheritance of a mutated DNA-mismatch repair gene. Non-familial MSI-H cancers arise mainly through the acquired methylation of the promoter region of hMLH1, leading to biallelic silencing.34 Genetic factors could underlie a tendency towards aberrant methylation, and the division into familial versus non-familial MSI-H cancers may not be absolute.

A surprising amount of basic and clinical research into MSI-H cancers has been done without discrimination

Hyperplastic polyposis

Hyperplastic (metaplastic) polyps have traditionally been regarded as small, innocuous lesions presenting mainly in the rectum and distal sigmoid colon. Colorectal cancer occurs in individuals with large or multiple hyperplastic polyps, and cancers are commonly multiple.39 Familial clusterings have been documented.40 Hyperplastic polyps can show clonal genetic alterations, including mutation of K-RAS41 and loss of chromosome 1p.42 A specific molecular pathway to cancer is associated with the

Mixed polyposis

The term mixed polyposis implies the presence of many polyps of different types (adenoma, serrated adenoma, juvenile polyp, hyperplastic polyp) and polyps combining the features of two or more of the classic types. Polyps are not generally present in large numbers (greater than 100), and no individual type dominates. Two hereditary syndromes have emerged from this loosely described entity: hereditary mixed polyposis syndrome12 and hereditary colorectal adenoma and carcinoma syndrome (Table 2).13

Search strategy and selection criteria

Published data were identified by searches of MEDLINE and the NHMRC (Australia) Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer (www.health.gov.au/nhmrc/publicat/pdf/cp62.pdf). Reports in English published from 1993 onwards were selected for inclusion in the reference list.

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