In Focus

Colorectal polyps and cancer – when to refer to genetics

Publish date: February 1, 2020

 

Polyp phenotype

In addition to personal and family history, colon polyp history (including number, size, and histology) can provide important clues to identifying individuals with genetic predisposition to CRC. Table 1 highlights hereditary syndromes and polyp phenotypes associated with increased CRC risk. Based on consensus guidelines, individuals with a history of greater than 10-20 adenomas, 2 or more hamartomas, or 5 or more sessile serrated polyps should be referred for genetic testing.5,7 Serrated polyposis syndrome (SPS) is diagnosed based on at least one of the following criteria: 1) 5 or more serrated polyps, all at least 5 mm in size, proximal to the rectum including at least 2 that are 10 mm or larger in size, or 2) more than 20 serrated polyps distributed throughout the colon with at least 5 proximal to the rectum.8 Pathogenic germline variants in RNF43, a tumor suppressor gene, have been associated with SPS in rare families; however, in most cases genetic testing is uninformative and further genetic and environmental discovery studies are needed to determine the underlying cause.8,9

Table 1. Hereditary colorectal cancer syndromes
Although they may not be diagnostic, specific histologic characteristics of polyps may also raise red flags for hereditary CRC syndromes. For example, presence of tumor-infiltrating lymphocytes, a Crohn’s-like peritumoral inflammatory reaction, or a medullary growth pattern can be markers for hypermutation seen in Lynch-associated neoplasms.10 In addition, adenomas in FAP are microscopically similar to sporadic adenomas, but histologic evaluation of the intervening normal-appearing mucosa may show microscopic dysplastic crypts or aberrant crypt foci, both of which are characteristic findings in FAP which can also be seen in some cases of MUTYH-associated polyposis.

Risk prediction models

Models have been developed that integrate family history and phenotype data to help identify patients who may be at risk for LS. The Amsterdam criteria (more than 3 relatives with LS-associated cancers, more than 2 generations involving LS-associated cancers, and more than 1 cancer diagnosed before the age of 50; “3:2:1” criteria) were initially developed for research purposes to identify individuals who were likely to be carriers of mutations of LS based on CRC and later revised to include extracolonic malignancies (Amsterdam II).11 However, they have limited sensitivity for identifying high-risk patients. Similarly, the Bethesda guidelines have also been modified and revised to identify patients at risk for LS whose tumors should be tested with microsatellite instability (MSI), but also with limited sensitivity.12

Several risk prediction models have been developed that perform better than the Amsterdam criteria or Bethesda guidelines for determining which patients should be referred for genetic testing for LS. These include MMRPredict, MMRpro, and PREMM5.13-16 These models use clinical data (personal and family history of cancer and tumor phenotypes) to calculate the probability of a germline mutation in one of the mismatch repair (MMR) genes associated with LS. The current threshold at which to refer a patient for genetic counseling and testing is a predicted probability of 5% or greater using any one of these models, though some have proposed lowering the threshold to 2.5%.16,17

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