The pathway to monitoring quality of care for patients with adenomatous oligopolyposis of unknown etiology

In typical colorectal cancer (CRC) screening programs, colonoscopists will eventually encounter a patient with ≥ 10 colonic adenomas or oligopolyposis. Multiple clinical questions then follow. To what extent will the patient’s high adenoma burden place them at future increased risk of developing CRC? What are the chances this high index of adenoma burden will progress over time and ultimately become unmanageable and require surgery? While there is some consensus that surveillance should initially start at a 1-year interval for those with oligopolyposis, the future long-term surveillance of these patients is not well defined, either in the literature or in management guidelines [1] [2].

Prior studies on the incidence and management of oligopolyposis have come from referral centers, who perform germline testing for high risk patients, and are confounded by referral bias [3]. A relatively small percentage of patients with oligopolyposis will carry a defined pathogenic genetic mutation, attributed chiefly to APC or MUTYH mutations. Stanich et al. reported that 7.6 % of patients with 10–19 adenomas undergoing a multigene panel test of at least 14 CRC genes were found to have a pathogenic variant; this rate increased to 13.7 % in those with 20–99 adenomas [4]. Therefore, even with multigene panel testing most oligopolyposis patients will not carry a definable pathogenic mutation and will ultimately be classified as oligopolyposis of unknown etiology (OPUE).

In this issue of Endoscopy, Carballal et al. of the Barcelona group report on an observational retrospective cohort study for those with a positive fecal immunochemical test (FIT) who harbored ≥ 10 colonic adenomas on index colonoscopy [5]. The authors assessed the yield of genetic testing in identifying a pathogenic variant and also reported the outcomes of their surveillance colonoscopy program in terms of the development of advanced neoplasia and post-colonoscopy CRC. These are welcome surveillance data on oligopolyposis derived from an actual screening program, rather than from aggregated referral at high risk clinics.

“… the presence of ≥ 10 adenomas on FIT-based screening is not particularly uncommon, occurring in 2.2 % of cases, with only eight patients (4.9 %) having ≥ 10 adenomas at first follow-up surveillance colonoscopy and not a single patient developing a classic polyposis phenotype.”

Carballal et al. reported 2.2 % of cases (n = 215) were found to meet the criteria for oligopolyposis. The authors mostly reserve genetic testing for those with ≥ 20 adenomas in their oligopolyposis cohort. Pathogenic mutations were found in 3.3 % of individuals (2/60), with one having a biallelic variant in MUTYH and another, who had > 70 adenomas, having a pathogenic variant in APC [5]. The relatively low yield of pathogenic variants on genetic testing of oligopolyposis patients in this study in comparison with other oligopolyposis studies is expected, as the Carballal et al. data come from a screening cohort rather than a high risk referral center. The Carballal et al. study reinforces that the vast majority of times a pathogenic genetic variant is not detected. That being said, other series have shown that referral rates for genetic testing in FIT-positive polyposis cohorts have been suboptimal and genetic testing should certainly be offered when ≥ 20 adenomas are found [6].

The most welcome data from this series are the surveillance data of OPUE patients. In the Carballal et al. cohort, the median interval between colonoscopies was 14 months. Only eight patients (4.9 %) showed ≥ 10 adenomas at first follow-up surveillance colonoscopy. Not a single patient developed a classic polyposis phenotype. The presence of an advanced adenoma at index colonoscopy was an independent risk factor for the development of advanced neoplasia on surveillance. No relationship was observed in terms of the multiplicity of the adenomas and advanced neoplasia on follow-up. Two CRCs were diagnosed during surveillance.

The take-home messages of the Carballal et al. study are the following. First, the presence of ≥ 10 adenomas on FIT-based screening is not particularly uncommon, occurring in 2.2 % of cases. Second, an oligopolyposis patient is unlikely to carry a defined syndromic condition informed by genetics. Third, it is exceedingly uncommon that an incidentally discovered attenuated polyposis ultimately becomes a classic polyposis phenotype (≥ 100 adenomas); in fact, this did not occur. Fourth, a quarter of the oligopolyposis patients had advanced neoplasia on first repeat colonoscopy and the cumulative incidence of advanced neoplasia was 32.3 %, with the presence of an advanced adenoma associated with metachronous advanced neoplasia. Finally, CRC was uncommon, occurring in 1 % of patients (n = 2).

In the Carballal et al. study, one can aggregate the negative outcomes into ultimately those oligopolyposis patients who were, for various reasons, surveillance colonoscopy failures. There are those who were referred to surgery either because of unmanageable polyposis or unresectable polyps or for perforation (n = 6) and there were those who over their surveillance developed a post-colonoscopy CRC (n = 2). In the Barcelona cohort, this is still a low frequency of negative outcomes (3.7 %) and can be considered a template with which other cohorts might compare their surveillance outcomes.

There are limitations to this study, 99 % of individuals had < 30 adenomas and there should be caution in extrapolating the findings to more extensive colonic polyposis. The study, because of its modest sample size of OPUE patients reports the secondary end point of advanced neoplasia, which is a surrogate for the ultimate end point of post-colonoscopy CRC. In addition, patients who met serrated polyposis syndrome criteria were excluded.

What are the necessary next steps to take toward better management of oligopolyposis patients? Collaborative efforts to characterize how the presence or absence of germline pathogenic variants impact future CRC risk are needed. Further work on the role of somatic mosaicism, in which post-zygotic genetic alterations occur in some but not all cells, deserves further study in oligopolyposis patients [7]. APC mosaicism is accepted as a cause of polyposis and the extent to which somatic mosaicism in general drives polyposis prevalence and impacts surveillance outcomes is not yet clear.

The Carballal et al. study is an important step toward the development of quality metrics for the management of OPUE. Centers should track the extent to which patients with OPUE in screening cohorts are adequately managed by colonoscopy versus those that ultimately fail because of the development of either unmanageable polyposis or post-colonoscopy CRC. In terms of the details of surveillance interval, more work needs to be done to refine the approach. Vigilance should be maintained and a more intensive surveillance strategy considered in the presence of an advanced adenoma. Future prospective studies that compare frequent or high intensity surveillance versus a lower intensity surveillance approach should be considered as a next step.

Publikationsverlauf

Artikel online veröffentlicht:
25. Februar 2022

• References

• 1 van Leerdam ME, Roos VH, van Hooft JE. et al. Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2019; 51: 877-895
• 2 Gupta S, Lieberman D, Anderson JC. et al. Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2020; 91: 463-485.e5
• 3 Grover S, Kastrinos F, Steyerberg EW. et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA 2012; 308: 485-492
• 4 Stanich PP, Pearlman R, Hinton A. et al. Prevalence of germline mutations in polyposis and colorectal cancer–associated genes in patients with multiple colorectal polyps. Clin Gastroenterol Hepatol 2019; 17: 2008-2015.e3
• 5 Carballal S, Sánchez A, Moreira L. et al. Prevalence of adenomatous polyposis in a fecal immunochemical test-based colorectal cancer screening program and risk of advanced neoplasia during follow-up. Endoscopy 2022; 54: 688-697 DOI: 10.1055/a-1660-5353.
• 6 Alexander JL, Johnston BJ, Smith TJ. et al. Low referral rates for genetic assessment of patients with multiple adenomas in United Kingdom Bowel Cancer Screening Programs. Dis Colon Rectum 2021; 64: 1058-1063
• 7 Jansen AML, Goel J. Mosaicism in patients with colorectal cancer or polyposis syndromes: a systematic review. Clin Gastroenterol Hepatol 2020; 18: 1949-1960