Understanding Colonic Oligopolyposis of Unknown Etiology: Insights from a Cleveland Clinic Study

Patients with colonic oligopolyposis of unknown etiology (CPUE) present a persistent clinical challenge. During this year’s American College of Gastroenterology (ACG) Annual Meeting, a team of Cleveland Clinic researchers shared a compelling study that provides much-needed clarity on this patient population.

Among their key findings: these patients tend to be older males with high rates of tobacco and alcohol use, and about one-third have a family history of colorectal cancer. Notably, nearly one-third of these patients also had adenomas in the upper GI tract, reinforcing the need for upper GI surveillance.

“Colonic oligopolyposis of unknown etiology, or CPUE, is defined as the presence of 10–99 cumulative colorectal adenomas in the absence of identifiable pathogenic variants in known polyposis-associated genes,” notes study author Carole Macaron, MD, of Cleveland Clinic. “Much of what we know about this group comes from registry-based studies, which are often limited by referral or ascertainment bias. Our goal was to take a different approach — using pathology data to identify patients in a way that gives us a more representative and unbiased clinical snapshot.”

Study rationale and design

With the rise of high-definition endoscopes and improved adenoma detection rates, clinicians are increasingly encountering patients with 10 or more adenomas. However, guidance on how to manage this group remains limited.

To gain a better understanding of these patients and their unique needs, Dr. Macaron and colleagues conducted a retrospective chart review to identify patients with 10–99 cumulative colorectal adenomas diagnosed between March 2009 and December 2023 through the Cleveland Clinic’s pathology database.

Patients with a known hereditary colorectal cancer syndrome—either personally or in their family—were excluded. Manual chart review ensured that each patient met the strict inclusion criteria: ≥10 adenomas and negative results on a multi-gene panel test.

Findings and clinical implications

Of 358 eligible patients with 10-99 cumulative colorectal adenomas, 188 (30.6%) were referred for genetic testing. Among those, 57 patients (48%) were ultimately diagnosed with CPUE. The median age at diagnosis was 60 years, with a majority being white (85.7%) and male (60.7%). Notably, 61.4% had a history of tobacco use, and 72% reported alcohol use. Additionally, 35.7% had a first- or second-degree family history of colorectal cancer.

Over the course of follow-up, patients underwent an average of four to five colonoscopies, with each procedure, with about four to five adenomas resected on average per procedure, Dr. Macaron reports. Among the 37 patients who underwent upper endoscopy, 32.4% had upper gastrointestinal adenomas — most commonly gastric (75%), followed by duodenal (42%) and ampullary (8.3%). Thyroid nodules were identified in five of the eight patients (62.5%) who underwent thyroid ultrasound. Fine-needle aspiration was performed in one patient, with no thyroid cancer detected.

“Upper gastrointestinal adenomas were present in approximately one-third of patients, consistent with prior studies, underscoring the risk of upper GI neoplasia in this population and supporting the need for upper gastrointestinal surveillance,” note Dr. Macaron and colleagues.

The study highlights several important considerations for practicing gastroenterologists, according to Dr. Macaron:

• Surveillance is essential: CPUE patients appear to have a persistent risk of polyp development throughout the GI tract.
• Upper GI screening should be considered: The consistent rate of upper GI adenomas—even in a broader, less-selected population—suggests the need for upper endoscopy surveillance protocols.
• Genetic counseling is underutilized: Despite recommendations, genetic testing referrals remain low.

Next steps and final takeaways

Reflecting on the broader implications of the study, Dr. Macaron emphasizes that the findings both reinforce existing data and underscore the importance of larger, multicenter investigations.

“To get such a clean group of patients using a strict definition, our sample narrowed down significantly,” she explains. “We started with around 300 patients and, after applying our inclusion criteria, ended up with just 57. That really highlights the need for collaborative, multicenter studies to better understand this population.”

Recognizing the limitations of a single-center, retrospective design, Dr. Macaron and her team are already preparing for the next phase of research. Plans are underway to establish a dedicated registry and partner with other institutions to build a larger, more diverse cohort of patients with CPUE.

The overarching goal is to better define the natural history, metachronous risk, and long-term cancer outcomes in this population. “Hopefully, within the next year or so, we’ll have a much larger sample and clearer estimates of the risk of developing new neoplasia or even cancer over time,” she says.

For endoscopists and GI specialists, the clinical message is clear: patients with multiple adenomas—regardless of known genetic mutations—warrant close attention. “Endoscopists will often be the ones to make the call when they realize a patient has had more than 10 adenomas over their lifetime,” Dr. Macaron notes. “At that point, think of a genetic testing referral.”

Through their research efforts, Dr. Macaron and colleagues offer evidence that supports broader screening, closer surveillance, and a renewed push for genetic counseling in a population that may otherwise be overlooked.

Presentation Information

Abstract: “Colonic Oligopolyposis of Unknown Etiology: A Single-Center Experience”