Clinical Context

Diverticular disease affects more than 60% of adults at least 70 years of age, according to a previous study, and can promote significant pain and even life-threatening infections. The linkage between diverticulosis and cancer is less established, but a register-based cohort study from Denmark by Mortensen and colleagues suggests that the association between diverticulosis and cancer is quite real. Their study was published in the May 2017 issue of the Annals of Surgery.^[1]

Researchers compared adults with diverticulitis with matched control patients who did not have a diagnosis code for diverticulitis or diverticulosis. The incident rate ratio associated with diverticulosis as a risk factor for colon cancer was 1.86 (95% CI, 1.77-1.96), and this risk grew afteradjustment for potential confounding factors.

Surveillance bias could clearly influence these results. However, even adults with diverticulitis who did not initially undergo colonoscopy had a higher risk for colon cancer.

The current study follows up this previous research with a hypothesis that diverticulosis may be associated with a higher risk for cancer beyond the colon.

Study Synopsis and Perspective

Patients with diverticular disease have a 33% increased risk for overall cancer, researchers have found, which is equivalent to 1 extra cancer case per 16 patients with diverticular disease followed for 10 years.

"In the United States, over 60% of the population ≥70 years of age are affected by diverticulosis, which is asymptomatic in most circumstances," note the authors, led by Wenjie Ma, MBBS, ScD, from Massachusetts General Hospital, Boston.

"Given [that] the prevalence of diverticular disease is high, these results highlight the need for awareness and preventive strategies such as lifestyle modifications for cancer, not only for CRC [colorectal cancer] [but also] in patients with diverticular disease," they recommend.

The results come from a large, population-based retrospective cohort study published online October 6 in the Journal of the National Cancer Institute.^[2]

For the study, the researchers mined data from the ESPRESSO bank in Sweden. This includes a total of 6.1 million histopathology records from between 1965 and 2017 obtained from all pathology departments in Sweden. Patients meeting criteria for diverticular disease were subsequently categorized into those with diverticula form, inflammation, or normal histology.

"We included 75,704 patients with both colorectal histopathology and a diagnosis of diverticular disease and 313,480 reference individuals from the general population [plus] 60,956 siblings as a secondary comparator," Dr Ma and colleagues explain. The mean age of those with diverticular disease was 62 years, whereas the mean age for reference individuals as well as sibling comparators was slightly younger, at 55 years.

During a median follow-up of 6 years there were 12,846 incident cancers among patients with diverticular disease (24.5 per 1000 person-years) and 43,354 incidence cancers among reference individuals (18.1 per 1000 person-years). The association was similar among both women and men, with hazard ratios of 1.31 and 1.37, respectively.

The association appeared to be stronger during the first year of follow-up, where that risk was more than 2 times higher for patients with diverticulosis, even though that risk remained significant after 5 years. Importantly, among patients with cardiovascular disease, having a concomitant diagnosis of diverticular disease was associated with a 47% increased risk for overall cancer.

Among patients who had siblings, there were 4305 incident cancers among those with diverticular disease (19.2 per 1000 person-years) and 6544 incident cancers among their sibling comparatives (14.4 per 1000 person-years). In an adjusted model, this translated into a 26% increased risk for overall cancer among patients with diverticular disease compared with their siblings.

Patients with diverticular disease also had an increased risk for specific cancer types. For example, the risk for colon cancer was 71% higher among those with diverticular disease compared with the general population, whereas the risk for liver cancer was 72% higher. The risk for pancreatic cancer was 62% higher among those with diverticular disease, and the risk for lung cancer was 50% higher in patients with diverticular disease compared with the general population.

The risk for prostate cancer was modestly elevated in those with diverticular disease, at 13%, as was the risk for breast cancer, at 17%. Overall, rates of solid cancers were 33% higher in patients compared with the general population, and the rates of hematologic cancers and lymphoproliferative cancers were also higher, at 34% and 24% among those with diverticular disease, respectively.

"Analyses with siblings as the comparator yielded similar results," the investigators note. The significant excess of cancer risk was apparent in patients with diverticular disease both with a normal colorectal histopathology and among those with inflammation or diverticula or normal history, the authors add.

Patients with diverticular disease had a 13% lower risk for rectal cancer compared with reference individuals, note the authors of an accompanying editorial, headed by Veronika Fedirko, PhD, University of Texas MD Anderson Cancer Center, Houston.^[3] "One might postulate that the lower risk could be due, at least in part, to exclusion of patients with concomitant undiagnosed diverticular disease and rectal cancer from the study and/or more effective removal of pre-cancerous lesions in the rectum. . .during an initial diagnostic colonoscopy," they suggest.

Why patients with diverticular disease are so cancer-prone might be a result of several factors. First, patients with undiagnosed cancer might be misclassified as having diverticular disease initially because symptoms of diverticular disease and cancer can overlap, as the authors suggest. Second, diverticular disease is likely to be confirmed on imaging tests through which cancers are concurrently diagnosed.

This could lead to an increase in cancer incidence during the first year after the screening, which the study found. Third, a follow-up colonoscopy is recommended by several guidelines committees after diverticulitis is diagnosed to rule out a missed malignancy; thus, patients with a history of diverticulitis may undergo more colonoscopies and thus have a higher chance of having CRC diagnosed.

Last, there is growing evidence that chronic inflammation and gut dysbiosis in involved in the pathogenesis of diverticular disease, thus supporting chronic inflammation as a potential mechanism contributing to the link between diverticular disease and cancer.

There is also a plausible lifestyle link between diverticular disease and cancer, say the editorialists. "Advanced age and Western lifestyle are two important risk factors for both diseases," they note. Moreover, several lifestyle factors including low intake of dietary fiber and high intake of red meat, physical inactivity, obesity, and current smoking are all known to be associated with increased cancer risk as well as diverticular disease.

"Low overall diet quality is associated with less favorable gut microbiome profiles or dysbiotic (unbalanced) communities that are more vulnerable to pathogens," the editorialists point out.

"Thus, risk of both diverticular disease and cancer may reflect the gut microbiome's responsiveness to diet and ability to calibrate the host immune response through the intestinal epithelial barrier and inflammation," they observe.

There is also a possible genetic link between the 2 diseases, as in the current study the strongest estimates for diverticular disease and cancer risk were seen in patients between 18 and 29 years of age, the editorialists also point out.

"The clinical implications of the findings are modest," the editorialists note, "[but] results prompt further exploration of the biological mechanisms underlying the association between diverticular disease and cancer, especially non-gastrointestinal cancers," they suggest.

The study was supported by the Swedish Cancer Foundation. Dr Ma and Dr Fedirko have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online October 6, 2022.

Clinical Implications

• A previous study found that diverticulitis was associated with a higher risk for colon cancer, and this association strengthened after adjustment for potential confounders. Diverticulitis was associated with a higher risk for cancer even among patients without colonoscopy, reducing the risk for surveillance bias.
• In the current study, diverticulosis was associated with a significantly elevated risk not just for colon cancer but also for multiple other types of cancer.
• Implications for the healthcare team: The healthcare team should acknowledge that adults with diverticulosis may have symptoms or signs that actually represent cancer. More research is needed into the potential mechanisms explaining why diverticulosis might promote cancer.

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