Positive fecal immunochemical test but negative colonoscopy: what’s next?

Screening for colorectal cancer (CRC) using the fecal immunochemical test (FIT) has been rapidly implemented worldwide. Alongside primary colonoscopy, it is a first-tier recommended screening test. FIT testing offers several advantages, including noninvasiveness, high acceptance among the target population, and cost-effectiveness [11] [22] [33]. However, it is not without challenges, particularly concerning the management of individuals with a negative colonoscopy following a positive FIT result.

As globin (target for FIT) is degraded by digestive enzymes in the upper gastrointestinal tract, FIT testing is considered specific for lower-tract bleeding. In the absence of iron-deficiency anemia or signs/symptoms of upper gastrointestinal pathology, a positive FIT result and a negative colonoscopy should not trigger upper gastrointestinal evaluation [22]. Therefore, the clinical dilemma revolves around determining an appropriate screening interval for individuals whose subsequent CRC screening via colonoscopy does not reveal any abnormalities. The significance of this issue is substantial, as reports indicate that around 20%–50% of individuals who test positive with FIT will ultimately have a negative colonoscopy result [44].

Current European and US guidelines in this specific scenario recommend offering a subsequent screening test 10 years after negative colonoscopy. However, the strength of this recommendation is considered weak, and the level of supporting evidence is low. Consequently, several efforts have been undertaken to assess the risk of CRC in individuals with a positive FIT and a negative colonoscopy, and findings suggest that the risk of CRC in these individuals is higher compared with those with a negative FIT result or a negative primary screening colonoscopy [55].

“This paper adds to the existing evidence of the crucial impact of colonoscopy quality on the risk of post-colonoscopy CRC, especially in individuals with positive FIT results.”

In this issue of Endoscopy, van de Schootbrugge-Vandermeer et al. present an analysis conducted on data from the Dutch FIT-based national screening program [66]. This analysis focused on assessing the risk of CRC after a negative colonoscopy in individuals who tested positive through FIT. This marks the first published evaluation of the incidence of post-colonoscopy CRC (PCCRC) in FIT-positive individuals over an extended period.

The study included over 35 000 FIT-positive individuals who underwent a subsequent negative colonoscopy. With a median follow-up duration of 1.4 years, the authors identified 24 cases of PCCRC. This translated to an overall low absolute risk of PCCRC (6.85 per 10 000 individuals, with a 95%CI of 4.60–10.19) after 1.4 years.

The analysis revealed an interesting finding: after 2.5 years of follow-up, the age-adjusted PCCRC risk among individuals with positive FIT results resembled the CRC risk observed in individuals who had received negative FIT results 2 years prior. This specific time point marks when these individuals are invited for FIT screening again. In light of these outcomes, the authors pose the question of whether it would be appropriate to consider a reduction in the FIT screening interval following a negative colonoscopy.

Seeking answers to this question requires a detailed root cause analysis, as provided in the article. We observe that a majority of the PCCRC cases following positive FIT results were diagnosed in women (63%), within the 70–76 years age category (63%), at an advanced stage (55% in stage III or IV), and were located on the right side of the colon (67%). These characteristics strongly suggest missed lesions during colonoscopy.

When combining these data with the observation that the CRC risk in individuals with positive FIT results after 2.5 years of follow-up resembled the CRC risk in individuals with negative FIT results after 2 years, a critical consideration arises: whether offering FIT screening at a 2-year interval instead of the recommended 10-year interval could enhance outcomes for individuals diagnosed with CRC.

First, for over half (13/24) of the PCCRC cases, the time to diagnosis (due to symptoms) was shorter than 2 years. Thus, adopting the same 2-year interval as for individuals with negative FIT results would not prevent these diagnoses. Second, among the remaining 11 PCCRC cases diagnosed between 2.1 and 2.8 years after negative colonoscopy, five were at stage III or IV. This raises doubts about whether potential diagnosis at the 2-year time point would improve the overall prognosis for these individuals.

Third, FIT is not 100% sensitive for either CRC or advanced precancerous lesions. Therefore, it cannot be taken for granted that lesions missed by colonoscopy would be detected by subsequent FIT. Finally, when assessing potential benefits for these 24 individuals, we must consider the potential harms of introducing additional testing for a cohort of over 34 000 FIT-positive individuals.

Nevertheless, considering a negative colonoscopy in FIT screening programs as equivalent to negative findings in the primary screening colonoscopy setting is questionable. Individuals with positive FIT results are at a significantly higher risk of CRC, making the chance of missing CRC during colonoscopy higher than in a pooled cohort screened primarily by colonoscopy [77] [88]. This paper adds to the existing evidence of the crucial impact of colonoscopy quality on the risk of PCCRC, especially in individuals with positive FIT results. Although only 3 out of 24 diagnosed PCCRC cases had inadequate bowel preparation or incomplete colonoscopies, data on endoscopists’ adenoma detection rate or proximal serrated polyp detection rate were unavailable. Therefore, it is difficult to assess whether additional considerations for offering a colonoscopy, including examination quality, would decrease the risk of PCCRC.

In conclusion, the data presented in this paper provide a valuable assessment of the absolute risk of PCCRC in individuals with positive FIT results but negative colonoscopy results. Assuming that increasing the frequency of diagnostic tests will decrease this risk is debatable, as quantity will never compensate for quality.

Publication History

Article published online:
03 November 2023

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