Dra. Raquel Vicente
Hospital Universitario Miguel Servet. Zaragoza

Dra. Lara Arias
Hospital Universitario de Burgos

Dra. Beatriz Sicilia
Hospital Universitario de Burgos

Not all patients with inflammatory bowel disease (IBD) are candidates for a specific colorectal cancer (CRC) screening programme because, as we shall see, there are a number of risk factors that will condition this decision. This is very important, as chromoendoscopy, currently the gold standard technique for this specific screening, is an invasive procedure with risks of complications, in addition to being a medical resource that needs optimising like any other diagnostic test.

RISK FACTORS FOR CRC IN PATIENTS WITH IBD

1. Duration of disease

An increased incidence of CRC has classically been described in patients with long-standing IBD1 and although this percentage has decreased globally over the last decades as reflected in the meta-analysis published in 2014,  the risk is still higher than than in the general population2 (Fig.1). The duration of the disease continues to be one of the most important factors for the development of CRC in patients with IBD.  The cumulative incidence of CRC in the first decade after diagnosis is estimated to be usually < 0.5%, increasing to 1% at 10 years, 3% at 20 years and 7% at 30 years after the diagnosis of  ulcerative colitis (UC)3-5. Other studies and meta-analyses have supported these findings6-8. Colonic CD also presents this risk, doubling after 10 years of evolution4,5 (Fig.1 bis).

Section II.4.1. Figure 1: CRC incidence in UC.  Castaño-Milla C, Chaparro M, and Gisbert, JP. Systematic review with meta-analysis: the declining risk of colorectal cancer in ulcerative colitis. Aliment. Pharmacol. Ther 2014; 39 (7): 645–659

Section II.4.1. Figure 1 bis: Cumulative incidence of CRC in IBD.  Castaño-Milla C, Chaparro M, and Gisbert, JP. Systematic review with meta-analysis: the declining risk of colorectal cancer in ulcerative colitis. Aliment. Pharmacol. Ther 2014; 39 (7): 645–659

2. Extension of disease

The increased extension of UC is clearly associated with higher risk of CRC. In the historic study by Ekbom et al.9, more than 3000 patients with UC were followed up and the risk of CRC increased from 1.7 to 2.8 and 14.8 times in patients with proctitis, left-sided colitis  and pancolitis, respectively (compared to the general population). Another classic European study shows excess risk of 19.2  for extensive colitis 10. Recent studies, like the Scandinavian one by Olén et al.11, have also shown higher risk of CRC in patients with more extensive colitis (1.88, CI 95%: 1.72–2.07) compared to those with left-sided colitis or proctitis (Fig. 2).

A recent study shows a univariate clustered OR of 2.43 (CI of 95 %: 2.01–2.93) for extensive disease compared to left-sided colitis12.

Regarding CRC risk in patients with left-sided UC, although the risk outlined in the nineties is uncommon in the first 2 decades of disease, this incidence is equalised in these studies in the fourth decade10,12 and even at 15 years in more recent studies13.

3. Disease activity

Inflammation and disease activity are also risk factors associated with neoplasia, and their role has been analysed in different studies14, and although it is very likely that the development of CRC is related to the underlying inflammatory process, there is some controversial data. In a case-control study on 68 patients with UC and CRC, it was proven that greater levels of inflammation in both colonoscopy (OR: 2.5; p = 0.001) and histology (OR: 5.1; p = 0.001) are also associated with increased risk of CRC 15. Nevertheless, more recent studies did not observe significant differences between people with mild, moderate or severe inflammation on assessing CRC risk.  Matsuoka et al.16 reported that CRC risk was exclusively associated with inflammation in the active phase (RR: 0.04; CI 95%: 0.01-0.11) or mild colitis (RR: 5.80; CI 95%: 3.52-9.55) at 5-year follow-up. The association of a higher level of  endoscopic and histological inflammation with the risk of CRC has also been confirmed by other studies 17,18 and supported by meta-analysis 19,20. A recent meta-analysis by Wijnands et al. 19 shows a univariate clustered OR of 1.98 (CI of 95%: 0.68 to 5.73) in studies that assessed the impact of histological inflammation on the risk of CRC (Fig. 3).

4. Stenosis

The existence of dysplasia and CRC in colonic stenosis was described by Lashner et al.21 in 27 stenoses of patients with IBD primarily located in the left colon. More recent studies22 confirm this increase of neoplasia in patients with stenosis (OR: 5.7; CI 95%: 1.7-18.9), describing percentages of malignity in up to 25% of cases23 and risk factors identified as late onset during the course of the disease (61% if more than 20 years vs. 0% if less than 10 years of progression) and the location proximal to the splenic flexure (86% vs. 47% in sigma and 10% in rectum). A recent meta-analysis has shown an OR of 7.78 (CI of 95 %: 3.74–16.18) in all grouped UC and CD data assessing the association between stenosing disease and CA-CRC19 (Fig. 4).

5. Pseudopolyps

Probably due to the fact that they reflect a previous significant inflammation of the mucosa, post-inflammatory polyps or pseudopolyps are also associated with an increased risk of  CRC24,22. In the presence of pseudopolyps, inspecting the mucosa surrounding the polyp with caution is recommended because of the difficulty in differential diagnosis with adenomas or the possibility of concealed adenomas among the pseudopolyps, if very numerous.  The presence of pseudopolyps may shorten endoscopic screening intervals25.

6. Primary sclerosing cholangitis (PSC)

PSC is one of the most consistent risk factors established for developing CRC in IBD patients with an absolute risk of up to 31%26 and with incidences of CRC of 4.9% vs 0% and 11% vs 0% in 2 cohort studies published27,28 – an up to 9-fold risk has been described especially 10 to 20 years after diagnosing PSC (Fig. 5). Although the risk clearly increases with years of progression, CRC screening in these patients is established from the same year of diagnosis as both diseases present subclinically, often with a significant delay in diagnosis. Screening frequency should be annual.

7. Family history of CRC

Some studies find a significant risk of IBD in IBD patients with CRC29 whereas others show no statistical association29,30. In a recent meta-analysis, an OR of 2.59–2.62 was observed, depending on how the studies have defined the family history of CRC (studies included a variety of definitions for family history, including first-degree relatives only, second-degree relatives, or “any relatives” over and under 55 years of age19). Patients with such characteristics are checked more frequently in surveillance programmes31.

8. Dysplasia

Data on risk of advanced neoplasia after detecting visible low-grade dysplasia (LGD) is limited and variable, frequently generated based on small cohort studies. Records from St. Mark’s Hospital with 1375 patients shows that cancer risk at 10 years associated with the detection of LGD and high-grade dysplasia (HGD) is 30% and 50%, respectively, with a statistically significantly higher risk compared to patients without dysplasia (2%) and/or sporadic adenomas (7%)32. A recent large national cohort with long-term follow-up (n = 4284 patients with IBD and LGD) showed a cumulative incidence of advanced neoplasia of 21.7% after 15 years33.

Some of the meta-analyses published provide limited data because of the heterogeneity of the studies included with poor quality evidence34. A more recent meta-analysis, although citing a wide variation in results, shows univariate OR clustered from 10.7 to 10.85 (CI of 95 %: 4.60 to 24.87)19.

Lesions detected with LGD with any of the following characteristics: non-polypoid (HR 8.6, p < 0.001), endoscopically invisible (HR 4.1, p = 0.02), over 1 cm (HR 3.8, p = 0.01), preceded by undefined dysplasia (HR 2.8, p=0.01),with metachronous or mutifocal dysplasia are independent risk factors for the development of HGD or CRC in patients diagnosed with LGD34,35,36 (Video 1).

Section II.4.1. Video 1: Monitoring of dysplasia and detection of lesions using chromoendoscopy with dye

To more accurately substantiate the link between dysplasia and progression to CRC, prospective multicentre studies are needed.

9. Ulcerative colitis diagnosed during childhood or at an early age

Regardless of the duration of disease, could increase risk of CRC, although data is scarce. A major Scandinavian study carried out by Olén et al.37 showed a particularly high HR of CRC incident for childhood onset UC (HR 37.0, CI of 95 %: 25.1–54.4), compared to older patients with UC (0.98; 0.88–1.08); however, it is not clear if these groups have a comparable duration of disease. Most respective data38  including a meta-analysis also confirm these results on showing a standardised incidence of proportions of 8.6 (CI of 95 %, 3.8–19.50)6 .

CRC PROTECTIVE FACTORS IN PATIENTS WITH IBD

Some medical treatments could protect against the progression to neoplasm in UC patients:

  • Several meta-analyses support the use of 5-aminosalicylates (5-ASA) as chemoprotective agents in IBD with similar results in all of them (OR 0.58; CI 95 %: 0.45–0.75) (OR 0.63; CI 95 %: 0.48–0.84) 19,39,40
  • Despite older studies showing limited chemopreventive effect with immunomodulatory drugs41,42 there has been growing evidence to support the potential chemopreventive effect of thiopurines43,44 with a more recent meta-analysis that reached the same conclusions showing an OR of 0.67 (CI 95 % 0.45–0.98) and 0.49 (CI 95 % 0.34–0.70) respectively.
  • The role of anti-TNF-alpha in this clinical setting has been assessed in 6 studies and a meta-analysis showed no protective effect45.

It is likely that reaching the therapeutic objective of endoscopic/histological cure is the real factor responsible for decreasing the risk of CRC, more than the use of different drugs and their specific effects. The use of 5-ASA as a chemopreventive in UC seems rational, above all in patients with several risk factors, given the available evidence, but data on thiopurines or biologics is much more limited and there are no clinical trials in this context46.

INDICATIONS FOR SCREENING FOR DYSPLASIA IN PATIENTS WITH IBD

Based on the evidence available regarding risk factors, chromoendoscopy is indicated for all patients diagnosed with left-sided or extensive UC and in all patients diagnosed with CD with at least 1/3 colonic involvement for more than 8 years. An exception is patients with associated PSC, in which follow-up should start at diagnosis.
UC with only rectal involvement (proctitis [E1]) and Crohn’s ileitis or < 1/3 of colonic involvement are excluded from specific endoscopic follow-up with chromoendoscopy, as these patient subgroups do not appear to show an increased risk of CRC. Table 1 summarises the recommended monitoring intervals.

Section II.4.1 Table 1: Endoscopic follow-up according to risk factors. Sicilia B, Vicente R, Arias L, et al en nombre de GETECCU. Recommendations of the Spanish Working Group on Crohn’s disease and Ulcerative Colitis (GETECCU) on dysplasia screening in inflammatory bowel disease patients. Gastroenterol Hepatol. 2021 Jun-Jul;44(6):435-447

FUTURE PROSPECTS FOR CRC SCREENING: MOLECULAR FACTORS THAT LEAD TO CRC PROGRESSION

Different endoscopic and clinical factors currently stratify the risk of CRC in IBD patients; nonetheless, they are substandard methods that are far from ideal and are mediocre in predicting individual risk in our IBD patients. In this regard and as a not-too-distant goal, molecular medicine, novel biomarkers and specific mucosal profiling could be valuable tools to improve risk prediction in these patients.

  • Aneuploidy detected in colon tissue is a candidate for a molecular biomarker that has been associated with field cancerisation (the process by which the normal cell population is replaced by a cancer-primed cell population that may show no morphological change47) and with colitis-associated CRC. To date, only aneuploidy measured by flow cytometry has been shown to have a potential predictive role of CRC in IBD48.
  • Certain gene mutational panels48 have also emerged as biomarkers. For example, the TP53 mutation is typically an early colitis-associated CRC event49 , while mutations of the APC and K-ras genes50 are less frequent in colitis-associated CRC compared to sporadic CRC.
  • Additionally, developments in transcriptomics or the study of the level of expression of all the transcribed genes in a cell (of RNA molecules) suggest that it may be possible to incorporate gene expression analysis in identifying UC patients at high risk of progressive disease, with subsequent implications for improving the effectiveness of surveillance and management of these patients51.
  • On the other hand, it has been proven that chronic inflammation promotes aberrant DNA methylation in conditions such as in UC52 and that a clone with altered methylation status can undergo clonal expansion47. A systematic review suggests that certain genes are highly methylated in colitis-associated CRC (RUNX3, MINT1, MYOD, CDKN2A exon1 and the regions promoting EYA4 and ESR53). Further studies are needed to verify and validate these findings.
  • Other less-explored study lines to date include:
    • Circulating tumour DNA (ctDNA) and circulating cell-free DNA (cfDNA): So-called “liquid biopsies” are the analysis of DNA fragments in blood samples, and can provide information on disease activity and could simultaneously allow detection and analysis of tumour components without the need for tissue biopsy54 . To date, their application in IBD has been limited to a study that has shown usefulness in mouse and human models (n = 123)55. This study shows that in plasma, cfDNA concentrations correlate significantly with other inflammatory markers, such as the percentage of neutrophils, (p = 0.0079) and CRP (p = 0.0052), as well as being positively correlated with the clinical severity of UC55. To date, no studies have proven the correlation between cfDNA and dysplasia or CRC and IBD, but a meta-analysis suggests its potential use in sporadic CRC as a tool for detecting early disease, identifying residual disease, assessing treatment response, mapping prognosis and identifying mechanisms of treatment resistance56. Some studies have shown the potential of cfDNA in identifying genetic mutations that are known to be associated with response to targeted therapy in S-CRC, and in detecting K-ras mutations57. If this method eventually proves to be effective, cfDNA could then potentially be used in the context of monitoring patients with IBD without the need for repeat biopsies. These methods could be applied when patients are in remission, during an outbreak and/or escalation/de-escalation of treatment58 assisting in risk stratification and decision-making with regard to surveillance of these patients.
    • Stool DNA: Another attractive non-invasive biomarker is stool DNA, as large numbers of colonic epithelial cells can be isolated from stools, which makes it possible to sample a patient’s genomics and proteomics as well as their gut microbiome59. There is already some evidence that targeted mutational analysis of stool DNA identified patients with UC, with or without neoplasia, suggesting a high specificity and sensitivity for the detection of dysplasia60. These studies highlight the potential usefulness of this analysis in diagnosing and monitoring progressive lesions in IBD with the additional benefit of cost-effectiveness when combined with chromoendoscopy61, representing a very attractive non-invasive biomarker for monitoring the progression of neoplasia.
    • Immune microenvironment: Severity and extension of the inflammation are associated with the cancer risk in IBD19,15, but the underlying mechanisms by which inflammation causes cancer progression have not been fully determined. Aberrant changes in the stroma and microenvironment lead to field cancerisation62 and, therefore, could provide selective pressures, promoting clonal expansion of cancer-causing lineages.
    • Microbiome: Changes in the microbiome such as dysbiosis may be associated with cancer risk although this remains unclear63.
    • Artificial intelligence: Artificial intelligence applied to endoscopy deserves special mention for its rapid development, as it has already been used to detect colonic polyps/colonic lesions64 and identify Barrett’s oesophagus. In IBD it has already been employed in diagnosing and assessing severity of IBD, identifying endoscopic inflammation and classifying severity in UC patients65,66. Furthermore, artificial intelligence has the potential to be applied in identifying dysplasia (endoscopically and histologically), increasing inter-observer agreement and ultimately guiding subsequent surveillance strategies.

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