Inflammatory bowel diseases (IBDs) are a group of idiopathic conditions, including both ulcerative colitis (UC) and Crohn’s disease (CD), caused by interplays between environmental and patient-related factors which result in dysregulated immune responses directed mainly towards the small and large bowel [1]. While in UC the damage is limited to the colonic mucosa, in CD it is transmural and can involve any segment of the digestive system from the mouth to the perianal area [2].

The persistent relapse and remission levels of inflammation in IBDs are responsible for most of their complications, including, above all, colorectal cancer (CRC)—one of the most feared complications since its first description ^[3][4][3,4]. Indeed, IBD-associated CRC arises from a specific carcinogenic pathway involving chronic inflammation which is distinct from the traditional adenoma–carcinoma and serrated adenoma pathways [5].

Globally, CRC is currently the third most frequent form of malignancy and the second in terms of mortality, and its incidence has steadily increased worldwide over the past 40 years [6]. It places a serious burden on both patients and national health systems, since it represents the second leading cause of cancer-related disability-adjusted life-years (DALYs) and is responsible for high direct and indirect costs in developed and developing countries [7].

In patients affected by UC and CD, the risk of CRC-related death seems to have declined over time [8]. Successful surveillance strategies, more effective therapies and better indications to colectomy are likely responsible for this trend [9]. This notwithstanding, patients with IBDs affected by CRC have poorer 5-year survival than the general population [6]. Strong evidence-based prevention strategies are needed in order to mitigate the burden of this malignancy among these patients [10].

In the last few years, several innovations that have modified the management of patients with IBDs have been the subject of experimentation. These innovations are mainly represented by advancements in therapeutics and endoscopic techniques, although their roles have not yet been fully included in international guidelines.

The incidence of CRC has been increasing over time. According to the 2020 Global Cancer statistics, CRC is currently the third most frequent form of malignancy in both males and females, with 1.9 million new diagnoses, while it ranks second in terms of mortality, with 935,000 deaths [11]. CRC incidence is four times higher in developed than in emerging countries, while mortality rates seem to be comparable due to a worse case–fatality rate in developing economies. CRC is more frequent in Europe, Oceania and North America, while the incidence tends to be low in most regions of Africa and Asia [11]. The occurrence of CRC is responsible for a significant decrease in both life expectancy and quality of life. Indeed, it caused 24 million disability-adjusted life-years (DALYs) globally in 2019, with an age-standardized rate of 295.5 (275–316) DALYs per 100,000 person-years, showing a clear declining rate between 1990 and 2019 [6].

The incidence and prevalence of IBDs have been increasing in recent decades, worldwide [12]. Currently, over one million subjects in the US and 2.5 million in Europe are affected by IBDs, with an estimated prevalence of 0.5% in the general population in the Western world [13]. The highest prevalence of IBDs is reported in Europe, with 505 cases of UC per 100,000 inhabitants in Norway and 322 cases per 100,000 of CD in Germany, followed by 286 cases of UC per 100,000 in the USA and 319 cases of CD per 100,000 in Canada. Despite the lower availability of epidemiological data in newly industrialized countries, recent studies have shown an increased prevalence of IBD in South America, Eastern Europe, Asia and Africa [14].

It is now widely demonstrated that patients with longstanding colonic IBD have a higher risk of developing CRC when compared with the general population ^{[15][16][17][18]}[15,16,17,18]. Its incidence varies according to geographical distribution, with higher rates in the US and UK, and lower incidence in Scandinavian countries [17]. The worldwide incidence rate of CRC in CD is estimated to be between 19.5 and 344.9/100,000 per year, and between 54.5 and 543.5/100,000 per year in patients with UC [19]. The standardized incidence ratios (SIRs) for developing CRC in Europe and in the US are, respectively, 1.9 and 3.4 times higher in those with CD than in the general population, while these figures are 2.4 and 5.2 times higher in patients with UC ^[4][20][4,20]. In Asia, although data are limited, the prevalence of IBD-associated CRC is lower than in other regions [21]. The roles of ethnic origins and geographical location have still to be investigated, but it has to be emphasized that the abovementioned estimates should be considered in the context of differences in the availability of IBD therapies, surveillance practices, access to specialized gastroenterological care and diets. For instance, lower access to more efficacious medical treatments could determine a higher rate of patients who undergo surgery, thus decreasing the likelihood of cancer.

Furthermore, CRC-related mortality is higher in those affected by IBDs. In particular, when compared with the general population, the rate is 1.4 times higher both in CD and UC patients ^[22][23][22,23]. Data on indeterminate colitis (IC) are lacking: only one study has shown that the risk of developing CRC in patients with IC is higher than in patients with UC [24].

As far as time trends are concerned, the incidence of CRC in patients with UC has been declining over the last few decades, from 4.29 per 1000 per year to 1.21 per 1000 per year [25], while in patients with CD it seems to have been stable over time [26].

CRC plays a role in the natural history of these inflammatory diseases, since it represents one of the main causes of death in these patients (15% of all deaths in IBD patients), while IBD-associated CRC represents only 1–2% of all cases of CRC in the general population [27].

Comparing sporadic and IBD-associated CRC, there appear to be several differences in terms of age at diagnosis, the segment of the colon involved and mortality rates. Diagnosis of CRC in those with IBDs occurs earlier in life, with a mean age at diagnosis of 50–60 years compared to 65–75 years in sporadic CRC [28]. Localization of the underlying IBD affects directly the risk of CRC development. In those with colonic CD, it is four times higher than in those with a pure ileal involvement [29]. In particular, the right colon is the segment more frequently affected by CRC in these patients [30]. Despite being previously debated in the literature, recent studies have demonstrated that patients affected by IBD-associated CRC have a 1.2 to 2 times higher risk of death and a shorter overall survival than those with sporadic cancer ^[31][32][33][31,32,33]. A Japanese study focused on differential survival on the basis of cancer stage and showed that those with UC and stage III CRC had worse prognoses than patients with sporadic CRC, while no survival differences were observed in patients with earlier cancer stages [34]. Prognosis is influenced, also, by age. In patients with IBDs aged above 65 years, 5-year survival is similar to those with sporadic CRC, while in those aged below 50 years it is appreciably lower in patients with IBDs than in the general population (58.8% vs. 71.4%, p < 0.001) [35].

Despite these findings, it seems that the risk of death from CRC in patients with IBDs has been decreasing over time ^[4][36][4,36].

In order to improve patient prognosis and quality of life, the optimization of primary prevention strategies is crucial. The identification of risk factors involved in the development of CRC in patients with IBD represents an essential step in this process.

Risk factors can be categorized into “patient-related” factors, such as young age at diagnosis of IBD (<20 years), male gender and family history of CRC (especially in patients aged <50 years), and “disease-related” factors, such as extension of colitis and its duration (>10 years), concomitant history of primary sclerosing cholangitis (PSC) and presence of endoscopic and histologic inflammation (including post-inflammatory polyps) ^{[37][38][39][40]}[37,38,39,40].

In particular, duration of disease greatly influences the risk of CRC both in patients with UC (cumulative risk of 2%, 8% and 18% after 10, 20 and 30 years of disease duration) and in those with CD (cumulative risk of 2.9% at 10 years from diagnosis) ^[17][29][17,29]. Among all patients with IBDs, the cumulative risk of developing CRC reaches 1%, 2% and 5% after 10, 20 and more than 20 years of disease duration, respectively [41]. In a recent review of the literature on the development of CRC in patients with UC with low-grade dysplasia (LGD), the annual incidence of progression to CRC was reported as being 0.8%, and the risk of CRC was higher when LGD was confirmed by an experienced pathologist (i.e., 1.5%) [42].

Furthermore, the inflammatory activity of underlying IBD plays a central part in CRC development, generating oxidative-stress-induced damage to DNA that may activate tumor-promoting and disable tumor-suppressing genes ^[30].