Inflammatory Bowel Disease and Colorectal Cancer: An Eternal Fire in a Beautiful Garden

Abstract

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, significantly increases the risk of colitis-associated cancer (CAC). Chronic inflammation, a key contributor to carcinogenesis, disrupts immune surveillance, induces deoxyribonucleic acid (DNA) damage, and alters genetic and epigenetic pathways. Molecular pathways such as STAT3, mTOR, and NF-κB drive CAC progression, while unique microbiome alterations—loss of Faecalibacterium prausnitzii and increases in Escherichia coli and Fusobacterium species—exacerbate the inflammatory milieu. CAC accounts for 2% of all colon cancers and up to 15% of IBD-related deaths. Risk correlates with IBD duration, increasing approximately 1% annually after the first decade. Surveillance via colonoscopy is crucial, with chromoendoscopy recommended for high-risk cases. Preventive drugs, including aminosalicylates, thiopurines, and biologics, offer modest benefits but lack conclusive evidence. Post-CAC diagnosis, immunosuppressants are discontinued in favor of corticosteroids, with 5-aminosalicylates continued as needed. The use of immune checkpoint inhibitors remains controversial due to exacerbation of colitis. Emerging insights into the gut microbiota's role in IBD and CAC may revolutionize prevention and management strategies. Advances in screening, surveillance, and therapeutic approaches have reduced CAC mortality, underscoring the importance of personalized medicine and ongoing research to address these complex conditions.

Keywords

hereditary risk - immune deficiency - cytokine - precancerous

Venkata Pradeep Babu Koyyala

Introduction

As described decades ago, inflammation is the fertile soil in which seed of cancer arises. Inflammation is a double-edged sword, which, under physiological conditions, supports the immune surveillance that prevents any frank transformation of cells into cancer. Escape from immune surveillance and altering immune equilibrium are recognized mechanisms of carcinogenesis. Lack of immune surveillance can result in frank cancers as seen in conditions like acquired immune deficiency syndrome.[1] The other extreme is excessive, persistent, and dysregulated activity of immune cells as seen in inflammatory bowel disease (IBD) associated colon cancer, a prototypical example of inflammation-mediated carcinogenesis. Other such examples are hepatocellular cancer, Schistosoma-induced bladder cancer, and Helicobacter pylori–induced gastric cancer. Two important forms of IBD are Crohn's disease and ulcerative colitis. Approximately 2 out of every 100 colon cancers are IBD related. The risk of cancer increases with the duration from diagnosis of IBD and it is estimated that with each year, the risk of developing colorectal cancer increases.

Terminology Associated with IBD and Colitis-Associated Cancer

Dysplasia-associated lesion or mass (DALM) is a sessile lesion, seemingly polypoid in shape, occurring in the area affected by IBD. The inflammation in that area may be current or past.

Adenoma-like mass (ALM), also called polypoid dysplasia, is a pedunculated-like lesion resembling adenoma occurring in the colonic mucosa previously or currently not affected by inflammation.

Flat dysplasia: These lesions are difficult to visualize due to minimally elevated or depressed lesions from the mucosal surface. Whenever these are identified, they raise a red flag about the possibility of other invisible dysplastic coexistent lesions, often leading to clinical decision of total colectomy.

However, the American Gastroenterological Association (AGA) has suggested abandoning the terms like DALM, ALM, and flat dysplasia and proposed using the following terms:

• Polypoid precancerous lesion: ≥2.5 mm tall.

• Nonpolypoid precancerous lesion: less than 2.5 mm tall.

• Invisible: precancerous lesion detected on nontargeted biopsy.

Epidemiology

The first report of cancer occurring in a patient with ulcerative colitis was made by Dr. Burrill Crohn in the early 1920s. However, it took more than 50 years to establish Crohn's disease as a risk factor for colon cancer because most of the studies published during that period had a small sample size and the findings were not statistically significant. However, mechanistically it is very clear that IBD can result in cancer.[2] The overall risk of colorectal cancer in the patients with IBD is approximately 20 times higher as compared with the general population. Colitis-associated cancer (CAC) accounts for nearly 2% of all diagnosed colon cancers as per western data, yet it accounts for 10 to 15% of all deaths in IBD.[3] There are no Indian data to exactly define the incidence of CAC. The most important factor in initiating carcinogenesis is the duration of colitis, with risk increasing at approximately 1% per year after a decade of onset of the disease. The cumulative risk after three decades is approximately 8%.[4] It was seen that the actual incidence of CAC-associated mortality has been reduced. The factors for such trends are advanced screening, surveillance, and treatment modalities as well as improvements in data collection, quality, and analysis overcoming the limitations of older study designs that did not take into count disease severity, duration, all-cause mortality, etc.[5]

The association between CAC and ulcerative colitis is well established, while the association between CAC and Crohn's disease is variedly reported, with relative risk between 0.8 and 20. The risk factors associated with IBD and colon cancer are age, duration of IBD, extent of inflammation, and presence of history of primary sclerosing cholangitis ([Table 1]). It was seen that colonic involvement in Crohn's disease is the most important risk factor for the development of CAC.[6]

Table 1 Risk factors for colitis-associated cancer in inflammatory bowel disease (IBD)

Risk factors for colitis-associated cancer in IBD
Age of diagnosis (y)	0–19 (risk ratio [RR]: 43.8)
	20–29 (RR: 2.65)
Duration of IBD
Extent of inflammation
Primary sclerosing cholangitis
Presence of inflammatory pseudo-polyps
Family history of colorectal cancers

Pathogenesis

Inflammation is an integral part of pathogenesis of the majority of gastrointestinal cancers.[7] [8] The reason for this inflammatory microenvironment studded with seeping in leucocytes and cytokines, activation of inflammatory pathways, receptors can be identified and can be traced in some of these cancers to inciting agents or conditions, while many remain to be elucidated yet. It has been observed that there are two pathways that drive inflammation in these tumors: intrinsic pathway by the mutated proto-oncogenes and extrinsic pathway by a factor such as infection or IBD.[8] This is the reason why inflammation is characterized as one of the hallmarks of cancer.[9]

The pathogenic events are depicted in the flowchart in [Fig. 1]. The key mediators involved in CAC from initiation of carcinogenesis to progression were revealed by rodent experiments done by oral injection of DSS (dextran sulfate sodium), which causes colitis.[10] The chronic inflammation is the result of alteration of balance between proinflammatory molecules such as chemokines, interleukin-6, and interleukin and tumor necrosis factor-alpha (TNF-α) and negative regulatory factors such as cyclooxygenase-2, interleukin-10, and transforming growth factor-beta. Among cellular factors, dendritic cells, macrophages, and T cells in particular CD4, CD8, and CD25 are critical. Among the most important pathways, alterations of the mTOR-STAT3 pathway and NF-κB pathways were found to be the most important, resulting in excessive proliferation and disruption of homeostasis in the epithelium.[11]

Fig. 1 Pathogenesis of inflammatory bowel disease (IBD) associated colon cancer. DNA, deoxyribonucleic acid; ROS, reactive oxygen species.

Toll-like receptors play an important role in preventing gut infections as well as responding to intracellular stress, and when they are activated, they recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) of endogenous cellular stress. Polymorphisms of this receptor with altered recognition pattern may result in failure to inactivation of secondary pathways of inflammation and are implicated in both ulcerative colitis and Crohn's disease.[12] At the same time, anti-inflammatory mechanisms including T regulator cells and interleukin-10 are inhibited with a spurt of increase in proinflammatory cytokines.[13]

The molecular features of CAC are different from that of sporadic colon cancers, with less incidence of KRAS and APC gene mutations, while mutations in the P53, MYC, and IDH genes are found to be more common.[14]

Diagnosing Cancer in IBD

Because of overlapping symptomatology, diagnosis of cancer in a patient with IBD is challenging, and aggravation of symptoms should prompt more frequent endoscopy to rule out CAC, particularly in those with long duration (>8–10 years) of IBD, presence of primary sclerosing cholangitis, and with family history of colon cancer.

Prevention of CRC in IBD

Three important groups of drugs are used in clinical practice to prevent CAC: aminosalicylates, thiopurines, biological drugs. However, strong data corroborating their preventive effect on CAC are lacking.

Aminosalicylates

The usage of these drugs is recommended from the data of meta-analysis of more than 900 patients, showing its benefit against the development of dysplasia as well as colorectal cancer.[15] Theoretically, due to anti-inflammatory properties by modulation of β-catenin pathway, these drugs should completely prevent the development of CAC. However, long-term follow-up studies have failed to show the confirmatory benefit of preventive effect of these drugs.[16] [17]

Thiopurines

The usage of these drugs protects against high-grade dysplasia and CAC. However, due to lack of a control arm in the studies for estimating the benefit on inflammation, the data are ambiguous about their actual benefit in preventing CAC.[18]

Biological Drugs

The data on these drugs are conflicting, and the prototypical drug of this group is vedolizumab, which approved for both Crohn's disease and ulcerative colitis; it acts by decreasing the influx of white blood cells.

Surveillance in Inflammatory Bowel Disease

• The preferred modality for screening for precancerous lesions/dysplasia is colonoscopy.[19]

• Surveillance should be started after 8 to 10 years from the diagnosis of IBD.

• Surveillance for colon cancer should be started immediately after the diagnosis of sclerosing cholangitis.

• In visible precancerous lesions, the details of usage of any special visualization technique, size of the lesion, morphology, presence of ulceration, and location should be documented for future reference.

• Targeted biopsies should be done for mucosal irregularities and those areas visibly suspicious of dysplasia.

• Dye spray chromoendoscopy should be used whenever available, particularly in persons who have a history of dysplasia.

• Nontargeted biopsies are not required if chromoendoscopy is employed. However, if standard endoscopy is used, then at least four nontargeted biopsies should be done every 10 cm of normal colonic mucosa in addition to biopsies from prior dysplasia and from the areas of poor mucosal visibility.

• In case the nontargeted biopsy shows dysplasia, repeat endoscopy with an experienced physician using chromoendoscopy should be done. In the case of visible nonresectable dysplasia and nonvisible lesions showing multifocal dysplasia, the patient should be considered for total colectomy.

• In a patient with initial negative surveillance endoscopy, it is suggested that the next endoscopy be done after a gap of 5 years based on the risk factors.

Drugs to Reduce Progression or Recurrence in CAC

Managing IBD medically in a patient diagnosed with colorectal cancer presents challenges due to drug interaction and concerns of immunosuppression, especially with the advent of immune checkpoint inhibitors (ICPis) in the management of CRC. The data are limited to support a particular drug or combination, and the majority of the data in this condition are extrapolated from the literature of management of transplant-associated malignancies.

It is suggested to discontinue or reduce the use of immunosuppressive medication and switch to corticosteroids in patients diagnosed with CRC in the background of IBD.[20] It is suggested to discontinue thiopurines and anti-TNF treatments soon after diagnosis, while methotrexate and 5-amino salicylic acid (5-ASA) can be continued. After surgery for early-stage cancer, if IBD symptoms persist or recur on 5-ASA, anti-TNF therapies can be used and thiopurines is recommended to be avoided in this clinical setting.[21]

Role of ICPis in IBD-Associated Cancers

The role of ICPis is controversial due to their mechanism of action and conflicting results from preclinical and clinical studies. Studies have shown that ICPis may increase the risk of CAC without increasing or independent of colonic inflammation.[22]

However, several meta-analyses have shown that ICPis can be safely used in patients with nonactive autoimmune disease and in those without requiring therapy.[23]

Due to proven benefit of ICPis in several cancers, ICPis were used in cancer patients with autoimmune diseases, but it was found that in patients with IBD, immune-associated colitis due to these drugs can be severe and patients should be counselled accordingly to reach medical attention early after the onset of symptoms.[24] This is important in countries like India, where general physicians may not be aware of immune-related adverse events due to which these may progress to a higher grade of toxicity.[25]

Future Insights: Gut Microbiome in IBD and Colon Cancer

The role of microbiome is evolving in many diseases and is widely implicated in IBD. However, the role of microbiome as a cause of effect is still debated. The changes that were reported in the microbiome in the gut in both IBD and CAC are loss of biodiversity in microbiome, marked reduction in the colonies of Faecalibacterium prausnitzii, and increased colonies of Escherichia coli, E. faecalis, and Fusobacterium species.[26] [27]

Conflict of Interest

None declared.

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Publication History

Article published online:
28 January 2025