Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives

Table 1 The difference in the incidence of inflammatory bowel disease related colorectal cancer, past and present

Epidemiology		CRC in ulcerative colitis	CRC in indeterminate colitis	CRC in Crohn's disease
Annual incidence	Past	Stewénius et al[111], 1995, 1.4/1000 PYD; Eaden et al[2], 2001, 2/1000 PYD-after 10 yr of initial onset; 7/1000 PY (patients with extensive colitis 90%) 30 yr of initial onset; Castaño-Milla et al[112], 2012, 1.01/1000 PYD - after 10 yr of initial onset; 3.75/1000 PYD - after 20 yr of initial onset; 5.85/1000 PYD - after 30 yr of initial onset	Stewénius et al[111], 1995, 2.4/1000 PYD	Olén et al[113], 2020, a Scandinavian population-based cohort study 0.31 per 1000 PY(1968); Laukoetter et al[114], 2011, 0.5/1000 PYD
	Present	Fumery et al[115], 2017, the annual incidence of CRC was 0.8% (95%CI: 0.4-1.3)		Olén et al[113], 2020, a Scandinavian population-based cohort study 0.47 per 1000 person-years (2017)
Risk	Past	Eaden et al[2], 2001, 0.3% after 30 yr of initial onset		Canavan et al[3], 2006, 2.9% after 10 yr of initial onset; 5.6% after 20 yr; 8.3% after 30 yr. Friedman et al[116], 2008, 7% by 10th surveillance (patients with extensive colitis 90%). Basseri et al[117], 2012, 5.6% by 10th surveillance (patients with extensive colitis 55%)
	Present	Fumery et al[115], 2017, the risk of CRC was higher when LGD was diagnosed by an expert gastrointestinal pathologist (1.5%) than by community pathologists (0.2%). Factors significantly associated with dysplasia progression were concomitant: PSC (OR, 3.4; 95% CI: 1.5-7.8); Invisible dysplasia (vs visible dysplasia; OR, 1.9; 95% CI: 1.0-3.4), distal location (vs proximal location; OR, 2.0; 95% CI: 1.1-3.7); Multifocal dysplasia (vs unifocal dysplasia; OR, 3.5; 95% CI: 1.5-8.5)	Keller et al[118], 2019, IBD-CRC is responsible for approximately 2% of the annual mortality from CRC overall, but 10%-15% of the annual deaths in IBD patients	Olén et al[113], a Scandinavian population-based cohort study. Patients with Crohn's disease who were diagnosed with CRC were at increased risk of CRC mortality compared with reference individuals also diagnosed with CRC [HR 1.42 (1.16-1.75) when adjusted for tumour stage]

PYD: Patient year days; LGD: Low-grade dysplasia; CRC: Colorectal cancer; IBD-CRC: Inflammatory bowel disease-related colorectal cancer; PSC: Primary sclerosing cholangitis; HR: Hazard ratio; OR: Odds ratio; CI: Confidence interval.

Table 2 Cytokines implicated in tumorigenesis in the colon

Cytokines	The mechanism	Potential target of therapy?	Ref.
TNF-α	Triggers systemic inflammation and is one of the cytokines that make up the acute phase reaction in IBD and other chronic inflammatory diseases TNF-α regulates the induction MACC1 via the NF-κB subunit p65 and the transcription factor c-Jun in CRC cells	Yes: Anti TNF used to control inflammation in IBD; hence may reduce incidence of CRC but this is debatable	Pache et al[119], Kobelt et al[120]
IL-6 family	In the chronic phase of inflammation, IL-6 is able to activate almost all the cells of the body: trans-signalling-Increased formations of IL-6-sIL-6R complexes interact with gp130 on the membrane of CD4+T-cells and leads to an increased expression and nuclear translocation of STAT3, which causes the induction of anti-apoptotic genes, e.g., Bcl-xl. This leads to resistance of lamina propria T-cells to apoptosis. T-cell expansion contributes to chronic intestinal inflammation	No: Anti IL-6 antibodies not successfully used in IBD. Unlikely to be useful in reducing risk of IBD-CRC	Atreya and Neurath[121], Allocca et al[122], Coskun et al[123], Danese et al[124]
IL-11	IL-11 belongs to the IL-6 family of cytokines. IL-11 has pro-tumorigenic activities such as proliferation, self-renewal, invasion and angiogenesis	No: No evidence to suggest it could be used as therapeutic agent. Could be useful as a diagnostic and prognostic biomarker	Murakami et al[125], Johnstone et al[126], Ren et al[127], Unver and McAllister[128], Pastor et al[129], Putoczki et al[130]
IL-17	IL-7 is a cytokine that helps the long-term survival of Th17 cells and innate lymphoid cells that express the transcription factor RORγt. It is suspected to be important for maintaining populations of T cells that induce and induce mucosal inflammation in IBD. IL-7 also maintains NKT cells that produce IL-17, using the PI3K/AKT/mTOR pathway	No: Anti-IL-17 medications are associated with IBD exacerbation	Hohenberger et al[131], Moschen et al[132]
IL-21	IL21 plays a dual role: IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development. Reduced numbers of circulating CD19 (+) B cells, including IgM (+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers. IL-21 Overproduction: IL-21 plays an important role in sustaining tissue-damaging immune responses	Yes: Could be used as a potential new therapeutic target in CD but unclear if it will influence IBD-CRC	Di Fusco et al[133], Salzer et al[134]
IL-23	IL-23R signalling affects disease susceptibility increased production of IL-23 by macrophages, dendritic cells or granulocytes has been observed in various mouse models of colitis, colitis-associated cancer and IBD patients	Yes: Currently in clinical trials for CD but too early to comment on effect on IBD-CRC	Moschen et al[132], Neurath[135]

NKT: Natural killer cells; MACC1: MET transcriptional regulator; UC: Ulcerative colitis; IBD-CRC: Inflammatory bowel disease-related colorectal cancer; AKT/PKB: Protein kinase B; IL: Interleukins; TNF-α: Tumor necrosis factor-α; RORγ: DNA-binding transcription factor; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: Phosphoinositide 3-kinases; gp130: Glycoprotein 130; Bcl-xl: B-cell lymphoma-extra large; c-Jun: c-Jun proto-oncogene; p65: Nuclear factor NF-kappa-B p65 subunit.

Table 3 Summary of studies over decades reporting on surveillance in inflammatory bowel disease

Ref.	Number of patients and cohort	Results	Conclusions benefit-yes/no
Rosenstock et al[136], 1985, Retrospective Review	248 chronic UC patients	In this cohort of patients: Overall incidence of HGD was 6%; HGD or carcinoma found in 24 procedures in 16 patients, mean disease duration of 16 yr, 15 patients had HGD; DALM most consistent indicator of carcinoma. > 95% of cancers 6 recognized at colonoscopy	The presence/absence of dysplasia a reliable histological marker that correlates with the presence/absence of cancer in UC. DALM with HGD had the strongest indication for surgery. Benefit- yes
Lashner et al[137], 1990, Prospective surveillance programme	99 patients with pancolitis	In this cohort of patients: Both groups comparable in terms of age at onset, disease duration and gender; Total 8 fewer deaths in the surveillance group (P < 0.05); Colectomy was less common and was performed 4 yr later in the surveillance group (P < 0.05)	Screening in UC associated with improved survival and delayed colectomy. Findings did not show improvement in cancer-related survival. Benefit-equivocal
Löfberg et al[138], 1990, 15-yr Prospective surveillance programme	72 UC, 12 patients developed definite dysplasia	In this cohort of patients: LGD detected in 7 patients; HGD in 4 and 1 Dukes' Stage-A cancer at operation; The cumulative risk of developing at least LGD was 14% after 25 yr of disease; Abnormal, aneuploid DNA content detected in biopsies of 12/59 patients (20.3%) this correlated significantly with LGD and HGD	Long-term use of surveillance in UC is reliable in detecting dysplasia and identify patients for prophylactic surgery. Benefit-yes; Earlier detection of neoplasia
Nugent et al[139], 1991, 13-yr Prospective surveillance programme	213 UC patients	In this cohort of patients: A total of 15 patients underwent colectomy; A total of 7 patients had unsuspected carcinoma at various stages; Dysplasia detected among 11 patients; No difference in the prevalence of dysplasia between left-sided v/s extensive disease; No carcinoma detected among 175 patients without dysplasia on initial biopsies	Surveillance programme effective aid in reducing the risk of carcinoma in UC. Short term risk of CRC low if biopsy negative. Colectomy deferred in this group. Benefit-yes
Lynch et al[140], 1993, Prospective surveillance(between 1978 and 1990)	160 UC patients	In this cohort of patients: A total of 739 colonoscopies carried out (4.6 colonoscopies/per patient); A 709 patient-years follow-up was carried out; In 1 patient Dukes's A cancer was detected; IBD-CRC caused the death of 1 patient; Overall, 9 IBD-CRC cases were diagnosed during the study period but only 1 case was detected by way of the surveillance programme	Results of this large study with long follow-up cast doubts on the effectiveness of the surveillance programmes in detecting CRC in patients with UC. Benefit-no
Jonsson et al[141], 1994, Prospective, longitudinal study between 1977 and 1991	131 patients with UC	In this cohort of patients: A total of 632 colonoscopies performed, dysplasia was diagnosed in 24 (4 HGD), other than those with cancer; CRC diagnosed in 4 patients, of whom 2 included in the programme with a diagnosis of cancer; CRC and dysplasia are seen mainly in the left colon and in pancolitis patients	The surveillance programme was resource consuming and the cost-benefit must be questioned. Benefit-no. No cost-benefit as per authors
Karlén et al[142], 1998, Prospective case-control study	4664 patients with UC, 142 patients with definite UC	In this cohort of patients: In 2 out of 40 patients with UC and 18/102 controls had at least one-surveillance colonoscopy (RR 0.29, 95% CI: 0.06-1.31); Out of 12 controls, only one patient with UC had two or more surveillance colonoscopies (RR 0.22, 95%CI: 0.03-1.74), indicating a protective dose-response relation	Surveillance may be associated with decreased risk of death from CRC in patients with long-standing UC. Benefit-yes. May improve survival
Friedman et al[143], 2001, Prospective Longitudinal study	259 patients with chronic Crohn's colitis	In this cohort of patients: A total of 663 examinations were performed on 259 patients; The median interval between examinations was 24 mo; More frequent examinations were carried out(1-6 mo) in patients with dysplasia; Dysplasia or cancer was detected in 16% (10 indefinite, 23 LGD, 4 HGD and 5 cancers); Definite dysplasia or cancer was associated with age > 45 yr and had increased symptoms	Colonoscopic surveillance should be strongly considered in chronic extensive Crohn's colitis. Benefit-yes. May improve survival
Biasco et al[144], 2002, Prospective Longitudinal study (20 yr duration)	65 patients with UC > 7 yr	In this cohort of patients: A total of 23 (35.3%) patients had surgery; A total of 29 (44.66%) patients discontinued the programme; Only 11 (16.9%) patients have remained in the programme	Results cast some doubts on the significance of such a programme and on its long-term feasibility. Benefit-no. Long-term feasibility doubtful
Hata et al[145] 2003, Retrospective January 1979 and December 2001	217 UC patients	In this cohort of patients: A total of 15 patients were detected to have definite dysplasia; Among 5/15 proved to have invasive cancer in resected specimens; cumulative risk for development of definite dysplasia at 10, 20 and 30 yr was 3.1%, 10.0%, and 15.6% respectively; A cumulative risk for the development of invasive cancer at 10, 20, and 30 yr was 0.5%, 4.1%, and 6.1%, respectively	The surveillance programme is useful for detecting IBD-CRC and survival may be improved by surveillance colonoscopy. Benefit-yes. May improve survival

UC: Ulcerative colitis; IBD-CRC: Inflammatory bowel disease related colorectal cancer; LGD: Low-grade dysplasia; HGD: High-grade dysplasia; DALM: Dysplasia-associated lesion/mass; RR: Relative risk; CI: Confidence interval.