Scandinavian Journal of Gastroenterology. 2015; 50: 81–89

REVIEW

Malignancies in inflammatory bowel disease

URPO NIEMINEN1 & MARTTI FÄRKKILÄ1,2 Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 02/03/15 For personal use only.

1

Helsinki University Hospital, Department of Medicine, Division of Gastroenterology, Helsinki, Finland, and 2Helsinki University, Institute of Clinical Medicine, Helsinki, Finland

Abstract Patients with inflammatory bowel diseases (IBDs) are at increased risk of colorectal cancer (CRC), but the risk varies between different studies and seems to be decreasing. The cumulative risk of CRC has been reported to be 1%, 2%, and 5% after 10, 20, and over 20 years of disease duration, respectively, in recent meta-analysis. Disease duration and grade of inflammation are the main driving forces of dysplasia and CRC development. Also, the risk of extraintestinal cancers is increased in IBD, where the degree of immunosuppression and its duration are the most important risk factors. Most important extraintestinal malignancies are lymphomas and non-melanoma skin cancers, both of which are increased in patients receiving thiopurines. Also, extraintestinal manifestations or concomitant diseases such as primary sclerosing cholangitis predispose IBD patients to malignancies such as cholangiocarcinoma. History of previous cancer increases the risk of developing either new or recurrent cancers and should be taken into account when choosing therapy and planning surveillance. Dysplasia and cancer screening and surveillance must be individualized according to patients’ risk factors. Malignancies are the second most common cause of death after cardiovascular diseases in both genders in patients with IBD.

Key Words: colorectal cancer, extraintestinal malignancies, inflammatory bowel disease, malignancy

Introduction Inflammatory bowel diseases (IBD), both ulcerative colitis (UC) and Crohn’s disease (CD), are associated with increased risk of intestinal and extraintestinal malignancies. Chronic inflammation and the degree of immunosuppression are the main driving factors for IBD-related carcinogenesis [1]. Disease extent, its duration, and the grade of inflammation are associated with increased risk of colorectal and intestinal cancer [2]. Due to the many confounding factors such as patient populations studied, time of the study, and duration of follow-up time, the actual risk has been difficult to estimate [3]. Recent meta-analysis reported increased, but declining risk of colorectal cancer (CRC) in IBD [4]. Extraintestinal malignancies in IBD are associated with the immunosuppression induced by drugs used, such as thiopurines. In addition, the extraintestinal manifestations such as primary sclerosing cholangitis (PSC) can

increase the risk of malignancies, such as cholangiocarcinoma and CRC [5]. Lymphoproliferative diseases have increased in especially Western countries, and Epstein–Barr virus together with long-term immunosuppressive therapy has been associated with increased risk of lymphoma, especially in post-transplantation settings [6]. IBD patients are also at increased risk of lymphoma [7–9] and non-melanoma skin cancer (NMSC) [10–12] among others. Moreover, patients with IBD and a history of cancer are at increased risk of developing either new or recurrent cancers [13]. CRC in IBD Association of CRC with IBD was first described by Crohn and Rosenberg in 1925 [14]. Many studies have investigated this risk and reported widely varying risk ratios (RRs) revealing that the risk of CRC in UC is controversial.

Correspondence: Urpo Nieminen, MD, PhD, Department of Medicine, Clinic of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland. E-mail: [email protected]

(Received 12 November 2014; revised 23 November 2014; accepted 23 November 2014) ISSN 0036-5521 print/ISSN 1502-7708 online  2015 Informa Healthcare DOI: 10.3109/00365521.2014.992041

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U. Nieminen & M. Färkkilä

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Ulcerative colitis Early studies were predominantly from tertiary referral centers and they tended to overestimate the risk of CRC in UC. These series were based on patients admitted to hospital, and risks were related to the hospital population rather than general IBD population [15]. Population based studies from late 1900s were reviewed by Eaden et al. [15] and based on 116 studies they found that the overall prevalence of CRC in any UC patient was estimated to be 3.7%, and the overall incidence rate was 3/1000 person-years disease duration (pyd). The incidence rates corresponded to cumulative probabilities of 2% by 10 years, 8% by 20 years, and 18% by 30 years. The cancer incidence rates also vary geographically, being 5/1000 pyd in the USA, 4/1000 pyd in the UK, and 2/1000 pyd in Scandinavia and other countries. In a meta-analysis, IBD-associated CRC was reported to occur at age of 43.2 years, at younger age than sporadic CRC [15,16]. IBD-associated CRC has been shown to manifest at age 10–15 years earlier than sporadic CRC [17]. In two population-based studies standardized incidence ratio (SIR) of CRC compared with the general population and expected incidence of CRC were as high as 5.7 (95% confidence interval [CI]: 4.6–7.0) and 2.3 (95% CI: 2.0–2.6), respectively [18,19]. In Hungary, the cumulative risk of CRC at 30 years was found to be 7.5% [17]. Other population-based studies report lower risk. In a study from Olmsted County, USA, the cumulative risk of IBD-associated CRC was 2% at 30 years [18]. They observed CRC in 6 UC patients compared to 5.38 expected incidence and the SIR as low as 1.1 (95% CI: 0.4–2.4). In Denmark, the observed number of CRCs was almost exactly equal

to expected: 13 cases versus 12.42 (standardized morbidity ratio [SMR] = 1.05; 95% CI, 0.56–1.79), and the cumulative probability of CRC was 2.1% by 30 years of disease [19]. In extensive colitis or pancolitis, SIR for CRC was 2.4 (95% CI: 0.6–6.0). In a study by Rutter et al. [20], the cumulative probability of CRC in extensive colitis was 7.6% at 30 years. In their study, a declining CRC incidence over time was identified. Accordingly, Jess et al. [21] reported CRC incidence decline from 1.34 between 1979 and 1988 to 0.57 between 1999 and 2009.

Crohn’s disease Patients with ileal CD have equal risk of CRC than the general population, but in colonic disease the RR is likely elevated, but results in different studies are controversial. Ekbom et al. [22] followed a cohort of 1655 patients with CD diagnosed during 1983 in the Uppsala healthcare region, Sweden, to the end of 1984. They found 12 CRC, yielding an increased overall risk of 2.5. The relative risk was similar for males and females. Relative risk of disease of the terminal ileum alone was 1.0; of terminal ileum and parts of colon 3.2; and of colon alone 5.6. Patients with CD diagnosed before age 30 without colonic involvement at diagnosis had a higher relative risk (20.9) than those diagnosed at older ages (2.2). Also, in a Canadian study, the incidence of CRC in CD was increased (RR = 2.64; 95% CI: 1.69–4.12), which is equal to that detected in UC (2.75; 95% CI: 1.91–3.97) [23]. However, four recent studies did not show any increased risk of CRC in CD patients [12,21,24,25]. Summary of the risk of CRC in IBD is presented at Table I, including the most recent and largest studies.

Table I. Risk of colorectal cancer in UC and CD. Disease

Country

Period

UC UC UC UC UC UC UC UC

Canada Denmark Denmark Sweden Denmark Finland Denmark Finland

CD CD CD CD CD CD

Canada Denmark Denmark Finland Denmark Finland

1984–1997 1962–1997 1962–2005 1954–2004 1979–2008 1985–2007 1978–2010 1986–1993; 2000–2010 1984–1997 1962–2005 1979–2008 1985–2007 1978–2010 1986–1993; 2000–2010

No. of patients 2672 1160 1575 4125 32,911 1254 35,152 16,646 2857 641 14,463 550 13,756 5315

SIR (95% CI)

Reference

2.46 (1.82–3.25) 1.05 (0.56–1.79) 1.1 (0.6–1.8) 2.7 (2.3–3.2) 1.07 (0.95–1.21), RR 1.99 (1.14–3.25) 1.0 (0.9.–1.1) Colon: 1.81 (1.43–2.21) Rectum: 1.76 (1.35–2.25) 2.11 (1.41–3.04) 1.4 (0.5–3.1) 0.85 (0.67–1.07), RR 1.92 (0.62–4.49) 0.9 (0.7–1.2) Colon: 1.55 (0.92–2.44) Rectum: 1.80 (0.99–3.22)

[23] [19] [74] [31] [21] [24] [25] [12]

Abbreviations: UC = Ulcerative colitis; CD = Crohn’s disease; SIR = Standardized incidence ratio; RR = Risk ratio.

[23] [74] [21] [24] [25] [12]

Malignancies in IBD

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Small bowel adenocarcinoma The risk of small bowel adenocarcinoma (SBA) is markedly increased in CD, compared to general population. The recent study of Kappelman et al. [25] demonstrated an increased risk with SIR of 8.4 (95% CI: 4.3–14.7). The three published meta-analysis analyzing the risk of SBA in CD found that the pooled SIRs of SBA in different studies were 27.1 (95% CI: 14.9–49.2), 33.2 (95% CI: 15.9–60.9), and 28.4 (95% CI: 14.46–55.66) [26–28]. It has been concluded that there is no statistically significant difference in risk of small bowel cancer among different countries or study centers, or change in risk of small bowel cancer in CD over 45 years, using median year of diagnosis with CD as the marker for passage of time. This suggested that steroids, azathioprine or even anti-tumor necrosis factor (TNF) therapy have not modified the pathological process that increases the risk of intestinal cancer. In fact, the pathogenesis of SBA in CD is poorly defined. Much of the current understanding of the molecular alterations involved in the development of neoplasia in IBD comes from studies of patients with UC who develop colorectal carcinoma, also considered to be valid in CD. SBA is usually found in inflammatory areas, which suggests that the sequence inflammation–dysplasia–carcinoma is valid [29]. Risk factors of IBD-associated CRC Several colitis-associated risk factors for occurrence of CRC have been described. Increased risk for CRC is associated with long disease duration [2,15], extensive disease [15,21–23,30], male gender [23,31], young age at diagnosis [15,21,30], family history of CRC [32], coexisting PSC [33–35], and persistent colonic inflammation [2,36,37]. Disease duration In patients with disease duration up to 30 years, the cumulative incidence of CRC varies from 7.5% [17] and 7.6% [20] up to as high as 18% in a meta-analysis [15]. The mean duration of UC at occurrence of CRC has varied from 16.3 years [15] to 23.5 years [20]. In a tertiary center, the mean disease duration before CRC was 15.7 years [2]. Disease extension Disease extension has been shown to influence the risk of CRC. In proctitis and proctosigmoiditis, the risk is lowest, and in pan-colitis it is highest [38,39]. Söderlund et al. [40] have reported the relative risk of CRC in pan-colitis to be 5.6 (95% CI: 4.0–4.7) and in

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proctitis to be 1.7 (95% CI: 1.2–2.4). Also Ekbom et al. [41] showed the relative risk as high as 14.8 (95% CI: 11.4–18.9) in pan-colitis, 2.8 (95% CI: 1.6–4.4) in leftside colitis, and 1.7 (95% CI: 0.8–3.2) in proctitis. Gender In a study from Sweden, males with IBD had a 60% higher risk of CRC (RR = 1.6; 95% CI: 1.2–2.2) than females [31]. Males cumulative incidence 40 years after IBD diagnosis was 8.3% versus 3.5% in females. Compared with the rate of CRC among the general population, in males with IBD the RR was 2.6 (95% CI: 2.2–3.1). The relative risk for females was 1.9 (95% CI: 1.5–2.4), but the effect of sex was limited to the period after 10 years of follow-up evaluation and to patients 1 year of continuous moderate-tosevere symptoms during the disease course was invariably associated with colorectal neoplasia (OR = 3.2; 95% CI: 1.2–8.6). Using cumulative time with active disease (as a percentage of the total disease course) as the measure of IBD severity, a borderline significant association with risk of colorectal neoplasia was observed (OR = 1.2; 95% CI: 0.99–1.4). In a recent case–control study, high grade of inflammation was

U. Nieminen & M. Färkkilä

OR for dysplasia or cancer

84

1000

100

10

Inflammation activity High Mild-moderate

1 Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 02/03/15 For personal use only.

10 year

20 year

30 year

No

Disease duration Figure 1. The additive effect of inflammation activity and disease duration on the risk of dysplasia or colorectal cancer is shown. Abbreviation: OR = Odds ratio.

shown to be a risk factor for CRC with OR of 8.48 (95% CI: 1.44–49.8) [2]. The effect of inflammation on developing CRC over time was also detected as the OR at 30 years was as high as 261.6 (95% CI: 24.2– 1541.1), if the inflammation activity was high, and 27.4 (95% CI: 6.3–49.0), if it was mild-to-moderate, and 30.9 (95% CI: 19.5–43.0), if disease was inactive (Figure 1).

Drugs Immunosuppressive therapy with thiopurines or antiTNF-a seems not to increase the risk of CRC in IBD. Actually, use of thiopurines seems to decrease the risk of colorectal neoplasia. In a meta-analysis by Gong et al. [45], use of thiopurines was associated with a statistically significant decreased incidence of any colorectal neoplasm (RR = 0.71; 95% CI: 0.54–0.94). The RR of advanced neoplasm (high-grade dysplasia and cancer) was 0.72 (95% CI: 0.50–1.03) and that of cancer was 0.70 (95% CI = 0.46–1.09; p = 0.111) for thiopurine-treated patients. In another meta-analysis, Jess et al. [46] did not observe a significant effect of thiopurines on risk of colorectal neoplasia (dysplasia and/or cancer) in patients with IBD (OR = 0.87; 95% CI: 0.71–1.06). Further, in a study, from the Netherlands, van Schaik et al. [47] showed that thiopurine use significantly decreased the risk of developing advanced neoplasia (adjusted hazard ratio [HR] = 0.10; 95% CI: 0.01–0.75). In a German study, Beigel et al. [48] analyzed the malignancy rates and predictors for the development of malignancies in a large cohort of IBD patients treated with thiopurines and/or anti-TNF-a-antibodies. They established an increased risk of developing malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti-TNF

antibodies with or without thiopurines. About 20 malignancies were observed in 18 patients in the thiopurine group compared with 8 malignancies in 7 patients in the anti-TNF group (HR = 4.15; 95% CI: 1.82–9.44). Moreover, 18.2% of all patients in the thiopurine group aged ‡50 years developed a malignancy, compared with 3.8% of all patients 50 years

5 years

3 years

Elevated risk • Moderate or severe histological activity • Stricture in colon ≤ 5 years • Previous dysplasia • PSC • Family history of CRC aged ≤ 50 years

1 year

Figure 2. Dysplasia surveillance in patients with ulcerative colitis and Crohn’s colitis. Abbreviations: CRC = Colorectal cancer; PSC = Primary sclerosing cholangitis.

independent risk factors for CRC. For each increase in age group at diagnosis (30 years compared to those with diagnosis aged 365 days) was associated with NMSC (OR = 4.27; 95% CI: 3.08–5.92), and also recent thiopurine use (£90 days) was associated with NMSC (adjusted OR = 3.56; 95% CI: 2.81–4.50) [65]. In another study, no increased risk of NMSC compared with general population patients was found among patients never exposed to thiopurines, whereas both current and past exposure to thiopurines were associated with increased risk of NMSC (HR = 5.9; 95 CI: 2.1–16.6 and HR = 4.1; 95%CI: 1.3–13.3, respectively) [10]. Anti-TNF therapy may also increase the risk of NMSC, especially when used together with thiopurines. Long et al. [65] reported persistent and also recent use of biological medication among patients with CD to have an increased risk of NMSC (adjusted OR = 2.18; 95% CI: 1.07– 4.46 and adjusted OR = 2.07; 95% CI: 1.28–3.33, respectively. The risk was increased if anti-TNF was used with immunomodulators. Cervical cancer The risk of cervical cancer does not seem to be increased in IBD in majority of studies and the role of immunosuppression on the risk of cervical dysplasia in IBD is not clear [9]. However, it is currently recommended that all women with IBD, particularly those on immunosuppressive therapy, take part in a screening program of cervical surveillance and undergo vaccination against HPV, if appropriate [66]. Mortality Ulcerative colitis A slightly increased overall mortality in UC patients compared with the background population has been reported in earlier population-based studies [67–70]. However, most recent population-based studies could not find any increased risk of mortality compared to general population [24,71,72]. In recent Finnish nationwide register-based study by Jussila et al. [73], the overall mortality was slightly increased in UC. The SMR in males was 1.12 (95% CI:

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Malignancies in IBD 1.06–1.18) and was 1.07 in females (95% CI: 0.99– 1.15), the most common causes of death being cardiovascular diseases (42%) and malignancies (23%) in both genders. The risk of overall gastrointestinal disease mortality was highest within the first 3 years after the UC diagnosis but remained significantly elevated in the long term (SMR = 2.81; 95% CI: 2.32–3.34; ‡10 years after UC diagnosis). The overall mortality rate in UC of malignancies was not increased, but an excess mortality from colon (SMR = 1.90; 95% CI: 1.38–2.55) and rectal cancers (SMR = 1.79; 95% CI: 1.14–2.69) and especially from intrahepatic cholangiocarcinoma was seen (SMR = 5.65; 95% CI: 3.54–8.54). Crohn’s disease In the study by Jussila et al. [73], the overall mortality was increased in both genders (SMR = 1.23; 95% CI: 1.07–1.39 in males and SMR = 1.48; 95% CI: 1.28–1.68 in females). The most common causes of death were cardiovascular diseases (32%) and malignancies (24%) in both genders like in UC. Overall gastrointestinal disease mortality was markedly elevated in CD (SMR = 6.53; 95% CI: 4.91–8.52). The risk of gastrointestinal disease mortality was highest within the first 3 years after CD diagnosis (SMR = 12.3; 95% CI: 8.09–17.86) but remained significantly elevated even in the long term(SMR = 3.92; 95% CI: 1.79–7.74; ‡10 years after CD diagnosis). Increased mortality from intrahepatic cholangiocarcinoma (SMR = 4.51; 95% CI: 1.23–11.54) and malignant neoplasm of lymphoid and hematopoietic tissue (SMR = 2.95; 95% CI: 1.85–4.45) was seen. Conclusion Patients with IBDs are at increased risk of CRC and extraintestinal cancers, and malignancies are the second most common cause of death in both genders in CD and UC. Most important extraintestinal malignancies are lymphomas and NMSCs, both of which are increased in patients receiving thiopurines in treatment duration manner. Dysplasia and cancer screening and surveillance must be individualized according to patients’ individual risk factors such as history of previous cancer, family history of cancer concomitant diseases, such as PSC, and the grade of inflammation and degree of immunosuppression. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Malignancies in inflammatory bowel disease.

Patients with inflammatory bowel diseases (IBDs) are at increased risk of colorectal cancer (CRC), but the risk varies between different studies and s...
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