Scandinavian Journal of Gastroenterology. 2015; 50: 188–196
ORIGINAL ARTICLE
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The risk of colorectal cancer in inflammatory bowel disease: a hospital-based cohort study from Korea
HO-SU LEE*1, SANG HYOUNG PARK*1, SUK-KYUN YANG1, BYONG DUK YE1, JI-HUN KIM2, SEON-OK KIM3, JAE SEUNG SOH1, SEOHYUN LEE1, JUNG HO BAE1, HYO JEONG LEE1, DONG-HOON YANG1, KYUNG-JO KIM1, JEONG-SIK BYEON1, SEUNG-JAE MYUNG1, YONG SIK YOON4, CHANG SIK YU4 & JIN-HO KIM1 1
Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, 3Department of Biostatistics and Clinical Epidemiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, and 4 Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2
Abstract Objective. Limited data are available on the incidence and risk factors of colorectal cancer (CRC) in Asian patients with inflammatory bowel disease (IBD). Material and methods. Information on 5212 Korean patients with IBD (2414 with Crohn’s disease [CD] and 2798 with ulcerative colitis [UC]) was retrieved from the IBD registry of Asan Medical Center. Data on CRC incidence for the entire Korean population were derived from the Korean Statistical Information Service. Results. During 39,951 person-years of follow-up (17,679 for CD and 22,272 for UC), 30 patients (12 with CD and 18 with UC) developed CRC. The standardized incidence ratio (SIR) of CRC was 6.0 (95% confidence interval [CI], 3.10–10.48) for CD and 1.68 (95% CI, 1.00–2.66) for UC; it was 9.69 (95% CI, 5.01–16.93) for CD with colonic involvement and 4.31 (95% CI, 2.46–7.00) for extensive UC. The SIR was also increased in patients diagnosed with IBD at younger than 30 years old. CRC location was the low rectum in 11 of 12 CD patients (91.7%). The cumulative probability of rectal cancer was higher in CD patients with a perianal fistula than in those without a perianal fistula (p = 0.02). Conclusions. A high prevalence of perianal fistulas in Korean CD patients may be the cause of the predominance of low rectal cancer in this population and the higher SIR of CRC in Koreans than in Westerners. In contrast, the SIR of CRC in Korean UC patients may be similar to that in Western UC patients.
Key Words: colorectal cancer, Crohn’s disease, inflammatory bowel disease, Korea, ulcerative colitis
Introduction Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC). In 2001, a landmark meta-analysis of the risk of colitisassociated CRC reported that the cumulative risk of CRC was 2% at 10 years, 8% at 20 years and 18% at 30 years after the diagnosis of ulcerative colitis (UC) [1]. However, the risk of colitis-associated CRC is considered to have steadily decreased over the last few
decades [2]. A recent meta-analysis of Western population-based studies demonstrated that the standardized incidence ratio (SIR) of CRC was just 1.7 in patients with Crohn’s disease (CD) and UC [3]. Furthermore, some recent population-based studies have suggested that the overall risk of CRC is no longer increased in IBD patients, although the risk remains elevated in subgroups of patients [4,5]. However, the risk of CRC in IBD patients is highly variable among IBD populations. According to a meta-
Correspondence: Suk-Kyun Yang, MD, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82 2 3010 3901. Fax: +82 2 476 0824. E-mail: [email protected] *Ho-Su Lee and Sang Hyoung Park contributed equally to this article.
(Received 19 August 2014; revised 12 October 2014; accepted 16 November 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.989538
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Colorectal cancer risk of IBD in Korea analysis by Eaden et al. [1], the overall incidence of CRC in UC patients was lower in Scandinavia (2/1000 person-years) than in the United States (5/1000 person-years) or the United Kingdom (4/1000 person-years). Therefore, more studies are needed from a variety of ethnic groups. Although the incidence rate of IBD in Asian countries is still very low when compared with that of Western countries, the burden of IBD has been rapidly increasing and the risk of CRC in long-standing IBD patients has become a matter of concern in Asian countries. However, no population-based studies to date have examined the risk of colitis-associated CRC in this region. In 2009, a multicenter study from Korea reported that the cumulative incidence of CRC was 0.7% at 10 years, 7.9% at 20 years and 33.2% at 30 years after UC diagnosis [6]. Recently, a multicenter study from China reported that the cumulative risk of CRC was 1.5% at 10 years, 3.6% at 20 years and 14.4% at 30 years after UC diagnosis [7]. For CD, a single hospital-based cohort study from Japan reported that the cumulative risk of CRC was 0.2% at 10 years and 1.3% at 20 years after onset of CD [8]. However, these Asian studies did not provide information on duration of follow-up [6], completeness of follow-up [6–8], colectomy rates [6–8] or SIR [6,7], which precludes adequate comparison of the results between these Asian and Western studies. In addition, they did not censor person-years at risk of total colectomy [6–8] or stratify for isolated ileal CD [8], which might lead to an underestimation of the CRC risk. Furthermore, no Asian studies have compared the risk of CRC in UC patients with that in CD patients. Hence, the aim of this study was to assess the risk and characteristics of CRC in a well-defined hospital-based cohort of Korean IBD patients. Methods Study population Patients with CD and UC who were seen at Asan Medical Center, a tertiary university hospital in Seoul, South Korea, between June 1989 and December 2013 were enrolled in the present study. All patients were first diagnosed with CD between 1981 and 2013 and with UC between 1977 and 2013. Diagnosis of CD and UC was based on conventional clinical, radiologic, endoscopic and histopathologic criteria [9–11]. Our treatment strategies for IBD are similar to those of Western countries and were detailed previously [9,11,12]. Endoscopic surveillance for CRC every 1–3 years is usually recommended to patients with a disease duration greater than 8–10 years after
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the diagnosis of IBD [13–15]. Patients were subclassified as a referred cohort (those who were referred to Asan Medical Center after the diagnosis of IBD had been made at other clinics or hospitals) and an inception cohort (those who were first diagnosed with IBD at Asan Medical Center). Study design Patient demographic and clinical information was retrieved from the IBD registry of Asan Medical Center. The Asan IBD registry has been prospectively maintained since 1997 and was described in detail previously [12]. Retrieved data included sex, date of birth, date of IBD diagnosis, date of CRC diagnosis, family history of IBD, smoking status, disease extent and behavior, presence of a perianal fistula or primary sclerosing cholangitis and colectomy. When information was missing from the IBD registry, attempts were made to obtain the missing data by reviewing medical records or by interviewing patients. Information on the histological type, stage and location of CRC was retrospectively collected from medical records. Stage of CRC at the time of diagnosis was classified according to the TNM classification [16]. The pathologic specimens of CRC patients were reviewed by a single pathologist (J.H.K.). The Institutional Review Board of Asan Medical Center approved this study protocol (IRB number: 2013-0753). Statistics Continuous variables are expressed as medians with ranges unless otherwise stated. Discrete data are expressed as numbers and percentages. The chisquared test was used to compare proportions and a t test was used to compare quantitative variables. The cumulative probabilities of CRC from the diagnosis of IBD were calculated using the Kaplan–Meier method and were compared between groups using the log-rank test. Patients were followed from the date of IBD diagnosis until the date of CRC diagnosis, proctocolectomy, death or end of the study, whichever occurred first. To estimate the risk of CRC associated with colitis, CRCs diagnosed within a month of the IBD diagnosis were excluded, and person-years of follow-up were censored at the time of total proctocolectomy. SIRs (observed/expected numbers) of CRC with 95% confidence intervals (CIs) were calculated assuming a Poisson distribution of observed cases. The expected number of CRC cases was calculated by multiplying the person-years at risk in the study cohort by the age-, sex- and calendar periodmatched incidence rates for the Korean background population. Incidence data for the entire Korean
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population were derived from the Korean Statistical Information Service [17]. Analyses for SIR were stratified by sex, age at IBD diagnosis, disease duration, maximal extent of disease, presence of primary sclerosing cholangitis or a perianal fistula and source of patients (referred cohort versus inception cohort). Ratio of SIRs that were additionally adjusted for age at IBD diagnosis and duration of IBD served as our measure of the relative risk (RR) of developing CRC within the IBD cohort. RRs with 95% CIs were estimated by the use of Poisson regression. Statistical analysis was performed using SPSS for Windows, version 21.0 (SPSS, Inc., Chicago, IL, USA) or R software version 3.0.2 (Institute for Statistics and Mathematics of WU Wien, Austria, 2014) [18]. Results Patient population A total of 5212 patients with IBD (2414 with CD and 2798 with UC) were followed up for 39,951 personyears (17,679 for CD and 22,272 for UC) before total proctocolectomy, resulting in a mean follow-up duration of 7.7 years (7.4 years in CD and 8.0 years in UC). The median age at IBD diagnosis was 22 years (range, 9–74 years) for CD and 36 years (range, 9–90 years) for UC. By the end of our current study period, 190 CD patients (7.9%) and 393 UC patients (14.0%) were lost to follow-up without having undergone total proctocolectomy. Total proctocolectomy was performed in 44 CD patients (1.8%) and 189 UC patients (6.8%). Demographic and clinical characteristics of the patients are shown in Table I. Incidence of CRC CRC was found in 30 patients with IBD (12 with CD and 18 with UC) during the follow-up after IBD diagnosis; four cases (one with CD and three with UC) in which CRC and IBD were diagnosed at the same time were not included in the 30 patients and were excluded from analyses. Among the 12 CD patients who developed CRC during the course, the median age at CD diagnosis was 21 years (range, 15–36 years), the median age at CRC diagnosis was 32 years (range, 28–50 years) and the median duration of CD at CRC diagnosis was 12.5 years (range, 5–17 years). Among the 18 UC patients who developed CRC during the course, the median age at UC diagnosis was 33 years (range, 14–64 years), the median age at CRC diagnosis was 48 years (range, 27–73 years) and the median duration of UC at CRC diagnosis was 15 years (range, 1–25 years). The cumulative probabilities of developing CRC were
Table I. Demographic and clinical characteristics of patients with Crohn’s disease and ulcerative colitis. Crohn’s disease, n (person-years) Overall 2414 (17,679) Sex Men 1744 (12,268) Women 670 (5411) Age at IBD diagnosis 0–29 1844 (13,634) 30+ 570 (4045) Disease duration 0–10 1746 (8071) 10+ 668 (9608) Source of patients Inception cohort 608 (4545) Referred cohort 1806 (13,134) Maximal disease location Small bowel 518 (3416) Colon 132 (1040) Small bowel and colon 1751 (13,102) Unknown 13 (121) Maximal disease extent Proctitis Left-sided colitis Extensive colitis Unknown Perianal fistula at diagnosis of IBD Absence 1351 (10,177) Presence 1063 (7502) Primary sclerosing cholangitis Absence Presence
Ulcerative colitis, n (person-years) 2798 (22,272) 1503 (11,264) 1295 (11,008) 938 (7746) 1860 (14,526) 1881 (8238) 917 (14,034) 527 (4284) 2271 (17,988)
802 827 1143 26
(5293) (7252) (9531) (195)
2767 (21,964) 31 (307)
Abbreviations: IBD = Inflammatory bowel disease; n = Number.
0.3% at 10 years, 3.8% at 20 years and 3.8% at 30 years after CD diagnosis and 0.3% at 10 years, 3.4% at 20 years and 9.4% at 30 years after UC diagnosis (Figure 1). The SIR of CRC was 6.00 (95% CI, 3.10–10.48) for CD patients and 1.68 (95% CI, 1.00–2.66) for UC patients. Among the 30 IBD patients who developed CRC during the course, 7 patients (1 with CD and 6 with UC) were referred to our hospital after CRC was diagnosed at other hospitals. After exclusion of these seven patients, the cumulative probabilities of developing CRC decreased to 0.3% at 10 years, 3.6% at 20 years and 3.6% at 30 years after CD diagnosis and to 0.1% at 10 years, 3.0% at 20 years and 5.0% at 30 years after UC diagnosis, and the SIR of CRC decreased to 5.50 (95% CI, 2.75–9.85) for CD patients and to 1.12 (95% CI, 0.58–1.96) for UC patients. In contrast, when we excluded 526 CD patients with only small bowel involvement from the calculation of CRC risk, the cumulative probabilities of developing CRC increased to 0.3% at 10 years, 4.7% at 20 years and 4.7% at 30 years after CD diagnosis and the SIR of CRC for CD patients
Colorectal cancer risk of IBD in Korea A
B 20 Observed Expected p = 0.03
15
9.4
10
5
3.4 0.3
0 0
10 20 30 Years after diagnosis
Colorectal cancer (%)
Colorectal cancer (%)
20
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Observed Expected p < 0.001
15
10
5
3.8
3.8
0.3
0 0
10 20 30 Years after diagnosis
Figure 1. (A) Cumulative probability of colorectal cancer (CRC) in patients with ulcerative colitis compared with the expected incidence of cancer (p = 0.03, log-rank). (B) Cumulative probability of CRC in patients with Crohn’s disease compared with the expected incidence of cancer (p < 0.001, log-rank). Solid line, observed incidence; dotted line, expected incidence.
with colonic involvement increased to 9.69 (95% CI, 5.01–16.93). Characteristics of CRC Crohn’s disease. Histological types of CRC were mucinous adenocarcinoma in five patients, adenocarcinoma in four patients, signet ring cell carcinoma in two patients and neuroendocrine carcinoma in one patient. The stages of CRC at diagnosis were stage I in one patient, stage II in three patients, stage III in three patients and stage IV in five patients. The locations of CRC were the low rectum in 11 patients (91.7%) and the ascending colon in 1 patient (8.3%). Among the 11 CD patients with rectal cancer, 8 (72.7%) had a history of chronic perianal fistulas. We reviewed the surgical specimens from these eight patients to evaluate the association between chronic perianal fistulas and the development of rectal cancer. In four patients, cancers developed along the fistulous tract. In another two patients with a clinical suspicion of fistulaassociated rectal cancer, the association between perianal fistulas and rectal cancer was considered probable, although it was not confirmed due to the extensive destruction of anatomic structures by cancer. In the remaining two patients, cancers developed nearby but not inside the fistula. The date of last colonoscopy prior to CRC diagnosis was available in 11 of the 12 patients. In these 11 patients, the last colonoscopy had been performed a median of 34.2 months (range, 9.1–60.6 months) prior to the diagnosis of CRC. Ulcerative colitis. Histological types of CRC were adenocarcinoma in 17 patients and mucinous adenocarcinoma in 1 patient. The stages of CRC at diagnosis were stage I in five patients, stage II in three patients,
stage III in four patients and stage IV in six patients. Sixteen patients had single cancers and two patients had synchronous cancers at two different locations. The locations of 20 CRCs in 18 patients were the sigmoid colon in 7 patients (35%), the rectum in 6 patients (30%), the ascending colon in 4 patients (20%), the descending colon in 2 patients (10%) and the transverse colon in 1 patient (5%). In total, 75% of CRCs occurred distal to the splenic flexure. The date of the last colonoscopy prior to CRC diagnosis was available in 15 of the 18 patients. In these 15 patients, the last colonoscopy had been performed a median of 36.6 months (range, 6.9–213.0 months) prior to the diagnosis of CRC.
Factors associated with CRC The SIRs of CRC in a variety of subgroups of IBD patients are provided in Tables II and III. Compared with the background population, the risk of CRC was significantly increased as follows: in both sexes among CD patients, but only in females among UC patients; in patients diagnosed with IBD at younger than 30 years of age, but not in those diagnosed at older than 30 years of age; in UC patients with extensive colitis, but not in those with left-sided colitis or proctitis; in CD patients with colonic or ileocolonic type, but not in those with ileal type; in CD patients with a perianal fistula, but not in those without a perianal fistula; in UC patients with primary sclerosing cholangitis, but not in those without primary sclerosing cholangitis; in IBD patients with a disease duration longer than 10 years, but not in those with a disease duration shorter than 10 years; and in patients who were referred to our hospital after being diagnosed with IBD at other hospitals or clinics, but not in those diagnosed with IBD at our hospital (Tables II
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Table II. Standardized incidence ratios and RRs of CRC in 2414 patients with Crohn’s disease.
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Observed CRCs
RRa, within CD cohort
95% CI
2.39–10.91 1.97–18.48
1 (reference) 1.45
0.32–6.65
16.77 2.05
7.67–31.83 0.42–5.99
7.76 1 (reference)
0.79 1.21
3.78 7.47
0.78–11.04 3.41–14.18
1 (reference) 1.34
0.84 1.16
2.38 8.62
0.29–8.61 4.13–15.85
0.47 1 (reference)
0.75 0.12 1.12 0.01
0.00 16.92 8.94 0.00
– 2.05–61.12 4.29–16.44 –
N/A 1.96 1 (reference) N/A
1.40 0.60
2.85 13.44
0.78–7.29 5.80–26.49
1 (reference) 3.33
Expected CRCs
Standardized incidence ratio
95% CI
2.00
6.00
3.10–10.48
1.45 0.55
5.54 7.22
0.54 1.46
Overall 12 Sex Men 8 Women 4 Age at IBD diagnosis 0–29 9 30+ 3 Disease duration 0–10 3 10+ 9 Source of patients Inception cohort 2 Referred cohort 10 Maximal disease location Small bowel 0 Colon 2 Small bowel and colon 10 Unknown 0 Perianal fistula at diagnosis of IBD Absence 4 Presence 8
1.46–41.24
0.25–7.12 0.07–3.15
0.32–12.00
0.63–17.69
a
RR within the CD cohort standardized for sex, attained age and calendar time, and additionally adjusted for age at IBD diagnosis and duration of IBD. Abbreviations: CD = Crohn’s disease; CI = Confidence interval; CRC = Colorectal cancer; IBD = Inflammatory bowel disease; N/A = Not applicable; RRs = Relative risks.
Table III. Standardized incidence ratios and RRs of CRC in 2798 patients with ulcerative colitis. RRa, within UC cohort
95% CI
0.42–2.13 1.40–5.02
1 (reference) 2.07
0.41–10.38
18.50 0.97
7.99–36.45 0.47–1.79
17.50 1 (reference)
4.12 6.57
0.97 2.13
0.26–2.49 1.17–3.58
1 (reference) 1.41
1 17
2.94 7.75
0.34 2.19
0.01–1.90 1.28–3.51
0.21 1 (reference)
0 2 16 0
2.89 3.98 3.71 0.11
0.00 0.50 4.31 0.00
– 0.06–1.82 2.46–7.00 –
1 (reference) 1 (reference) 11.80b N/A
16 2
10.62 0.07
1.51 30.54
0.86–2.45 3.70–110.33
1 (reference) 12.52
Observed CRCs Overall Sex Men Women Age at IBD diagnosis 0–29 30+ Disease duration 0–10 10+ Source of patients Inception cohort Referred cohort Maximal disease extent Proctitis Left-sided colitis Extensive colitis Unknown Primary sclerosing cholangitis Absence Presence
Expected CRCs
Standardized incidence ratio
18
10.69
1.68
1.00–2.66
7 11
6.77 3.92
1.03 2.81
8 10
0.43 10.26
4 14
95% CI
3.64–84.15
0.22–9.24 0.01–5.13
2.20–63.15
1.12–140.28
a RR within the UC cohort standardized for sex, attained age and calendar time, and additionally adjusted for age at IBD diagnosis and duration of IBD. b RR of CRC analyzed within the UC cohort using left-sided colitis or proctitis as a reference. Abbreviations: CI = Confidence interval; CRC = Colorectal cancer; N/A = Not applicable; IBD = Inflammatory bowel disease; RRs = Relative risks; UC = Ulcerative colitis.
Colorectal cancer risk of IBD in Korea
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Table IV. Standardized incidence ratios and RRs of CRC in 1888 patients with any colonic involvement of Crohn’s disease.
Overall 12 Sex Men 8 Women 4 Age at IBD diagnosis 0–29 9 30+ 3 Disease duration 0–10 3 10+ 9 Source of patients Inception cohort 2 Referred cohort 10 Maximal disease location Colon 2 Small bowel and colon 10 Unknown 0 Perianal fistula at diagnosis of IBD Absence 4 Presence 8
RRa within CD cohort
95% CI
3.94–17.96 3.02–28.41
1 (reference) 1.41
0.34–5.81
20.89 3.72
9.55–39.65 0.77–10.86
5.41 1 (reference)
0.45 0.79
6.68 11.41
1.38–19.51 5.22–21.66
1 (reference) 1.29
0.42 0.81
4.71 12.30
0.57–17.01 5.90–22.61
0.53 1 (reference)
0.09–3.21
0.12 1.12 0.00
16.92 8.94 0.00
2.05–61.12 4.29–16.44 –
1.96 1 (reference) N/A
0.32–12.00
0.82 0.42
4.91 18.93
1.34–12.56 8.17–37.29
1 (reference) 3.17
Expected CRCs
Standardized incidence ratio
95% CI
1.24
9.69
5.01–16.93
0.88 0.36
9.12 11.10
0.43 0.81
1.14–25.57
0.27–6.09
0.77–16.61
a RR within the CD cohort standardized for sex, attained age and calendar time, and additionally adjusted for age at IBD diagnosis and duration of IBD. Abbreviations: CD = Crohn’s disease; CI = Confidence interval; CRC = Colorectal cancer; IBD = Inflammatory bowel disease; N/A = Not applicable; RRs = Relative risks.
and III). When the analysis was confined to 1888 CD patients with colonic involvement, additional subgroups of patients, including those without a perianal fistula and those with a disease duration shorter than 10 years, showed an increased risk of CRC compared with the background population (Table IV). Next, the RRs of CRC within the IBD cohort are provided in Tables II, III, IV. The RR of CRC was increased among patients diagnosed at younger than 30 years of age in both CD and UC groups. For UC, the RRs of CRC were increased among patients with extensive colitis and with primary sclerosing cholangitis. For CD, there was a trend toward a higher risk of CRC in patients with a perianal fistula at diagnosis compared with those without a perianal fistula. Furthermore, the cumulative probability of rectal cancer was statistically higher in patients with a perianal fistula than in patients without a perianal fistula (p = 0.02, log-rank test) (Figure 2). Discussion The cumulative risk of CRC for UC patients in this single hospital-based cohort study from Korea was lower than that in a landmark meta-analysis by Eaden et al. [1], which included both hospital-based and population-based studies from Western countries. However, when compared with recent population-based studies from Western countries,
the SIR of CRC for UC patients in this study was similar to that of Western population-based studies. The risk of CRC is known to be higher in hospitalbased studies than in population-based studies because hospital-based studies have a lower proportion of patients with proctitis and a higher proportion of patients with intractable or frequently relapsing disease [1–3,19]. Moreover, hospital-based studies may include patients who were referred to the study hospital after the diagnosis of CRC was made. 20
Rectal cancer (%)
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Observed CRCs
Perianal fistula (+) Perianal fistula (-) p = 0.02
15
10
5
0 0
10 20 Years after diagnosis
30
Figure 2. Cumulative probability of rectal cancer in patients with Crohn’s disease depending on perianal fistula presence (p = 0.02, log-rank).
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Therefore, a similar risk of CRC between our hospital-based study and Western population-based studies suggests that Korean patients with UC might have a lower risk of CRC than Western patients. Probert et al. [20] reported that colonic mucin patterns are different between South Asian and European patients with UC, suggesting that this difference may contribute to the difference in CRC risk between the two populations. In addition, Eaden et al. [1] suggested in their metaanalysis that the incidence rates of CRC in UC patients varies geographically, with lower risk in Scandinavia than in the United States or in the United Kingdom. However, it remains uncertain whether there are any intrinsic differences in the risk of colitis-associated CRC among different ethnic populations. To conclude that the risk of CRC in Korean UC patients is lower than that in Western patients, it is necessary to analyze factors that may affect the risk of CRC, including disease extent, disease duration, primary sclerosing cholangitis and treatment strategy, such as CRC surveillance and colectomy. In this study, among the 15 UC patients with CRC whose date of last colonoscopy prior to CRC diagnosis was available, only 4 (26.7%) underwent surveillance colonoscopy within 2 years prior to CRC diagnosis. In addition, only 6.8% of UC patients underwent colectomy. The low rate of adherence to CRC surveillance guidelines and the low colectomy rate might contribute to increase the SIR of CRC in this study. In contrast, although this study was hospital-based, the maximal extent of disease was proctitis in almost 30% and primary sclerosing cholangitis was present in only 1.1% of UC patients. Moreover, the mean duration of follow-up was just 8 years. All these factors might contribute to decrease the SIR of CRC in this study. Therefore, it would be premature to conclude that the risk of CRC in Korean UC patients is lower than that in Western patients. In contrast to UC, the SIR of CRC for CD patients in this study was higher than that in Western populationbased studies. In addition, when analyzed within this study, the SIR of CRC was higher in CD patients than in UC patients. These findings might be partly explained by the fact that the frequency of perianal fistulas in Korean CD patients was higher than that in Western patients, as discussed below, and that the median age at diagnosis of IBD was younger in CD patients than in UC patients by 14 years in our study. The most notable finding of our study is that most CRCs (91.7%) were located in the low rectum in CD patients and that the cumulative probability of rectal cancer was statistically higher in CD patients with a perianal fistula than in those without a perianal fistula. One study from Germany reported six cases of
adenocarcinoma arising from long-standing perianal CD with a review of the literature involving 59 patients in 23 studies [21]. However, previous Western studies have reported that colon cancers were more frequently observed than rectal cancers in CD patients. In a study from Canada, an increased risk of rectal cancer was not evident in CD patients, although an increased risk of colon cancer was seen [22]. In addition, only two of six CD patients with CRC (33.3%) had rectal cancer in both studies from Olmsted County and Denmark [4,23]. Moreover, a meta-analysis of four population-based studies reported that the overall pooled SIR for rectal cancer was not significantly increased among CD patients (SIR, 1.4; 95% CI, 0.8–2.6) [24]. In contrast, in two recent hospital-based studies from Japan [8,25], the location of CRC was the rectum or anorectal area in 88.9% (8/9) and 100% (6/6), respectively, in Japanese CD patients with CRC, which is comparable to the 91.7% (11/12) of our study. However, these Japanese studies did not disclose the prevalence of perianal fistulas in their study population. Instead, one of the two studies mentioned the proportion of patients with anal lesions without specifying the characteristics of the anal lesions. In our previous studies [11,12,26], we reported a high rate (~40%) of perianal fistulas in Korean CD patients at diagnosis and suggested that this might be a feature of Korean CD patients distinct from Western CD patients. In our present study, the SIR of CRC was 13.44 in CD patients with a perianal fistula; when we excluded CD patients without colonic involvement from the analysis, the SIR further increased to 18.93 in patients with a perianal fistula. Furthermore, when we reviewed the surgical specimens of the eight rectal cancer patients with a perianal fistula, the association between perianal fistulas and rectal cancer was histologically identified in four patients and was considered probable on clinical arguments in another two patients. These findings suggest that the high risk of rectal cancer in Korean CD patients is attributable to the high prevalence of perianal fistulas in this population and that adequate treatment of perianal fistulas may play an important role in reducing the risk of rectal cancer in CD patients. Moreover, strict application of cancer surveillance programs may be needed in CD patients with chronic perianal fistula. A previous Korean multicenter study [6] reported the cumulative risk of CRC at 30 years after UC diagnosis to be 33.2%, which is much higher than the 18% of the meta-analysis of Eaden et al. [1] as well as the 9.4% we report here. The very high 30-year cumulative risk of CRC in the previous Korean study was likely due to incomplete enrollment of patients with mild long-standing disease. A complete enrollment and
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Colorectal cancer risk of IBD in Korea follow-up of patients with mild long-standing disease may reduce the rate of CRC development. In our current study, the risk of CRC was assessed in a well-defined hospital-based cohort with a high rate of follow-up; the rate of follow-up loss was just 7.9% in CD patients and 14.0% in UC patients, which is exceptionally low for a Korean situation. In the present study, UC-related cancers were predominated by distal cancers (75%, 15 of the 20 CRCs) and this predominance corresponds well with that reported in the previous studies from Japan and Korea [6,27]; however, this result does not correspond with that of several Western reports [28–30]. The reason for this difference remains to be fully elucidated, but the discrepancy in the anatomical distributions of CRC may be influenced by certain factors, including race [31,32]. The results of our present study should be interpreted against the background of potential limitations. First, our current findings cannot be generalized to community IBD patients in Korea because they were obtained from a single tertiary referral center. To reduce the selection bias of a referral center-based study, we separately analyzed patients who were first diagnosed with IBD at our hospital. Although this approach would not remove the selection bias caused by self-referral, we found that the risk of CRC in our inception cohort was not higher than that in the background population, which was consistent with the recent Western population-based studies. In addition, the need remains to perform a population-based study to minimize the referral bias. Second, the duration of follow-up is relatively short in our study because the incidence rate of IBD is not static but has been rapidly increasing in recent years in Korea. Therefore, the number of patients who developed CRC is small despite the large number of IBD patients included in our study, which precluded an adequate subgroup analysis. In conclusion, in contrast to Western CD patients, the most common site of CRC in Korean CD patients is the low rectum, probably due to the higher prevalence of perianal fistulas in Korean CD patients. For the same reason, the SIR of CRC in Korean CD patients may be higher than that in Western CD patients. In contrast, the SIR of CRC in Korean UC patients may be similar to that in Western UC patients.
Acknowledgment This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120176).
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Declaration of interest: Suk-Kyun Yang has received a research grant from Janssen Korea Ltd., but this grant is not related to the topic of the current study. The remaining authors also have no competing interests.
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ORIGINAL ARTICLE
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The risk of colorectal cancer in inflammatory bowel disease: a hospital-based cohort study from Korea
HO-SU LEE*1, SANG HYOUNG PARK*1, SUK-KYUN YANG1, BYONG DUK YE1, JI-HUN KIM2, SEON-OK KIM3, JAE SEUNG SOH1, SEOHYUN LEE1, JUNG HO BAE1, HYO JEONG LEE1, DONG-HOON YANG1, KYUNG-JO KIM1, JEONG-SIK BYEON1, SEUNG-JAE MYUNG1, YONG SIK YOON4, CHANG SIK YU4 & JIN-HO KIM1 1
Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, 3Department of Biostatistics and Clinical Epidemiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, and 4 Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2
Abstract Objective. Limited data are available on the incidence and risk factors of colorectal cancer (CRC) in Asian patients with inflammatory bowel disease (IBD). Material and methods. Information on 5212 Korean patients with IBD (2414 with Crohn’s disease [CD] and 2798 with ulcerative colitis [UC]) was retrieved from the IBD registry of Asan Medical Center. Data on CRC incidence for the entire Korean population were derived from the Korean Statistical Information Service. Results. During 39,951 person-years of follow-up (17,679 for CD and 22,272 for UC), 30 patients (12 with CD and 18 with UC) developed CRC. The standardized incidence ratio (SIR) of CRC was 6.0 (95% confidence interval [CI], 3.10–10.48) for CD and 1.68 (95% CI, 1.00–2.66) for UC; it was 9.69 (95% CI, 5.01–16.93) for CD with colonic involvement and 4.31 (95% CI, 2.46–7.00) for extensive UC. The SIR was also increased in patients diagnosed with IBD at younger than 30 years old. CRC location was the low rectum in 11 of 12 CD patients (91.7%). The cumulative probability of rectal cancer was higher in CD patients with a perianal fistula than in those without a perianal fistula (p = 0.02). Conclusions. A high prevalence of perianal fistulas in Korean CD patients may be the cause of the predominance of low rectal cancer in this population and the higher SIR of CRC in Koreans than in Westerners. In contrast, the SIR of CRC in Korean UC patients may be similar to that in Western UC patients.
Key Words: colorectal cancer, Crohn’s disease, inflammatory bowel disease, Korea, ulcerative colitis
Introduction Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC). In 2001, a landmark meta-analysis of the risk of colitisassociated CRC reported that the cumulative risk of CRC was 2% at 10 years, 8% at 20 years and 18% at 30 years after the diagnosis of ulcerative colitis (UC) [1]. However, the risk of colitis-associated CRC is considered to have steadily decreased over the last few
decades [2]. A recent meta-analysis of Western population-based studies demonstrated that the standardized incidence ratio (SIR) of CRC was just 1.7 in patients with Crohn’s disease (CD) and UC [3]. Furthermore, some recent population-based studies have suggested that the overall risk of CRC is no longer increased in IBD patients, although the risk remains elevated in subgroups of patients [4,5]. However, the risk of CRC in IBD patients is highly variable among IBD populations. According to a meta-
Correspondence: Suk-Kyun Yang, MD, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82 2 3010 3901. Fax: +82 2 476 0824. E-mail: [email protected] *Ho-Su Lee and Sang Hyoung Park contributed equally to this article.
(Received 19 August 2014; revised 12 October 2014; accepted 16 November 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.989538
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Colorectal cancer risk of IBD in Korea analysis by Eaden et al. [1], the overall incidence of CRC in UC patients was lower in Scandinavia (2/1000 person-years) than in the United States (5/1000 person-years) or the United Kingdom (4/1000 person-years). Therefore, more studies are needed from a variety of ethnic groups. Although the incidence rate of IBD in Asian countries is still very low when compared with that of Western countries, the burden of IBD has been rapidly increasing and the risk of CRC in long-standing IBD patients has become a matter of concern in Asian countries. However, no population-based studies to date have examined the risk of colitis-associated CRC in this region. In 2009, a multicenter study from Korea reported that the cumulative incidence of CRC was 0.7% at 10 years, 7.9% at 20 years and 33.2% at 30 years after UC diagnosis [6]. Recently, a multicenter study from China reported that the cumulative risk of CRC was 1.5% at 10 years, 3.6% at 20 years and 14.4% at 30 years after UC diagnosis [7]. For CD, a single hospital-based cohort study from Japan reported that the cumulative risk of CRC was 0.2% at 10 years and 1.3% at 20 years after onset of CD [8]. However, these Asian studies did not provide information on duration of follow-up [6], completeness of follow-up [6–8], colectomy rates [6–8] or SIR [6,7], which precludes adequate comparison of the results between these Asian and Western studies. In addition, they did not censor person-years at risk of total colectomy [6–8] or stratify for isolated ileal CD [8], which might lead to an underestimation of the CRC risk. Furthermore, no Asian studies have compared the risk of CRC in UC patients with that in CD patients. Hence, the aim of this study was to assess the risk and characteristics of CRC in a well-defined hospital-based cohort of Korean IBD patients. Methods Study population Patients with CD and UC who were seen at Asan Medical Center, a tertiary university hospital in Seoul, South Korea, between June 1989 and December 2013 were enrolled in the present study. All patients were first diagnosed with CD between 1981 and 2013 and with UC between 1977 and 2013. Diagnosis of CD and UC was based on conventional clinical, radiologic, endoscopic and histopathologic criteria [9–11]. Our treatment strategies for IBD are similar to those of Western countries and were detailed previously [9,11,12]. Endoscopic surveillance for CRC every 1–3 years is usually recommended to patients with a disease duration greater than 8–10 years after
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the diagnosis of IBD [13–15]. Patients were subclassified as a referred cohort (those who were referred to Asan Medical Center after the diagnosis of IBD had been made at other clinics or hospitals) and an inception cohort (those who were first diagnosed with IBD at Asan Medical Center). Study design Patient demographic and clinical information was retrieved from the IBD registry of Asan Medical Center. The Asan IBD registry has been prospectively maintained since 1997 and was described in detail previously [12]. Retrieved data included sex, date of birth, date of IBD diagnosis, date of CRC diagnosis, family history of IBD, smoking status, disease extent and behavior, presence of a perianal fistula or primary sclerosing cholangitis and colectomy. When information was missing from the IBD registry, attempts were made to obtain the missing data by reviewing medical records or by interviewing patients. Information on the histological type, stage and location of CRC was retrospectively collected from medical records. Stage of CRC at the time of diagnosis was classified according to the TNM classification [16]. The pathologic specimens of CRC patients were reviewed by a single pathologist (J.H.K.). The Institutional Review Board of Asan Medical Center approved this study protocol (IRB number: 2013-0753). Statistics Continuous variables are expressed as medians with ranges unless otherwise stated. Discrete data are expressed as numbers and percentages. The chisquared test was used to compare proportions and a t test was used to compare quantitative variables. The cumulative probabilities of CRC from the diagnosis of IBD were calculated using the Kaplan–Meier method and were compared between groups using the log-rank test. Patients were followed from the date of IBD diagnosis until the date of CRC diagnosis, proctocolectomy, death or end of the study, whichever occurred first. To estimate the risk of CRC associated with colitis, CRCs diagnosed within a month of the IBD diagnosis were excluded, and person-years of follow-up were censored at the time of total proctocolectomy. SIRs (observed/expected numbers) of CRC with 95% confidence intervals (CIs) were calculated assuming a Poisson distribution of observed cases. The expected number of CRC cases was calculated by multiplying the person-years at risk in the study cohort by the age-, sex- and calendar periodmatched incidence rates for the Korean background population. Incidence data for the entire Korean
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population were derived from the Korean Statistical Information Service [17]. Analyses for SIR were stratified by sex, age at IBD diagnosis, disease duration, maximal extent of disease, presence of primary sclerosing cholangitis or a perianal fistula and source of patients (referred cohort versus inception cohort). Ratio of SIRs that were additionally adjusted for age at IBD diagnosis and duration of IBD served as our measure of the relative risk (RR) of developing CRC within the IBD cohort. RRs with 95% CIs were estimated by the use of Poisson regression. Statistical analysis was performed using SPSS for Windows, version 21.0 (SPSS, Inc., Chicago, IL, USA) or R software version 3.0.2 (Institute for Statistics and Mathematics of WU Wien, Austria, 2014) [18]. Results Patient population A total of 5212 patients with IBD (2414 with CD and 2798 with UC) were followed up for 39,951 personyears (17,679 for CD and 22,272 for UC) before total proctocolectomy, resulting in a mean follow-up duration of 7.7 years (7.4 years in CD and 8.0 years in UC). The median age at IBD diagnosis was 22 years (range, 9–74 years) for CD and 36 years (range, 9–90 years) for UC. By the end of our current study period, 190 CD patients (7.9%) and 393 UC patients (14.0%) were lost to follow-up without having undergone total proctocolectomy. Total proctocolectomy was performed in 44 CD patients (1.8%) and 189 UC patients (6.8%). Demographic and clinical characteristics of the patients are shown in Table I. Incidence of CRC CRC was found in 30 patients with IBD (12 with CD and 18 with UC) during the follow-up after IBD diagnosis; four cases (one with CD and three with UC) in which CRC and IBD were diagnosed at the same time were not included in the 30 patients and were excluded from analyses. Among the 12 CD patients who developed CRC during the course, the median age at CD diagnosis was 21 years (range, 15–36 years), the median age at CRC diagnosis was 32 years (range, 28–50 years) and the median duration of CD at CRC diagnosis was 12.5 years (range, 5–17 years). Among the 18 UC patients who developed CRC during the course, the median age at UC diagnosis was 33 years (range, 14–64 years), the median age at CRC diagnosis was 48 years (range, 27–73 years) and the median duration of UC at CRC diagnosis was 15 years (range, 1–25 years). The cumulative probabilities of developing CRC were
Table I. Demographic and clinical characteristics of patients with Crohn’s disease and ulcerative colitis. Crohn’s disease, n (person-years) Overall 2414 (17,679) Sex Men 1744 (12,268) Women 670 (5411) Age at IBD diagnosis 0–29 1844 (13,634) 30+ 570 (4045) Disease duration 0–10 1746 (8071) 10+ 668 (9608) Source of patients Inception cohort 608 (4545) Referred cohort 1806 (13,134) Maximal disease location Small bowel 518 (3416) Colon 132 (1040) Small bowel and colon 1751 (13,102) Unknown 13 (121) Maximal disease extent Proctitis Left-sided colitis Extensive colitis Unknown Perianal fistula at diagnosis of IBD Absence 1351 (10,177) Presence 1063 (7502) Primary sclerosing cholangitis Absence Presence
Ulcerative colitis, n (person-years) 2798 (22,272) 1503 (11,264) 1295 (11,008) 938 (7746) 1860 (14,526) 1881 (8238) 917 (14,034) 527 (4284) 2271 (17,988)
802 827 1143 26
(5293) (7252) (9531) (195)
2767 (21,964) 31 (307)
Abbreviations: IBD = Inflammatory bowel disease; n = Number.
0.3% at 10 years, 3.8% at 20 years and 3.8% at 30 years after CD diagnosis and 0.3% at 10 years, 3.4% at 20 years and 9.4% at 30 years after UC diagnosis (Figure 1). The SIR of CRC was 6.00 (95% CI, 3.10–10.48) for CD patients and 1.68 (95% CI, 1.00–2.66) for UC patients. Among the 30 IBD patients who developed CRC during the course, 7 patients (1 with CD and 6 with UC) were referred to our hospital after CRC was diagnosed at other hospitals. After exclusion of these seven patients, the cumulative probabilities of developing CRC decreased to 0.3% at 10 years, 3.6% at 20 years and 3.6% at 30 years after CD diagnosis and to 0.1% at 10 years, 3.0% at 20 years and 5.0% at 30 years after UC diagnosis, and the SIR of CRC decreased to 5.50 (95% CI, 2.75–9.85) for CD patients and to 1.12 (95% CI, 0.58–1.96) for UC patients. In contrast, when we excluded 526 CD patients with only small bowel involvement from the calculation of CRC risk, the cumulative probabilities of developing CRC increased to 0.3% at 10 years, 4.7% at 20 years and 4.7% at 30 years after CD diagnosis and the SIR of CRC for CD patients
Colorectal cancer risk of IBD in Korea A
B 20 Observed Expected p = 0.03
15
9.4
10
5
3.4 0.3
0 0
10 20 30 Years after diagnosis
Colorectal cancer (%)
Colorectal cancer (%)
20
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Observed Expected p < 0.001
15
10
5
3.8
3.8
0.3
0 0
10 20 30 Years after diagnosis
Figure 1. (A) Cumulative probability of colorectal cancer (CRC) in patients with ulcerative colitis compared with the expected incidence of cancer (p = 0.03, log-rank). (B) Cumulative probability of CRC in patients with Crohn’s disease compared with the expected incidence of cancer (p < 0.001, log-rank). Solid line, observed incidence; dotted line, expected incidence.
with colonic involvement increased to 9.69 (95% CI, 5.01–16.93). Characteristics of CRC Crohn’s disease. Histological types of CRC were mucinous adenocarcinoma in five patients, adenocarcinoma in four patients, signet ring cell carcinoma in two patients and neuroendocrine carcinoma in one patient. The stages of CRC at diagnosis were stage I in one patient, stage II in three patients, stage III in three patients and stage IV in five patients. The locations of CRC were the low rectum in 11 patients (91.7%) and the ascending colon in 1 patient (8.3%). Among the 11 CD patients with rectal cancer, 8 (72.7%) had a history of chronic perianal fistulas. We reviewed the surgical specimens from these eight patients to evaluate the association between chronic perianal fistulas and the development of rectal cancer. In four patients, cancers developed along the fistulous tract. In another two patients with a clinical suspicion of fistulaassociated rectal cancer, the association between perianal fistulas and rectal cancer was considered probable, although it was not confirmed due to the extensive destruction of anatomic structures by cancer. In the remaining two patients, cancers developed nearby but not inside the fistula. The date of last colonoscopy prior to CRC diagnosis was available in 11 of the 12 patients. In these 11 patients, the last colonoscopy had been performed a median of 34.2 months (range, 9.1–60.6 months) prior to the diagnosis of CRC. Ulcerative colitis. Histological types of CRC were adenocarcinoma in 17 patients and mucinous adenocarcinoma in 1 patient. The stages of CRC at diagnosis were stage I in five patients, stage II in three patients,
stage III in four patients and stage IV in six patients. Sixteen patients had single cancers and two patients had synchronous cancers at two different locations. The locations of 20 CRCs in 18 patients were the sigmoid colon in 7 patients (35%), the rectum in 6 patients (30%), the ascending colon in 4 patients (20%), the descending colon in 2 patients (10%) and the transverse colon in 1 patient (5%). In total, 75% of CRCs occurred distal to the splenic flexure. The date of the last colonoscopy prior to CRC diagnosis was available in 15 of the 18 patients. In these 15 patients, the last colonoscopy had been performed a median of 36.6 months (range, 6.9–213.0 months) prior to the diagnosis of CRC.
Factors associated with CRC The SIRs of CRC in a variety of subgroups of IBD patients are provided in Tables II and III. Compared with the background population, the risk of CRC was significantly increased as follows: in both sexes among CD patients, but only in females among UC patients; in patients diagnosed with IBD at younger than 30 years of age, but not in those diagnosed at older than 30 years of age; in UC patients with extensive colitis, but not in those with left-sided colitis or proctitis; in CD patients with colonic or ileocolonic type, but not in those with ileal type; in CD patients with a perianal fistula, but not in those without a perianal fistula; in UC patients with primary sclerosing cholangitis, but not in those without primary sclerosing cholangitis; in IBD patients with a disease duration longer than 10 years, but not in those with a disease duration shorter than 10 years; and in patients who were referred to our hospital after being diagnosed with IBD at other hospitals or clinics, but not in those diagnosed with IBD at our hospital (Tables II
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Table II. Standardized incidence ratios and RRs of CRC in 2414 patients with Crohn’s disease.
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Observed CRCs
RRa, within CD cohort
95% CI
2.39–10.91 1.97–18.48
1 (reference) 1.45
0.32–6.65
16.77 2.05
7.67–31.83 0.42–5.99
7.76 1 (reference)
0.79 1.21
3.78 7.47
0.78–11.04 3.41–14.18
1 (reference) 1.34
0.84 1.16
2.38 8.62
0.29–8.61 4.13–15.85
0.47 1 (reference)
0.75 0.12 1.12 0.01
0.00 16.92 8.94 0.00
– 2.05–61.12 4.29–16.44 –
N/A 1.96 1 (reference) N/A
1.40 0.60
2.85 13.44
0.78–7.29 5.80–26.49
1 (reference) 3.33
Expected CRCs
Standardized incidence ratio
95% CI
2.00
6.00
3.10–10.48
1.45 0.55
5.54 7.22
0.54 1.46
Overall 12 Sex Men 8 Women 4 Age at IBD diagnosis 0–29 9 30+ 3 Disease duration 0–10 3 10+ 9 Source of patients Inception cohort 2 Referred cohort 10 Maximal disease location Small bowel 0 Colon 2 Small bowel and colon 10 Unknown 0 Perianal fistula at diagnosis of IBD Absence 4 Presence 8
1.46–41.24
0.25–7.12 0.07–3.15
0.32–12.00
0.63–17.69
a
RR within the CD cohort standardized for sex, attained age and calendar time, and additionally adjusted for age at IBD diagnosis and duration of IBD. Abbreviations: CD = Crohn’s disease; CI = Confidence interval; CRC = Colorectal cancer; IBD = Inflammatory bowel disease; N/A = Not applicable; RRs = Relative risks.
Table III. Standardized incidence ratios and RRs of CRC in 2798 patients with ulcerative colitis. RRa, within UC cohort
95% CI
0.42–2.13 1.40–5.02
1 (reference) 2.07
0.41–10.38
18.50 0.97
7.99–36.45 0.47–1.79
17.50 1 (reference)
4.12 6.57
0.97 2.13
0.26–2.49 1.17–3.58
1 (reference) 1.41
1 17
2.94 7.75
0.34 2.19
0.01–1.90 1.28–3.51
0.21 1 (reference)
0 2 16 0
2.89 3.98 3.71 0.11
0.00 0.50 4.31 0.00
– 0.06–1.82 2.46–7.00 –
1 (reference) 1 (reference) 11.80b N/A
16 2
10.62 0.07
1.51 30.54
0.86–2.45 3.70–110.33
1 (reference) 12.52
Observed CRCs Overall Sex Men Women Age at IBD diagnosis 0–29 30+ Disease duration 0–10 10+ Source of patients Inception cohort Referred cohort Maximal disease extent Proctitis Left-sided colitis Extensive colitis Unknown Primary sclerosing cholangitis Absence Presence
Expected CRCs
Standardized incidence ratio
18
10.69
1.68
1.00–2.66
7 11
6.77 3.92
1.03 2.81
8 10
0.43 10.26
4 14
95% CI
3.64–84.15
0.22–9.24 0.01–5.13
2.20–63.15
1.12–140.28
a RR within the UC cohort standardized for sex, attained age and calendar time, and additionally adjusted for age at IBD diagnosis and duration of IBD. b RR of CRC analyzed within the UC cohort using left-sided colitis or proctitis as a reference. Abbreviations: CI = Confidence interval; CRC = Colorectal cancer; N/A = Not applicable; IBD = Inflammatory bowel disease; RRs = Relative risks; UC = Ulcerative colitis.
Colorectal cancer risk of IBD in Korea
193
Table IV. Standardized incidence ratios and RRs of CRC in 1888 patients with any colonic involvement of Crohn’s disease.
Overall 12 Sex Men 8 Women 4 Age at IBD diagnosis 0–29 9 30+ 3 Disease duration 0–10 3 10+ 9 Source of patients Inception cohort 2 Referred cohort 10 Maximal disease location Colon 2 Small bowel and colon 10 Unknown 0 Perianal fistula at diagnosis of IBD Absence 4 Presence 8
RRa within CD cohort
95% CI
3.94–17.96 3.02–28.41
1 (reference) 1.41
0.34–5.81
20.89 3.72
9.55–39.65 0.77–10.86
5.41 1 (reference)
0.45 0.79
6.68 11.41
1.38–19.51 5.22–21.66
1 (reference) 1.29
0.42 0.81
4.71 12.30
0.57–17.01 5.90–22.61
0.53 1 (reference)
0.09–3.21
0.12 1.12 0.00
16.92 8.94 0.00
2.05–61.12 4.29–16.44 –
1.96 1 (reference) N/A
0.32–12.00
0.82 0.42
4.91 18.93
1.34–12.56 8.17–37.29
1 (reference) 3.17
Expected CRCs
Standardized incidence ratio
95% CI
1.24
9.69
5.01–16.93
0.88 0.36
9.12 11.10
0.43 0.81
1.14–25.57
0.27–6.09
0.77–16.61
a RR within the CD cohort standardized for sex, attained age and calendar time, and additionally adjusted for age at IBD diagnosis and duration of IBD. Abbreviations: CD = Crohn’s disease; CI = Confidence interval; CRC = Colorectal cancer; IBD = Inflammatory bowel disease; N/A = Not applicable; RRs = Relative risks.
and III). When the analysis was confined to 1888 CD patients with colonic involvement, additional subgroups of patients, including those without a perianal fistula and those with a disease duration shorter than 10 years, showed an increased risk of CRC compared with the background population (Table IV). Next, the RRs of CRC within the IBD cohort are provided in Tables II, III, IV. The RR of CRC was increased among patients diagnosed at younger than 30 years of age in both CD and UC groups. For UC, the RRs of CRC were increased among patients with extensive colitis and with primary sclerosing cholangitis. For CD, there was a trend toward a higher risk of CRC in patients with a perianal fistula at diagnosis compared with those without a perianal fistula. Furthermore, the cumulative probability of rectal cancer was statistically higher in patients with a perianal fistula than in patients without a perianal fistula (p = 0.02, log-rank test) (Figure 2). Discussion The cumulative risk of CRC for UC patients in this single hospital-based cohort study from Korea was lower than that in a landmark meta-analysis by Eaden et al. [1], which included both hospital-based and population-based studies from Western countries. However, when compared with recent population-based studies from Western countries,
the SIR of CRC for UC patients in this study was similar to that of Western population-based studies. The risk of CRC is known to be higher in hospitalbased studies than in population-based studies because hospital-based studies have a lower proportion of patients with proctitis and a higher proportion of patients with intractable or frequently relapsing disease [1–3,19]. Moreover, hospital-based studies may include patients who were referred to the study hospital after the diagnosis of CRC was made. 20
Rectal cancer (%)
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Observed CRCs
Perianal fistula (+) Perianal fistula (-) p = 0.02
15
10
5
0 0
10 20 Years after diagnosis
30
Figure 2. Cumulative probability of rectal cancer in patients with Crohn’s disease depending on perianal fistula presence (p = 0.02, log-rank).
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H.-S. Lee et al.
Therefore, a similar risk of CRC between our hospital-based study and Western population-based studies suggests that Korean patients with UC might have a lower risk of CRC than Western patients. Probert et al. [20] reported that colonic mucin patterns are different between South Asian and European patients with UC, suggesting that this difference may contribute to the difference in CRC risk between the two populations. In addition, Eaden et al. [1] suggested in their metaanalysis that the incidence rates of CRC in UC patients varies geographically, with lower risk in Scandinavia than in the United States or in the United Kingdom. However, it remains uncertain whether there are any intrinsic differences in the risk of colitis-associated CRC among different ethnic populations. To conclude that the risk of CRC in Korean UC patients is lower than that in Western patients, it is necessary to analyze factors that may affect the risk of CRC, including disease extent, disease duration, primary sclerosing cholangitis and treatment strategy, such as CRC surveillance and colectomy. In this study, among the 15 UC patients with CRC whose date of last colonoscopy prior to CRC diagnosis was available, only 4 (26.7%) underwent surveillance colonoscopy within 2 years prior to CRC diagnosis. In addition, only 6.8% of UC patients underwent colectomy. The low rate of adherence to CRC surveillance guidelines and the low colectomy rate might contribute to increase the SIR of CRC in this study. In contrast, although this study was hospital-based, the maximal extent of disease was proctitis in almost 30% and primary sclerosing cholangitis was present in only 1.1% of UC patients. Moreover, the mean duration of follow-up was just 8 years. All these factors might contribute to decrease the SIR of CRC in this study. Therefore, it would be premature to conclude that the risk of CRC in Korean UC patients is lower than that in Western patients. In contrast to UC, the SIR of CRC for CD patients in this study was higher than that in Western populationbased studies. In addition, when analyzed within this study, the SIR of CRC was higher in CD patients than in UC patients. These findings might be partly explained by the fact that the frequency of perianal fistulas in Korean CD patients was higher than that in Western patients, as discussed below, and that the median age at diagnosis of IBD was younger in CD patients than in UC patients by 14 years in our study. The most notable finding of our study is that most CRCs (91.7%) were located in the low rectum in CD patients and that the cumulative probability of rectal cancer was statistically higher in CD patients with a perianal fistula than in those without a perianal fistula. One study from Germany reported six cases of
adenocarcinoma arising from long-standing perianal CD with a review of the literature involving 59 patients in 23 studies [21]. However, previous Western studies have reported that colon cancers were more frequently observed than rectal cancers in CD patients. In a study from Canada, an increased risk of rectal cancer was not evident in CD patients, although an increased risk of colon cancer was seen [22]. In addition, only two of six CD patients with CRC (33.3%) had rectal cancer in both studies from Olmsted County and Denmark [4,23]. Moreover, a meta-analysis of four population-based studies reported that the overall pooled SIR for rectal cancer was not significantly increased among CD patients (SIR, 1.4; 95% CI, 0.8–2.6) [24]. In contrast, in two recent hospital-based studies from Japan [8,25], the location of CRC was the rectum or anorectal area in 88.9% (8/9) and 100% (6/6), respectively, in Japanese CD patients with CRC, which is comparable to the 91.7% (11/12) of our study. However, these Japanese studies did not disclose the prevalence of perianal fistulas in their study population. Instead, one of the two studies mentioned the proportion of patients with anal lesions without specifying the characteristics of the anal lesions. In our previous studies [11,12,26], we reported a high rate (~40%) of perianal fistulas in Korean CD patients at diagnosis and suggested that this might be a feature of Korean CD patients distinct from Western CD patients. In our present study, the SIR of CRC was 13.44 in CD patients with a perianal fistula; when we excluded CD patients without colonic involvement from the analysis, the SIR further increased to 18.93 in patients with a perianal fistula. Furthermore, when we reviewed the surgical specimens of the eight rectal cancer patients with a perianal fistula, the association between perianal fistulas and rectal cancer was histologically identified in four patients and was considered probable on clinical arguments in another two patients. These findings suggest that the high risk of rectal cancer in Korean CD patients is attributable to the high prevalence of perianal fistulas in this population and that adequate treatment of perianal fistulas may play an important role in reducing the risk of rectal cancer in CD patients. Moreover, strict application of cancer surveillance programs may be needed in CD patients with chronic perianal fistula. A previous Korean multicenter study [6] reported the cumulative risk of CRC at 30 years after UC diagnosis to be 33.2%, which is much higher than the 18% of the meta-analysis of Eaden et al. [1] as well as the 9.4% we report here. The very high 30-year cumulative risk of CRC in the previous Korean study was likely due to incomplete enrollment of patients with mild long-standing disease. A complete enrollment and
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Colorectal cancer risk of IBD in Korea follow-up of patients with mild long-standing disease may reduce the rate of CRC development. In our current study, the risk of CRC was assessed in a well-defined hospital-based cohort with a high rate of follow-up; the rate of follow-up loss was just 7.9% in CD patients and 14.0% in UC patients, which is exceptionally low for a Korean situation. In the present study, UC-related cancers were predominated by distal cancers (75%, 15 of the 20 CRCs) and this predominance corresponds well with that reported in the previous studies from Japan and Korea [6,27]; however, this result does not correspond with that of several Western reports [28–30]. The reason for this difference remains to be fully elucidated, but the discrepancy in the anatomical distributions of CRC may be influenced by certain factors, including race [31,32]. The results of our present study should be interpreted against the background of potential limitations. First, our current findings cannot be generalized to community IBD patients in Korea because they were obtained from a single tertiary referral center. To reduce the selection bias of a referral center-based study, we separately analyzed patients who were first diagnosed with IBD at our hospital. Although this approach would not remove the selection bias caused by self-referral, we found that the risk of CRC in our inception cohort was not higher than that in the background population, which was consistent with the recent Western population-based studies. In addition, the need remains to perform a population-based study to minimize the referral bias. Second, the duration of follow-up is relatively short in our study because the incidence rate of IBD is not static but has been rapidly increasing in recent years in Korea. Therefore, the number of patients who developed CRC is small despite the large number of IBD patients included in our study, which precluded an adequate subgroup analysis. In conclusion, in contrast to Western CD patients, the most common site of CRC in Korean CD patients is the low rectum, probably due to the higher prevalence of perianal fistulas in Korean CD patients. For the same reason, the SIR of CRC in Korean CD patients may be higher than that in Western CD patients. In contrast, the SIR of CRC in Korean UC patients may be similar to that in Western UC patients.
Acknowledgment This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120176).
195
Declaration of interest: Suk-Kyun Yang has received a research grant from Janssen Korea Ltd., but this grant is not related to the topic of the current study. The remaining authors also have no competing interests.
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