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. 2019 Nov 3;2019:5363261. doi: 10.1155/2019/5363261

Risk of Colorectal Cancer in Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis

Qing Zhou 1, Zhao-Feng Shen 1, Ben-sheng Wu 2, Cheng-biao Xu 3, Zhong-qi He 2, Tuo Chen 4, Hong-tao Shang 1, Chao-fan Xie 5, Si-yi Huang 6, Yu-gen Chen 1,✉, Hai-bo Chen 4,✉, Shu-tang Han 1,✉
PMCID: PMC6874962  PMID: 31781191

Abstract

Background

Ulcerative colitis (UC) patients have an increased risk for the development of colorectal cancer (CRC). Our aim was to assess the risk of CRC in UC patients compared with disease extent, disease duration, and geographic variation.

Methods

In this systematic review and meta-analysis, we searched PubMed, scientific meetings, and the bibliographies of identified articles, with English language restrictions for studies published from 1988 to 2018, and assessed the risk of CRC in UC patients. Patients with Crohn's disease, family history of CRC, and colorectal adenomatous polyp (CAP) were excluded from this research. The study was registered with PROSPERO, number CRD42018102213.

Findings

We included 58 studies that included 267566 UC patients. Extensive UC and left-sided UC had a higher risk of CRC than proctitis UC. Geography also played a role in UC-associated CRC development. The time of malignant transformation in Asian UC patients started after 10-20 years of this disease duration. North American UC-associated CRC patients significantly increased in more than 30 years of this disease duration.

Conclusion

In a systematic review of the literature, we found that disease extent, disease duration, and geography were strong, independent risk factors in UC-associated CRC development.

1. Introduction

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa, which started in the rectum and generally extended proximally in a continuous manner through part of, or the entire, colon [1]. The clinical course was unpredictable, marked by alternating periods of exacerbation and remission [2]. UC-associated colorectal cancer (CRC) represented a fraction of CRC cases, accounted for up to 5% of all CRC [3]. In contrast to sporadic CRC, UC-associated CRC did not follow the typical “adenoma-carcinoma” sequences [1]. Due to limited understanding of the natural history of UC-associated CRC, the knowledge concerning the CRC risk in UC patients was still inadequate.

The first retrospective analysis on the risk of CRC in UC was published in 1988. In this publication, the overall incidence of CRC in UC was reported as 4.25% [4]. Recent mounting evidences from numerous countries suggested that the CRC standardised incidence ratio (SIR) in UC may differ based on disease duration and geographic variation. For example, the 10-year cumulative probability of cancer after the diagnosis of UC was 4.9%, not having a higher risk of cancer than an age-and sex-matched general population [5]. However, there was no synthesis of risk factors associated with disease extent, disease duration, and geographic variation. Therefore, we did a systematic review and meta-analysis to investigate the risk of CRC in UC patients compared with disease extent, disease duration, and geographic variation.

2. Methods

2.1. Search Strategy and Selection Criteria

We did a comprehensive literature research according to the Cochrane Handbook for Systematic Reviews of Interventions and followed the PRISMA and MOOSE guidelines for the reporting of meta-analyses. We searched PubMed, scientific meetings, and the bibliographies of identified articles, with English language restrictions for studies published from 1988 to Dec. 2018. All relevant articles included UC-associated CRC patients. Medical subject heading or keywords used in the search included the following: “Ulcerative Colitis” or “Inflammatory Bowel Disease (IBD)” or “Colorectal Cancer” or “Colorectal Neoplasia”. The full search strategies used for each database were described in Figure 1.

Figure 1.

Figure 1

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Flow chart of study selection.

Articles were eligible for inclusion if they reported the UC patients were associated with CRC in terms of the sample size. We included incidence rates in our analyses as an indirect method of adjustment for disease extent, disease duration, and geography.

Two authors (Qing Zhou and Zhao-Feng Shen) independently screened the title and abstract according to these eligibility criteria, screened data extraction, and did quality evaluation. When the evaluation result was not consistent, they consulted other researchers to further resolve differences through consultation according to the literature on the raw data. When the title and abstract met the requirements of the literature, the full text was retrieved for data extraction. NoteExpress 2.0 was adopted to manage the literature, and the repeated literature was removed. The inclusion of the literature was checked according to the abovementioned inclusion criteria, and the related references were traced.

2.2. Exclusion Criteria

We excluded the studies in this meta-analysis that met the following inclusion criteria:

  1. The literature type did not belong to the category of UC-associated CRC

  2. The literature type was a meta-analysis or summarization

  3. The literature type data was incomplete (UC and Crohn's disease could not be distinguished effectively) and the additional data could not be further obtained

  4. The literature type outcome evaluation index was not CRC

  5. The literature type was Crohn's disease, CAP, family history of CRC, or colectomy for UC

  6. The literature type was repeated or republished

2.3. Data Extraction

Two researchers (Qing Zhou and Zhao-Feng Shen) independently extracted relevant information from all eligible studies using a predefined data extraction form: author, publication year, sample size, age, country, gender, disease extent, and disease duration. Diagnosis and confirmation of UC and CRC were according to the criteria [6]. For missing data, the researchers tried to contact the original literature author by e-mail to obtain relevant data. Data that cannot be obtained was converted according to the relevant requirements of the Cochrane evaluation manual (such as the calculation of standard deviation in continuous data).

2.4. Outcomes

The primary outcome measure was the incidence of CRC in UC patients, reported as SIR. We included SIR in our analyses as a direct method of adjustment. No restrictions about publication year, sample size, age, country, gender, disease extent, and disease duration were applied.

The secondary outcomes were measuring the incidence of CRC in UC patients from disease extent, disease duration, geographic variation, and literature reporting time.

2.5. Analysis

We used random-effects meta-analysis to assess the incidence of CRC in UC patients. To calculate the pooled SIR of CRC, we combined the extracted study-specific estimates and 95% CIs using the DerSimonian-Laird random-effects model.

Publication bias (small-study effects) was examined with visual assessment of the symmetry of a funnel plot, the asymmetry of which will be assessed through Begg-Mazumdar's rank test. Forest plots were made for the prevalence of the outcomes in overall and within groups.

Data manipulation and statistical analyses were undertaken using the R Software (version 3.4.4). All statistical tests, with the exception of the Q statistic, used a two-sided α value of 0.05 for significance.

The study was registered with PROSPERO, number CRD42018102213.

2.6. Role of the Funding Source

This study was supported by the Ministry of Science and Technology of the People's Republic of China (2017YFC1700602), the National Natural Science Foundation of China (Grant No. 81573978), and the State Clinical Research of TCM (JDZX2015086).

3. Results

From 285 articles of potential relevance, 71 full-text articles were examined in detail and 58 studies were included in the final analysis; studies which identified 267566 UC patients, published from Nov. 1988 to Dec. 2018, with 2663 patients that reported UC-associated CRC were included in the meta-analysis. The population characteristics and outcomes of the included studies were summarized in Table 1.

Table 1.

Population and study characteristics.

Author Sample size (UC) Study period Mean age at diagnosis (UC) Country Sample size (CRC) Mean age at diagnosis (CRC) Gender Disease extent Time of duration (year)
Men Women Extensive Left-sided Proctitis
Hata et al. [7] 217 1979-2001 31.4 Japan 5 46.6 0 0 4 1 0 15.2
Kim et al. [8] 7061 1970-2005 37.9 Korea 26 49.6 8 18 0 0 0 12.7
Gong et al. [9] 3922 1998-2009 40 China 34 57.5 14 20 10 12 12 12.8
Matsuoka et al. [10] 1274 1984-2010 30 Japan 83 52 43 40 66 17 10 22
Zhang et al. [11] 624 2000-2012 39 China 4 54.5 2 2 4 0 0 15.5
Lee et al. [12] 2798 1989-2013 33 Korea 18 48 7 11 16 2 0 15
Choi et al. [13] 522 2003-2013 0 Korea 12 0 0 0 0 0 0 0
Shi et al. [14] 1225 1981-2013 41 China 15 0 0 0 0 0 0 0
Yoshino et al. [15] 2137 2003-2013 0 Japan 43 53 28 15 34 8 1 13
Wang et al. [16] 2663 1998-2013 43.1 China 18 0 0 0 0 0 0 19.27
Jung et al. [17] 9785 2011-2014 0 Korea 31 0 20 11 0 0 0 0
Kishikawa et al. [18] 289 1979-2014 33 Japan 9 49 5 4 28 5 0 16
Bopanna et al. [19] 1012 2004-2015 32.1 India 20 53.25 14 6 16 4 0 18.7
Selinger et al. [20] 504 1977-1992 0 Australia 24 0 0 0 12 8 4 0
Gupta et al. [21] 418 1996-1997 26.8 USA 1 0 0 0 0 0 0 0
Jess et al. [22] 378 1940-2001 34 USA 6 50.67 4 2 4 2 0 13.67
Bitton et al. [23] 15346 1999-2008 0 Canada 53 0 37 16 0 0 0 0
Hou et al. [24] 20949 1998-2009 0 USA 168 67 97 71 0 0 0 3.6
Ananthakrishnan et al. [25] 5569 1998-2010 0 USA 126 0 0 0 0 0 0 0
Navaneethan et al. [26] 997 1998-2011 0 USA 2 0 0 0 0 0 0 0
Yadav et al. [5] 462 1940-2011 35 USA 13 66 6 7 0 0 0 31
Ananthakrishnan et al. [27] 3546 2010-2013 0 USA 83 0 0 0 0 0 0 0
Sonnenberg and Genta [28] 37043 2008-2014 49.6 USA 54 0 0 0 0 0 0 0
Hou et al. [29] 881 1999-2014 0 USA 21 0 0 0 0 0 0 0
Bettner et al. [30] 75 1990-2015 29 USA 1 59 0 0 0 0 0 11.1
Gyde et al. [4] 823 1944-1976 33.66 UK/Sweden 35 56.69 13 22 28 7 0 23.03
Moody et al. [31] 175 1972-1981 58.4 UK 10 67 6 4 7 3 0 9.6
Ekbom et al. [32] 3117 1922-1983 0 Sweden 91 0 52 39 35 17 9 0
Lennard-Jones et al. [33] 401 1966-1987 29.73 UK 22 50.05 13 9 0 0 0 20.31
Löfberg et al. [34] 72 1973-1988 0 Sweden 1 42.25 0 0 0 0 0 0
Stewtnius et al. [35] 471 1958-1990 38.3 Sweden 9 49.88 3 6 7 1 1 12.22
Biasco et al. [36] 65 1980-1992 32.9 Italy 4 59.5 0 0 0 0 0 13
Wandall et al. [37] 801 1973-1993 41 Denmark 6 57.33 4 2 4 1 1 10.83
Palli et al. [38] 689 1978-1996 0 Italy 4 0 0 0 0 0 0 0
Winther et al. [39] 1160 1962-1997 0 Denmark 8 0 6 2 0 0 0 0
Viscido et al. [40] 2006 1964-1997 38.5 Italy 28 0 0 0 0 0 0 0
Goldacre et al. [41] 6990 1963-1999 0 UK 103 0 0 0 0 0 0 0
Lindberg et al. [42] 90 1977-2002 0 Sweden 8 0 0 0 0 0 0 0
Jess et al. [43] 1437 1978-2002 0 Denmark 15 0 0 0 0 0 0 0
Hemminki et al. [44] 27606 1964-2004 0 Germany/Sweden 482 0 0 0 0 0 0 0
Katsanos et al. [45] 182 1983-2004 51.2 Greece 3 0 2 1 0 0 0 0
Katsanos et al. [46] 776 1991-2004 0 Netherlands 7 61.3 0 0 0 0 0 5.4
Jess et al. [47] 1575 1962-2005 0 Denmark 14 0 8 6 0 0 0 0
Stolwijk et al. [48] 293 1980-2005 33.8 Netherlands 23 49.2 14 9 22 1 0 10.2
Lakatos et al. [49] 723 2002-2005 36 Hungary 13 51 0 0 8 5 0 19
Cheddani et al. [50] 474 1998-2006 69 France 8 75 0 0 0 0 0 7.4
Manninen et al. [51] 1254 1986-2007 34 Finland 16 47.69 14 2 10 6 0 16.1875
Jess et al. [52] 32911 1979-2008 44.9 Denmark 268 64 132 136 0 0 0 19.1
Gordillo et al. [53] 403 2006-2009 42.91 Spain 3 58.9 3 0 2 1 0 12.5
Kappelman et al. [54] 35152 1978-2010 46.5 Denmark 437 0 0 0 0 0 0 7.8
Choi et al. [55] 1375 2003-2012 30 UK 88 55.5 54 34 0 0 0 25.5
Choi et al. [56] 987 2003-2012 30 UK 14 0 0 0 0 0 0 0
Hovde et al. [57] 519 1990-2013 0 Norway 14 0 10 4 0 0 0 0
Van den Heuvel et al. [58] 1644 1991-2013 45 Netherlands 12 62.75 6 6 4 7 1 3.42
Nowacki et al. [59] 434 2013-2013 45.7 Germany 10 54.7 5 5 6 4 0 12
Rutegård et al. [60] 323 1977-2014 0 Sweden 10 0 0 0 0 0 0 0
Biancone et al. [61] 22666 2012-2014 0 Italy 24 64 0 0 0 0 0 12
Kekilli et al. [62] 275 1994-2008 35.9 Turkey 3 0 0 0 0 0 0 0
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3.1. Overall Risk of CRC in UC Patients

The overall risk of CRC in UC patients among the 58 studies was 1.4% (95% CI: 1.2-1.6; Figure 2). Gender-specific risk estimate for CRC in UC was reported in 30 of the 58 studies and varied from 0.89 (95% CI: 0.56-1.43) to 1.05 (95% CI: 0.68-1.63) in women and men, which has no difference (P = 0.62). Disease extent-specific risk estimates for CRC in UC were reported in 21 of the 58 studies, which show that extensive UC and left-sided UC had a higher risk of CRC (SIR: 1.42, 95% CI: 0.83-2.42; SIR: 0.56, 95% CI: 0.38-0.83) than proctitis UC (SIR: 0.18, 95% CI: 0.01-0.03) (P < 0.01) (Tables 2 and 3).

Figure 2.

Figure 2

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Individual and SIRs of CRC risk in UC: a meta-analysis of population-based cohort studies.

Table 2.

Gender-specific risk of CRC in UC patients.

Gender Proportion 95% CI
Men 0.0105 0.0068-0.0163
Women 0.0089 0.0056-0.0143
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▲P < 0.05 vs. women; ▲▲P < 0.01 vs. women.

Table 3.

Disease extent risk of CRC in UC patients.

Extent Proportion 95% CI
Extensive 0.0142▲▲ 0.0083-0.0242
Left-sided 0.0056▲▲ 0.0038-0.0083
Proctitis 0.0018 0.0010-0.0031
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▲P < 0.05 vs. proctitis; ▲▲P < 0.01 vs. proctitis.

3.2. Disease Duration Risk of CRC in UC Patients

In the subgroup analysis by disease duration, the incidence of CRC in UC patients rose after 20 years of this disease duration (Table 4).

Table 4.

Disease duration risk of CRC in UC patients.

Follow-up Article (n) Proportion 95% CI Weight (random)
1-9 years 11 0.007 0.005-0.009 22.40%
10-20 years 22 0.013 0.010-0.016 36.60%
21-30 years 11 0.02▲ 0.014-0.026 15.60%
More than 30 years 14 0.017▲ 0.013-0.022 25.40%
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▲P < 0.05 vs. 1-9 years; ▲▲P < 0.01 vs. 1-9 years.

3.3. Geographic Variation Risk of CRC in UC Patients

In the subgroup analysis by geographic variation, Oceania has a higher incidence than other continents; however, it has only one article (Tables 1 and 5). In Europe, the risk of CRC in UC patients has no statistical difference in disease duration for 1-9 years, 10-20 years, 21-30 years, or more than 30 years. In Asia, the risk of CRC in UC increased after 10-20 years of this disease duration. In North America, the risk of CRC in UC increased significantly in more than 30 years of this disease duration (Tables 5 and 6).

Table 5.

Geographic variation risk of CRC in UC patients.

Area Article (n) Proportion 95% CI Weight (random)
Asia 13 0.013 0.009-0.017 24.90%
North America 11 0.011 0.007-0.014 22.20%
Europe 33 0.017 0.014-0.020 52.20%
Oceania 1 0.048▲ 0.029-0.066 0.70%
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▲P < 0.05 vs. Europe; ▲▲P < 0.01 vs. Europe.

Table 6.

Geographic variation in UC patients in different disease durations.

Area 1-9 years 10-20 years 21-30 years More than 30 years
Asia 0.0032
[0.0022; 0.0045] n = 1		 0.0128
[0.0081; 0.0201]▲ n = 6		 0.0188
[0.0051; 0.0671]▲ n = 4		 0.0106
[0.0013; 0.0819]▲ n = 2
North America 0.0043
[0.0009; 0.0196] n = 4		 0.0120
[0.0058; 0.0245] n = 5		 — 0.0228
[0.0132; 0.0390]▲ n = 2
Europe 0.0097
[0.0020; 0.0461] n = 6		 0.0141
[0.0089; 0.0221] n = 10		 0.0222
[0.0104; 0.0465] n = 7		 0.0193
[0.0144; 0.0257] n = 10
Oceania — 0.048
[0.029; 0.066] n = 1		 — —
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▲P < 0.05 vs. 1-9 years; ▲▲P < 0.01 vs. 1-9 years.

Furthermore, we analyzed the CRC incidence in UC patients in each country; we found that Japan, UK, and Austria have the highest incidence, while Canada and Korea have the lowest incidence (Table 7).

Table 7.

CRC incidence in UC patients by country.

Nation Article (n) Proportion 95% CI Weight (random)
Canada 1 0.003 0.003-0.004 2.80%
Korea 4 0.005 0.002-0.007 9.30%
Spain 11 0.007 0.000-0.016 1.70%
China 4 0.008 0.006-0.010 9.40%
Italy 4 0.008 0.000-0.016 7.40%
Denmark 6 0.009 0.007-0.012 14.70%
Turkey 1 0.011 0.000-0.023 1.20%
Finland 1 0.013 0.007-0.019 2.10%
USA 10 0.013 0.008-0.017 19.40%
Greece 1 0.016 0.000-0.035 0.70%
France 1 0.017 0.005-0.028 1.30%
Germany 2 0.018 0.016-0.019 3.80%
Hungary 1 0.018 0.008-0.028 1.50%
Netherlands 3 0.019 0.004-0.035 4.80%
India 1 0.02 0.011-0.028 1.70%
Norway 1 0.027 0.013-0.041 1%
Sweden 5 0.027 0.017-0.036 4.50%
Japan 4 0.035 0.012-0.058 4.50%
UK 6 0.039 0.022-0.055 7.50%
Austria 1 0.048 0.029-0.066 0.70%
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3.4. The Literature Reporting Time of CRC Risk in UC Patients

In the subgroup analysis by literature reporting time, we found that the risk of CRC in UC patients was higher in 1988-1995. As the research progresses, the CRC risk in UC was stable and maintained between 1.1% and 1.6% (Table 8).

Table 8.

The literature reporting time in CRC risk in UC patients.

Reporting time Article (n) Proportion 95% CI Weight (random)
1988-1995 6 0.033 0.022-0.043 5.40%
1996-2000 3 0.011 0.000-0.021 4.60%
2001-2005 5 0.014 0.006-0.023 6%
2006-2010 9 0.011 0.005-0.016 6%
2011-2015 17 0.016 0.013-0.020 6%
2016-today 18 0.012 0.009-0.015 6%
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4. Discussion

UC, an uncontrolled colorectal inflammation, associated with systemic immune dysregulation, which impaired tumor surveillance, might play a role in colorectal carcinogenesis. Unlike the “adenoma-carcinoma sequence” classically described in sporadic CRC, UC-associated CRC arose from a larger field of colorectal mucosa that was “preconditioned” with a mutational burden that conferred an increased propensity for further dysplasia progression, a phenomenon known as “field cancerization” [55], which followed a sequence of genetic alterations “inflammation-dysplasia-carcinoma” [63]. Chronic colorectal inflammation generated extensive damage to epithelial cells that led to increased cell replication and/or direct DNA damage [1], which was known as one risk factor for the occurrence of CRC in UC patients [28].

This study first provided a picture of the incidence rate of UC-associated CRC from disease extent, disease duration, and geographic variation. Results showed that the overall risk of UC-associated CRC was 1.4%, which increased with disease duration. Extensive UC and left-sided UC had a greater risk of CRC than proctitis UC. There was no obvious gender specificity in CRC risk in UC patients. The strength of this study lies in the fact that we chose to focus on the CRC risk in UC patients from geographic variation. Results showed that the Asian and North American UC patients seemed to have a higher CRC risk. The time of malignant transformation in Asian UC patients started after 10-20 years of this disease duration. North American UC-associated CRC patients significantly increased in more than 30 years of this disease duration.

In this study, we can find that UC patient-relevant endpoint, the risk of CRC, has not decreased over the past decade, and the overall CRC incidence was stable from 1996 until today, which stayed around 1.1% to 1.6%. So the management of UC is still complex, and significant gaps in the literature remained regarding how clinicians could identify the risk associated with CRC and enhance the prevention of UC-associated CRC. 5-Aminosalicylate medications (mesalamine or sulfasalazine), the foundational first-line therapy for the induction and maintenance of mild-to-moderate UC, seemed not to protect against the likelihood of carcinogenesis at doses greater than 2.4 grams daily and still needed to be proven [64]. Other medicines, such as thiopurines, reduced the immunosurveillance of malignant cells and impaired control of oncogenic viruses [65]. Prolonged treatment with thiopurines has been shown to determine an increased risk of a broad range of cancers in UC patients [66]. The impact of UC-related drug therapy on CRC development remained a matter of debate, and the potential benefit of surgery should need to be placed in the context of the risks associated with undertaking complex abdominopelvic reconstructive surgery. Therefore, UC-associated CRC rates still remained a challenging problem for UC patients.

At present, the majority of CRC cases (70%) could be explained by an inadequate surveillance procedure before the CRC diagnosis, and CRC is responsible for approximately 15% of deaths due to UC [67]. Therefore, it is not surprising that researchers have focused efforts on surveillance screening as an adjunct therapy to UC patients for CRC occurrence. UC patients need to be accurately evaluated for the risk of CRC according to the disease extent, disease duration, and geography and need to adhere to a surveillance schedule, such as screening colonoscopy, which should be performed every 1 to 3 years, because the malignant changes and the surrounding inflammation often grow flat and multifocal [68].

5. Conclusion

In a systematic review of the literature, we found that the incidence of CRC in UC patients increased with the disease duration. Asian and North American UC patients were more prone to concomitant CRC.

6. Limitations

Our study has limitations. Patients with Crohn's disease, CAP, and a family history of CRC and who have undergone colectomy for UC were not included in this study. Patients with UC associated with extracolorectal malignancies (small intestine, blood systems, lung, thyroid, hepatobiliary, skin, melanoma, urinary bladder, breast, genital tract, and so on) were not included, which greatly reduced the risk of cancer in UC. Moreover, our search had English language restrictions. Articles in languages other than English were not included.

Abbreviations

UC:

Ulcerative colitis

CRC:

Colorectal cancer

IBD:

Inflammatory bowel disease

SIR:

Standardised incidence ratio

CAP:

Colorectal adenomatous polyp.

Contributor Information

Yu-gen Chen, Email: chenyg666@126.com.

Hai-bo Chen, Email: haibocheng@njucm.edu.cn.

Shu-tang Han, Email: 317544025@qq.com.

Data Availability

The clinical data supporting this systematic review and meta-analysis are from previously reported studies and datasets, which have been cited. The processed data are available in Table 1 of our manuscript.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

Qing Zhou and Zhao-Feng Shen independently screened the literature, extracted the data, performed the statistical analysis, cowrote the manuscript, and interpreted the statistical results. Ben-sheng Wu, Cheng-biao Xu, Zhong-qi He, Tuo Chen, Hong-tao Shang, Chao-fan Xie, and Si-yi Huang checked this work again and critically revised the paper. Yu-gen Chen was the project leader for this research and participated in the critical revision of the manuscript. Corresponding authors (Yu-gen Chen, Hai-bo Chen, and Shu-tang Han) had the final responsibility to submit for publication. All authors have read and approved the final manuscript. Qing Zhou and Zhao-Feng Shen are the first two authors who contributed equally to this paper.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The clinical data supporting this systematic review and meta-analysis are from previously reported studies and datasets, which have been cited. The processed data are available in Table 1 of our manuscript.

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