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

Authors: Qing Zhou; Zhao-Feng Shen; Ben-sheng Wu; Cheng-biao Xu; Zhong-qi He; Tuo Chen; Hong-tao Shang; Chao-fan Xie; Si-yi Huang; Yu-gen Chen; Hai-bo Chen; Shu-tang Han
Journal: Gastroenterology Research and Practice
 (2019)

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## 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.


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## Body

## 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 theCochrane 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
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 theQ statistic, used a two-sided α value of 0.05 for significance.The study was registered with PROSPERO, numberCRD42018102213.


### 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).


## 2.1. Search Strategy and Selection Criteria

We did a comprehensive literature research according to theCochrane 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
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 theQ statistic, used a two-sided α value of 0.05 for significance.The study was registered with PROSPERO, numberCRD42018102213.


## 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 Table1.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


### 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; Figure2). 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
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
▲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
▲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 (Table4).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%
▲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 (Tables1 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%
▲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
—
—
▲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 (Table7).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%


### 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% (Table8).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%


## 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; Figure2). 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
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
▲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
▲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 (Table4).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%
▲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 (Tables1 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%
▲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
—
—
▲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 (Table7).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%


## 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% (Table8).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%


## 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.



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*Source: 5363261-2019-11-03.xml*