|Year : 2015 | Volume
| Issue : 4 | Page : 899-903
Prevalence of colorectal cancer in patients with ulcerative colitis: A retrospective, monocenter study in China
Qin Zhang, Sumei Sha, Bin Xu, Shuhui Liang, Kaichun Wu
State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, P. R. China
|Date of Web Publication||15-Feb-2016|
17, Changle Western Road, Xi'an 710032, Shaanxi Province
P. R. China
Source of Support: This study was supported by grants from the National
Healthcare Research Project (no. 201002020), National Scientific Support
Project (nos. 2012BAI06B03 and BSW11J013), National Natural Science
Foundation of China (Nos. 81322037, 81170360 and 81370504) and
National Excellent Doctoral Dissertation of PR China (No. 201182), Conflict of Interest: None
Background: Ulcerative colitis-associated colorectal cancer (UC-CRC) is a serious complication of UC. Data on the clinical characteristics of patients in China are scarce.
Aims: We aimed to study the incidence, characteristics, treatment, and prognosis of CRC patients with a history of UC.
Materials and Methods: We identified patients with UC and followed them until the first occurrence of cancer, death, or emigration in a single study center in China.
Results: A total of 4 UC-associated CRC patients were identified among the 642 cases recorded from January 2000 to December 2012. The overall risk of cancer was 0.64%. The overall median duration of UC was 15.5 years (range 6-21 years) in patients with UC-associated CRC. Of these patients, 75% (3/4) were at an advanced stage when they were diagnosed. Longer disease duration and extensive colitis were identified as risk factors for developing CRC, and 5-aminosalicylic acid and steroid therapies were not identified as protective factors against UC-associated CRC.
Conclusions: Patients with UC are at an increased risk for CRC. However, the prevalence of CRC in China remains lower than that in the West.
Keywords: Colorectal cancer, ulcerative colitis, ulcerative colitis-associated colorectal cancer
|How to cite this article:|
Zhang Q, Sha S, Xu B, Liang S, Wu K. Prevalence of colorectal cancer in patients with ulcerative colitis: A retrospective, monocenter study in China. J Can Res Ther 2015;11:899-903
|How to cite this URL:|
Zhang Q, Sha S, Xu B, Liang S, Wu K. Prevalence of colorectal cancer in patients with ulcerative colitis: A retrospective, monocenter study in China. J Can Res Ther [serial online] 2015 [cited 2020 Jul 3];11:899-903. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/899/143345
| > Introduction|| |
Colorectal cancer (CRC) is the one of the leading causes of cancer-related deaths in the world. Each year more than 1.2 million cases are diagnosed with about 600,000 deaths.  CRC is the third most common cancer diagnosed in both men and women in the US and the fourth most common cause of cancer mortality worldwide.  CRC is also the second most common cause of cancer deaths in the United States and other developed countries, despite important advances in detection, surgery, and chemotherapy.  It has been known that patients with inflammatory bowel disease (IBD) are at increased risk for cancer. Systematic review pointed out the overall risk of CRC in 181,923 ulcerative colitis (UC) patients was 1.69/1000 py, 0.91/1000 py in the first decade after the diagnosis of UC, 4.07/1000 py in the second and 4.55/1000 py in the third decade.  These rates are considerably higher than the incidence of CRC reported in the general population.  The incidence of CRC in the general population ranges from 0.4/1000 py in Australia, New Zealand, USA and Western Europe to 0.1/1000 py in Africa.  Meta-analysis  of population-based cohort studies also revealed a significant 2.4-fold increased risk of CRC among patients with UC belonging to population-based cohorts, with an average follow-up time of 14 years. Besides, UC-CRC is 15-20 years earlier at the age when diagnosed compared to sporadic CRC.  Since Crohn and Rosenberg  reported the first case of IBD-associated CRC, numerous studies have been conducted on the association between UC and CRC, especially in Western countries. Several decades ago, de Dombal reported that the cumulative risk of CRC in patients with extensive UC was approximately 5% after 10 years and 41.8% after 25 years in Leeds.  Currently, the increased risk of CRC in UC patients is widely accepted, and there is a general consensus that longer duration and extensive UC are risk factors for developing CRC.  Several papers have reported that the prevalence of CRC in IBD patients ranges from 0.6% to 17%.  Although such cases account for only 1-2% of all CRC cases in the general population, CRC is considered a serious complication of IBD and accounts for approximately 10-15% of all deaths in patients with IBD. 
A meta-analysis of studies in Western countries estimated that the risk of CRC in UC (cumulative incidence) is 1.6% after 10 years, 8.3% after 20 years, and 18.4% after 30 years of the disease, with overall prevalence of 3.7%.  Studies with patients in tertiary care centers or hospitals have demonstrated a higher cancer risk and worse prognosis. One study also suggested that CRC incidence rates in UC patients varied geographically, with higher risk among the residents of the USA and the UK than among Scandinavians and residents of other countries. The limited data available from other countries such as India,  South Korea,  and Hungary  show a lower risk than that reported in the West. Retrospective studies have shown UC cancer rates of 0.87% and 1.5% in Mainland China and Taiwan, respectively. , However, the number of patients with UC has increased three-fold in the past 10 years in China.  There is limited knowledge about the possible relationship between clinical parameters and the incidence rate of cancer in UC. The risk factors and clinical features of UC-CRC patients are not well understood.
In the current study, we retrospectively observed the malignant transformation of UC patients who had been diagnosed with CRC from January 2000 to December 2012 in a single center. The purpose of this study was to determine the variability of the incidence of UC-CRC in a relatively large cohort of patients. We also analyzed whether demographic and clinical factors had an effect on the incidence of CRC in UC.
| > Materials and methods|| |
This study was a retrospective cohort analysis of all patients with a confirmed diagnosis of UC. The diagnosis was confirmed using clinical, endoscopic, histopathological, and radiologic findings according to the internationally accepted Lennard-Jones criteria.  The majority of patients were advised to undergo a mapping colonoscopy during their first visit and yearly follow-up colonoscopies after 7 years of disease. Therefore, patients were included in the study only if they had undergone colonoscopy. Cancers diagnosed within 1 year of the UC diagnosis were excluded. From January 2000 to December 2012, 624 patients were reviewed. CRC was diagnosed by one experienced gastrointestinal pathologist and confirmed by another. The current study was performed with the approval of the local ethics committee, and informed consent was obtained from the patients.
During colonoscopy, biopsies were taken when there was an abnormal pit pattern according to Kudo's classification.  The patients' complete medical history was assessed, including prior colonoscopies and pathology reports. Patient records were reviewed for demographic features, endoscopic characteristics, operative approaches, and vital status at last follow-up. Data on gender, age, disease location, disease duration, colonoscopic follow-up, 5-aminosalicylic acid (5-ASA), and steroid therapy were collected from all of patients for analysis. The extent of inflammation was retrieved from histology and colonoscopy reports or barium enema X-ray reports, as recorded in medical records at the time of the UC diagnosis. The prevalence of UC-CRC was estimated, and the clinical characteristics of these patients were observed. The localization of CRC was described in terms of the eight segments of the colorectum, as follows: The cecum, the ascending colon, hepatic flexure, the transverse colon, splenic flexure, the descending colon, the sigmoid colon, and rectum. For the statistical analyses, the localization was re-coded as the right colon (cecum, ascending or transverse colon), the left colon (splenic flexure and descending and sigmoid colon), or rectum. The cancer site was classified according to the International Classification of Diseases for Oncology.  The extent of cancer at the time of diagnosis was classified according to the TNM classification.  The follow-up time was defined as the time in years from the diagnosis of UC to the diagnosis of CRC.
The associations between categorical variables were analyzed using the χ2 test. Mean age was compared using the two-tailed Student's t-test. Cox's proportional hazards regression was used to estimate univariable and multivariable hazard ratios to analyze the effect of several risk factors on the development of UC-CRC. Odds ratios and 95% confidence interval were calculated. All the data analyses were performed using SPSS 19.0 software (SPSS, Inc., Chicago, IL, USA). P < 0.05 were considered as statistically significant.
| > Results|| |
Clinical characteristics and incidence of ulcerative colitis in ulcerative colitis patients
A total of 624 patients with UC were enrolled [Table 1]. Altogether, excluding the cancers diagnosed within 1 year of the UC diagnosis, four of the 624 patients were diagnosed with UC-CRC by both colonoscopy and biopsy pathology. The overall risk of cancer was 0.64%. All of patients with UC-CRC had received regular colonoscopy examinations. The clinical features of the UC group and the UC-CRC group are shown in [Table 1]. Of the UC-CRC patients, 50% (2/4) were male. The median age at the time of the CRC diagnosis was 54.5 years (range 48-63 years), compared with 39.0 years (10-86 years) for the UC patients (P < 0.01). The overall median duration of UC was 15.5 years (range 6-21 years) in patients with UC-associated CRC and 1 year (range 0.1-40 years) in the UC patients without CRC. 75% (3/4) of the UC-CRC patients and 11.8% (112/620) of the UC patients were the severity disease according to the Truelove-Witts index scoring system.  Of the UC-CRC patients, 75% (3/4) were at an advanced stage when diagnosed. All four patients had extensive colitis.
Tumor characteristics of ulcerative colitis in ulcerative colitis patients
By the time they were diagnosed with CRC, all of the patients had progressed to total colitis. Of the four tumors, 25% (n = 1) were located in the rectum, 25% (n = 1) in the sigmoid colon, and 50% (n = 2) in the transverse and right colon. The distribution of the CRC stages at diagnosis in patients with UC was as follows: 50% (n = 2) in situ and 50% (n = 2) in Stage I. The histological type was available for all cases of CRC, and the distribution was as follows: 50% (n = 2) severe a typical hyperplasia and 50% (n = 2) well-differentiated adenocarcinoma. With regard to the treatment, a total proctocolectomy with end ileostomy (EI) was performed on two patients (50%) and a subtotal colectomy with EI was performed on two patients (50%). One of the 4 UC-CRC patients was treated with chemotherapy after surgery.
Risk factors for ulcerative colitis in ulcerative colitis patients
As shown in [Table 1], there were statistically significant differences between the UC and the UC-CRC patients in terms of gender, age, the duration of UC, the degree of pathological changes, the extent of disease, and whether corticosteroids or 5-ASA medications were used. We further analyzed these factors using logistic regression. As shown in [Table 2], disease duration and extensive colitis were identified as risk factors of UC-CRC. Symptom activity was also significantly related to colitis-CRC. The results also showed that UC duration >10 years, entire colon lesions, and severe inflammatory lesions were risk factors for UC-CRC. However, gender and the use of 5-ASA/sulfasalazine or corticosteroids were not identified as protective factors or risk factors for UC-CRC; the difference did not reach significance [Table 2].
| > Discussion|| |
Ulcerative colitis is associated with a marked increased risk of colonic dysplasia and CRC. Specifically, the risk is estimated to be 1.5-5 times higher than that of non-UC controls.  After 8-10 years, since the diagnosis of UC, the cancer risk increases annually by a proportion of 0.5 ~ 1%.  Although it only accounts for 1 ~ 2% of all CRC cases, 15% of the UC-related deaths were due to CRC. Numerous studies have been carried out in Western countries, and the risk of CRC in UC varied substantially across studies. This variation can be attributed to many factors, including the study design. Moreover, studies have suggested that CRC incidence rates in UC patients vary geographically, with a higher risk among the residents of the USA and the UK than among Scandinavians and the residents of other countries. Data from Asian countries were limited, potentially due to the lower UC incidence. A national population survey in South Korea showed that the prevalence of CRC in patients with UC was 0.37%,  whereas the prevalence was 0.94% in India.  The number of UC patients in China has increased in the past decade.  It is anticipated that the incidence of UC-CRC will increase simultaneously. Meta-analysis recently  revealed the risk of patients with UC developing CRC has decreased over the last six decades, the risk of CRC in UC are lower than those reported by Eaden et al.  in 2001. With a tighter control of the inflammation, higher colectomy rates, the use of drugs with chemopreventive effects and a better adherence to endoscopic surveillance programs in high-risk patients, the incidence of CRC in UC patients seems to have decreased during the last few decades. Moreover, Jess and co-investigators  published a meta-analysis of population-based cohort studies to determine the risk of CRC in patients with UC. In these population-based cohorts, the authors also suggested that the long-term risk of CRC among patients with UC was overestimated in the previous meta-analysis performed by Eaden et al.  However, data on the incidence, characteristics, treatment modalities, and prognosis of UC-CRC in China are scarce. The present study reports the frequency of UC-CRC and the survival rates in China over a period of 12 years. In this single-center retrospective study, the data showed that the prevalence of CRC in Chinese UC patients was 0.64%. In accordance with previous reports in other Asian countries, the prevalence of UC-CRC observed in this study was lower than that in the global meta-analysis. In a multi-center retrospective study,  data showed that the period prevalence of CRC in Chinese UC patients was 0.87%, which was similar to our results, indicated that while there is a trend of declining risk of developing CRC in UC patients, this trend is also confirmed by our study.
Several factors may contribute to the low incidence. First, although the incidence of UC in China increased in recent years, it was lower than that in Western countries. Second, the severity of inflammation is a risk factor for CRC in UC.  However, most UC patients in China have mild inflammation and can maintain remission with proper treatment. Third, this study was retrospective and some of the patients did not complete follow-up visits regularly. Even among patients who completed regular follow-up visits, fewer specimens from fewer parts were taken. As a result, certain findings may have been missed.
In chronic UC, risk largely depends on the duration and extent of the disease. Research studies have shown that a variety of inflammatory factors, such as tumor necrosis factor alpha, interleukin (IL-31), IL-6, IL-23, and the nuclear factor-κB, predominate the related network signaling pathways in the inflammation of UC and play an important role in the process of cancer.  In accordance with previous studies, of the 4 UC-CRC patients in the current cohort, three had the disease for more than 10 years and all had extensive colitis or pancolitis. The statistical analyses also revealed that disease duration longer than 10 years and extensive colitis were risk factors for CRC in UC patients.
Given the theory that chronic inflammation plays the most important role in malignant transformation, it can be reasonably concluded that anti-inflammatory therapy, such as 5-ASA or steroid use, may serve as a protective factor against malignant transformation in UC patients. In particular, 5-ASA  and thiopurines are thought to decrease or increase the risk of cancer development in IBD patients.  However, there is a debate concerning whether they can prevent CRC progression in UC patients. Eaden et al. had reported that the use of sulfasalazine can reduce the risk of colon cancer by 75%, but it does not affect the risk.  Bernstein indicated that 5-ASA medications did not have a protective function in patients with UC.  The current study found no association between 5-ASA or corticosteroid use and UC-CRC. The risk of CRC was similar between users and non-users of 5-ASA and thiopurines, suggesting that these treatments may not be protective against UC-CRC.
Gyde et al.  investigated 35 patients with CRC in a retrospective cohort of 823 patients with UC onset between 1945 and 1965 and showed that age at the onset of IBD symptoms was associated with the colitis-CRC interval. The risk of CRC was higher in patients who were diagnosed with UC at a young age. The UC patients who were smokers tended to have a lower risk of CRC than nonsmokers. With regard to gender, studies in the United States and Canada , reported that two-thirds of UC-CRC patients were male. In addition, the literature indicates that primary sclerosing cholangitis, diabetes, and appendix resections for cancer are risk factors for UC;  however, we did not analyze these factors in the present retrospective study. Endoscopic surveillance remains an important method for detecting UC-CRC. Regular colonoscopy examinations could help to identify a typical hyperplasia or CRC at an early stage and administer the proper treatment quickly, reducing the incidence of UC-CRC and mortality. 
Studies on the outcomes and prognosis of UC-CRC have reached conflicting results. , Some of these studies have suggested that survival is similar between sporadic CRC and IBD-associated CRC. In fact, IBD-related CRC is generally more poorly differentiated and exhibits differing frequencies of genetic alterations (p53 and K-ras mutations) in comparison with sporadic CRC. , In the current study, the 4 patients with UC-CRC were treated with either chemotherapy or surgery, and all of them were alive when the study concluded.
| > Conclusion|| |
We identified patients with a diagnosis of UC recorded from January 2000 to December 2012 and followed them until the first occurrence of cancer, death, or emigration. We found that the cumulative risk of CRC was high in patients with UC; however, it was lower than that in Western countries. While there is a trend of declining risk of developing CRC in UC patients, this trend is also confirmed by our study. Disease duration >10 years and extensive colitis were identified as important risk factors for developing CRC. Symptoms, but not gender or the use of 5-ASA/sulfasalazine or corticosteroids, had an effect on the UC-CRC interval.
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[Table 1], [Table 2]