Risk Factors for Coexisted Colorectal Polyps in Patients with Ulcerative Colitis

1. Introduction

Colorectal Cancer (CRC) is one of the most common cancer around the world, with the incidence rate ranks third among 36 cancer types, and its mortality rate ranks second, posing a significant threat to human health [1]. While the overall incidence rate of CRC is declining slowly, the incidence rate among individuals under 50 years is increasing. [1,2] Carcinogenesis in CRC primarily occurs through four pathways: the conventional adenoma-carcinoma sequence, the serrated pathway, the De novo pathway and the inflammation-cancer pathway [3]. And the inflammation-cancer pathway is frequently observed in patients with inflammatory bowel disease (IBD), where chronic intestinal inflammation progresses through dysplasia to ultimately develop into carcinoma. With the rising incidence of IBD, the proportion of CRC cases arising via the inflammation-cancer pathway is increasing [4].

IBD encompasses a group of chronic relapsing inflammatory bowel diseases involving multiple factors and aberrant immune-mediated responses, including Crohn’s disease (CD), ulcerative colitis (UC), and IBD Unclassified (IBD-U). CD patients carry a higher risk of small bowel malignancies, lung cancer, and hematological malignancies than UC patients, whereas UC patients have a higher risk of developing CRC compared to CD patients [5,6,7]. UC often follows a chronic relapsing course, repeated inflammatory insults can lead to colonic mucosal hyperplasia, resulting in the development of colorectal polyps and CRC. Ashktorab et al [8] found that compared to Non-IBD/Non-Infectious Colitis, polyps in IBD patients have a higher proportion of inflammatory polyps, and UC patients had more polyps than CD patients. And IBD patients with post-inflammatory polyps have an increased risk of colorectal neoplasia [9,10]. While several studies have investigated risk factors for colorectal polyps in IBD/UC patients, the reported risk factors are not entirely consistent and often do not stratify the analysis of risk factors based on polyp histology (e.g., adenomatous vs. non-adenomatous) or the presence of carcinoma [11,12]. This retrospective study analyzes the clinical data of 549 UC patients to identify the risk factors associated with UC complicated by colorectal polyps, UC with adenomatous polyps, and UC with CRC, intending to provide a theoretical reference for the early identification and intervention of colorectal polyps, particularly adenomatous polyps and CRC in UC patients.

2. Materials and Methods

This is a retrospectively study conducted in a tertiary hospital in China (Second Xiangya Hospital of Central South University), and the study was approved by the Ethics Committee of our hospital (No. LYEC2026-K0163). UC patients diagnosed in our hospital between January 1, 2015, and December 31, 2022 were enrolled. The inclusion criteria were as follows: 1) Diagnosed of UC. 2) Having undergone at least one colonoscopy examination with available histopathological results. 3) If complicated with colorectal polyps, adenomas, or CRC, diagnosis must be confirmed by histopathology (via endoscopic biopsy, endoscopic resection, or surgery). Exclusion criteria were: 1) Inadequate bowel preparation compromising visualization and precluding satisfactory assessment, or incomplete colonoscopy examination. 2) History of colorectal polypectomy or familial polyposis syndromes. 3) Concurrent presence of malignancies in other organs or systems. 4) Coexisting pregnancy. 5) Missing crucial data such as pathological or colonoscopy reports.

2.1. Parameter Definitions

Data collected in this study included the following aspects: 1) demographic data: age, gender, smoking history, alcohol consumption history, family history, etc. 2) UC-related data: disease duration, UC type and disease extent, treatment details (types of medications, history of surgery), etc. 3) Polyp-related data: number, size, pathological type, etc. 4) CRC-related data: time of detection, location, pathological type, presence of metastasis, etc. Given the chronic relapsing nature of UC, patients might have had multiple hospital admissions or outpatient reviews, including repeated colonoscopies and pathological examinations, during the study period. The data inclusion time point for this study was defined as the time when colorectal polyps or CRC were first detected (for patients with polyps or CRC) or the most recent colonoscopy examination within the study period for other patients.

Since the risk of carcinogenesis in UC patients increases with disease duration, particularly beyond 10 years, patients were stratified into long disease duration (>10 years) and short disease duration (≤10 years) groups based on this threshold. UC was classified by clinical course into initial-onset type and chronic relapsing type. Based on the Montreal classification, UC was categorized into proctitis (E1), left-sided colitis (E2), and extensive colitis (E3) [13]. Disease activity was classified as mild, moderate, or severe according to the modified Truelove and Witts severity criteria [14]. Based on treatment strategies (whether or not use biologics ever), patients were divided into a biologics-treated group and a non-biologics-treated group. For UC patients with colorectal polyps, polyps were classified histologically into adenomatous polyps and non-adenomatous polyps. Polyp number was categorized as single or multiple (≥2 polyps). Polyp size was determined based on the diameter of the largest polyp in each patient and classified as diminutive (≤5 mm), small (5–10 mm), large (10–20 mm), or giant (≥20 mm). UC patients with CRC were subdivided into an adenoma-carcinoma sequence group and a de-novo carcinoma group (non-adenoma-carcinoma sequence group) based on the presence or absence of adjacent adenomatous components in the histopathological specimen.

2.2. Statistical Analysis

Results were expressed as frequencies, mean and standard deviation (SD) or median and range, as required. For the univariate analysis, categorical variables were analyzed using Pearson’s χ2 or Fisher’s exact test, as required, and continuous variables were compared using Student’s t test. For multivariate analyses, factors with a p value < 0.1 in the univariate analysis were included in a stepwise multiple logistic regression analysis. The adjusted odds ratio (OR) and its 95% confidence intervals (CI) were calculated for each independent predictor included in the final model. All statistical analyses were conducted using IBM SPSS Statistics software (Version 26.0). A two-sided P-value < 0.05 was considered statistically significant.

3. Results

3.1. Patients’ Characteristics

From January 1, 2015, to December 31, 2022, a total of 815 patients were diagnosed of UC, among whom 58 were duplicate cases and 208 cases had incomplete data, and 549 patients were included in the final analysis. Among the 549 patients, 335 were male and 214 were female, with a mean age of 43.85 years (range: 9–85 years). A history of smoking was reported in 268 patients, and alcohol consumption was reported in 46 patients. The median disease duration of the 549 UC patients was 12 years (interquartile range: 10.2–16 years). 235 patients had a disease duration of ≤10 years, while the other 314 patients >10 years. According to clinical classification, 165 patients belong to initial-onset disease, and 384 had chronic relapsing disease. Based on the Montreal classification, 57 cases were classified as proctitis (E1), 243 as left-sided colitis (E2), and 249 as extensive colitis (E3). Disease activity was mild in 84 patients, moderate in 194, and severe in 271 patients. Regarding initial symptoms, 489 patients (89.10%) presented with abdominal pain, 505 (92.00%) with diarrhea, 498 (90.71%) with hematochezia, and 428 (77.96%) with tenesmus. Extraintestinal manifestations were observed in 37 patients (6.74%).

Among the 549 patients, 261 had colorectal polyps, while 288 had no polyps. Additionally, 7 patients were diagnosed with CRC. All the 261 patients with UC and colorectal polyps underwent endoscopic treatment during hospitalization, among whom 54 had adenomatous polyps and 207 had non-adenomatous polyps. Of the 54 adenomatous polyps, 42 were tubular adenomas, 9 were tubulovillous adenomas, and 3 were of other types. Among the 7 patients with CRC, 6 were diagnosed more than 10 years after UC onset, and the other 1 within 10 years. Pathological examination confirmed adenocarcinoma in all 7 cases, tumor locations were as follows: rectum (4 cases), sigmoid colon (2 cases), and descending colon (1 case). Adenomatous components were observed adjacent to the tumor in 6 cases, while the other 1 case showed no significant adenomatous component. Two of the 7 CRC cancer patients had metastasis and underwent surgical resection, while the other 5 received endoscopic treatment. Three patients received postoperative chemotherapy or radiotherapy.

3.2. Risk Factors for Colorectal Polyps in UC Patients

Univariate analysis revealed that age, disease duration, disease severity, and use of biologics had significantly difference between UC patients with and without colorectal polyps. Multivariate analysis found that age at onset >40 years and use of biologics were protective factors, while disease duration >10 years and greater disease severity were identified as risk factors (Table 1).

3.3. Risk Factors for Adenomatous Polyps in UC Patients

Univariate analysis indicated that age, disease duration, UC type, and polyp size were significantly different between the UC patients with adenomatous polyps group and the non-adenomatous polyps group. Multivariate analysis found that age at onset >40 years, disease duration >10 years, chronic relapsing disease type, and the presence of large polyps were identified as risk factors for the development of adenomatous polyps (Table 2).

3.4. Risk Factors for CRC in UC Patients

Univariate analysis showed that age, disease duration, and the presence of concomitant polyps had significant difference between the UC patients with CRC group and the non-CRC group. Multivariate analysis revealed that age at onset >40 years, disease duration >10 years, and the presence of concomitant polyps were identified as risk factors for the development of CRC (Table 3).

4. Discussion

UC is a chronic relapsing inflammatory bowel disease involving multiple etiologies, including genetic, environmental, immune factors, and gut microbiota. The inflammation typically begins in the rectum and extends proximally in a continuous manner, potentially involving the entire colon, and in some cases, the terminal ileum (backwash ileitis) [15]. Over the past decade, the incidence of UC has been increasing. A recent meta-analysis incorporating 215 studies reported global prevalence rates of UC as 120.4 (95% CI, 110.5-130.3) per 100,000 persons, respectively, and Europe had the highest prevalence of UC. The global incidence rate was 5.0 (95% CI, 4.6-5.3) for UC per 100,000 persons, and North America had the highest incidence of UC [16].

Most IBD patients have a chronic relapsing course. Repeated inflammatory stimulation can lead to mucosal hyperplasia and the formation of polypoid lesions; consequently, IBD patients have a higher risk of developing colorectal polyps than non-IBD individuals [8]. Ashktorab et al [8] found the probability of various types of polyps was 15.7% in IBD patients compared to only 8.2% in non-IBD, non-infectious colitis patients. Among IBD patients, UC patients had a higher probability (27%) of developing various types of colorectal polyps than CD patients (5%). That study also found a significantly higher proportion of inflammatory polyps (some researchers also termed pseudopolyps) in IBD patients (55%) compared to non-IBD, non-infectious colitis patients (12%). Studies show pseudopolyps are present in up to 52% of patients with a disease duration of 8 years or more, with a significantly higher occurrence in UC patients (76.19%) than in CD patients (23.81%)[17]. Ellul et al. [18], in a study of 504 IBD patients with inflammatory polyps, also found these polyps more common in UC patients (74.8%), and their presence was positively correlated with treatment escalation, number of hospitalizations, and surgery rates in IBD patients. However, these polyps differ from common sporadic hyperplastic polyps and carry a risk of progressing to dysplasia and even CRC [9,10,12,17,18,19]. In our study, 261 out of 549 patients (47.54%) had colorectal polyps, among whom 54 (20.69%) had adenomatous polyps, consistent with the literature, suggesting non-adenomatous polyps predominate in UC patients. The relatively high polyp prevalence in our study might be related to the longer median disease duration (12 years, 57.19% >10 years). Our multivariate analysis identified age >40 years and use of biologics as protective factors, while disease duration >10 years and active disease were risk factors for colorectal polyps in UC. This indicates that UC patients with younger age at onset, longer disease duration, more severe activity, and no biologic therapy are at high risk for developing polyps. It is easy to understand that patients with younger age at onset, longer disease duration may and more severe activity were risk factors, as they experienced more recurrent inflammation. Our study is the first to identify biologic therapy as a protective factor, suggesting lower polyp incidence in treated patients, possibly due to better and sustained inflammatory control, reducing recurrent inflammatory stimulation.

Most sporadic CRCs develop via the adenoma-carcinoma sequence. Although UC patients may develop CRC directly via the inflammation-dysplasia-carcinoma pathway, the adenoma-carcinoma sequence remains a significant route in UC-associated carcinogenesis[4,7]. While most studies (including our study) show inflammatory and hyperplastic polyps are most common in UC [8,9,10], adenomatous polyp was still nonnegligible in UC patients. A large Swedish study of 41,880 IBD patients (12,850 CD, 29,030 UC) found neoplastic polyps in 1,648 (3.9%) patients, with a higher proportion in UC (1,241, 4.3%) than CD (407, 3.2%). Pathologically, tubular adenomas were most common (71.4%), followed by tubulovillous adenomas (23.1%), with rarer types like villous adenomas and serrated adenomas [12]. And they also identified younger age at diagnosis and disease duration >10 years as risk factors for neoplastic polyps in IBD. Loffeld et al. [20] reported a detection rate of 3.69% for adenomatous polyps in 1029 IBD patients. Gordillo et al. [11], following 403 UC patients for a median of 6.3 years, found an overall colorectal adenoma detection rate of 11.7%, increasing over time: 4.7%, 16.7%, 23.6%, and 34.4% at 10, 20, 30, and 40 years post-diagnosis, respectively. Multivariate analysis identified older age at UC diagnosis and longer disease duration as risk factors. Nishio et al. [21] specifically reported on serrated lesions in UC: among 2035 UC patients, 252 neoplastic lesions were detected, 36 (1.8%) were serrated lesions (26 within, 10 outside inflamed areas), with extensive colitis, active disease, and longer duration as risk factors. In our study, adenomatous polyp detection rate was 9.84% (54/549), predominantly tubular adenomas, consistent with literature [12]. Multivariate analysis identified age at onset ≥40 years, disease duration >10 years, chronic relapsing type, and large polyp size as risk factors for adenomatous polyps in UC. The first three factors are reported elsewhere; longer duration and chronic relapsing course lead to sustained mucosal injury and hyperplasia. Our study newly identifies large polyp size as a risk factor.

UC patients have a higher risk of CRC than the general population and are considered a high-risk group, with risk increasing with disease duration. A meta-analysis of 58 studies involving 267,566 UC patients found a pooled CRC prevalence of 1.4% (95% CI, 1.2-1.6). CRC was more common in extensive and left-sided colitis than proctitis, in patients with disease duration >10 years, and in Japan, UK, and Australia [22]. Compared to sporadic CRC, IBD-associated CRC is diagnosed at a younger age, has fewer stage IV cases, but higher proportions of mucinous carcinoma, emergency surgery, and synchronous tumors, with an overall worse prognosis [23]. Most studies focus on risk factors for dysplasia in UC; studies specifically on CRC risk factors are fewer. One study of 1386 IBD patients found 153 (11.5%) had colorectal neoplasia (11 CRC, 12 HGD, 112 LGD). UC patients had a higher neoplasia rate (15.1%) than CD (6.2%). Multivariate analysis identified post-inflammatory polyps (PIPs) and smoking history were risk factors for neoplasia in UC [24]. Goldstone et al. [25] analyzed 103 UC patients with neoplasia (55 advanced neoplasia: HGD/CRC), and found that their mean disease duration of 24.8 years, 93% had extensive colitis, and 71.2% of tumors were in the rectosigmoid. A multicenter real-world study of 144 UC patients reported detection rates of 11.1% (16/144) for LGD, 1.4% (2/144) for HGD, and 2.1% (3/144) for CRC, and further multivariate analysis identified long disease duration and PIPs as risk factors for neoplasia [26]. Jiang et al. analyzed 147 UC-associated neoplasias (137 LGD, 7 HGD, 3 CRC), and found older age at UC diagnosis, high endoscopic score, and large polyp size as risk factors [27]. However, Wolf et al [28] and Mahmoud et al [29] found that PIPs were not a risk factor. Our study reported a 1.21% (7/549) of CRC in UC patients, and multivariate analysis identified age at onset >40 years, disease duration >10 years, and presence of polyps as high-risk factors for CRC in UC, consistent with most literature.

The present study had limitations. First, this was a retrospective, single-center study, but the sample size was acceptable with 549 UC patients enrolled. Secondly, we did not include laboratory results, specific treatment drug when analyzing the risk factors, which could not analyze their relationship with colorectal polyps, adenoma and CRC. In a word, our study demonstrated that: UC patients with a junior age, long disease duration, severe disease activity, and non-biologic treatment are likely to have colorectal polyps. While patients with a senior age, long disease duration, a chronic relapsing disease course, and larger polyp size should be screened for adenomatous polyps, and with senior age, long disease duration, and the presence of polyps should be screened for CRC.