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Original Article

Korean J Gastroenterol 2025; 85(1): 34-43

Published online January 25, 2025 https://doi.org/10.4166/kjg.2024.105

© The Korean Society of Gastroenterology.

Frequency and Risk Factors of Advanced Neoplasia in Korean Inflammatory Bowel Disease Patients with Low-grade Dysplasia

저도이형성증이 진단된 한국인 염증성장질환에서 진행성 신생물의 발생빈도 및 위험인자

Yong Eun Park1, Kyeong Ok Kim2 , Dong Hyun Kim3, Soo-Kyung Park4, Yoo Jin Lee5, Chang Kyun Lee6, IBD Research Group of the Korean Association for the Study of Intestinal Diseases (KASID)

박용은1, 김경옥2, 김동현3, 박수경4, 이유진5, 이창균6; 대한장연구학회 IBD연구회

Division of Gastroenterology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan1; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu2; Division of Gastroenterology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju3; Division of Gastroenterology, Department of Internal Medicine and Inflammatory Bowel Disease Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul4; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu5; Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul6, Korea

인제대학교 의과대학 해운대백병원 소화기내과1, 영남대학교 의과대학 소화기내과2, 전남대학교 의과대학 전남대학교병원 소화기내과3, 성균관대학교 의과대학 강북삼성병원 소화기내과, 염증성 장질환 센터4, 계명대학교 의과대학 동산의료원 소화기내과5, 경희대학교 의과대학 내과학교실6

Correspondence to: Kyeong Ok Kim, Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea. Tel: +82-53-620-3835, Fax: +82-53-623-8038, E-mail: kokim@yu.ac.kr, ORCID: https://orcid.org/0000-0001-5799-7436

Financial support: This study was supported by 2021 Yeungnam University Research grant.

Received: September 23, 2024; Revised: October 25, 2024; Accepted: October 29, 2024

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background/Aims: Studies on the clinical outcomes after detecting low-grade dysplasia (LGD) in patients with inflammatory bowel disease (IBD) are insufficient. This study evaluated the clinical features, frequency, and risk factors for advanced neoplasia in patients with IBD after an LGD diagnosis.
Methods: The medical records of 166 patients with IBD from six university hospitals in Korea from 2010 to 2019 were reviewed retrospectively. LGD was diagnosed in all patients during surveillance. The frequency and risk factors for advanced neoplasia were evaluated, and the clinical features of patients with and without advanced neoplasia were compared.
Results: Advanced neoplasia developed in 12 patients (six with large LGD, three with tubulovillous adenoma, and three with high-grade dysplasia), and all cases developed from UC. Patients with advanced neoplasia had significantly higher Mayo scores, and colitis-associated dysplasia was more common than sporadic lesions (83.3% vs. 29.9%; p<0.001). Multivariate analysis showed that colitis-associated LGD significantly increased the risk of developing advanced neoplasia (odds ratio [OR], 10.516; 95% confidence interval [CI], 2.064–53.577). Among patients with colitis-associated lesions, a significant risk factor for advanced neoplasia was a prior history of LGD (OR, 9.429; 95% CI, 1.330–66.863).
Conclusions: Advanced neoplasia developed in 7.2% of patients with IBD and LGD. Most advanced neoplasms developed from colitis-associated lesions, and the risk was higher in patients with a history of LGD before index colonoscopy.

KeywordsColorectal neoplasm; Inflammatory bowel disease; Risk factors

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammatory gastrointestinal (GI) disorders1 that carry a significant risk of colorectal cancer (CRC).2,3 Patients with IBD have a 1.7-fold higher risk of CRC because of long-standing chronic inflammation and the possible occurrence of colitis-associated and sporadic neoplasia.2 Therefore, most guidelines recommend surveillance colonoscopy to reduce the risk of dysplasia and CRC.4-7 In particular, the ECCO guidelines recommend surveillance colonoscopy based on the patient’s risk.4 Nevertheless, interval cancer may still occur in patients with IBD if the lesions are missed during surveillance, and one study reported that it occurred in up to 30% of patients.8

In IBD patients, colitis-associated CRC (CA-CRC) progresses from chronic inflammation to CRC through dysplastic precursor lesions such as indefinite, low-grade, and high-grade dysplasia.9 A follow-up cohort study after diagnosing low-grade dysplasia (LGD) in IBD patients reported a 21.7% incidence of advanced colorectal neoplasia (ACRN) after 15 years.10 On the other hand, the frequency of progression to high-grade dysplasia (HGD) or CRC varied from 16 to 54%.11 Indefinite dysplasia (IND) was diagnosed when regeneration and dysplasia could not be distinguished clearly in an environment such as severe active inflammation.12 The risk of ACRN was reported to increase in those with IND. Moreover, LGD was associated with a significantly higher risk of ACRN compared with IND.13

Regarding management, endoscopic resection and regular close follow-up could also be considered in visible colitis- associated dysplasia with clear margins. Nevertheless, limited data exist for LGD/IND in patients with IBD regarding endoscopic treatment (endoscopic resection or surgery), follow- up interval, clinical course, or associated risks. Therefore, this study conducted a multicenter analysis of the clinical features, treatment, follow-up period, incidence of advanced adenoma, and risk factors for LGD/IND in Korean patients with IBD.

1. Patients

This study retrospectively reviewed patients with IBD who had been diagnosed with low-grade/indefinite dysplasia on surveillance colonoscopy and underwent at least one surveillance colonoscopy after detection at one of six university hospitals in Korea. The diagnoses of UC and CD were based on clinical, endoscopic, histopathological, and radiology findings.14,15 The baseline characteristics of the patients were obtained from the electronic medical data of each hospital, including the patient’s demographics, type and disease status of IBD, comorbid diseases, accompanying primary sclerosing cholangitis (PSC), family history of CRC, smoking status, and medication records at the time of diagnosis of colon dysplasia (<3 months).

The inclusion criteria were IBD patients with low-grade/indefinite dysplasia between 2010 and December 2019, who had undergone at least one surveillance colonoscopy, and who satisfied any of the following conditions: i) disease duration of eight years or more, ii) patients with PSC regardless of disease duration, iii) patients with a history of diagnosis of LGD, or iv) family history of CRC in first-degree relatives under the age of 50.

Thirty-seven patients were excluded based on the following exclusion criteria: i) patients with ulcerative proctitis or Crohn’s colitis with less than 30% colonic involvement, ii) no history of PSC or dysplasia in IBD patients with disease duration of less than eight years, iii) patients previously diagnosed with HGD and CRC, iv) difficulty observing the entire large intestine due to stenosis or resection, and v) other cases where the researcher judged that it was inappropriate. Thus, 166 patients were included in the final analysis. The patients were divided into groups with and without advanced lesions, and the disease status of IBD, polyp type, treatment methods, and risk factors were investigated (Fig. 1). This study was performed according to the ethical guidelines of the 1975 Declaration of Helsinki and approved by the Institutional Review Board of each hospital.

Figure 1. Flow diagram of patient selection. LGD, low grade dysplasia; IND, indefinite dysplasia; IBD, Inflammatory bowel disease; PSC, primary sclerosing cholangitis; HGD, high grade dysplasia; CRC, colorectal cancer.

2. Assessment of IBD

The disease extent and severity were classified using the Montreal classification in patients with UC, and the Vienna Montreal classification was used in CD patients.16 The IBD disease status was evaluated based on the endoscopic disease activity and clinical activity within three months of dysplasia detection. The disease activity of UC was evaluated using the Mayo score, and the endoscopic disease activity was evaluated using the Mayo endoscopic score (MES).17,18 In CD patients, the disease activity was assessed using the Crohn’s Disease Activity Index19 and the endoscopic disease activity was evaluated using the Simple Endoscopic Score for Crohn’s Disease.20 In addition, this study assessed the types of medications used and whether there were any changes in IBD treatment after the adenoma diagnosis.

3. Assessment and management of polyps

1) Definition of polyps

ACRN was defined as an adenocarcinoma or advanced adenoma. Advanced adenoma included adenoma ≥10 mm or with tubulovillous/villous histology or HGD.21,22

2) Characteristics of polyps and diagnostic tools

The lesions were classified as visible or invisible. In the case of visible lesions, the morphology of the polyps was classified as pedunculated (Ip), subpedunculated (Isp), sessile (Is), slightly elevated (0-IIa), flat (0-IIb), slightly depressed (0-IIc), excavated (0-III), or no visible lesion.23 The lesions were divided into polypoid (Ip, Isp, and Is) and non-polypoid (IIa, IIb, IIc, III, and invisible dysplasia). The size (mm), number, and location of polyps, as well as the presence of metachronous, colitis-associated, or sporadic lesions, were also investigated. Lesions found in areas with IBD-related chronic inflammation were defined as colitis-associated lesions; those unrelated to chronic inflammation were defined as sporadic lesions.

The endoscopic modalities used to detect dysplasia were evaluated, including standard white-light endoscopy high-definition WLE (HD-WLE), and pan-chromoendoscopy. Furthermore, this study investigated whether random biopsies or targeted biopsies detected the lesions; if the lesions were diagnosed by random biopsy, they were defined as invisible lesions based on the SCENIC consensus.24

3) Treatment for polyps

The treatment method was also evaluated. A physician made decisions based on the lesion characteristics and patient risk. Endoscopic mucosal resection or endoscopic submucosal dissection was considered for lesions with distinct borders based on the decision of the endoscopist. In contrast, surgery was considered for endoscopically unresectable lesions and invisible dysplasia, and total proctocolectomy with ileal-pouch anal anastomosis was considered for HGD or CRC.25,26 For patients diagnosed with LGD that did not involve the rectum or had comorbidities, partial colectomy or segmental resection was considered and performed in consultation with the surgeon.27

4. Statistical analysis

The variables are expressed as median (interquartile range [IQR]) or n (%). The baseline characteristics were compared using an independent Student’s t-test (or Mann–Whitney U test) for continuous variables and the χ2 test (or Fisher’s exact test) for categorical variables. The disease status and polyp characteristics of patients with IBD were divided into “ACRN” and “no ACRN” groups and compared. Logistic regression analysis was used to analyze the independent predictors of the risk factors for advanced polyps. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. The data were analyzed using the SPSS software (version 25.0; IBM Corp., Armonk, NY, USA). A p-value of <0.05 was considered significant.

1. Comparison of the baseline characteristics and disease status of ACRN and no-ACRN groups

Table 1 lists the baseline characteristics of the ACRN and no-ACRN groups. The median age of the patients was 57 years (IQR, 48–64 years), and 74.7% of patients were male. Four patients had PSC, one of whom developed ACRN. Despite no significant difference among the patients in whom index LGD was discovered during the study period, 33.3% of patients who developed ACRN had already been diagnosed with LGD. No significant differences in medication use or underlying diseases were observed between the patients with and without ACRN (Table 1).

Table 1 Baseline Characteristics of the Study Subjects

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Age57 (48–64)54 (50–63)57 (48–64)0.864
Male sex124 (74.7)9 (75.0)115 (74.7)0.980
Accompanying PSC4 (2.4)1 (8.3)3 (1.9)0.165
Underlying disease42 (25.3)2 (16.7)40 (26.0)0.475
Hypertension9 (5.4)0 (0)9 (5.8)0.389
Diabetes7 (4.2)0 (0)7 (4.5)0.450
Cardiovascular disease11 (6.6)1 (8.3)10 (6.5)0.805
Liver disease8 (4.8)0 (0)8 (5.2)0.418
Malignancy3 (1.8)0 (0)3 (1.9)0.626
Othersa18 (10.8)2 (16.7)16 (10.4)0.501
Family history of CRC1 (0.6)0 (0)1 (0.6)0.779
Operationb6 (3.6)1 (8.3)5 (3.2)0.363
Smoking30 (18.1)0 (0)30 (19.5)0.091
Type of IBD0.098
Crohn’s disease29 (17.5)0 (0)29 (18.8)
Ulcerative colitis137 (82.5)12 (100.0)125 (81.2)
Disease duration11.48 (7.85–14.50)11.63 (1.59–14.53)11.48 (7.87–14.50)0.143
Previous diagnosis of LGD34 (27.7)4 (33.3)34 (27.2)0.650
Medication
5-ASA150 (90.4)11 (91.7)139 (90.3)0.874
Steroid26 (15.7)3 (25.0)23 (14.9)0.355
Immunomodulator38 (22.9)1 (8.3)37 (24.0)0.213
Anti-TNF21 (12.7)0 (0)21 (13.6)0.171
Other biologicsc5 (3.0)0 (0)5 (3.2)0.526

Data are expressed as median (interquartile range) or number (%).

ACRN, advanced colorectal neoplasia; PSC, primary sclerosing cholangitis; CRC, colorectal cancer; IBD, inflammatory bowel disease; LGD, low-grade dysplasia; 5-ASA, 5-aminosalicylic acid; anti-TNF, antitumor necrosis factor.

aCKD, hereditary spherocytosis; RA, Tuberculosis; infarction; AS, Parkinson’s disease. bExcluded IBD-related bowel operation. cUstekinumab, vedolizumab, mirikizumab.

*p-value for comparing patients with and without ACRN.


One hundred and thirty-seven patients with UC (82.5%) and 29 with CD (17.5%) were evaluated. Left-sided UC (E2) accounted for 72.3% of patients, and 27.7% had pancolitis (E3). Six of the 38 patients with pancolitis developed ACRN (15.8%), which was not significant but showed a higher tendency than that of patients with left-sided UC (6.06%, six of 99). The disease activity was significantly higher in the ACRN group (Mayo score, 3.5 [2.0–6.0] vs. 1.0 [0–2.0]; p=0.010), but the endoscopic activity was similar in UC patients (MES, 2.0 [1.0–2.0] vs. 1.0 [0–2.0]; p=0.383). ACRN did not develop in patients with CD, but most showed ileocolonic involvement (62.1%) and non-stricturing and non-penetrating behavior (66.7%) (Table 2).

Table 2 Disease Status of the Patients with Inflammatory Bowel Disease

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Ulcerative colitis137 (82.5)12 (100.0)125 (81.2)
Disease extension0.071
E2a99 (72.3)6 (50.0)93 (74.4)
E3b38 (27.7)6 (50.0)32 (25.6)
Mayo score1.0 (0–3.0)3.5 (2.0–6.0)1.0 (0–2.0)0.010
MES1.0 (0–2.0)2.0 (1.0–2.0)1.0 (0–2.0)0.383
Crohn’s disease29 (17.5)0 (0)29 (18.8)
Disease location-
L2c18 (62.1)0 (0)18 (62.1)
L3d11 (37.9)0 (0)11 (37.9)
Disease behavior-
Inflammatory18 (66.7)0 (0)18 (66.7)
Stricturing7 (25.9)0 (0)7 (25.9)
Penetrating2 (7.4)0 (0)2 (7.4)
CDAI72.15 (45.38–179.27)0 (0)72.15 (45.38–179.27)
SES-CD4.0 (0.25–11.25)0 (0)4.0 (0.25–11.25)

Data are expressed as number (%) or median (interquartile range).

ACRN, advanced colorectal neoplasia; MES, Mayo endoscopic score; CDAI, Crohn's disease activity index; SES-CD, Simple endoscopic score for Crohn’s disease.

aLeft sided, bPancolitis, cIleocolonic, dColonic.

*p-value for comparing patients with and without ACRN.


2. Clinical features and outcomes of index LGD

From January 2010 to December 2019, LGD was detected in 166 patients with IBD, of whom 33.7% had colitis-associated LGD (56 cases). An endoscopic resection was performed in 152 cases (91.6%), and biopsy removal was the most common method (83 of 152, 54.6%), followed by an endoscopic mucosal resection (EMR) (57 of 152, 37.5%) and cold snaring (12 of 152, 7.9%). In patients with UC who developed ACRN, colitis-associated LGD on the index colonoscopy was more common than in those with sporadic LGD (83.3% vs. 29.9%; p<0.001). In addition, the median size of the index LGD was 11.50 mm (IQR, 7.25–16.75) in the ACRN group, which was significantly larger than that in the no ACRN group (p<0.001). A total of 66.7% of patients with UC were examined using HD-WLE, and all index LGD cases in the ACRN group were diagnosed using a targeted biopsy. No significant differences in the shape, location, or number of polyps were noted. In patients with UC in the ACRN group, 66.7% of those with index LGD underwent endoscopic removal, while 33.3% underwent close follow-up (Table 3).

Table 3 Characteristics of Index LGD and Comparison between Patients With and Without Advanced Neoplasia

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Type of endoscopy0.944
SD-WLE51 (30.7)4 (33.3)47 (30.5)
HD-WLE114 (68.7)8 (66.7)106 (68.8)
Panchromoendoscopy1 (0.6)0 (0)1 (0.6)
Targeted biopsy153 (92.2)12 (100.0)141 (91.6)0.294
Colitis associated lesion56 (33.7)10 (83.3)46 (29.9)<0.001
Location0.498
Cecum13 (7.8)0 (0)13 (8.4)
Ascending colon36 (21.7)2 (16.7)34 (22.1)
Transverse colon35 (21.1)2 (16.7)33 (21.4)
Descending colon25 (15.1)1 (8.3)24 (15.6)
Sigmoid colon38 (22.9)4 (33.3)34 (22.1)
Rectum19 (11.4)3 (25.0)16 (10.4)
Morphology0.610
Polypoida146 (88.0)10 (83.3)136 (88.3)
Non-polypoidb20 (12.0)2 (16.7)18 (11.7)
Number of polyps (mean)1.0 (1.0–1.0)1.0 (1.0–1.0)1.0 (1.0–1.0)0.420
Size of polyp (mm)5.0 (3.0–6.5)11.50 (7.25–16.75)4.0 (3.0–6.0)<0.001
Treatment modality0.003
Endoscopic resection152 (91.6)8 (66.7)144 (93.5)
Close follow-up14 (8.4)4 (33.3)10 (6.5)

Data are expressed as number (%) or median (interquartile range).

ACRN, advanced colorectal neoplasia; SD-WLE, standard definition white-light endoscopy; HD-WLE, high-definition white-light endoscopy.

aPolypoid lesions: Ip, Isp, and Is. bNon-polypoid lesion: IIa, IIb, IIc, III, No visible lesion (random biopsy).

*p-value for comparing patients with and without ACRN.


ACRN developed in 12 cases (7.2%), with a median duration of 3.05 years (IQR, 0.73–3.63) after the LGD diagnosis. Among these cases, six, three, and three patients had large LGD, tubulovillous adenoma, and HGD, respectively. All ACRN cases occurred in patients with UC (12 of 137, 8.8%), with a median disease duration of 11.48 years (IQR, 7.85–14.50). The sigmoid colon was the most frequent location (66.7%), followed by the transverse colon (16.7%), ascending colon, and rectum (8.3%). The most common morphology was sessile (Is) (83.3%), with a median size of 11.50 mm (IQR, 7.25– 16.75) (Table 4). Among the patients who underwent an endoscopic resection, ACRN occurred in eight of 152 cases (5.3%) in a different area from the previous lesions. No cases of CRC were encountered during the follow-up period, but HGD was found in 25% of patients. Regarding the treatment of ACRN, four cases underwent an endoscopic resection (including EMR or endoscopic submucosal dissection [ESD]); one was removed surgically, and seven were lost to follow-up before receiving proper treatment. Azathioprine was initiated as part of the treatment in one patient who underwent an endoscopic resection. Although ACRN did not develop in patients with CD, they had fewer colitis-associated lesions than sporadic lesions compared to those with UC (UC, 36.5% vs. CD, 20.7%) (Data not shown).

Table 4 Characteristics of ACRN

VariablesTotal (n=12)
Follow-up duration (years)3.05 (0.73–3.63)
Number of surveillance colonoscopy2.0 (1.0–3.0)
Location of polyp
Ascending colon1 (8.3)
Transverse colon2 (16.7)
Sigmoid colon8 (66.7)
Rectum1 (8.3)
Morphology
Polypoid lesiona10 (83.3)
Non-polypoid lesionb2 (16.7)
Size (mm)11.50 (7.25–16.75)
Pathologic finding
Tubular adenoma6 (50.0)
Tubulovillous adenoma3 (25.0)
Villous adenoma0 (0)
High-grade dysplasia3 (25.0)

Data are expressed as medians (interquartile ranges) or number (%).

ACRN, advanced colorectal neoplasia.

aPolypoid lesions: Ip, Isp, and Is. bNon-polypoid lesion: IIa, IIb, IIc, III, No visible lesion (random biopsy).


3. Risk factors of ACRN

Univariate analysis of the logistic regression model revealed colitis-associated lesions (OR, 11.739; 95% CI, 2.474– 55.692; p=0.002) and polyp size (OR, 1.131; 95% CI, 1.029– 1.243; p=0.010) to be significant factors for ACRN. Variables including male sex, age, lesion characteristics, polyp size, and colitis-associated LGD significantly increased the risk of developing ACRN (OR, 10.516; 95% CI, 2.064–53.577; p=0.005) (Table 5). Among the patients with colitis-associated lesions (n=56), a history of LGD was a significant risk factor for ACRN (OR, 9.429; 95% CI, 1.330–66.863; p=0.025) (Table 6).

Table 5 Logistic Analysis of Risk Factors for ACRN (Logistic Analysis)

VariableUni-variate analysisMulti-variate analysis
p-valueOR (95% CI)p-valueAdjusted OR (95% CI)
Male sex0.9801.017 (0.262–3.949)0.7301.298 (0.295–5.717)
Age0.8630.996 (0.955–1.039)0.8691.004 (0.960–1.049)
Accompanying PSC0.2044.576 (0.439–47.716)
Disease extension (excluded E1)
E2, Left sided1.0 (Ref.)
E3, Pancolitis0.0822.906 (0.875–9.656)
Medication
5-ASA0.8741.187 (0.143–9.843)
Steroid0.3621.899 (0.478–7.545)
Immunomodulator0.2400.287 (0.036–2.302)
Previous diagnosis of dysplasia0.7261.250 (0.358–4.363)
Characteristics of lesion
Sporadic lesion1.0 (Ref.)
Colitis associated lesion0.00211.739 (2.474–55.692)0.00510.516 (2.064–53.577)
Number of polyps0.4410.534 (0.108–2.632)
Size of polyp0.0101.131 (1.029–1.243)0.0861.085 (0.989–1.190)

ACRN, advanced colorectal neoplasia; OR, odds ratio; CI, confidence interval; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid.


Table 6 Risk Factors for ACRN in IBD Patients with Colitis-associated Lesion (n=56; Logistic Analysis)

VariableUni-variate analysis
p-valueOR (95% CI)
Age0.8841.003 (0.958–1.051)
Accompanying PSC0.4842.444 (0.200–29.936)
Disease extension (excluded E1)
E2, Left sided1.0 (Ref.)
E3, Pancolitis0.7771.222 (0.305–4.894)
Medication
5-ASA0.9361.098 (0.114–10.571)
Steroid0.9780.980 (0.221–4.352)
Immunomodulator0.2520.282 (0.032–2.454)
Previous diagnosis of dysplasia0.0259.429 (1.330–66.863)
Number of polyps0.7440.738 (0.119–4.566)
Size of polyp0.1091.080 (0.983–1.187)

ACRN, advanced colorectal neoplasia; IBD, inflammatory bowel disease; OR, odds ratio; CI, confidence interval; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid.

The risk of ACRN in patients with IBD requires attention, and many controversies remain regarding the diagnosis, treatment, and follow-up. This study investigated the frequency and risk factors of ACRN development after diagnosing LGD in Korean IBD patients. In this study, patients with colitis- associated LGD, particularly those with a history of LGD, had a higher risk of ACRN. This result underscores the importance of rigorous inflammation control in patients with IBD and a history of LGD.

The mechanism for the development of CRC has been known as sporadic CRC of the “adenoma–carcinoma sequence”28 and CA-CRC of “inflammation–dysplasia–carcinoma sequence”.29 Sporadic CRC can also occur in patients with IBD,30 and chronic inflammation may generate oxidative stress-induced DNA damage and develop CRC from a non-dysplastic inflamed epithelium to dysplasia.29,31 In CA-CRC, the extent and severity of intestinal inflammatory lesions are well-known risk factors.32-34 In addition, variables including PSC, older age, family history of CRC, and male sex are risk factors for CA-CRC.35,36 Unlike sporadic cancers, CA-CRC occurs at a younger age, is often located proximally, and presents synchronous lesions more frequently.37

Several guidelines recommend the duration of CRC surveillance in patients with IBD based on the risk.6,38,39 An annual colonoscopy is recommended for high-risk patients with pancolitis, moderate-to-severe inflammation, dysplasia, strictures within the past five years, PSC, or a family history of CRC in first-degree relatives <50 years of age.4,6,24,38,39 In this study, high-risk patients with CRC were included, and patients with ulcerative proctitis and Crohn’s disease with less than 30% colonic involvement were excluded, making it suitable for investigating the course of CA-CRC. Furthermore, in this study, ACRN was diagnosed at a median follow-up of three years after LGD detection, and the median number of colonoscopies performed was two, indicating that examinations were conducted approximately once every one to two years. This frequent monitoring increases the likelihood of detecting LGD with larger sizes or HGD rather than cancer. In addition, the number of polyps discovered during endoscopic surveillance is important. In the present study, patients had between one and five polyps discovered at the index colonoscopy. Among them, one patient had five polyps, while 92.6% of patients had only one to two polyps, with no significant difference in the occurrence of ACRN (p=0.622). This was because there was only one patient with five polyps, which is insufficient for investigating the risk of ACRN occurrence based on the number of polyps. Therefore, further large-scale studies are necessary. Among the 12 patients with ACRN, four (33.3%) had a prior history of LGD, and all lesions originated from colitis-associated lesions. Therefore, if colitis-associated LGD is identified in a previous colonoscopy, subsequent colonoscopies should be performed within one to three years, according to the guidelines. On the other hand, further evidence and recommendations for surveillance of sporadic neoplasia in patients with IBD are currently lacking.

Regarding the treatment of patients with IBD with dysplasia, small polypoid and non-polypoid visible lesions with clear margins can be removed with an endoscopic resection technique using biopsy removal or snares.5 Moreover, EMR or ESD has been used for larger lesions.40 In particular, ESD using an endoknife is generally considered for large (>20 mm) lesions, particularly those with high-risk features and flat lesions.25,40 Recent guidelines recommend surveillance colonoscopy rather than colectomy after removing polypoid/ non-polypoid dysplastic lesions that can be removed endoscopically.24 Mohan et al.41 conducted a meta-analysis of 1,037 patients with IBD who underwent endoscopic resection of dysplasia and reported that the pooled risk after lesion removal was two per 1,000 person-years of follow-up. In the present study, the index LGD was removed by endoscopy in 91.6% of the patients, and no cases of recurrence or ACRN development occurred in the same area. This result could be explained by the high prevalence of sporadic LGD on index colonoscopy in this study. On the other hand, endoscopic resection is useful for small LGD, considering that no ACRN developed in the same lesion, irrespective of sporadic or colitis-associated LGD. Furthermore, the present study reported that ACRN developed in 7.2% of IBD patients with LGD diagnosed during previous surveillance in Korea, and endoscopic resections had been performed for most visible LGD cases (91.6%). A European study examining the incidence of ACRN in patients with UC and LGD reported ACRN in 33 (19.1%) out of 172 patients at a median 48-month follow- up.42 The incidence of ACRN in this study was relatively low compared to Western data. This may be because the duration of subject enrollment in this study was less than 10 years compared to 20 years in the previous study. In contrast, a nationwide cohort study of 4,284 patients with IBD collected from the Dutch National Pathology Registry showed that the cumulative incidence of subsequent advanced neoplasia was 3.6, 8.5, 14.4%, and 21.7% after one, five, 10, and 15 years, respectively.10 This can be regarded as a similar incidence rate, considering that the median follow-up period in the present study was 3.74 years. Nevertheless, additional large-scale studies will be needed as the number of patients in this study was small compared to other studies.

In addition, patients with colitis-associated lesions had a significantly higher risk of ACRN (OR, 10.516; 95% CI, 2.064– 53.577; p=0.005). Among them, patients with a history of previous LGD showed a high risk of ACRN (OR, 9.429; 95% CI, 1.330–66.863; p=0.025). Other studies have reported that invisible or endoscopic non-polypoid dysplasia is an independent risk factor for developing HGD or CRC in patients with UC.11,42 A meta-analysis35 reported that LGD, strictures, PSC, post-inflammatory polyps, family history of CRC, and UC versus CD were the risk factors for ACRN according to univariate analysis. Multivariate analysis revealed histological inflammation as a risk factor, and the results of this study confirmed that inflammation is a major factor in ACRN. Furthermore, considering that all ACRNs in the present study were from colitis-associated lesions, these patients may require special care, and more active inflammation control is needed because persistent inflammation can increase the risk of dysplasia.

This study had several limitations. First, data heterogeneity occurred from the retrospective analysis of six different hospitals. On the other hand, significant differences in patient groups or treatment patterns were not expected, considering that all participating institutions are specialized institutions, such as IBD clinics or centers. Second, inconsistencies in pathological and endoscopic findings were noted, possibly because of variations among pathologists and endoscopists across different hospitals. For example, the pathologist may have interpreted the colitis-associated lesion as dysplasia. In addition, although IND was also examined in this study, no case of IND was encountered. Hence, the diagnosis of IND may vary according to the pathologist, so bias due to differences in interpretation cannot be excluded. In addition, being a multicenter study, there may have been variations in the endoscopic findings and follow-up periods, which could introduce potential selection bias. Furthermore, the follow-up period of 4.9 years may not provide sufficient data to determine the long-term risk of ACRN, highlighting the need for further research with extended follow-up. Nevertheless, this study is significant because it was the first in Korea to analyze the clinical features, progression, and risk factors of LGD in a relatively large number of centers. This study provides valuable insights by showing that the risk of ACRN in Korea is not higher than expected.

In conclusion, ACRN occurred at a median of 3.05 years in 7.2% of IBD patients with previous LGD, and an increased risk of colitis-associated cases was observed. Therefore, adherence to surveillance guidelines and more careful examination are recommended in patients with colitis-associated LGD, particularly those with a previous history of dysplasia. Hence, studies with a larger number of patients and longer duration are needed.

This study was supported by 2021 Yeungnam University Research grant.

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Article

Original Article

Korean J Gastroenterol 2025; 85(1): 34-43

Published online January 25, 2025 https://doi.org/10.4166/kjg.2024.105

Copyright © The Korean Society of Gastroenterology.

Frequency and Risk Factors of Advanced Neoplasia in Korean Inflammatory Bowel Disease Patients with Low-grade Dysplasia

Yong Eun Park1, Kyeong Ok Kim2 , Dong Hyun Kim3, Soo-Kyung Park4, Yoo Jin Lee5, Chang Kyun Lee6, IBD Research Group of the Korean Association for the Study of Intestinal Diseases (KASID)

Division of Gastroenterology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan1; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu2; Division of Gastroenterology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju3; Division of Gastroenterology, Department of Internal Medicine and Inflammatory Bowel Disease Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul4; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu5; Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul6, Korea

Correspondence to:Kyeong Ok Kim, Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea. Tel: +82-53-620-3835, Fax: +82-53-623-8038, E-mail: kokim@yu.ac.kr, ORCID: https://orcid.org/0000-0001-5799-7436

Financial support: This study was supported by 2021 Yeungnam University Research grant.

Received: September 23, 2024; Revised: October 25, 2024; Accepted: October 29, 2024

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Studies on the clinical outcomes after detecting low-grade dysplasia (LGD) in patients with inflammatory bowel disease (IBD) are insufficient. This study evaluated the clinical features, frequency, and risk factors for advanced neoplasia in patients with IBD after an LGD diagnosis.
Methods: The medical records of 166 patients with IBD from six university hospitals in Korea from 2010 to 2019 were reviewed retrospectively. LGD was diagnosed in all patients during surveillance. The frequency and risk factors for advanced neoplasia were evaluated, and the clinical features of patients with and without advanced neoplasia were compared.
Results: Advanced neoplasia developed in 12 patients (six with large LGD, three with tubulovillous adenoma, and three with high-grade dysplasia), and all cases developed from UC. Patients with advanced neoplasia had significantly higher Mayo scores, and colitis-associated dysplasia was more common than sporadic lesions (83.3% vs. 29.9%; p<0.001). Multivariate analysis showed that colitis-associated LGD significantly increased the risk of developing advanced neoplasia (odds ratio [OR], 10.516; 95% confidence interval [CI], 2.064–53.577). Among patients with colitis-associated lesions, a significant risk factor for advanced neoplasia was a prior history of LGD (OR, 9.429; 95% CI, 1.330–66.863).
Conclusions: Advanced neoplasia developed in 7.2% of patients with IBD and LGD. Most advanced neoplasms developed from colitis-associated lesions, and the risk was higher in patients with a history of LGD before index colonoscopy.

Keywords: Colorectal neoplasm, Inflammatory bowel disease, Risk factors

INTRODUCTION

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammatory gastrointestinal (GI) disorders1 that carry a significant risk of colorectal cancer (CRC).2,3 Patients with IBD have a 1.7-fold higher risk of CRC because of long-standing chronic inflammation and the possible occurrence of colitis-associated and sporadic neoplasia.2 Therefore, most guidelines recommend surveillance colonoscopy to reduce the risk of dysplasia and CRC.4-7 In particular, the ECCO guidelines recommend surveillance colonoscopy based on the patient’s risk.4 Nevertheless, interval cancer may still occur in patients with IBD if the lesions are missed during surveillance, and one study reported that it occurred in up to 30% of patients.8

In IBD patients, colitis-associated CRC (CA-CRC) progresses from chronic inflammation to CRC through dysplastic precursor lesions such as indefinite, low-grade, and high-grade dysplasia.9 A follow-up cohort study after diagnosing low-grade dysplasia (LGD) in IBD patients reported a 21.7% incidence of advanced colorectal neoplasia (ACRN) after 15 years.10 On the other hand, the frequency of progression to high-grade dysplasia (HGD) or CRC varied from 16 to 54%.11 Indefinite dysplasia (IND) was diagnosed when regeneration and dysplasia could not be distinguished clearly in an environment such as severe active inflammation.12 The risk of ACRN was reported to increase in those with IND. Moreover, LGD was associated with a significantly higher risk of ACRN compared with IND.13

Regarding management, endoscopic resection and regular close follow-up could also be considered in visible colitis- associated dysplasia with clear margins. Nevertheless, limited data exist for LGD/IND in patients with IBD regarding endoscopic treatment (endoscopic resection or surgery), follow- up interval, clinical course, or associated risks. Therefore, this study conducted a multicenter analysis of the clinical features, treatment, follow-up period, incidence of advanced adenoma, and risk factors for LGD/IND in Korean patients with IBD.

SUBJECTS AND METHODS

1. Patients

This study retrospectively reviewed patients with IBD who had been diagnosed with low-grade/indefinite dysplasia on surveillance colonoscopy and underwent at least one surveillance colonoscopy after detection at one of six university hospitals in Korea. The diagnoses of UC and CD were based on clinical, endoscopic, histopathological, and radiology findings.14,15 The baseline characteristics of the patients were obtained from the electronic medical data of each hospital, including the patient’s demographics, type and disease status of IBD, comorbid diseases, accompanying primary sclerosing cholangitis (PSC), family history of CRC, smoking status, and medication records at the time of diagnosis of colon dysplasia (<3 months).

The inclusion criteria were IBD patients with low-grade/indefinite dysplasia between 2010 and December 2019, who had undergone at least one surveillance colonoscopy, and who satisfied any of the following conditions: i) disease duration of eight years or more, ii) patients with PSC regardless of disease duration, iii) patients with a history of diagnosis of LGD, or iv) family history of CRC in first-degree relatives under the age of 50.

Thirty-seven patients were excluded based on the following exclusion criteria: i) patients with ulcerative proctitis or Crohn’s colitis with less than 30% colonic involvement, ii) no history of PSC or dysplasia in IBD patients with disease duration of less than eight years, iii) patients previously diagnosed with HGD and CRC, iv) difficulty observing the entire large intestine due to stenosis or resection, and v) other cases where the researcher judged that it was inappropriate. Thus, 166 patients were included in the final analysis. The patients were divided into groups with and without advanced lesions, and the disease status of IBD, polyp type, treatment methods, and risk factors were investigated (Fig. 1). This study was performed according to the ethical guidelines of the 1975 Declaration of Helsinki and approved by the Institutional Review Board of each hospital.

Figure 1. Flow diagram of patient selection. LGD, low grade dysplasia; IND, indefinite dysplasia; IBD, Inflammatory bowel disease; PSC, primary sclerosing cholangitis; HGD, high grade dysplasia; CRC, colorectal cancer.

2. Assessment of IBD

The disease extent and severity were classified using the Montreal classification in patients with UC, and the Vienna Montreal classification was used in CD patients.16 The IBD disease status was evaluated based on the endoscopic disease activity and clinical activity within three months of dysplasia detection. The disease activity of UC was evaluated using the Mayo score, and the endoscopic disease activity was evaluated using the Mayo endoscopic score (MES).17,18 In CD patients, the disease activity was assessed using the Crohn’s Disease Activity Index19 and the endoscopic disease activity was evaluated using the Simple Endoscopic Score for Crohn’s Disease.20 In addition, this study assessed the types of medications used and whether there were any changes in IBD treatment after the adenoma diagnosis.

3. Assessment and management of polyps

1) Definition of polyps

ACRN was defined as an adenocarcinoma or advanced adenoma. Advanced adenoma included adenoma ≥10 mm or with tubulovillous/villous histology or HGD.21,22

2) Characteristics of polyps and diagnostic tools

The lesions were classified as visible or invisible. In the case of visible lesions, the morphology of the polyps was classified as pedunculated (Ip), subpedunculated (Isp), sessile (Is), slightly elevated (0-IIa), flat (0-IIb), slightly depressed (0-IIc), excavated (0-III), or no visible lesion.23 The lesions were divided into polypoid (Ip, Isp, and Is) and non-polypoid (IIa, IIb, IIc, III, and invisible dysplasia). The size (mm), number, and location of polyps, as well as the presence of metachronous, colitis-associated, or sporadic lesions, were also investigated. Lesions found in areas with IBD-related chronic inflammation were defined as colitis-associated lesions; those unrelated to chronic inflammation were defined as sporadic lesions.

The endoscopic modalities used to detect dysplasia were evaluated, including standard white-light endoscopy high-definition WLE (HD-WLE), and pan-chromoendoscopy. Furthermore, this study investigated whether random biopsies or targeted biopsies detected the lesions; if the lesions were diagnosed by random biopsy, they were defined as invisible lesions based on the SCENIC consensus.24

3) Treatment for polyps

The treatment method was also evaluated. A physician made decisions based on the lesion characteristics and patient risk. Endoscopic mucosal resection or endoscopic submucosal dissection was considered for lesions with distinct borders based on the decision of the endoscopist. In contrast, surgery was considered for endoscopically unresectable lesions and invisible dysplasia, and total proctocolectomy with ileal-pouch anal anastomosis was considered for HGD or CRC.25,26 For patients diagnosed with LGD that did not involve the rectum or had comorbidities, partial colectomy or segmental resection was considered and performed in consultation with the surgeon.27

4. Statistical analysis

The variables are expressed as median (interquartile range [IQR]) or n (%). The baseline characteristics were compared using an independent Student’s t-test (or Mann–Whitney U test) for continuous variables and the χ2 test (or Fisher’s exact test) for categorical variables. The disease status and polyp characteristics of patients with IBD were divided into “ACRN” and “no ACRN” groups and compared. Logistic regression analysis was used to analyze the independent predictors of the risk factors for advanced polyps. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. The data were analyzed using the SPSS software (version 25.0; IBM Corp., Armonk, NY, USA). A p-value of <0.05 was considered significant.

RESULTS

1. Comparison of the baseline characteristics and disease status of ACRN and no-ACRN groups

Table 1 lists the baseline characteristics of the ACRN and no-ACRN groups. The median age of the patients was 57 years (IQR, 48–64 years), and 74.7% of patients were male. Four patients had PSC, one of whom developed ACRN. Despite no significant difference among the patients in whom index LGD was discovered during the study period, 33.3% of patients who developed ACRN had already been diagnosed with LGD. No significant differences in medication use or underlying diseases were observed between the patients with and without ACRN (Table 1).

Table 1 . Baseline Characteristics of the Study Subjects.

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Age57 (48–64)54 (50–63)57 (48–64)0.864
Male sex124 (74.7)9 (75.0)115 (74.7)0.980
Accompanying PSC4 (2.4)1 (8.3)3 (1.9)0.165
Underlying disease42 (25.3)2 (16.7)40 (26.0)0.475
Hypertension9 (5.4)0 (0)9 (5.8)0.389
Diabetes7 (4.2)0 (0)7 (4.5)0.450
Cardiovascular disease11 (6.6)1 (8.3)10 (6.5)0.805
Liver disease8 (4.8)0 (0)8 (5.2)0.418
Malignancy3 (1.8)0 (0)3 (1.9)0.626
Othersa18 (10.8)2 (16.7)16 (10.4)0.501
Family history of CRC1 (0.6)0 (0)1 (0.6)0.779
Operationb6 (3.6)1 (8.3)5 (3.2)0.363
Smoking30 (18.1)0 (0)30 (19.5)0.091
Type of IBD0.098
Crohn’s disease29 (17.5)0 (0)29 (18.8)
Ulcerative colitis137 (82.5)12 (100.0)125 (81.2)
Disease duration11.48 (7.85–14.50)11.63 (1.59–14.53)11.48 (7.87–14.50)0.143
Previous diagnosis of LGD34 (27.7)4 (33.3)34 (27.2)0.650
Medication
5-ASA150 (90.4)11 (91.7)139 (90.3)0.874
Steroid26 (15.7)3 (25.0)23 (14.9)0.355
Immunomodulator38 (22.9)1 (8.3)37 (24.0)0.213
Anti-TNF21 (12.7)0 (0)21 (13.6)0.171
Other biologicsc5 (3.0)0 (0)5 (3.2)0.526

Data are expressed as median (interquartile range) or number (%)..

ACRN, advanced colorectal neoplasia; PSC, primary sclerosing cholangitis; CRC, colorectal cancer; IBD, inflammatory bowel disease; LGD, low-grade dysplasia; 5-ASA, 5-aminosalicylic acid; anti-TNF, antitumor necrosis factor..

aCKD, hereditary spherocytosis; RA, Tuberculosis; infarction; AS, Parkinson’s disease. bExcluded IBD-related bowel operation. cUstekinumab, vedolizumab, mirikizumab..

*p-value for comparing patients with and without ACRN..



One hundred and thirty-seven patients with UC (82.5%) and 29 with CD (17.5%) were evaluated. Left-sided UC (E2) accounted for 72.3% of patients, and 27.7% had pancolitis (E3). Six of the 38 patients with pancolitis developed ACRN (15.8%), which was not significant but showed a higher tendency than that of patients with left-sided UC (6.06%, six of 99). The disease activity was significantly higher in the ACRN group (Mayo score, 3.5 [2.0–6.0] vs. 1.0 [0–2.0]; p=0.010), but the endoscopic activity was similar in UC patients (MES, 2.0 [1.0–2.0] vs. 1.0 [0–2.0]; p=0.383). ACRN did not develop in patients with CD, but most showed ileocolonic involvement (62.1%) and non-stricturing and non-penetrating behavior (66.7%) (Table 2).

Table 2 . Disease Status of the Patients with Inflammatory Bowel Disease.

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Ulcerative colitis137 (82.5)12 (100.0)125 (81.2)
Disease extension0.071
E2a99 (72.3)6 (50.0)93 (74.4)
E3b38 (27.7)6 (50.0)32 (25.6)
Mayo score1.0 (0–3.0)3.5 (2.0–6.0)1.0 (0–2.0)0.010
MES1.0 (0–2.0)2.0 (1.0–2.0)1.0 (0–2.0)0.383
Crohn’s disease29 (17.5)0 (0)29 (18.8)
Disease location-
L2c18 (62.1)0 (0)18 (62.1)
L3d11 (37.9)0 (0)11 (37.9)
Disease behavior-
Inflammatory18 (66.7)0 (0)18 (66.7)
Stricturing7 (25.9)0 (0)7 (25.9)
Penetrating2 (7.4)0 (0)2 (7.4)
CDAI72.15 (45.38–179.27)0 (0)72.15 (45.38–179.27)
SES-CD4.0 (0.25–11.25)0 (0)4.0 (0.25–11.25)

Data are expressed as number (%) or median (interquartile range)..

ACRN, advanced colorectal neoplasia; MES, Mayo endoscopic score; CDAI, Crohn's disease activity index; SES-CD, Simple endoscopic score for Crohn’s disease..

aLeft sided, bPancolitis, cIleocolonic, dColonic..

*p-value for comparing patients with and without ACRN..



2. Clinical features and outcomes of index LGD

From January 2010 to December 2019, LGD was detected in 166 patients with IBD, of whom 33.7% had colitis-associated LGD (56 cases). An endoscopic resection was performed in 152 cases (91.6%), and biopsy removal was the most common method (83 of 152, 54.6%), followed by an endoscopic mucosal resection (EMR) (57 of 152, 37.5%) and cold snaring (12 of 152, 7.9%). In patients with UC who developed ACRN, colitis-associated LGD on the index colonoscopy was more common than in those with sporadic LGD (83.3% vs. 29.9%; p<0.001). In addition, the median size of the index LGD was 11.50 mm (IQR, 7.25–16.75) in the ACRN group, which was significantly larger than that in the no ACRN group (p<0.001). A total of 66.7% of patients with UC were examined using HD-WLE, and all index LGD cases in the ACRN group were diagnosed using a targeted biopsy. No significant differences in the shape, location, or number of polyps were noted. In patients with UC in the ACRN group, 66.7% of those with index LGD underwent endoscopic removal, while 33.3% underwent close follow-up (Table 3).

Table 3 . Characteristics of Index LGD and Comparison between Patients With and Without Advanced Neoplasia.

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Type of endoscopy0.944
SD-WLE51 (30.7)4 (33.3)47 (30.5)
HD-WLE114 (68.7)8 (66.7)106 (68.8)
Panchromoendoscopy1 (0.6)0 (0)1 (0.6)
Targeted biopsy153 (92.2)12 (100.0)141 (91.6)0.294
Colitis associated lesion56 (33.7)10 (83.3)46 (29.9)<0.001
Location0.498
Cecum13 (7.8)0 (0)13 (8.4)
Ascending colon36 (21.7)2 (16.7)34 (22.1)
Transverse colon35 (21.1)2 (16.7)33 (21.4)
Descending colon25 (15.1)1 (8.3)24 (15.6)
Sigmoid colon38 (22.9)4 (33.3)34 (22.1)
Rectum19 (11.4)3 (25.0)16 (10.4)
Morphology0.610
Polypoida146 (88.0)10 (83.3)136 (88.3)
Non-polypoidb20 (12.0)2 (16.7)18 (11.7)
Number of polyps (mean)1.0 (1.0–1.0)1.0 (1.0–1.0)1.0 (1.0–1.0)0.420
Size of polyp (mm)5.0 (3.0–6.5)11.50 (7.25–16.75)4.0 (3.0–6.0)<0.001
Treatment modality0.003
Endoscopic resection152 (91.6)8 (66.7)144 (93.5)
Close follow-up14 (8.4)4 (33.3)10 (6.5)

Data are expressed as number (%) or median (interquartile range)..

ACRN, advanced colorectal neoplasia; SD-WLE, standard definition white-light endoscopy; HD-WLE, high-definition white-light endoscopy..

aPolypoid lesions: Ip, Isp, and Is. bNon-polypoid lesion: IIa, IIb, IIc, III, No visible lesion (random biopsy)..

*p-value for comparing patients with and without ACRN..



ACRN developed in 12 cases (7.2%), with a median duration of 3.05 years (IQR, 0.73–3.63) after the LGD diagnosis. Among these cases, six, three, and three patients had large LGD, tubulovillous adenoma, and HGD, respectively. All ACRN cases occurred in patients with UC (12 of 137, 8.8%), with a median disease duration of 11.48 years (IQR, 7.85–14.50). The sigmoid colon was the most frequent location (66.7%), followed by the transverse colon (16.7%), ascending colon, and rectum (8.3%). The most common morphology was sessile (Is) (83.3%), with a median size of 11.50 mm (IQR, 7.25– 16.75) (Table 4). Among the patients who underwent an endoscopic resection, ACRN occurred in eight of 152 cases (5.3%) in a different area from the previous lesions. No cases of CRC were encountered during the follow-up period, but HGD was found in 25% of patients. Regarding the treatment of ACRN, four cases underwent an endoscopic resection (including EMR or endoscopic submucosal dissection [ESD]); one was removed surgically, and seven were lost to follow-up before receiving proper treatment. Azathioprine was initiated as part of the treatment in one patient who underwent an endoscopic resection. Although ACRN did not develop in patients with CD, they had fewer colitis-associated lesions than sporadic lesions compared to those with UC (UC, 36.5% vs. CD, 20.7%) (Data not shown).

Table 4 . Characteristics of ACRN.

VariablesTotal (n=12)
Follow-up duration (years)3.05 (0.73–3.63)
Number of surveillance colonoscopy2.0 (1.0–3.0)
Location of polyp
Ascending colon1 (8.3)
Transverse colon2 (16.7)
Sigmoid colon8 (66.7)
Rectum1 (8.3)
Morphology
Polypoid lesiona10 (83.3)
Non-polypoid lesionb2 (16.7)
Size (mm)11.50 (7.25–16.75)
Pathologic finding
Tubular adenoma6 (50.0)
Tubulovillous adenoma3 (25.0)
Villous adenoma0 (0)
High-grade dysplasia3 (25.0)

Data are expressed as medians (interquartile ranges) or number (%)..

ACRN, advanced colorectal neoplasia..

aPolypoid lesions: Ip, Isp, and Is. bNon-polypoid lesion: IIa, IIb, IIc, III, No visible lesion (random biopsy)..



3. Risk factors of ACRN

Univariate analysis of the logistic regression model revealed colitis-associated lesions (OR, 11.739; 95% CI, 2.474– 55.692; p=0.002) and polyp size (OR, 1.131; 95% CI, 1.029– 1.243; p=0.010) to be significant factors for ACRN. Variables including male sex, age, lesion characteristics, polyp size, and colitis-associated LGD significantly increased the risk of developing ACRN (OR, 10.516; 95% CI, 2.064–53.577; p=0.005) (Table 5). Among the patients with colitis-associated lesions (n=56), a history of LGD was a significant risk factor for ACRN (OR, 9.429; 95% CI, 1.330–66.863; p=0.025) (Table 6).

Table 5 . Logistic Analysis of Risk Factors for ACRN (Logistic Analysis).

VariableUni-variate analysisMulti-variate analysis
p-valueOR (95% CI)p-valueAdjusted OR (95% CI)
Male sex0.9801.017 (0.262–3.949)0.7301.298 (0.295–5.717)
Age0.8630.996 (0.955–1.039)0.8691.004 (0.960–1.049)
Accompanying PSC0.2044.576 (0.439–47.716)
Disease extension (excluded E1)
E2, Left sided1.0 (Ref.)
E3, Pancolitis0.0822.906 (0.875–9.656)
Medication
5-ASA0.8741.187 (0.143–9.843)
Steroid0.3621.899 (0.478–7.545)
Immunomodulator0.2400.287 (0.036–2.302)
Previous diagnosis of dysplasia0.7261.250 (0.358–4.363)
Characteristics of lesion
Sporadic lesion1.0 (Ref.)
Colitis associated lesion0.00211.739 (2.474–55.692)0.00510.516 (2.064–53.577)
Number of polyps0.4410.534 (0.108–2.632)
Size of polyp0.0101.131 (1.029–1.243)0.0861.085 (0.989–1.190)

ACRN, advanced colorectal neoplasia; OR, odds ratio; CI, confidence interval; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid..



Table 6 . Risk Factors for ACRN in IBD Patients with Colitis-associated Lesion (n=56; Logistic Analysis).

VariableUni-variate analysis
p-valueOR (95% CI)
Age0.8841.003 (0.958–1.051)
Accompanying PSC0.4842.444 (0.200–29.936)
Disease extension (excluded E1)
E2, Left sided1.0 (Ref.)
E3, Pancolitis0.7771.222 (0.305–4.894)
Medication
5-ASA0.9361.098 (0.114–10.571)
Steroid0.9780.980 (0.221–4.352)
Immunomodulator0.2520.282 (0.032–2.454)
Previous diagnosis of dysplasia0.0259.429 (1.330–66.863)
Number of polyps0.7440.738 (0.119–4.566)
Size of polyp0.1091.080 (0.983–1.187)

ACRN, advanced colorectal neoplasia; IBD, inflammatory bowel disease; OR, odds ratio; CI, confidence interval; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid..


DISCUSSION

The risk of ACRN in patients with IBD requires attention, and many controversies remain regarding the diagnosis, treatment, and follow-up. This study investigated the frequency and risk factors of ACRN development after diagnosing LGD in Korean IBD patients. In this study, patients with colitis- associated LGD, particularly those with a history of LGD, had a higher risk of ACRN. This result underscores the importance of rigorous inflammation control in patients with IBD and a history of LGD.

The mechanism for the development of CRC has been known as sporadic CRC of the “adenoma–carcinoma sequence”28 and CA-CRC of “inflammation–dysplasia–carcinoma sequence”.29 Sporadic CRC can also occur in patients with IBD,30 and chronic inflammation may generate oxidative stress-induced DNA damage and develop CRC from a non-dysplastic inflamed epithelium to dysplasia.29,31 In CA-CRC, the extent and severity of intestinal inflammatory lesions are well-known risk factors.32-34 In addition, variables including PSC, older age, family history of CRC, and male sex are risk factors for CA-CRC.35,36 Unlike sporadic cancers, CA-CRC occurs at a younger age, is often located proximally, and presents synchronous lesions more frequently.37

Several guidelines recommend the duration of CRC surveillance in patients with IBD based on the risk.6,38,39 An annual colonoscopy is recommended for high-risk patients with pancolitis, moderate-to-severe inflammation, dysplasia, strictures within the past five years, PSC, or a family history of CRC in first-degree relatives <50 years of age.4,6,24,38,39 In this study, high-risk patients with CRC were included, and patients with ulcerative proctitis and Crohn’s disease with less than 30% colonic involvement were excluded, making it suitable for investigating the course of CA-CRC. Furthermore, in this study, ACRN was diagnosed at a median follow-up of three years after LGD detection, and the median number of colonoscopies performed was two, indicating that examinations were conducted approximately once every one to two years. This frequent monitoring increases the likelihood of detecting LGD with larger sizes or HGD rather than cancer. In addition, the number of polyps discovered during endoscopic surveillance is important. In the present study, patients had between one and five polyps discovered at the index colonoscopy. Among them, one patient had five polyps, while 92.6% of patients had only one to two polyps, with no significant difference in the occurrence of ACRN (p=0.622). This was because there was only one patient with five polyps, which is insufficient for investigating the risk of ACRN occurrence based on the number of polyps. Therefore, further large-scale studies are necessary. Among the 12 patients with ACRN, four (33.3%) had a prior history of LGD, and all lesions originated from colitis-associated lesions. Therefore, if colitis-associated LGD is identified in a previous colonoscopy, subsequent colonoscopies should be performed within one to three years, according to the guidelines. On the other hand, further evidence and recommendations for surveillance of sporadic neoplasia in patients with IBD are currently lacking.

Regarding the treatment of patients with IBD with dysplasia, small polypoid and non-polypoid visible lesions with clear margins can be removed with an endoscopic resection technique using biopsy removal or snares.5 Moreover, EMR or ESD has been used for larger lesions.40 In particular, ESD using an endoknife is generally considered for large (>20 mm) lesions, particularly those with high-risk features and flat lesions.25,40 Recent guidelines recommend surveillance colonoscopy rather than colectomy after removing polypoid/ non-polypoid dysplastic lesions that can be removed endoscopically.24 Mohan et al.41 conducted a meta-analysis of 1,037 patients with IBD who underwent endoscopic resection of dysplasia and reported that the pooled risk after lesion removal was two per 1,000 person-years of follow-up. In the present study, the index LGD was removed by endoscopy in 91.6% of the patients, and no cases of recurrence or ACRN development occurred in the same area. This result could be explained by the high prevalence of sporadic LGD on index colonoscopy in this study. On the other hand, endoscopic resection is useful for small LGD, considering that no ACRN developed in the same lesion, irrespective of sporadic or colitis-associated LGD. Furthermore, the present study reported that ACRN developed in 7.2% of IBD patients with LGD diagnosed during previous surveillance in Korea, and endoscopic resections had been performed for most visible LGD cases (91.6%). A European study examining the incidence of ACRN in patients with UC and LGD reported ACRN in 33 (19.1%) out of 172 patients at a median 48-month follow- up.42 The incidence of ACRN in this study was relatively low compared to Western data. This may be because the duration of subject enrollment in this study was less than 10 years compared to 20 years in the previous study. In contrast, a nationwide cohort study of 4,284 patients with IBD collected from the Dutch National Pathology Registry showed that the cumulative incidence of subsequent advanced neoplasia was 3.6, 8.5, 14.4%, and 21.7% after one, five, 10, and 15 years, respectively.10 This can be regarded as a similar incidence rate, considering that the median follow-up period in the present study was 3.74 years. Nevertheless, additional large-scale studies will be needed as the number of patients in this study was small compared to other studies.

In addition, patients with colitis-associated lesions had a significantly higher risk of ACRN (OR, 10.516; 95% CI, 2.064– 53.577; p=0.005). Among them, patients with a history of previous LGD showed a high risk of ACRN (OR, 9.429; 95% CI, 1.330–66.863; p=0.025). Other studies have reported that invisible or endoscopic non-polypoid dysplasia is an independent risk factor for developing HGD or CRC in patients with UC.11,42 A meta-analysis35 reported that LGD, strictures, PSC, post-inflammatory polyps, family history of CRC, and UC versus CD were the risk factors for ACRN according to univariate analysis. Multivariate analysis revealed histological inflammation as a risk factor, and the results of this study confirmed that inflammation is a major factor in ACRN. Furthermore, considering that all ACRNs in the present study were from colitis-associated lesions, these patients may require special care, and more active inflammation control is needed because persistent inflammation can increase the risk of dysplasia.

This study had several limitations. First, data heterogeneity occurred from the retrospective analysis of six different hospitals. On the other hand, significant differences in patient groups or treatment patterns were not expected, considering that all participating institutions are specialized institutions, such as IBD clinics or centers. Second, inconsistencies in pathological and endoscopic findings were noted, possibly because of variations among pathologists and endoscopists across different hospitals. For example, the pathologist may have interpreted the colitis-associated lesion as dysplasia. In addition, although IND was also examined in this study, no case of IND was encountered. Hence, the diagnosis of IND may vary according to the pathologist, so bias due to differences in interpretation cannot be excluded. In addition, being a multicenter study, there may have been variations in the endoscopic findings and follow-up periods, which could introduce potential selection bias. Furthermore, the follow-up period of 4.9 years may not provide sufficient data to determine the long-term risk of ACRN, highlighting the need for further research with extended follow-up. Nevertheless, this study is significant because it was the first in Korea to analyze the clinical features, progression, and risk factors of LGD in a relatively large number of centers. This study provides valuable insights by showing that the risk of ACRN in Korea is not higher than expected.

In conclusion, ACRN occurred at a median of 3.05 years in 7.2% of IBD patients with previous LGD, and an increased risk of colitis-associated cases was observed. Therefore, adherence to surveillance guidelines and more careful examination are recommended in patients with colitis-associated LGD, particularly those with a previous history of dysplasia. Hence, studies with a larger number of patients and longer duration are needed.

Financial support

This study was supported by 2021 Yeungnam University Research grant.

Conflict of interest

None.

Fig 1.

Figure 1.Flow diagram of patient selection. LGD, low grade dysplasia; IND, indefinite dysplasia; IBD, Inflammatory bowel disease; PSC, primary sclerosing cholangitis; HGD, high grade dysplasia; CRC, colorectal cancer.
The Korean Journal of Gastroenterology 2025; 85: 34-43https://doi.org/10.4166/kjg.2024.105

Table 1 Baseline Characteristics of the Study Subjects

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Age57 (48–64)54 (50–63)57 (48–64)0.864
Male sex124 (74.7)9 (75.0)115 (74.7)0.980
Accompanying PSC4 (2.4)1 (8.3)3 (1.9)0.165
Underlying disease42 (25.3)2 (16.7)40 (26.0)0.475
Hypertension9 (5.4)0 (0)9 (5.8)0.389
Diabetes7 (4.2)0 (0)7 (4.5)0.450
Cardiovascular disease11 (6.6)1 (8.3)10 (6.5)0.805
Liver disease8 (4.8)0 (0)8 (5.2)0.418
Malignancy3 (1.8)0 (0)3 (1.9)0.626
Othersa18 (10.8)2 (16.7)16 (10.4)0.501
Family history of CRC1 (0.6)0 (0)1 (0.6)0.779
Operationb6 (3.6)1 (8.3)5 (3.2)0.363
Smoking30 (18.1)0 (0)30 (19.5)0.091
Type of IBD0.098
Crohn’s disease29 (17.5)0 (0)29 (18.8)
Ulcerative colitis137 (82.5)12 (100.0)125 (81.2)
Disease duration11.48 (7.85–14.50)11.63 (1.59–14.53)11.48 (7.87–14.50)0.143
Previous diagnosis of LGD34 (27.7)4 (33.3)34 (27.2)0.650
Medication
5-ASA150 (90.4)11 (91.7)139 (90.3)0.874
Steroid26 (15.7)3 (25.0)23 (14.9)0.355
Immunomodulator38 (22.9)1 (8.3)37 (24.0)0.213
Anti-TNF21 (12.7)0 (0)21 (13.6)0.171
Other biologicsc5 (3.0)0 (0)5 (3.2)0.526

Data are expressed as median (interquartile range) or number (%).

ACRN, advanced colorectal neoplasia; PSC, primary sclerosing cholangitis; CRC, colorectal cancer; IBD, inflammatory bowel disease; LGD, low-grade dysplasia; 5-ASA, 5-aminosalicylic acid; anti-TNF, antitumor necrosis factor.

aCKD, hereditary spherocytosis; RA, Tuberculosis; infarction; AS, Parkinson’s disease. bExcluded IBD-related bowel operation. cUstekinumab, vedolizumab, mirikizumab.

*p-value for comparing patients with and without ACRN.


Table 2 Disease Status of the Patients with Inflammatory Bowel Disease

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Ulcerative colitis137 (82.5)12 (100.0)125 (81.2)
Disease extension0.071
E2a99 (72.3)6 (50.0)93 (74.4)
E3b38 (27.7)6 (50.0)32 (25.6)
Mayo score1.0 (0–3.0)3.5 (2.0–6.0)1.0 (0–2.0)0.010
MES1.0 (0–2.0)2.0 (1.0–2.0)1.0 (0–2.0)0.383
Crohn’s disease29 (17.5)0 (0)29 (18.8)
Disease location-
L2c18 (62.1)0 (0)18 (62.1)
L3d11 (37.9)0 (0)11 (37.9)
Disease behavior-
Inflammatory18 (66.7)0 (0)18 (66.7)
Stricturing7 (25.9)0 (0)7 (25.9)
Penetrating2 (7.4)0 (0)2 (7.4)
CDAI72.15 (45.38–179.27)0 (0)72.15 (45.38–179.27)
SES-CD4.0 (0.25–11.25)0 (0)4.0 (0.25–11.25)

Data are expressed as number (%) or median (interquartile range).

ACRN, advanced colorectal neoplasia; MES, Mayo endoscopic score; CDAI, Crohn's disease activity index; SES-CD, Simple endoscopic score for Crohn’s disease.

aLeft sided, bPancolitis, cIleocolonic, dColonic.

*p-value for comparing patients with and without ACRN.


Table 3 Characteristics of Index LGD and Comparison between Patients With and Without Advanced Neoplasia

VariablesTotal (n=166)ACRN (n=12, 7.2%)No ACRN (n=154, 92.8%)p-value*
Type of endoscopy0.944
SD-WLE51 (30.7)4 (33.3)47 (30.5)
HD-WLE114 (68.7)8 (66.7)106 (68.8)
Panchromoendoscopy1 (0.6)0 (0)1 (0.6)
Targeted biopsy153 (92.2)12 (100.0)141 (91.6)0.294
Colitis associated lesion56 (33.7)10 (83.3)46 (29.9)<0.001
Location0.498
Cecum13 (7.8)0 (0)13 (8.4)
Ascending colon36 (21.7)2 (16.7)34 (22.1)
Transverse colon35 (21.1)2 (16.7)33 (21.4)
Descending colon25 (15.1)1 (8.3)24 (15.6)
Sigmoid colon38 (22.9)4 (33.3)34 (22.1)
Rectum19 (11.4)3 (25.0)16 (10.4)
Morphology0.610
Polypoida146 (88.0)10 (83.3)136 (88.3)
Non-polypoidb20 (12.0)2 (16.7)18 (11.7)
Number of polyps (mean)1.0 (1.0–1.0)1.0 (1.0–1.0)1.0 (1.0–1.0)0.420
Size of polyp (mm)5.0 (3.0–6.5)11.50 (7.25–16.75)4.0 (3.0–6.0)<0.001
Treatment modality0.003
Endoscopic resection152 (91.6)8 (66.7)144 (93.5)
Close follow-up14 (8.4)4 (33.3)10 (6.5)

Data are expressed as number (%) or median (interquartile range).

ACRN, advanced colorectal neoplasia; SD-WLE, standard definition white-light endoscopy; HD-WLE, high-definition white-light endoscopy.

aPolypoid lesions: Ip, Isp, and Is. bNon-polypoid lesion: IIa, IIb, IIc, III, No visible lesion (random biopsy).

*p-value for comparing patients with and without ACRN.


Table 4 Characteristics of ACRN

VariablesTotal (n=12)
Follow-up duration (years)3.05 (0.73–3.63)
Number of surveillance colonoscopy2.0 (1.0–3.0)
Location of polyp
Ascending colon1 (8.3)
Transverse colon2 (16.7)
Sigmoid colon8 (66.7)
Rectum1 (8.3)
Morphology
Polypoid lesiona10 (83.3)
Non-polypoid lesionb2 (16.7)
Size (mm)11.50 (7.25–16.75)
Pathologic finding
Tubular adenoma6 (50.0)
Tubulovillous adenoma3 (25.0)
Villous adenoma0 (0)
High-grade dysplasia3 (25.0)

Data are expressed as medians (interquartile ranges) or number (%).

ACRN, advanced colorectal neoplasia.

aPolypoid lesions: Ip, Isp, and Is. bNon-polypoid lesion: IIa, IIb, IIc, III, No visible lesion (random biopsy).


Table 5 Logistic Analysis of Risk Factors for ACRN (Logistic Analysis)

VariableUni-variate analysisMulti-variate analysis
p-valueOR (95% CI)p-valueAdjusted OR (95% CI)
Male sex0.9801.017 (0.262–3.949)0.7301.298 (0.295–5.717)
Age0.8630.996 (0.955–1.039)0.8691.004 (0.960–1.049)
Accompanying PSC0.2044.576 (0.439–47.716)
Disease extension (excluded E1)
E2, Left sided1.0 (Ref.)
E3, Pancolitis0.0822.906 (0.875–9.656)
Medication
5-ASA0.8741.187 (0.143–9.843)
Steroid0.3621.899 (0.478–7.545)
Immunomodulator0.2400.287 (0.036–2.302)
Previous diagnosis of dysplasia0.7261.250 (0.358–4.363)
Characteristics of lesion
Sporadic lesion1.0 (Ref.)
Colitis associated lesion0.00211.739 (2.474–55.692)0.00510.516 (2.064–53.577)
Number of polyps0.4410.534 (0.108–2.632)
Size of polyp0.0101.131 (1.029–1.243)0.0861.085 (0.989–1.190)

ACRN, advanced colorectal neoplasia; OR, odds ratio; CI, confidence interval; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid.


Table 6 Risk Factors for ACRN in IBD Patients with Colitis-associated Lesion (n=56; Logistic Analysis)

VariableUni-variate analysis
p-valueOR (95% CI)
Age0.8841.003 (0.958–1.051)
Accompanying PSC0.4842.444 (0.200–29.936)
Disease extension (excluded E1)
E2, Left sided1.0 (Ref.)
E3, Pancolitis0.7771.222 (0.305–4.894)
Medication
5-ASA0.9361.098 (0.114–10.571)
Steroid0.9780.980 (0.221–4.352)
Immunomodulator0.2520.282 (0.032–2.454)
Previous diagnosis of dysplasia0.0259.429 (1.330–66.863)
Number of polyps0.7440.738 (0.119–4.566)
Size of polyp0.1091.080 (0.983–1.187)

ACRN, advanced colorectal neoplasia; IBD, inflammatory bowel disease; OR, odds ratio; CI, confidence interval; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid.


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