Risk of Development of More-advanced Lesions in Patients
With Inflammatory Bowel Diseases and Dysplasia
Q9
Anneline Cremer,
*
Pieter Demetter,
‡Martine De Vos,
§Jean-François Rahier,
kFilip Baert,
¶Tom Moreels,
#Elisabeth Macken,
#Edouard Louis,
**
Liesbeth Ferdinande,
‡‡Caroline Fervaille,
§§Franceska Dedeurwaerdere,
kkNoela Bletard,
¶¶Ann Driessen,
##Gert De Hertogh,
***
Séverine Vermeire,
‡‡‡and
Denis Franchimont,
*
for the Belgian In
flammatory Bowel Disease Research and
Development (BIRD) Group
*Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium;‡Department of Pathology, Erasme University Hospital, Brussels, Belgium;§Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium;kDepartment of
Gastroenterology, University Hospital Mont-Godinne, Yvoir, Belgium;¶Department of Gastroenterology, Academisch Ziekenhuis Delta, Roeselare, Belgium;#Department of Gastroenterology, University Hospital Antwerp, Edegem, Belgium; **Department of Gastroenterology, University Hospital Liège, Liège, Belgium;‡‡Department of Pathology, University Hospital Ghent, Ghent, Belgium;§§Department of Pathology, University Hospital Mont-Godinne, Yvoir, Belgium;kkDepartment of Pathology, Academisch Ziekenhuis Delta, Roeselare, Belgium;¶¶Department of Pathology, University Hospital Liège, Liège, Belgium;##Department of Pathology, University Hospital Antwerp, University Antwerp, Edegem, Belgium; ***Department of Pathology, University Hospital Leuven, Leuven, Belgium; and‡‡‡Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium
BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBD) have increased risks of dysplasia and colitis-associated cancer (CAC). We evaluated the risk of development of high-grade dysplasia (HGD) or CAC after diagnosis of dysplasia using data from a national cohort of patients with IBD.
METHODS: We performed a multicenter retrospective analysis of data collected from 7 tertiary referral regional or academic centers in Belgium. In searches of IBD pathology databases, we identified 813 lesions (616 low-grade dysplasias [LGDs], 64 high-grade dysplasias [HGDs], and 133 CACs) in 410 patients with IBD: 299 had dysplasia (73%) and 111 had CAC (27%). The primary aim was to determine the risk of more-advanced lesions after diagnosis of LGD or HGD.
RESULTS: Of the 287 patients with LGD, 21 (7%) developed more-advanced lesions (HGD or CAC) after a me-dian time period of 86 months (interquartile range, 34–214). Of the 28 patients with HGD, 4 (14%) developed CAC after a median time period of 180 months (interquartile range, 23–444). The overall cumulative incidence of CAC at 10 years after an initial diagnosis of HGD was 24.3% and after an initial diagnosis of LGD was 8.5% (P < .05). Metachronous lesions, non-polypoid lesions, and colonic stricture were associated with risk of occurrence of more-advanced lesions after LGD (P < .05). Of the 630 dysplastic lesions identified during endoscopy, 545 (86%) were removed during the same procedure or during a follow-up endoscopy or by surgery. Of 111 patients with CAC, 95 (86%) did not have prior detection of dysplasia and 64 of these 95 patients (67%) developed CAC outside of the screening or surveillance period recommended by the European Crohn’s and Colitis Organisation.
CONCLUSIONS: In an analysis of pathology data from 7 medical centers in Belgium, we found a low rate of detection of more-advanced lesions following detection of LGD or HGD—taking into account that most of the lesions were removed. Main risk factors for development of more-advanced lesions after LGD were metachronous lesions, non-polypoid lesions, and colon strictures. Keywords: Colorectal Cancer; CRC; Endoscopy Resection; Crohn’s Disease; Ulcerative Colitis.
Abbreviations used in this paper: CAC, colitis-associated colorectal cancer; CD, Crohn’s disease; CE, chromoendoscopy; CI, confidence in-terval; CRC, colorectal cancer; ECCO, European Crohn’s and Colitis Organisation; HGD, high-grade dysplasia; IBD, inflammatory bowel dis-ease; IQR, interquartile range; LGD, low-grade dysplasia; PSC, primary sclerosing cholangitis; RR, relative risk; SE, standard error; UC, ulcerative colitis.
© 2019 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2019.05.062 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116
P
atients with inflammatory bowel disease (IBD)(Crohn’s disease [CD] and ulcerative colitis [UC]) are at increased risk of colorectal cancer (CRC), namely colitis-associated colorectal cancer (CAC).1,2 Carcinogenesis in IBD follows the inflammation-dysplasia-cancer sequence from inflammation to indefinite, low-grade dysplasia (LGD), high-grade dysplasia (HGD), with some progressing to cancer.3Screening/surveillance colonoscopy is therefore recommended to detect and treat dysplasia.Recent meta-analysis reported a 2-fold risk of devel-oping CAC compared with the general population.4 The pivotal role of inflammation is supported by disease dura-tion, extent, and activity (both endoscopically and histo-logically) as main risk factors for developing CAC.1,5,6 Primary sclerosing cholangitis (PSC),7 family history of CRC,8 post-inflammatory polyps,9 and dysplasia at colo-noscopy surveillance represent additional risks factors.
A few recent studies suggest decreasing incidence and mortality rates of CAC that may be related to improved IBD patient management, increased adherence to screening/surveillance recommendations, and enhanced quality criteria in performing colonoscopy and detecting/removing lesions.10CAC originates from either flat (endoscopically invisible) or raised (visible) dysplastic lesions as precursor lesions.11 Detection of dysplasia relies on both pathologic examination from random biopsies to identify invisible dysplasia and from targeted biopsies of visible (polypoid and non-polypoid) lesions. With the improvement of endoscopic techniques, most dysplastic lesions discovered in IBD patients are reported to be visible.12
The reported risk of CAC associated with HGD or LGD varies greatly between studies.13–16 Few studies have looked at the long-term outcome of endoscopically visible lesions removed by endoscopy. In nearly all studies, the treatment status is not even reported, and this might partly explain the different rates and risks of progression of dysplasia to more advanced lesion across these studies. Moreover, the term progression used in all studies is somewhat confusing when visible resectable lesions are for the most part removed as recommended in the management of dysplasia in IBD.
The aim of the study was to evaluate the risk of devel-opment of more advanced lesions after diagnosis of LGD or HGD in a large cohort of IBD patients with dysplasia.
Methods
This large national cohort study is a long-term follow-up retrospective study conducted across 7 Belgian tertiary centers within the Belgian Inflammatory Bowel Disease Research and Development Group. Pa-tients with histologically confirmed IBD who were diagnosed with at least 1 episode of dysplasia and/or CAC between January 1, 1990 and December 31, 2016 were retrospectively identified through IBD and pa-thology databases after Ethics Committee agreement
(reference number: P2013/331 approved February 25, 2014). Endoscopic, histologic, and clinical data were collected by electronic chart review. All authors had access to the study data and had reviewed and approved thefinal manuscript. Advanced neoplasia was defined as HGD or CAC and did not refer to the size, number, and villous content of the neoplasia. Patients were classified according to the most advanced lesion that the patients developed during colonoscopy or at surgery performed during their follow-up (Supplementary Materials).
Characterization of the
Dysplastic/Colitis-associated Colorectal Cancer Lesions
Each episode of dysplasia was graded according to the 1983 Inflammatory Bowel Disease Dysplasia Morphology Study group classification in LGD or HGD.17
Lesions indefinite for dysplasia were excluded. Because of poor interobserver agreement in grading dysplasia among pathologists,18 central review has been done by an independent expert IBD pathologist (P.D.). Lesions were categorized according to their macroscopic shape reported on endoscopy report. The Paris19or SCENIC20 classifications could not always be applied because of incomplete endoscopy reports. Therefore, lesions were defined as follows: Visible lesions include polypoid le-sions (Paris type 0-I lele-sions) and non-polypoid lele-sions (Paris type 0-II, 0-III, irregular, or plate-like lesions); invisible lesions were defined as absence of documented
What You Need to Know
Background
Patients with inflammatory bowel diseases (IBD) have increased risks of dysplasia and colitis-associated cancer (CAC). We evaluated the risk of development of high-grade dysplasia (HGD) or CAC after diagnosis of dysplasia using data from a na-tional cohort of patients with IBD.
Findings
In an analysis of pathology data from 7 medical centers, we found a low rate of detection of more advanced lesions following detection of LGD or HGD—taking into account that most of the lesions were removed. Main risk factors for development of more advanced lesions after LGD were metachronous lesions, non-polypoid lesions, and colon strictures.
Implications for patient care
Description of long-term outcome of endoscopically visible lesions removed by endoscopy or surgery and identification of risk factors for development of more advanced lesions could help increase awareness and adherence of clinicians to international guidelines in screening or surveillance endoscopy programs and in detection or treatment modalities of dysplasia. 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232
endoscopic abnormalities. Outside diseased area lesions, duplicates, misdiagnosed lesions, and recurrence were defined in Supplementary Materials. Screening/surveil-lance periods, namely the starting time of screening after IBD diagnosis and the interval of endoscopic surveil-lance, were defined according to European Crohn’s and Colitis Organisation (ECCO) guidelines.21 Patients were stratified as high, intermediate, or low risk according to those recommendations. Lesions were diagnosed outside screening/surveillance period when diagnosed before screening period or out of screening/surveillance period. Lesions were diagnosed out of screening/surveillance period when screening colonoscopy was not performed on time or when intervals between surveillance colo-noscopies were too long according to the risk strati fica-tion profile (Supplementary Materials). The term development was used on purpose in this study rather than “progression” used in all studies. In this study, development of more advanced lesion can be either a newly developed lesion or a recurrence when the index lesion has been removed, and progression to more advanced lesion was used when index lesion has been left untreated. Therefore, resected and unresected le-sions are considered for data analyses.
Statistical Analysis
Data were analyzed using MedCalc Statistical Soft-ware (version 18.5; MedCalc SoftSoft-ware bvba, Ostend, Belgium). Continuous variables were reported as
medians with interquartile ranges (IQRs) or ranges (minimum-maximum). Comparisons of continuous vari-ables were performed by using Mann-Whitney or Kruskal-Wallis test. Categorical variables were reported as numbers (n) and proportions (%). Comparisons of categorical variables were performed by using Fisher exact test or Pearsonc2test for trend. Results of logistic regression were expressed in odds ratios with 95% confidence intervals (CIs). Rates of development of more advanced lesion were analyzed using Kaplan–Meier survival analysis. Comparison of incidences was per-formed by using log-rank test. Results of Cox propor-tional hazards regression were expressed in Exp(b) and 95% CI for Exp(b). Exp(b) can be interpreted as the instantaneous relative risk (RR) of an event, at any time, for an individual. A P value<.05 was considered statis-tically significant.
Results
Study Population
A total of 549 IBD patients were diagnosed with LGD, HGD, or CAC between January 1, 1990 and December 31, 2016 (Figure 1). After exclusion of some patients and lesions (Supplementary Materials), patients were grouped according to the location of lesions within or outside diseased area. Finally, 410 IBD patients with 813 lesions inside diseased area from 645 procedures were included in the study.
Figure 1. CAC, colitis-associated colorectal can-cer; HGD, high-grade dysplasia; IBD, in flamma-tory bowel disease; LGD, low-grade dysplasia. Q5 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348
Patient Characteristics
Demographics and clinical variables of the study population are summarized in Table 1. Among UC pa-tients, 5 (2%) had proctitis, 68 (27%) had left-side co-litis, and 175 (71%) had pancolitis. As of December 31, 2016, 266 patients (65%) were still under follow-up (median, 70 months; IQR, 35–122), 60 patients (15%) died (median, 36 months; IQR, 6–85) (CAC [n ¼ 32] and non-CAC [(n ¼ 28] related mortality), and 84 patients (20%) were lost to follow-up (median, 40 months; IQR, 11–90). Of the 410 patients, 299 (73%) had only dysplasia (266 LGDs and 33 HGDs), whereas 111 (27%) had CAC during their follow-up. When comparing pa-tients with CAC with those with dysplasia (LGD and HGD), median age at IBD diagnosis was lower (29 [IQR, 22–49] vs 41 (IQR, 28–54) years; P ¼ .0001), and median
IBD disease duration at time of detection of index lesion was longer (19 [IQR, 10–28] vs 10 (IQR, 2–19] years; P < .0001). There were more metachronous (39% vs 29%; P ¼ .036) and multifocal synchronous lesions (38% vs 24%; P¼ .004) among patients with advanced neoplasia (HGD or CAC) compared with those with LGD.
Lesion Characteristics
Characteristics of the 813 dysplasia/CAC lesions are summarized inTable 2. Six hundred sixteen lesions were LGDs, 64 HGDs, and 133 CACs. Most of the lesions were endoscopically visible lesions (92%) that include polypoid (64%) and non-polypoid (36%) lesions. LGD lesions were more likely to be invisible than advanced neoplasia lesions (57/616, 9% vs 6/197, 3%; P¼ .003). Advanced neoplasia lesions were more likely to be
Table 1. Demographics and Clinical Variables for Patients With Dysplasia/Neoplasia (Most Advanced Grade) (n¼ Number of Patients) Variable Study population (n¼ 410) LGD (n¼ 266) HGD (n¼ 33) CAC (111) P valuea Type of IBD, n (%) NS - CD 162 (39) 99 (37) 9 (27) 54 (49) - UC 248 (61) 167 (63) 24 (73) 57 (51) Male, n (%) 248 (60) 158 (59) 23 (70) 67 (60) NS
Age (y) at IBD diagnosis, median (IQR) 37 (26–53) (n¼ 394) 41 (29–53) (n¼ 258) 40 (26–61) (n¼ 27) 29 (22–49) (n¼ 109) <.01 Follow-up duration (y) after IBD diagnosis,
median (IQR) 19 (10–29) (n¼ 396) 16 (9–26) (n¼ 260) 16 (10–27) (n¼ 27) 25 (16–33) (n¼ 109) <.01 Deceased, n (%) 60 (15) 20 (8) 4 (12) 36 (32) <.01 Smoking status, n (%) NS - Active 36 (9) 24 (9) 1 (3) 11 (10) - Stopped 88 (21) 57 (21) 7 (21) 24 (22) - No 139 (34) 90 (34) 12 (36.5) 37 (33) - Unknown 147 (36) 95 (36) 13 (39.5) 39 (35)
Age (y) at diagnosis of index lesion, median (IQR) 55 (45–65) (n¼ 408) 54 (46–65) (n¼ 264) 61 (40–72) (n¼ 33) 55 (45–62) (n¼ 111) NS Duration (y) of IBD at diagnosis of index lesion,
median (IQR) 13 (4–22) (n¼ 396) 10 (2–19) (n¼ 260) 10 (2–20) (n¼ 27) 19 (10–28) (n¼ 109) <.01 Follow-up duration (mo) after diagnosis of index
lesion, median (IQR)
60 (24–105) (n¼ 410) 56 (24–105) (n¼ 266) 77 (46–119) (n¼ 33) 53 (20–93) (n¼ 111) NS No. of neoplastic lesions per patient during
follow-up, median (IQR; range)
1 (1–2; 1–12) (n¼ 410) 1 (1–2; 1–12) (n¼ 266) 2 (1–5; 1–10) (n¼ 33) 1 (1–3; 1–11) (n¼ 111) <.01 No. of neoplastic lesions diagnosis procedures
per patient during follow-up, median (IQR; range) 1 (1–2; 1–9) (n¼ 410) 1 (1–1; 1–6) (n¼ 266) 2 (1–4; 1–9) (n¼ 33) 1 (1–2; 1–5) (n¼ 111) <.01 Metachronous lesions, n (%) 132 (32) (n¼ 410) 76 (29) (n¼ 266) 19 (58) (n¼ 33) 37 (33) (n¼ 111) <.01 Multifocal lesions, n (%) 117 (29) (n¼ 410) 63 (24) (n¼ 266) 18 (55) (n¼ 33) 36 (32) (n¼ 111) <.01 Family history of CRC, n (%) 36 (9) 28 (11) 1 (3) 7 (6) NS - First degree - 15 - 13 - 0 - 2 - Other degree - 20 - 14 - 1 - 5 - Unknown - 1 (n¼ 410) - 1 (n¼ 266) - 0 (n¼ 33) - 0 (n¼ 111) Associated PSC, n (%) 39 (10) (n¼ 410) 20 (8) (n¼ 266) 5 (15) (n¼ 33) 14 (13) (n¼ 111) NS
CAC, colitis-associated colorectal cancer; CD, Crohn’s disease; CRC, colorectal cancer; HGD, high-grade dysplasia; IBD, inflammatory bowel disease; IQR, interquartile range; LGD, low-grade dysplasia; PSC, primary sclerosing cholangitis; UC, ulcerative colitis.
a
P value for two-sidedc2
test or Kruskal-Wallis test. Bold values are significant.
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non-polypoid (151/191, 79% vs 121/559, 22%; P < .0001) and 1 cm than LGD lesions (117/127, 92% vs 118/422, 28%; P< .0001) (Supplementary Materialsfor risk factors associated with CAC.)
Diagnosis of Dysplasia and Colitis-associated
Colorectal Cancer
Fourteen patients (3%) had their first lesion diag-nosed before IBD diagnosis, 27 (7%) at IBD diagnosis, 111 (27%) before 8 years of disease, and 22 (5%) be-tween 8 and 10 years of disease. In total, 37% and 42% of the patients had their first lesion diagnosed before 8 and 10 years of disease, respectively. Seventy-six CACs (57%) were diagnosed during colonoscopy and 57 (43%) at surgery. Four CACs (3%) were diagnosed before IBD diagnosis, 4 (3%) at IBD diagnosis, 8 (6%) before screening period, 59 (44%) during screening/ surveillance period, and 58 (44%) out of screening/ surveillance period according to ECCO recommendations. Seventeen percent and 21% of the patients had their CAC diagnosed before 8 and 10 years of disease, respectively (Supplementary Materials for more details about diag-nostic circumstances of dysplasia and CAC).
Treatment of Dysplasia and Colitis-associated
Colorectal Cancer
Among the 630 dysplastic lesions reported during endoscopy, the majority were removed at the time of the endoscopy detection (436/630, 69%) or at a second follow-up procedure (endoscopy or surgery) (109/630,
17%), whereas only a minority were left untreated (61/ 630, 10%) or had an unknown treatment status (24/630, 4%) (Supplementary Materialsfor more details). Median duration between diagnostic and second procedure was significantly longer for LGD lesions compared with HGD lesions (103 [IQR, 58–240] vs 48 days (IQR, 40–123); P¼ .0039). Concerning the 76 CACs that were diagnosed during colonoscopy, 59 (78%) had surgery secondarily after a median duration of 35 days (IQR, 21–105).
Rate of Development to More Advanced
Lesions
Two hundred eighty-seven patients were initially diagnosed with LGD, 28 with HGD, and 95 with CAC. Table 3andFigure 2show the most advanced lesion that the patients developed during colonoscopies or at sur-gery performed during follow-up after the index lesion was diagnosed, according to the grade of this lesion. Twenty-one of 287 patients (7%) who were initially diagnosed with LGD developed more advanced lesions (9 HGDs and 12 CACs) after a median time of 86 months (IQR, 34–214) (137 [IQR, 40–232] for CAC vs 43 [IQR, 12–118] for HGD; P ¼ .0466), whereas 202 of 287 (71%) did not develop any further lesion. Four of 28 patients (14%) who were initially diagnosed with HGD developed CAC after a median time of 180 months (IQR, 23–444), whereas 15 of 2 (54%) did not develop any furtherQ4
lesion (Supplementary Materials for more details). Sixteen patients (14%) (12 with prior LGD, 4 with prior HGD) developed CAC secondarily after a median follow-up of 137 months (IQR, 39–260), whereas 95 (86%) were diagnosed with CAC without evidence of prior Table 2. Lesion Characteristics (N¼ Number of Lesions)
Variable Study population (n¼ 813) LGD (n¼ 616) HGD (n¼ 64) CAC (n¼ 133) P valuea Macroscopic shape <.01 - Visible 750 (92%) 559 (91%) 58 (91%) 133 (100%) - Invisible 63 (8%) 57 (9%) 6 (9%) 0 (0%)
For visible lesions <.01
- Polypoid 478 (64%) 438 (78%) 29 (50%) 11 (8%)
- Non-polypoid 272 (36%) 121 (22%) 29 (50%) 122 (92%)
Size of the lesion <.01
-<1 cm 235 (31%) 118 (21%) 25 (43%) 92 (69%) -1 cm 314 (42%) 304 (54%) 9 (16%) 1 (1%) - Unknown 201 (27%) 137 (25%) 24 (41%) 40 (30%) Diagnosis circumstances <.01 - Colonoscopy 706 (87%) 576 (94%) 54 (84%) 76 (57%) - Surgery 107 (13%) 40 (6%) 10 (16%) 57 (43%)
Treatment status of lesions diagnosed during endoscopy
<.01
- During the same procedure 443 (63%) 410 (71%) 26 (48%) 7 (9%)
- During a second procedure 168 (24%) 89 (15%) 20 (37%) 59 (78%)
- No treatment 71 (10%) 55 (10%) 6 (11%) 10 (13%)
- Unknown 24 (3%) 22 (4%) 2 (4%) 0 (0%)
CAC, colitis-associated colorectal cancer; HGD, high-grade dysplasia; LGD, low-grade dysplasia. a
P value for two-sidedc2
test. Bold values are significant.
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detected dysplasia. Sixty-seven percent of the patients diagnosed with CAC without prior detected dysplasia were diagnosed outside screening/surveillance period. Details are described in Supplementary Materials. Whereas 25 of 315 patients (8%) with LGD or HGD as index lesion developed more advanced lesion, 290 of 315 patients (92%) with LGD or HGD did not develop more advanced lesion (Supplementary Materialsfor more de-tails about completeness of follow-up).
Overall cumulative incidence of HGD or CAC devel-opment at 1 and 10 years after initial LGD diagnosis was 2.3% (standard error [SE], 1%) and 13.8% (SE, 3.2%), respectively (Figure 3A). Rate of development of CAC was higher after HGD compared with LGD (P ¼ .0364) (Figure 3B), with an overall cumulative incidence of CAC development at 1 and 10 years after LGD diagnosis of 0.5% (SE, 0.5%) and 8.5% (SE, 2.7%), respectively, whereas at 1 and 10 years after HGD diagnosis it was 9.1% (SE, 6.2%) and 24.3% (SE, 14.8%), respectively.
Risk Factors Associated With the Development
of More Advanced Lesions
In univariate analysis, metachronous lesions (P¼ .0003), multifocal lesions (P ¼ .0014), non-polypoid
lesions (P< .0001), associated PSC (P ¼ .0032), invisible lesions (P ¼ .0048), and colonic stricture (P < .0001) were associated with the risk of development of more advanced lesions. In multivariate analysis, metachronous lesions (P ¼ .0119), non-polypoid lesions (P ¼ .0006), and colonic stricture (P ¼ .0496) remained associated with the risk of development of more advanced lesions (Supplementary Table 4) (Supplementary Materials for risk factors associated with the development of CAC after dysplasia).
Discussion
This large national cohort study revealed that the rate of development of more advanced lesions after LGD was low (7%), and only 14% of the patients who were initially diagnosed with HGD developed CAC, considering that nearly all lesions had been removed. Most of the dysplastic lesions diagnosed during endoscopy were treated during the same procedure or at a second follow-up by endoscopy or surgery (86%). Main risk factors for development of more advanced lesion were the presence of metachronous lesions, non-polypoid lesions, and colonic stricture. Advanced neoplasia lesions were more likely to be visible, non-polypoid,1 cm, metachronous, and multifocal synchronous than LGD lesions. Our rate of invisible LGD lesions (9%) is close to the one reported in SCENIC consensus20(9.4% by high definition white light endoscopy and 9.8% by chromoendoscopy [CE]) or in study by Choi et al22(9.3%). Importantly, the majority of IBD patients with CAC (86%) were diagnosed without prior detected dysplasia, mainly because of outside screening/surveillance period for 67% of them.
The SCENIC international consensus statement on surveillance of dysplasia in IBD20recommends complete endoscopic removal of resectable polypoid dysplastic le-sions, followed by surveillance colonoscopy. However, in addition to poor reproducibility of Paris classification23
and no validation in IBD, it is not clear that the risk of CAC is the same for visible and invisible dysplastic lesions and for polypoid and non-polypoid dysplastic lesions. Very few studies have looked at long-term outcome of visible lesions removed by endoscopy because there are limited follow-up data especially for non-polypoid lesion resected by endoscopic submucosal dissection.24In many studies, treatment status is not even reported, and this might partly explain the different incidence rates for more advanced lesions across these studies in which CAC inci-dence was between 2% and 13% after a mean follow-up period of 36–82 months.13–15 In our study, overall
cu-mulative incidence of HGD or CAC development at 1 year after initial LGD diagnosis was 1.9%, which is much lower than the incidence of 10.9% at 1 year previously re-ported.22This difference can be explained by the fact that we excluded all misdiagnosed lesions. Indeed, median time to progression varied from 10.5 to 13 months,22 depending on whether LGD lesions on biopsies from Table 3. Findings on Follow-up Colonoscopies and Surgery
Based on Index Lesion (Number of Patients)
Index lesion
Most advanced follow-up lesion No dysplasia
or CAC LGD HGD CAC Total
LGD 202 (71%) 64 (22%) 9 (3%) 12 (4%) 287 HGD 15 (54%) 7 (25%) 2 (7%) 4 (14%) 28 CAC 77 (81%) 5 (5%) 3 (3%) 10 (11%) 95
Total 294 76 14 26 410
CAC, colitis-associated colorectal cancer; HGD, high-grade dysplasia; LGD, low-grade dysplasia.
Figure 2. CAC, colitis-associated colorectal cancer; HGD, high-grade dysplasia; LGD, low-grade dysplasia.
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colonoscopy progressed to CAC or HGD. This short time of progression suggests more hidden or missed HGD or CAC at the time of colonoscopy than real progression from LGD lesions. Such lesions were reported in our study directly as HGD or CAC diagnosed at surgery performed for preex-isting dysplasia (even if LGD) on biopsies from colonos-copy. Also, those patients were considered to be diagnosed with HGD or CAC without evidence of prior dysplasia because this is the same lesion (misdiagnosed lesion); indeed, the time between colonoscopy and surgery is very short (median, 57 days). This may explain why 86% of the patients with CAC were diagnosed without evidence of prior dysplasia, whereas 14% developed CAC secondarily after a median follow-up of 137 months. Our results are therefore more in concordance with those reported in 2 meta-analyses.4,16Thus, patients with IBD have a low risk of development of more advanced lesions after resection of dysplastic lesions.
Although many studies have examined risk factors associated with CAC, very few have examined risk factors associated with the risk of development of more advanced lesion after diagnosis of dysplasia. We have
shown that in IBD patients, non-polypoid lesions are the most important risk factor of development of CAC with a RR of 15, which is consistent with another study.22They reported that dysplastic lesions that are non-polypoid, endoscopically invisible, 1 cm, or preceded by indefi-nite dysplasia were associated with increased risk of progression to advanced lesion. Previous studies have shown that patients with polypoid LGD lesions have a low risk of development of CAC.25 PSC was also an important risk factor (3.4-fold increase) in our study to the same extent as in the meta-analysis by Fumery et al,4 where invisible dysplasia and multifocal dysplasia were also significantly associated with progression to advanced lesion.
Dysplasia is a reliable marker for the risk of devel-oping or having CAC. Indeed, when indication of surgery was HGD, 42% of the patients had CAC in their surgical specimen. For those who had colectomy for LGD, more advanced lesions were found in 23% of cases (CAC in 19% of cases). This is a little lower than the percentages reported by Choi et al22(46% and 39%, respectively). In the meta-analysis by Fumery et al,430% of the patients who underwent colectomy for LGD had more advanced lesions. Yet, CAC can develop in patients without history of dysplasia or from invisible dysplastic lesions. Also, not all patients with LGD may pass through a phase of detectable HGD before developing CAC.26 In this cohort, 86% of patients were diagnosed with CAC without prior detected dysplasia. This can be easily explained with 67% of them diagnosed outside screening/surveillance period; dysplasia had therefore not been previously re-ported in these patients. Previous colonoscopies may have been false negative in patients diagnosed with CAC inside screening/surveillance period because of subop-timal conditions (eg, inflammation, low rate of CE/ random biopsies performed, and poor colonic prepara-tion). Low quality endoscopy measures may likely play a role and are difficult to evaluate because of the retro-spective design of the study. Nevertheless, only 57% of CACs were diagnosed during colonoscopy. When CAC was diagnosed at surgery, surgery was initially per-formed for detected preexisting neoplasia in only 56% of the cases. Thus, low rate of detected preexisting neoplasia heralds the need for improved training in the detection of dysplastic lesions.
Most cases of CACs are believed to arise from dysplasia. Endoscopic screening/surveillance guidelines have been developed to enable the detection and po-tential removal of precancerous lesions. This strategy aims at decreasing the incidence of CAC and related mortality.27 However, we and others have shown that CACs are most often detected outside screening/sur-veillance period: at IBD diagnosis, before or out of screening/surveillance period. In a princeps study,28 only 25 of 149 patients (17%) were diagnosed with CAC during screening/surveillance period, and 22% developed CAC before 8 or 15 years of surveillance for pancolitis and left-side colitis, respectively. Eleven Figure 3. CAC, colitis-associated colorectal cancer; HGD,
high-grade dysplasia; LGD, low-grade dysplasia. 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812
percent of CACs were diagnosed before screening period and 17% before 8 years of disease in our cohort. Today, several guidelines recommend starting surveillance after 8–10 years of first symptoms.21,26
In the CESAME cohort,29colonoscopy surveillance rate was surprisingly low in IBD patients with longstanding extensive colitis, with only 54% of the patients who had at least 1 sur-veillance colonoscopy during the study period. Thus, the high rate of CACs outside screening/surveillance period in all the studies might be explained by poor adherence in routine practice to screening/surveillance programs according to recommendations.
This study has several limitations. This is a retro-spective study. We may underestimate the risk of development of more advanced lesions because of high number of CACs diagnosed without evidence of prior dysplasia and outside screening/surveillance period. This means that we can assume that if they had had proper surveillance, it is possible that dysplastic lesions would have been identified before the CAC diagnosis. The consensus statement by Rutter et al30 could help to better define diagnostic circumstances of neoplastic le-sions to limit the occurrence of interval lele-sions in the future management of dysplastic lesions in IBD.
In conclusion, the rate of development of more advanced lesion after LGD is low in patients in whom the majority of the lesions have been routinely removed. This reassuring real-life data must be balanced with the high rate of patients diagnosed with CAC without detected preexisting dysplasia. This heralds the need for improved training in the detection of dysplastic lesions, together with increased awareness of colon cancer screening and surveillance in IBD patients.
Supplementary Material
Note: To access the supplementary material accom-panying this article, visit the online version of Clinical Gastroenterology and Hepatology atwww.cghjournal.org, and athttps://doi.org/10.1016/j.cgh.2019.05.062.
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dis-ease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data. Int J Cancer 2014;134:189–196.
6. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year anal-ysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030–1038. 7. Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of
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8. Askling J, Dickman PW, Karlén P, et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 2001;120:1356–1362.
9. Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveil-lance in longstanding ulcerative colitis: endoscopic appear-ances help predict cancer risk. Gut 2004;53:1813–1816. 10. Ananthakrishnan AN, Cagan A, Cai T, et al. Colonoscopy is
associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2015;13:322–329.
11. Reynolds IS, O’Toole A, Deasy J, et al. A meta-analysis of the clinicopathological characteristics and survival outcomes of in-flammatory bowel disease associated colorectal cancer. Int J Colorectal Dis 2017;32:443–451.
12. Rutter MD, Saunders BP, Wilkinson KH, et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointest Endosc 2004;60:334–339.
13. Odze RD, Farraye FA, Hecht JL, et al. Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis. Clin Gastroenterol Hepatol 2004;2:534–541. 14. Kisiel JB, Loftus EV, Harmsen WS, et al. Outcome of sporadic
adenomas and adenoma-like dysplasia in patients with ulcera-tive colitis undergoing polypectomy. Inflamm Bowel Dis 2012; 18:226–235.
15. Navaneethan U, Jegadeesan R, Gutierrez NG, et al. Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis pa-tients with extensive colitis under colonoscopic surveillance. J Crohns Colitis 2013;7:e684–e691.
16. Wanders LK, Dekker E, Pullens B, et al. Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis. Clin Gastroenterol Hepatol 2014;12:756–764.
17. Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in in-flammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983; 14:931–968.
18. Eaden J, Abrams K, McKay H, et al. Inter-observer variation be-tween general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. J Pathol 2001;194:152–157. 19. Lambert R, Lightdale CJ. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon—Paris, France November 30 to December 1, 2002: foreword. Gastrointest Endosc 2003;58(Suppl):S3–S43. 20. Laine L, Kaltenbach T, Barkun A, et al. SCENIC international
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26. Farraye FA, Odze RD, Eaden J, et al. AGA medical position state-ment on the diagnosis and managestate-ment of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010;138:738–745. 27. Derikx LAAP, Nissen LHC, Smits LJT, et al. Risk of neoplasia after colectomy in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hep-atol 2016;14:798–806.e20.
28. Lutgens MWMD, Vleggaar FP, Schipper MEI, et al. High fre-quency of early colorectal cancer in inflammatory bowel dis-ease. Gut 2008;57:1246–1251.
29. Vienne A, Simon T, Cosnes J, et al. Low prevalence of colo-noscopic surveillance of inflammatory bowel disease patients with longstanding extensive colitis: a clinical practice survey nested in the CESAME cohort. Aliment Pharmacol Ther 2011; 34:188–195.
30. Rutter MD, Beintaris I, Valori R, et al. World Endoscopy Orga-nization consensus statements on colonoscopy and post-imaging colorectal cancer. Gastroenterology 2018; 155:909–925.e3.
Reprint requests Address requests for reprints to: Anneline Cremer, MD, Department of Gastroenterology, Erasme University Hospital, Route de Len-nik 808, 1070 Brussells, Belgium. e-mail:anneline.cremer@erasme.ulb.ac.be;
fax:þ 32-2-5554697. Q1
Conflictsof interest Q2
The authors disclose no conflicts.
Funding Q3
Supported by the Fonds Erasme for Medical Research (doctoral research
fellow grant [A.C.]). Q8
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Supplementary Materials
Methods
The Pathology database was established by using the International Classification of Diseases 9th revision code for the identification of IBD patients and neoplastic le-sions, with additional chart review performed to confirm IBD diagnosis. We optimized case retrieval by double cross-check through hand chart review using IBD regis-tries. Patients with not enough information about their IBD and/or dysplastic/CAC lesion were excluded as well as those whose lesion(s) did not show dysplasia or CAC after central review by an independent expert IBD pathologist (P.D.). Patients’ demographics, IBD pheno-typic characteristics, and data regarding IBD-related therapies were collected. Information on family history of IBD or CRC was also obtained.
Patients were classified according to the most advanced lesion during colonoscopy or at surgery per-formed at follow-up. The index lesion was thefirst lesion diagnosed in a patient during colonoscopy or surgery. When more than 1 lesion was found during the pro-cedure, we considered the lesion with maximal grade of dysplasia or CAC. The follow-up lesion is the most advanced lesion developed at follow-up procedure (either colonoscopy or surgery) after the index lesion. When more than 1 dysplasia/CAC lesion was found and more than 1 procedure was done during follow-up, the categorization of the follow-up lesion was based on the maximal grade of dysplasia or CAC. If no lesion was detected during follow-up, the follow-up lesion is re-ported as no dysplasia/CAC. Patients were considered to have multifocal neoplastic lesions when they had more than 1 lesion during the same procedure. They were considered to have metachronous neoplastic lesions when they had more than 1 episode of neoplasia in minimum 2 procedures during their follow-up.
Patients were considered lost to follow-up if in December 2016 they had not been seen at their IBD center for more than 1 year.
Patients were considered to have family history of CRC if he/she had either first-, second-, or third-degree relatives who had CRC at any age.
Patients were considered to have associated PSC only if the diagnosis was confirmed radiologically and/or histologically.
Characterization of the dysplastic/colitis-associated colorectal cancer lesions. Only lesions with available pathologic report after surgery or colonoscopy were taken into account. Lesions outside diseased area and lesions where dysplasia or CAC was not confirmed at review were excluded. A diseased area was defined as a colonic area that is histologically and/or endoscopically affected at least once in the follow-up of the patient. Lesions outside diseased area were therefore lesions located in a part of the colon that has not been histologically (even without apparent endoscopic
involvement) and/or endoscopically involved. Dupli-cates, defined as lesions being found either in the same procedure on different slides (same lesions in same procedure) or in another procedure that follows the diagnostic procedure if the lesions have not been treated or treated incompletely (same lesions in different pro-cedures), were also excluded. In the same way were excluded misdiagnosed lesions (same lesions in different procedures with a different grade of neoplasia), defined as lesions being found in another procedure that follows the diagnostic procedure if the lesions have not been treated or treated incompletely and have a different grade of neoplasia. Lesions affecting the small intestine were excluded. Recurrence, defined as a lesion occurring in the same diseased area as a lesion previously diag-nosed and treated, was considered as a new lesion and not as a duplicate in the follow-up of the patient.
Data concerning the diagnostic circumstances (colo-noscopy or surgery) and the indication of the diagnostic procedure (eg, surveillance colonoscopy or colonoscopy for therapeutic management) as well as the treatment of the lesion either at initial diagnosis procedure or during a following procedure and the follow-up of untreated lesions were collected. The treatment was defined as unknown when it was not specified in the endoscopy report whether the lesion was resected or not. Infor-mation about location of the lesions within or outside a diseased area (active or quiescent) and extension of the disease (Montreal classification) was also collected. Data on the presence or absence of a documented episode of colonic stricture or post-inflammatory polyp were collected.
ECCO guidelines1,2 were retrospectively applied to our study population to be able to categorize neoplastic lesions as diagnosed before, during, or out of screening/ surveillance period. According to ECCO guidelines, screening colonoscopy should be offered 8 years after the onset of colitis symptoms to all patients (UC and Crohn’s colitis) to reassess disease extent and exclude dysplasia. Patients were stratified as high, intermediate, or low risk for surveillance interval according to those guidelines. Ongoing surveillance should be performed in all patients apart from those with proctitis or Crohn’s colitis involving only 1 segment of colorectum. Patients with high risk features (stricture or dysplasia detected within the past 5 years, PSC, extensive colitis with severe active inflammation, or a family history of CRC in a first-degree relative when younger than 50 years) should have next surveillance colonoscopy scheduled for 1 year. In patients with concurrent PSC, annual surveillance colonoscopy should be performed after the diagnosis of PSC, irrespective of disease activity, extent, and duration. Patients with intermediate risk factors should have their next surveillance colonoscopy scheduled for 2–3 years. Intermediate risk factors include extensive colitis with mild or moderate active inflammation, post-inflammatory polyps, or a family history of CRC in a first-degree relative at 50 years and older. Patients with 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160
neither intermediate nor high risk features should have their next surveillance colonoscopy scheduled for 5 years.
Nevertheless, because of the difficulty of retrospec-tively determining the onset of colitis symptoms in all patients, it was the disease diagnosis rather than the onset of symptoms that was considered to define the screening period, namely the starting time of screening after disease diagnosis.
Lesions were diagnosed out of screening/surveillance period when screening colonoscopy was not performed on time (more than 8 years after disease diagnosis) or when intervals between surveillance colonoscopies were too long according to the risk stratification profile (more than 1 year in high risk patients, 3 years in intermediate risk patients, and 5 years in low risk patients). Lesions were diagnosed outside screening/surveillance period when diagnosed before screening period (before 8 years after the disease diagnosis) or out of screening/surveil-lance period.
Results
Study population. Eight patients were excluded for the following reasons: no neoplasia after pathology re-view (n ¼ 6), no IBD (n ¼ 1), and lack of clinical infor-mation (n¼ 1). Among the 541 remaining patients, 1443 lesions were identified. Two hundred sixty lesions were excluded for the following reasons: no neoplasia after pathology review (n ¼ 21), same lesion in same pro-cedure (n ¼ 36), same lesion in different procedures (n ¼ 142), ileal location of the lesion (n ¼ 7), lack of clinical/pathologic information (n ¼ 14), and mis-diagnosed lesion (n ¼ 40).
Risk factors associated with colitis-associated colorectal cancer. In univariate analysis performed by lo-gistic regression, CD, younger age at IBD diagnosis, and longer follow-up duration after IBD diagnosis were signif-icantly associated with the risk of developing a CAC, whereas in multivariate analysis, younger age at IBD diag-nosis and longer follow-up duration after IBD diagdiag-nosis remained statistically significant (Supplementary Table 1). Diagnosis of dysplasia and colitis-associated colorectal cancer. Ninety-four percent of LGDs were diagnosed during colonoscopy performed for IBD diagnosis in 6% of the cases, therapeutic management in 19% of the cases, screening in 11% of the cases, and surveillance in 64% of the cases. Eighty-four percent of HGDs were diagnosed during colonoscopy performed for IBD diag-nosis in 7% of the cases, therapeutic management in 32% of the cases, screening in 9% of the cases, and surveillance in 52% of the cases. Fifty-seven percent of CACs were diagnosed during colonoscopy performed for IBD diagnosis in 2% of the cases, therapeutic manage-ment in 54% of the cases, screening in 5% of the cases, and surveillance in 39% of the cases.
Chromoendoscopy was performed in 15% of the pa-tients, and 32 random biopsies were performed in less
than 1% of the patients. Method of resection as well as completeness of resection was specified in less than 50% of the endoscopy reports. For this reason, it was assumed that in case of resection and in the absence of additional precision, the lesions were completely resected.
Indications for surgeries when colitis-associated colorectal cancer was diagnosed at surgery. Regarding indications for surgery when CAC was diagnosed at surgery, surgery was initially performed for preexisting dysplasia on the biopsies from a colonoscopy in 22 CACs (39%) (13 preexisting HGDs, 9 preexisting LGDs), of which 10 had an associated stricture (5 HGDs and 5 LGDs). Those 22 CACs were diagnosed at surgery per-formed after a median time of 57 days (IQR, 28–86) after colonoscopy and were part of what we considered as misdiagnosed lesions. Ten synchronous CACs (18%) were diagnosed at surgery performed for another CAC diagnosed during colonoscopy. Surgery was performed because of a high clinical suspicion of CAC based on computed tomodensitometry in 7 CACs (12%). The last 18 CACs (33%) were diagnosed at surgery performed for IBD therapeutic management, mostly stricture (8 CACs) but also fistula or intra-abdominal collection (3 CACs), occlusion (3 CACs), refractory disease to medical treat-ment (1 CAC), and presence of a suspicious mass at endoscopy with negative pathology (3 CACs).
Indications for surgeries for the entire study population. Of the study population (n¼ 410), 194 pa-tients (47%) underwent 1 or more colonic surgical in-terventions during follow-up, with a total of 212 surgical interventions. The indications for surgery and the most advanced grade of neoplasia found on surgical specimens for the 194 patients and 212 surgeries are shown in Supplementary Tables 2and3, respectively. Twenty-five percent of the patients diagnosed with dysplasia (n ¼ 78/315; 31 HGDs, 47 LGDs) underwent surgery (partial or total colectomy) for dysplasia as indication. Histologic analysis of their surgical specimen revealed CAC in 22 patients (28%), HGD in 7 (9%), LGD in 25 (32%), and no neoplasia in 24 patients (31%). Overall, when the indi-cation for surgery was HGD, 42% of the patients (13/31) had CAC in their surgical specimen. For those who had surgery for LGD, HGD or CAC was found in 23% of cases (11/47). Indication for surgery was CAC in 63 surgeries, of which histologic analysis showed CAC in 59 specimens (94%), no neoplasia after chemoradiotherapy for rectal CAC in 1 specimen (1.5%), and dysplasia (2 LGDs, 1 HGD) in 3 specimens (4.5%) after CAC endoscopic resection. Sixty IBD patients with no previous dysplasia underwent surgery for therapeutic management (re-fractory disease, stenosis, fistula, collection) but also for high clinical suspicion of CAC based on computed tomodensitometry, and CAC was found on the surgical specimen in 21 patients (35%), whereas dysplasia was found in 16 patients (27%) (15 LGDs, 1 HGD).
Treatment of dysplastic/colitis-associated colorectal cancer lesions. Among the 61 dysplastic lesions left un-treated, 55 were LGD and 6 HGD. Twenty-nine LGDs 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276
were visible lesions (7 polypoid, 22 non-polypoid), whereas 26 were invisible lesions. Five HGDs were visible lesions (2 polypoid, 3 non-polypoid), and 1 was invisible lesion. Among the 24 dysplastic lesions with an unknown treatment status, all were visible lesions, with 17 polypoid (1 HGD, 16 LGD) and 7 non-polypoid lesions (1 HGD, 6 LGD).
Rate of development of more advanced lesions. Among the 25 patients (21 LGDs and 4 HGDs) who developed more advanced lesions during their follow-up, all but 2 were treated previously for their dysplastic lesions. Indeed, only 2 patients had untreated LGD and pro-gressed to HGD. One of the LGDs was a non-polypoid lesion left in place because of limited life expectancy, and the second one was an invisible lesion.
As of December 2016, 15 of the 290 patients who did not develop more advanced neoplasia during their follow-up had total colectomy during follow-follow-up, 49 had no sur-veillance colonoscopy after index lesion diagnosis, and the remaining 226 patients had their last surveillance colo-noscopy after a median follow-up of 55 months (IQR, 25–95). To analyze overall cumulative incidence of HGD and/or CAC development at 1 and 10 years after LGD or HGD diagnosis, patients who had total colectomy during follow-up after index lesion diagnosis and patients who had no surveillance colonoscopy were excluded.
Diagnostic circumstances of the patients diagnosed with high-grade dysplasia without prior detected low-grade dysplasia. Among the 28 patients diagnosed with HGD without prior LGD, 1 was diagnosed 20 months before IBD diagnosis with no colonoscopy performed before; 3 at IBD diagnosis with no colonoscopy per-formed before; 5 before screening colonoscopy after a mean time after IBD diagnosis of 65 months (IQR, 53–86) and with a mean interval to prior colonoscopy of 18 months (IQR, 14–23); 11 during screening or surveil-lance period according to the risk stratification profile (1 year in high risk patients, 3 years in intermediate risk patients, and 5 years in low risk patients) with a mean interval to prior colonoscopy of 18 months (IQR, 14–24); and 8 out of screening/surveillance period (when screening/surveillance colonoscopy was not performed on time (more than 8 years after disease diagnosis or when intervals between surveillance colonoscopies were too long according to the risk stratification profile). Most of the patients diagnosed out of screening/surveillance
period had an inappropriate follow-up, with a mean in-terval to prior colonoscopy of 8 years (IQR, 7–9). Sixty-one percent of the patients diagnosed with HGD without prior LGD were therefore diagnosed outside screening/surveillance period.
Diagnostic circumstances of the patients diagnosed with colitis-associated colorectal cancer without prior detected dysplasia. Among the 95 patients diagnosed with CAC without prior detected dysplasia, 4 (4%) were diagnosed before IBD diagnosis with a mean interval before IBD diagnosis of 31 months (IQR, 12–51) with either no colonoscopy performed before in 3 patients or a colonoscopy performed 5 years before the CAC diag-nosis in 1 patient; 4 (4%) at IBD diagdiag-nosis with either no colonoscopy performed before in 3 patients or a colo-noscopy performed 13 years before the CAC diagnosis in 1 patient; 8 (8%) before screening colonoscopy after a mean time after IBD diagnosis of 31 months (IQR, 2–57) and with a mean interval to prior colonoscopy of 12 months (IQR, 2–25); 31 (33%) during screening or sur-veillance period according to the risk stratification pro-file with a mean interval to prior colonoscopy of 15 months (IQR, 4–19); and 48 (51%) out of screening/ surveillance period with a mean interval to prior colo-noscopy of 8 years (IQR, 2–12).
Risk factors associated with the development of colitis-associated colorectal cancer after dysplasia. In univariate analysis, metachronous lesions (P ¼ .0086), multifocal lesions (P ¼ .005), non-polypoid lesions (P ¼ .0014), associated PSC (P ¼ .0005), and colonic stricture (P ¼ .0017) were significantly associated with the risk of development of CAC after dysplasia. In multivariate analysis, only the presence of non-polypoid lesions (P¼ .0106) and associated PSC (P ¼ .033) were significantly associated with the risk of development of CAC after dysplasia (Supplementary Table 5).
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Supplementary Table 1. Risk Factors Associated With CAC
Variable
Univariate analysis Multivariate analysis
Odds ratio 95% CI P valuea Odds ratio 95% CI P valuea
CD 1.68 1.08–2.60 .02 1.55 0.97–2.46 .07
Age at IBD diagnosis 0.97 0.96–0.99 <.01 0.98 0.97–0.99 .01
Follow-up duration after IBD diagnosis 1.04 1.02–1.06 <.01 1.03 1.01–1.05 <.01
Female 1.00 0.65–1.57 .97 Smoking status 1.08 0.63–1.87 .77 Metachronous lesions 1.07 0.68–1.71 .76 Multifocal lesions 1.29 0.81–2.07 .29 Family history of CRC 0.63 0.27–1.47 .28 Associated PSC 1.58 0.79–3.17 .20
CD, Crohn’s disease; CI, confidence interval; CRC, colorectal cancer; IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis. a
P value for logistic regression. Bold values are significant.
Supplementary Table 2. Indication for Surgery During Follow-up and the Maximal Grade of Neoplasia Found in Surgical Specimen (Number of Surgeries)
Q6
Indication for surgery
Findings in surgical specimen No neoplasia LGD HGD CAC Total
LGD 16 22 2 9 (18%) 49
HGD 8 6 5 13 (41%) 32
CAC 1 2 1 59 (94%) 63
Other reason 23 17 1 27 (40%) 68
Total 48 47 9 108 212
CAC, colitis-associated colorectal cancer; HGD, high-grade dysplasia; LGD, low-grade dysplasia.
Supplementary Table 3. Indication for Surgery During Follow-up and the Maximal Grade of Neoplasia Found in Surgical Specimen (Number of Patients)
Indication for surgery
Findings in surgical specimen No neoplasia LGD HGD CAC Total
LGD 16 20 2 9 (19%) 47
HGD 8 5 5 13 (42%) 31
CAC 1 2 1 52 (93%) 56
Other reason 23 15 1 21 (35%) 60
Total 48 42 9 95 194
CAC, colitis-associated colorectal cancer; HGD, high-grade dysplasia; LGD, low-grade dysplasia. 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505 1506 1507 1508
Supplementary Table 4. Risk Factors Associated With Development of More Advanced Lesion (HGD or CAC)
Variable
Univariate analysis Multivariate analysis
Relative risk 95% CI P valuea Relative risk 95% CI P valuea
Metachronous lesions 14.50 3.39–61.90 <.01 6.99 1.54–31.77 .01 Multifocal lesions 3.99 1.71–9.34 <.01 0.94 0.34–2.59 .90 Non-polypoid lesions 20.94 4.92–89.17 <.01 13.78 3.11–61.19 <.01 Associated PSC 3.78 1.56–9.14 <.01 1.45 0.52–4.03 .48 Invisible lesions 3.18 1.42–7.11 <.01 2.36 0.93–5.99 .07 Colonic stricture 7.48 3.08–18.17 <.01 2.64 1.00–6.96 <.05
Age at IBD diagnosis 0.99 0.97–1.01 .40
Family history of CRC 0.76 0.16–3.69 .73
Smoking status 0.37 0.12–1.17 .09
Age at diagnosis of the index lesion 1.01 0.98–1.03 .71
Family history of IBD 0.58 0.12–2.80 .50
CI, confidence interval; CRC, colorectal cancer; IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis. a
P value for Cox proportional hazards regression. Bold values are significant. Q7
Supplementary Table 5. Risk Factors Associated With Development of Colitis-associated Colorectal Cancer
Variable
Univariate analysis Multivariate analysis
Relative risk 95% CI P valuea Relative risk 95% CI P valuea
Metachronous lesions 7.47 1.67–33.42 <.01 3.72 0.76–18.21 .10 Multifocal lesions 5.17 1.64–16.27 <.01 1.44 0.41–5.05 .57 Non-polypoid lesions 26.94 3.55–204.35 <.01 14.96 1.88–119.25 .01 Associated PSC 6.35 2.26–17.85 <.01 3.41 1.10–10.56 .03 Colonic stricture 6.33 2.00–20.00 <.01 1.85 0.5550–6.18 .32 Invisible lesions 2.60 0.94–7.19 .07
Age at IBD diagnosis 0.98 0.95–1.01 .21
Family history of CRC 0.43 0.05–3.62 .44
Smoking status 0.36 0.07–1.77 .21
Age at diagnosis of the index lesion 1.00 0.96–1.03 .92
Family history of IBD 0.89 0.17–4.71 .89
CI, confidence interval; CRC, colorectal cancer; IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis. a
P value for Cox proportional hazards regression. Bold values are significant.
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