Missed Adenomas during Colonoscopic Surveillance in Individuals with Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Background and Aims: Lynch syndrome (also known as hereditary nonpolyposis colon cancer) is associated with an increased risk for colorectal cancer, which can arise despite frequent colonoscopic exams. We evaluated the adenoma miss rate of conventional colonoscopy in patients with Lynch syndrome, and compared the sensitivity of chromoendoscopy versus intensive inspection for detecting polyps missed by conventional colonoscopy.

Methods: Fifty-four subjects with Lynch syndrome underwent tandem colonoscopies at four centers of the Great Lakes-New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. All participants first had a conventional colonoscopy with removal of all visualized polyps. The second endoscopy was randomly assigned as either pancolonic indigo carmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and number of polyps detected on each exam were recorded.

Results: After undergoing standard colonoscopy, 28 individuals were randomized to a second exam with chromoendoscopy and 26 underwent intensive inspection. The mean interval since last colonoscopy was 17.5 months. Seventeen polyps (10 adenomas and 7 hyperplastic polyps) were identified on the first standard colonoscopies. Twenty-three additional polyps (12 adenomas and 11 hyperplastic polyps) were found on the second exams, yielding an adenoma miss rate of 55%. Fifteen polyps (5 adenomas and 10 hyperplastic polyps) were found in subjects who had chromoendoscopy and 8 polyps (7 adenomas and 1 hyperplastic polyp) in those who had intensive inspection. Chromoendoscopy was associated with more normal tissue biopsies (11 versus 5) and longer procedure times compared with intensive inspection (29.8 ± 9.5 versus 25.3 ± 5.8 minutes; P = 0.04). Controlling for age, number of previous colonoscopies, procedure time, and prior colonic resection, chromoendoscopy detected more polyps (P = 0.04), but adenoma detection was not significantly different compared with intensive inspection (P = 0.27).

Conclusions: Small adenomas are frequently missed in patients with Lynch syndrome. Although chromoendoscopy did not detect more missed adenomas than intensive inspection in this pilot study, larger trials are needed to determine optimal surveillance techniques in this high-risk population.

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer syndrome and is estimated to account for 3% to 5% of colorectal cancer cases (1). Lynch syndrome is caused by inherited mutations in genes involved in DNA mismatch repair, which predispose to cancers of the gastrointestinal, female reproductive, and urinary tracts, as well as other extracolonic tumors (2). Mismatch repair mutation carriers have a lifetime risk for developing colorectal cancer of 70% to 80% in the absence of colonoscopic screening, with a mean age of colorectal cancer diagnosis of 44 years (2). Despite the term “nonpolyposis colorectal cancer”, there is evidence that most colorectal cancers in patients with Lynch syndrome arise from adenomatous polyps, many of which have been described as small and/or flat with a higher degree of dysplasia compared with sporadic adenomas (3). Although colonoscopy has been found to be effective in reducing colorectal cancer–related mortality in families with Lynch syndrome, reports of tumors developing in the interval between colonoscopic exams are not infrequent (4, 5). Consequently, current colorectal cancer screening recommendations for individuals at risk for Lynch syndrome include colonoscopy every 1 to 2 years beginning at age 20 to 25 (6).

Conventional white-light colonoscopy is considered the gold standard for detecting adenomatous polyps; however, studies in average-risk and moderate-risk individuals have documented adenoma miss rates of 6% to 27% (7–9). Chromoendoscopy, done by spraying dye on the colorectal mucosa during colonoscopy, has been reported to improve visualization of mucosal lesions (10–12). Previous randomized trials examining chromoendoscopy for adenoma detection in average-risk and moderate-risk individuals have reached different conclusions about the utility of spraying dye because most of the additional lesions found during chromoendoscopy are small (13–15). Although recent reports show that advanced histology may be present in 10% of small (5-10 mm) colorectal adenomas (16), the clinical significance of missing these small lesions is not known. Because carcinogenesis may be accelerated in Lynch syndrome, improved detection of small lesions may be especially important in this patient population.

We conducted a randomized multicenter study to (a) determine the prevalence of missed lesions following a standard colonoscopy in patients with Lynch syndrome and (b) compare chromoendoscopy versus intensive inspection for detection of missed lesions in this population at high-risk for developing colorectal cancer.

Study subjects were enrolled at four collaborating study centers (University of Michigan, Dana-Farber/Brigham and Women's Hospital, M. D. Anderson Cancer Center, and the University of Toronto) associated with the Great Lakes-New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. In order to be eligible for the study, subjects had to have a clinical diagnosis of Lynch syndrome/hereditary nonpolyposis colorectal cancer, defined as (a) a documented history of a pathogenic mismatch repair gene mutation in one of the mismatch repair genes MLH1, MSH2, or MSH6, or (b) a personal history of a Lynch-associated cancer and family history meeting Amsterdam I or II criteria (17). Individuals under 18 years of age, with poor performance status, receiving active treatment for cancer, or using anticoagulant medications were ineligible for the study. This study was approved by the institutional review board or ethics board at each institution.

All subjects underwent back-to-back colonoscopy exams, with a conventional colonoscopy followed immediately by a second endoscopy done with either chromoendoscopy or intensive colonoscopy. Subjects were randomized after the cecum (or ileocolonic anastomosis) was reached during the second exam and randomization was done in block sizes of two, and stratified by study site. The endoscopist, study coordinator, and endoscopy nurse were not made aware which randomization arm had been assigned until the cecum/ileocolonic anastomosis was reached during the second colonoscopy and the randomization envelope was opened.

Subjects provided informed consent and completed demographic and medical history questionnaires prior to colonoscopy. Subjects took a standardized preparation on the day prior to colonoscopy [magnesium citrate (12 oz) followed by either a large volume (4 L) of polyethylene glycol colonic lavage, 1.5 oz of oral phosphosoda followed by 24 oz water (two doses), or Visicol tablet prep].

The first exam for all subjects was a standard colonoscopy with removal of all visualized polyps. Upon completion of the first colonoscopy, subjects were considered eligible to undergo the second exam if all of the following criteria were satisfied: the preparation was considered excellent, the first standard colonoscopy was completed in less than 30 min, the endoscopist considered the exam to be technically easy, and the endoscopist, study coordinator, and endoscopy nurse all agreed that the subject was comfortable and clinically able to immediately undergo a second procedure. Study participants were contacted 24 to 72 h after their procedures to determine if they had experienced any adverse effects.

All seven endoscopists participating in this study underwent training in chromoendoscopy technique and recognition of polyp morphology. Standard nonmagnifying Olympus 160 or Pentax 160 colonoscopes were used for all study procedures.

Study coordinators recorded the duration of the endoscopic procedures (including time from endoscope insertion to visualization of cecal landmarks, withdrawing from cecum to anal verge, and performing polypectomy) and assessed the location and size of each polyp as measured by placing an open standardized biopsy forceps (Bard 00823 C diameter 9.6 mm inner dimension) adjacent to the polyp. Endoscopists classified polyp morphology as polypoid or flat, with flat polyps defined as having a height of less than half of the diameter of the lesion (13, 14, 18). All polyps were numbered and photographed before they were fully removed with standardized biopsy forceps or snares, according to standard clinical practice.

For subjects randomized to chromoendoscopy as their second exam, the entire colon was sprayed during withdrawal of the colonoscope with 0.2% indigo carmine solution with a standardized (Olympus pw-5v-1) spraying catheter and the mucosa was inspected in 10-cm segments. Each 20 mL of indigo carmine solution contained 1 mL of simethicone as an antifoaming agent. An average of 100 mL of solution was used per patient.

Subjects randomized to intensive inspection received a thorough examination of the colon without indigo carmine dye. Endoscopists were instructed to spend at least 20 min visualizing the colonic mucosa during withdrawal from the cecum, exclusive of time spent performing the polypectomy.

All polyps or areas suspicious for neoplasia identified on withdrawal of the endoscope during each of the two colonoscopic examinations were removed, fixed in 10% buffered formalin, and examined by the pathologist at each of the four collaborating institutions as per routine practice. Lesions were categorized as adenomatous polyps, hyperplastic polyps, normal tissue, or “other.”

The primary objective of this study was to compare the adenoma detection rates of chromoendoscopy and intensive inspection colonoscopy without dye spraying after a standard colonoscopic examination. The study was designed as a multicenter randomized trial with 50 subjects, and was subsequently extended to 54 subjects. Polyp and biopsy counts were analyzed by means of generalized linear models (SAS Proc Genmod, SAS Institute), which assume that the number of lesions of any particular type identified in a given patient follows a Poisson distribution, with different means in each of the two study groups. Linear mixed models (SAS Proc Mixed) were used to compare the sizes of lesions between the treatment groups. Predictors in both patient-level and polyp-level models included clinical site, age, sex, race, smoking status, drinking status, total number of previous colonoscopies, number of months since most recent colonoscopy, history of previous surgical resection of the colon, and identified gene mutation. Descriptive statistics are reported as mean ± SD.

A total of 54 subjects completed the study. The mean age of the subjects was 43.1 years (19-68). Forty-six (85%) individuals carried pathogenic mutations in a mismatch repair gene, and 25 (46%) had a prior diagnosis of colorectal cancer. After the first routine colonoscopy was completed and the cecum (or ileocolonic anastomosis) was reached during the second exam, 28 subjects were randomized to undergo chromoendoscopy and 26 subjects to intensive inspection colonoscopy without dye spraying. The baseline characteristics of subjects are shown in Table 1. There were no statistically significant differences between the two arms with respect to baseline subject characteristics.

Prior to randomization, all subjects underwent an initial conventional colonoscopy. The average procedure time (from insertion of colonoscope to removal, minus time spent in removal of polyps) was 18.2 minutes and lesions were removed from 13 of 54 (24%) subjects. Of the 22 lesions biopsied, 10 (45%) were adenomatous polyps, 7 (32%) were hyperplastic polyps, and 5 (23%) were normal tissue.

The characteristics of the first colonoscopy procedures are presented in Table 2. There were no significant differences in the total number of adenomas detected (six versus four) or in the number of subjects with adenomas (five versus three) between those subsequently randomized to intensive inspection versus chromoendoscopy, respectively. Additional characteristics of polyps found on the first exam are presented in Table 3. There was no statistically significant variation by arm in location or distribution of adenomas, hyperplastic polyps, and normal biopsies (P = 0.40). The mean size of adenomas was 6.50 ± 6.95 mm compared with 4.53 ± 3.79 mm in subjects subsequently randomized to intensive inspection versus chromoendoscopy, respectively. This difference was not statistically significant (P = 0.62) and resulted from one large (20 mm) adenoma in one subject in the intensive inspection arm. Four of 10 (40%) of the adenomas found on first exams were considered flat. There was no association between procedure time of the first colonoscopy and number of adenomas detected.

Twenty-six subjects were randomized to intensive inspection without dye spraying for their second colonoscopy, with a mean procedure time of 25.3 ± 5.8 minutes (range, 15-39 minutes) and lesions were biopsied from 9 of 26 (35%) subjects. Five subjects had polyps and each of these had one or more adenomas (Table 2). Of the total of 13 lesions biopsied, 7 (53.8%) were adenomas, 1 (7.7%) was a hyperplastic polyp, and 5 (38.5%) were normal tissue (Table 3).

The adenomas detected on the intensive inspection exams were not significantly smaller than those removed during the first colonoscopy (1.86 ± 0.38 versus 6.50 ± 6.95 mm; P = 0.1) and all seven (100%) were classified as flat (Table 3). There was no association between procedure time and the number of polyps and adenomas identified. Of eight subjects randomized to intensive inspection who had adenomas discovered at either colonoscopy, three (38%) had adenomas found only on the second exam.

Twenty-eight subjects were randomized to chromoendoscopy, with an average procedure time of 29.8 ± 9.5 minutes (range, 8-43 minutes) and lesions were biopsied from 15 of 28 (54%) subjects. Ten subjects had polyps and three had adenomas (Table 2). Of the total of 26 lesions biopsied, 5 (19.2%) were adenomas, 10 (38.5%) were hyperplastic polyps, and 11 (42.3%) were normal tissue (Table 3). The adenomas found during chromoendoscopy exams were not significantly smaller than those found on the first exam (mean size, 3.80+1.92 versus 4.50+3.79 mm; P = 0.73) and three of five (60%) were classified as flat (Table 3). There was no association between procedure times and the numbers of polyps and adenomas identified during the exam. Of five subjects randomized to chromoendoscopy who had adenomas discovered at either colonoscopy, two (40%) had adenomas found only during the second exam.

Chromoendoscopy took significantly longer than intensive inspection, with an average procedure time of 29.8 ± 9.5 versus 25.3 ± 5.8 minutes, respectively (P = 0.04). Chromoendoscopy exams yielded significantly more hyperplastic polyps (10 versus 1 for intensive inspection exams; P = 0.01). Although subjects who underwent chromoendoscopy had more biopsies (0.9 ± 1.1 compared with 0.5 ± 0.8 biopsies/subject for intensive inspection), chromoendoscopy exams identified fewer total adenomas (5 versus 7 for intensive inspection); however, these differences did not achieve statistical significance (P = 0.1 and 0.77, respectively; Tables 2 and 3). The percentages of biopsies that were normal tissue were 5 of 22 (23%), 5 of 13 (38%), and 11 of 26 (42%) in the standard colonoscopy, intensive inspection, and chromoendoscopy examinations, respectively. There were no adverse events reported for any of the 54 subjects.

Three of 28 (11%) subjects in the chromoendoscopy arm and 5 of 26 (19%) in the intensive inspection arm had additional adenomas found during the second colonoscopy (Table 2). Overall, 12 of 22 (55%) total adenomas were found on second exams. The adenomas detected on the second exams were not significantly smaller than those removed during the first colonoscopy (2.67 ± 1.56 versus 5.7 ± 5.72 mm; P = 0.09; Table 3). There was no difference in adenoma detection rates between subjects with mismatch repair gene mutations and those with cancer histories that met Amsterdam criteria without mismatch repair gene mutations.

In multivariate analysis controlling for subject's age, number of previous colonoscopies, procedure time, and prior history of surgical resection of the colon, chromoendoscopy was associated with finding more overall polyps compared with intensive inspection (P = 0.04); however, there was no significant difference in adenoma detection between the two techniques(P = 0.27).

We designed this randomized trial of back-to-back colonoscopies (a) to determine the miss rate of adenomas during conventional colonoscopy in patients with Lynch syndrome and (b) to test whether chromoendoscopy is better than intensive inspection without dye spraying for detecting adenomatous polyps missed by routine exams. We found that the second colonoscopy exams more than doubled the adenoma yield after the standard colonoscopy exams; however, there was no statistical difference between the use of chromoendoscopy and intensive inspection in detection of additional adenomas.

Only two previous studies have examined the use of chromoendoscopy for screening and surveillance of patients with Lynch syndrome. Comparing back-to-back exams in which a standard colonoscopy was followed by a second chromoendoscopy exam, Hurlstone et al. (19) and Lecomte et al. (20) found that the number of adenomas detected in individuals with Lynch syndrome more than doubled with the second exam. In examining the yield of a second colonoscopy using narrow band imaging technology (which uses optical filters to provide an “electronic chromoendoscopy”), East et al. (21) also found that the second exam nearly doubled the number of adenomas detected in patients with Lynch syndrome. These studies all concluded that the enhanced endoscopic technique (chromoendoscopy or narrow band imaging) significantly improved adenoma detection in patients with Lynch syndrome. However, none of these studies of back-to-back colonoscopies compared the enhanced endoscopy technique of the second exam to a second standard colonoscopy “control” and, consequently, it is impossible to determine whether the increase in adenoma yield with the second exam is a result of the enhanced endoscopic technique or simply a careful “second look.”

Our study of back-to-back colonoscopies in 54 individuals with Lynch syndrome is unique in that subjects were randomized to a second exam which used either chromoendoscopy or intensive inspection. Although we also found that adenoma yield doubled after the second exams and chromoendoscopy exams detected more polyps overall; they did not identify more adenomas than the intensive standard white-light colonoscopy exams. Interestingly, these results differ from those of our randomized trial comparing chromoendoscopy to intensive inspection in subjects with a prior history of colorectal cancer and/or adenomas. In that trial, which used the same study design and endoscopists (conducted simultaneously with the present study, article in press),⁸

we found that chromoendoscopy significantly improved adenoma yield compared with intensive inspection alone. In comparing the two studies, it is evident that the overall prevalence of adenomas was very different between the two populations: only 22 adenomas in total were detected in 13 of 54 (24%) Lynch syndrome subjects, compared with 64 adenomas in 27 of 50 (54%) subjects in the sporadic cohort. In addition to being significantly younger, the subjects with Lynch syndrome reported more frequent colonoscopic screening, which likely contributed to the lower prevalence of adenomas. The small number of adenomas in our study population did not afford adequate statistical power to detect clinically meaningful differences in adenoma detection rates between the study arms. Thus, our finding that there is no difference in adenoma detection between chromoendoscopy and intensive inspection exams in patients with Lynch syndrome may be real, or may be the result of a type II statistical error.

We recognize that our study has other limitations. This was a small study and despite blinded randomization, there were differences between subjects by study arm, although none of these were statistically significant. Although endoscopists could not be blinded to procedure type, they were not aware of which randomization arm had been assigned until after the first colonoscopy was completed, and there were no differences in procedure characteristics of the first colonoscopy by randomization arm (procedure time, number of biopsies) to suggest differential bias in adenoma detection. We did all of the exams using standard colonoscopes, rather than high-definition or magnification colonoscopes because we believed this technique would be more exportable to other clinical practice settings; however, there are data showing that high-definition/magnification endoscopes increase the sensitivity of chromoendoscopy, so our results may underestimate the efficacy of chromoendoscopy.

Our results have several important implications. Twelve of the 22 (55%) adenomas in individuals with Lynch syndrome were found on the second exams, so half of the adenomas present in these high-risk patients may be missed by standard colonoscopy exams. Furthermore, 10 of 12 (83%) of the missed adenomas were flat. A recent large study showed that 15% of individuals (who did not have Lynch syndrome) had small nonpolypoid colorectal neoplasms seen with chromoendoscopy and these “flat” lesions were 10 times more likely to contain advanced dysplasia than polypoid lesions (22). Because small, flat adenomas may be more prevalent in patients with Lynch syndrome, additional studies are needed to determine the biological significance of these missed lesions.

Ours is the first multicenter North American trial to examine the utility of chromoendoscopy for adenoma detection in patients with Lynch syndrome and it is unique in its use of randomized tandem colonoscopies comparing chromoendoscopy to a time-intensive conventional colonoscopy control. Although our study was unable to detect a difference in adenoma detection between chromoendoscopy and intensive inspection exams, our findings suggest that larger studies are needed to be able to compare the adenoma yield of one colonoscopic imaging modality to another in these patients who undergo frequent endoscopic screenings. Lynch syndrome is the most common hereditary colorectal cancer syndrome; however, these patients are still quite rare. Larger randomized trials, organized through multicenter collaborations, are necessary to provide sufficient statistical power to test the effectiveness of new endoscopic techniques to improve cancer prevention for these individuals at highest risk for developing colorectal cancer.

No potential conflicts of interest were disclosed

The authors thank Dr. Patrick Lynch of M. D. Anderson Cancer Center for his involvement and collaboration with this study.