The “diagnose and leave in” strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial

• Abstract
• Introduction
• Methods
• Study design and endoscopic procedure
• Optical diagnosis
• Histopathology
• Study outcome
• Statistical analysis
• Results
• Accuracy of real-time optical diagnosis
• Sensitivity analysis based on center volume and prevalence
• Imaging modality
• Feasibility of the diagnose-and-leave-in strategy
• Per-patient analysis of the diagnose-and-leave-in strategy
• Discussion
• References

Abstract

Background The “diagnose-and-leave-in” policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome.

Methods We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard.

Results Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %–98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %–93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ.

Conclusion In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

Introduction

Lynch syndrome represents the main cause of inherited colorectal cancer (CRC) and accounts for up to 4 % of all CRCs [1]. Caused by germline mutations in DNA mismatch repair (MMR) genes (i. e. MLH1, MSH2, MSH6, PMS2, and EPCAM) [2], Lynch syndrome increases the lifetime risk of CRC and other extracolonic neoplasias by up to 60 % [3]. CRC has distinctive characteristics in Lynch syndrome, such as considerable mucinous component, signet ring cell or medullary histological type, poor differentiation or a brisk lymphocytic infiltrate, or rimmed by a Crohn’s-like germinal center-producing lymphoid reaction [4]. Adenomas in Lynch syndrome are thought to exhibit faster progression to CRC compared with sporadic adenomas [5], present a higher proportion of advanced histology (i. e. high grade dysplasia or a villous component) despite a small size [6], are usually nonpolypoid [7], and are prone to a proximal colon location [6]. Most of these adenomas display MMR deficiency and/or microsatellite instability, which can act either as an initiating event (i. e. nonpolypoid precursor lesion or a malignant polyp) or as an accelerating event in the adenoma–carcinoma sequence [3]. The removal of all detected lesions that can potentially be an “aggressive” adenoma is the rationale for the current annual/biennial surveillance strategy in MMR mutation carriers [8].

In the average-risk population, approximately 70 % of all polyps are diminutive (≤ 5 mm) and non-neoplastic, with 50 % located in the rectosigmoid [9]. The current strategy, namely the removal of all diminutive polyps in the average-risk population, may represent an unnecessary overtreatment, with its associated procedural risks and high costs. Real-time optical diagnosis allows the differentiation of neoplastic and non-neoplastic lesions [10] [11] [12] through visualization of the macroscopic morphology and crypt and vascular pattern architecture [11] [13] [14]. Based on optical diagnosis, the “diagnose-and-leave-in” policy involves determination of which diminutive polyp in the rectosigmoid should be removed (considered neoplastic) and which could be left in situ (considered non-neoplastic) [10]. Before this strategy is adopted in clinical practice, a negative predictive value (NPV) for neoplasia of at least 90 % is required [10]. Optical diagnosis aided by virtual chromoendoscopy has been demonstrated to exceed this benchmark only when performed by adequately trained endoscopists under controlled conditions [10].

The Lynch syndrome population represents a high-risk group in which even tiny lesions may harbor invasive cancer [5] [6]. The optical diagnosis in this population has not yet been specifically evaluated, and the general recommendation is to remove all polyps, irrespective of size and location. Thus, the aim of this study was to evaluate whether the diagnose-and-leave-in strategy could be applied to diminutive rectosigmoid polyps of individuals with Lynch syndrome.

Methods

Study design and endoscopic procedure

In vivo characterization of colorectal lesions was performed in the context of a multicenter, randomized, controlled, parallel, noninferiority study (the EndoLynch study; NCT02951390) [15]. Individuals older than 18 years with confirmed germline mutation in any of the MMR genes (MLH1, MSH2, MSH6, PMS2) or germline deletion in EPCAM were prospectively randomized 1:1 to white-light endoscopy or pancolonic indigo carmine chromoendoscopy. This study was conducted in 14 Spanish centers by 24 participating endoscopists from July 2016 to January 2018 according to the ethical principles of the Declaration of Helsinki, and was approved by the Institutional Research Board of each participating center. Study reporting followed the Standards for Reporting Diagnostic accuracy studies statement (http://www.stard-statement.org). Before participating in the study, all included patients signed an informed consent form after being provided with oral and written information. Personal and clinical data were coded, anonymously registered, and managed using REDCap electronic data capture tools hosted at Asociación Española de Gastroenterología (AEG; http://www.aegastro.es) [16]. The allocated endoscopic technique was also automatically provided by the online AEG-REDCap database. Other methodological details are provided in the abovementioned study [15].

Before recruitment started, a questionnaire was sent to all participating endoscopists to assess their adenoma detection rate in CRC screening, the number of dye-based chromoendoscopies performed, and their routine use of validated scales for optical diagnosis, such as the Narrow-band imaging International Colorectal Endoscopic (NICE) classification [14] and Kudo pit pattern classification [13] (see Table 1s in the online-only Supplementary material). There was no formal ex vivo training phase in the NICE, Kudo, or WASP [17] classifications or specific assessment protocols for predicting dysplastic component within a sessile serrated lesion (SSL) [18] [19].

All participating centers used high-definition technology, including screens, processors, and colonoscopes: series 180 and 190 combined with EVIS EXERA II and III (Olympus, Tokyo, Japan), series 590 and 600 combined with EPK-4450 (Fujifilm, Tokyo, Japan) or EC-2990Li combined with EKP-i5000 (Pentax, Tokyo, Japan).

A careful colonic examination was performed during the withdrawal of the endoscope according to the allocated technique (pancolonic chromoendoscopy with indigo carmine or white-light endoscopy). For the pancolonic chromoendoscopy group, 0.4 % indigo carmine solution was sprayed using a dye-spray catheter (PW-205 V-spray; Olympus, Hamburg, Germany) onto the colonic mucosa at segment intervals starting from the cecum to the anus. Any excess pools of indigo carmine were removed by suction.

All procedural data were prospectively registered by the endoscopist or research nurse on a collection datasheet during the colonoscopy.

Optical diagnosis

Before the polypectomy, all visible lesions were characterized according to the Paris classification [20] and the polyp size was estimated by an instrument of known size (opened biopsy forceps or polypectomy snare) placed next to the lesion before resection.

In all lesions, in vivo optical diagnosis was performed using virtual chromoendoscopy (narrow-band imaging [NBI] – Olympus; blue-light imaging – Fujifilm; I-SCAN – Pentax) (Table 2s) alone or with additional indigo carmine in patients allocated to pancolonic chromoendoscopy.

As the first step of the optical diagnostic process, endoscopists were asked to categorize all lesions according to the Kudo classification [13] (I, normal mucosa; II, hyperplastic polyp/SSL; IIIs/IIIL/IV, adenoma; V, carcinoma) and the NICE classification [14] (1, hyperplastic polyp/SSL; 2, adenoma; 3, carcinoma) without a detailed description of each characteristic of the NICE classification (i. e. color, vessels, and surface). However, a strict adherence to these classifications was not required for the final optical diagnosis; similarly, a specific classification for the optical diagnosis of SSLs [17] or protocol for the detection of dysplasia within an SSL [18] [19] (i. e. demarcated adenomatous pit pattern, Kudo type IIIL/IV, NICE type 2) was not included in the optical diagnostic process.

The study analysis was based exclusively on the final optical diagnosis. This included six categories: 1) adenoma; 2) carcinoma; 3) SSL; 4) SSL with dysplasia (SSL-D); 5) hyperplastic polyp; and 6) not performed/not valuable. Moreover, endoscopists provided the level of confidence in their diagnosis (high or low). Finally, all lesions were removed, retrieved, and sent in separate and properly labelled vials for histopathological analysis.

Histopathology

In each center, polyp histology was evaluated using the European guidelines for quality assurance in CRC screening and diagnosis [21] by expert pathologists dedicated to gastrointestinal oncology. A blinded histological evaluation for optical diagnosis was not required in this study. All lesions were classified according to the Vienna classification [22]. Serrated lesions (hyperplastic polyps, SSLs, and traditional serrated adenomas [TSAs]) were classified according to World Health Organization histological criteria [23].

Study outcome

The primary study outcome was the NPV of high-confidence optical diagnoses for neoplasia among diminutive rectosigmoid lesions. Histology was set as the reference standard. Considering a clinical approach based on the premalignant potential, adenomas, SSLs, and TSAs were grouped and defined as neoplastic lesions, whereas hyperplastic polyps and normal mucosa were grouped as non-neoplastic lesions. Secondary outcomes were the overall and high-confidence accuracies of optical diagnosis for differentiating neoplastic from non-neoplastic diminutive rectosigmoid lesions. We also performed sensitivity analyses according to imaging modality (virtual chromoendoscopy alone or with additional indigo carmine chromoendoscopy), and by center based on the volume of polyps included. Finally, we performed a per-patient analysis following an “intention-to-treat” strategy. If one or more polyps were misclassified in a patient, then this polyp was selected for analysis. If all polyps were correctly classified, the neoplastic lesion was chosen because it was deemed to be the lesion with the greatest clinical impact.

Statistical analysis

Diagnostic measures were calculated using a 2 × 2 table with the histopathology as the reference standard as follow: sensitivity was obtained by dividing true positives (neoplastic lesions with an optical diagnosis of neoplasia) by true positives plus false negatives (neoplastic lesions with an optical diagnosis of no-neoplasia); specificity was true negatives (non-neoplastic lesions with an optical diagnosis of no-neoplasia) divided by true negatives plus false positives (non-neoplastic lesions with an optical diagnosis of neoplasia); positive predictive value was true positives divided by true positives plus false positives; NPV was true negatives divided by false negatives plus true negatives; and accuracy was true positives plus true negatives divided by the total number of lesions. All measures were expressed as percentages along with 95 % confidence intervals (CIs) based on the Wilson method. We used Stata/IC version 14.0 (StataCorp, College Station, Texas, USA) and IBM SPSS Statistics version 23.0 (IBM Corp., Armonk, New York, USA).

Results

From July 2016 to January 2018, 256 patients with Lynch syndrome (60 % women; mean age 47 [standard deviation 14] years) were included in the EndoLynch study [15]. Of these, 150 (59 %) had at least one lesion, and 388 lesions were identified and removed. A total of 21 lesions were not retrieved for histopathology for technical reasons. Of the 367 lesions, 143 (39 %) were adenomas, 116 (32 %) were hyperplastic polyps, 18 (5 %) were SSLs, 1 (0.3 %) was a TSA, and 89 (24 %) were finally reported as normal mucosa ([Fig. 1]).

In total, 147 lesions (40 %) were located in the rectosigmoid colon; 128 (87 %) were diminutive. Of these 128 lesions, 30 (23 %) were neoplastic (26 adenomas [22 tubular adenomas with low grade dysplasia (TA-LGD), 3 tubular adenomas with high grade dysplasia (TA-HGD), and 1 villous adenoma with low grade dysplasia], 3 SSLs, and 1 TSA), whereas 98 (77 %) were non-neoplastic (72 hyperplastic polyps and 26 lesions reported as normal mucosa). No cancers or SSL-Ds were found.

Three centers (1, 4, and 6), which identified 59 % of the diminutive rectosigmoid lesions (76/128), were considered “high-volume” centers. Distributions of patients and lesions per center are shown in Table 3 s.

Accuracy of real-time optical diagnosis

In total, 128 diminutive rectosigmoid lesions were characterized in vivo before polypectomy. High-confidence optical diagnosis was obtained in 103 of the 128 lesions (81 %), of which 22 % were neoplastic (20 adenomas and 3 SSLs). Only three diminutive rectosigmoid neoplastic lesions were wrongly classified as hyperplastic polyps: two TA-LGDs (2 mm and 4 mm in size) and one nondysplastic SSL (3 mm in size). However, eight lesions classified as neoplastic by optical diagnosis (five SSLs and three adenomas) were recorded as non-neoplastic lesions in the pathology report. The overall accuracy of optical diagnosis for differentiating neoplastic from non-neoplastic lesions among diminutive rectosigmoid lesions was 85.2 % (95 %CI 78.0 %–90.3 %), with an NPV for neoplastic histology of 93.4 % (95 %CI 86.4 %–96.9 %). When the confidence of the optical diagnosis was high, the NPV and accuracy were 96.0 % (95 %CI 88.9 %–98.6 %) and 89.3 % (95 %CI 81.9 %–93.9 %), respectively ([Table 1]).

Regarding the optical diagnostic process, there was a negligible discrepancy between the assigned categories of both NICE and Kudo classifications and the final optical diagnosis provided by the endoscopist (Table 4 s). For instance, only one lesion that was assigned to NICE I category (hyperplastic polyp) was given a final optical diagnosis of adenoma (Table 4 s).

Sensitivity analysis based on center volume and prevalence

Sensitivity analysis per center according to lesion volume did not show clinically relevant differences. The NPVs exceeded 90 % in low-volume and high-volume centers (100 % and 93.8 %, respectively) ([Table 2]).

An exploratory analysis was performed to assess the predictive values of high-confidence optical diagnosis with different prevalence values of neoplastic histology among diminutive rectosigmoid lesions. Table 5s shows that the NPVs remained above 90 % for different hypothetical prevalences, indicating consistent sensitivity and specificity of the endoscopists’ high-confidence optical diagnosis.

Imaging modality

Sensitivity analysis by imaging modality used during the colonoscopy was performed to assess whether optical diagnosis of diminutive rectosigmoid lesions was more accurate when indigo carmine was sprayed onto the colonic mucosa. The optical diagnosis was slightly more accurate with indigo carmine (plus virtual) chromoendoscopy than with virtual chromoendoscopy alone (NPV and accuracy: 92.4 % and 87.2 % vs. 96.3 % and 80.8 %, respectively). Nevertheless, it is important to point out that the high-confidence NPVs for neoplasia were above 90 % with both modalities ([Table 3]).

Feasibility of the diagnose-and-leave-in strategy

[Fig. 2] displays the hypothetical flow if the diagnose-and-leave-in policy had been applied in our cohort of patients with Lynch syndrome. Only 53 out of the 128 diminutive rectosigmoid lesions (41 %) would have required polypectomy either because of low-confidence optical diagnosis (25 lesions) or due to suspicion of neoplastic histology (28 lesions). Only two diminutive TA-LGDs and one nondysplastic SSL would have been left in situ.

Per-patient analysis of the diagnose-and-leave-in strategy

In total, 128 diminutive rectosigmoid lesions were detected in 75 patients: 46 had one lesion, 14 had two lesions, 9 had three lesions, 4 had four lesions, 1 had five lesions, and 1 had six lesions. In 60 of the 75 patients (80 %), the optical diagnoses of all diminutive rectosigmoid lesions were performed with high confidence. [Table 4] shows the per-patient analyses for patients whose optical diagnosis of all lesions was performed with high confidence.

Of the 60 patients, 39 (65 %) were diagnosed as having no neoplastic lesion. However, three of them did indeed have a neoplastic lesion (two TA-LGDs and one nondysplastic SSL). In other words, in 39 of the 60 patients, polypectomy of all diminutive rectosigmoid lesions would have been avoided at the expense of erroneously classifying three lesions in three patients as “non-neoplastic” when they were actually neoplastic ([Table 4]).

Discussion

This prospective and multicenter post hoc analysis confirmed the high accuracy of in vivo optical diagnosis for diminutive rectosigmoid lesions when it is provided with high confidence in the Lynch syndrome population. The diagnostic accuracy for the high-confidence differentiation of neoplastic from non-neoplastic lesions was 89.3 % (95 %CI 81.9 %–93.9 %), whereas the NPV for neoplastic histology was 96.0 % (95 %CI 88.9 %–98.6 %). These results support the feasibility of the diagnose-and-leave-in strategy in patients with Lynch syndrome. By applying this strategy to our cohort, about 60 % of polypectomies of diminutive rectosigmoid lesions would have been avoided.

The relevance of optical diagnosis might increase as more irrelevant lesions are detected over time. For instance, in our study, the proportion of normal mucosa among diminutive rectosigmoid lesions (20 %) was higher than the rate reported in previous studies aimed at evaluating optical diagnosis in the general population [24] [25]. Moreover, from a per-patient perspective, 19 % (49 of 256) had at least one diminutive non-neoplastic rectosigmoid lesion (data not shown). This could be explained by the use of high-definition and dye-based chromoendoscopy in 100 % and 50 % of the cohort, respectively. Moreover, hyperalert endoscopists tend to overreact to any mucosal irregularity, even those with an inoffensive appearance (e. g. lymphoid hyperplasia), as a consequence of examining a high-risk population.

Not surprisingly, this “over”-detection could have artificially decreased the proportion of neoplasia among diminutive rectosigmoid lesions in our study (23 %), which is lower than the prevalence found in the average-risk population (30 %–52 %) [7]. Because the NPV depends on the prevalence of the disease, we performed an exploratory analysis with different values of neoplasia prevalence among diminutive rectosigmoid lesions. Assuming constant sensitivity (87 %) and specificity (90 %) of high-confidence optical diagnosis, the NPV for neoplastic histology remained above 90 % for hypothetical prevalence values from 5 % to 40 %.

Out of 103 diminutive rectosigmoid lesions assessed with high confidence, only two 2-mm and 4-mm TA-LGDs, and one nondysplastic 3-mm SSL were wrongly classified as non-neoplastic lesions. In a per-patient analysis, of 75 patients with diminutive rectosigmoid lesions, 60 (80 %) obtained a high-confidence optical diagnosis for all of their lesions. In 39 of the 60 patients (65 %), polypectomy of all diminutive rectosigmoid lesions would have been avoided at the expense of erroneously classifying three neoplastic lesions in three patients (two TA-LGDs and one SSL) as “non-neoplastic.”

The question is, what burden of false-negative diagnosis are we ready to accept in this specific context? Some might argue that it would be unacceptable to leave in place three diminutive neoplastic polyps in the rectosigmoid colon.

Several factors might explain the misclassification of these three lesions [15]. Although a strict adherence to NICE and Kudo classifications was not required, endoscopists used them as part of the optical diagnostic process. Hyperplastic polyps and SSLs cannot be differentiated within the NICE 1 category [27] and the WASP classification [28] was not recorded. In addition, the well-recognized interobserver variability for histological differentiation between SSLs and hyperplastic polyps might also bias the optical diagnosis results [29]. Furthermore, not all adenomas exhibit well-recognized features such as brown color, short and thick blood vessels, and tubular or oval pits [14], and there is variability in their identification among endoscopists [30] [31] especially in very small lesions. However, there was negligible discrepancy between the assigned categories of both NICE and Kudo classifications with the final optical diagnosis of adenoma. For instance, only one lesion that was assigned a NICE I category (hyperplastic polyp) was awarded a final optical diagnosis of adenoma. Another possible explanation could be histological, molecular, and morphological differences in adenomas in Lynch syndrome compared with sporadic ones [3] [5] that might translate into differences in the vascular pattern. However, a recent pilot case–control study that compared the microvessel density between Lynch syndrome adenomas and sporadic adenomas did not find differences in the vascular network [32].

Another important aspect is that the optical diagnosis was made without using magnification. Magnification can improve the characterization and increase the proportion of high-confidence optical diagnoses [24]. In our study, the proportion of high-confidence optical diagnoses for diminutive rectosigmoid lesions was 81 %, which is comparable to rates from landmark studies in the field [14]. An accurate and user-friendly classification system with or without magnification needs to be designed to guarantee the safe use of optical diagnosis for clinical purposes. This study may serve as a proof of concept for applying computer-aided diagnosis to improve the characterization of colorectal lesions in other high-risk conditions of CRC.

The results of this study have considerable potential for generalization to clinical practice because the data were prospectively collected and the optical diagnosis was made in real-time in a multicenter setting. However, some limitations must be acknowledged. First, there was no sample size calculation and the number of analyzed lesions was small in relation to other studies focused on the optical diagnosis of colorectal lesions. This precludes us from analyzing data using a multilevel model that could account for the variability introduced by endoscopist and center. However, our exploratory and descriptive analysis failed to find relevant differences between high- and low-volume centers or when a per-patient analysis strategy was applied. Moreover, this was a post hoc per-polyp analysis from the EndoLynch study [15], which is currently the largest prospective cohort of individuals with Lynch syndrome. MMR mutation carriers are more difficult to recruit and are usually a less polyp-enriched population compared with average-risk or screening populations. Second, there was no ex vivo specific training in optical diagnosis before patient recruitment started. However, previous experience, including frequent use of either the NICE or Kudo classification in daily practice, was a prerequisite for participating endoscopists. These results might reflect the current status of optical diagnosis in real life. Third, the pathology assessment was not centralized, and pathologists were not blinded to the endoscopic prediction. This might bias the final histological diagnosis, particularly considering the high interobserver variability in the differentiation between hyperplastic polyps and SSLs [29]. Fourth, the participation of only expert and dedicated endoscopists would hinder generalization of the results outside academic centers. However, as stated in the guidelines [8] [32], we believe that individuals with Lynch syndrome should be managed in experienced centers where quality standards of colonoscopies are guaranteed.

In conclusion, real-time optical diagnosis in individuals with Lynch syndrome is highly accurate when performed with high confidence by dedicated endoscopists. The NPV for neoplastic histology among diminutive rectosigmoid lesions exceeded the benchmark of 90 %, indicating the feasibility and safety of the diagnose-and-leave-in strategy. However, these findings deserve to be tested in a study specifically designed for this purpose. Well-recognized issues such as reluctance to alter practice, standardized training, accreditation, patient acceptability, and availability of a monitoring system must also be taken into account by endoscopists and health care policymakers before a diagnose-and-leave-in strategy is adopted in Lynch syndrome.

Competing interests

María Pellisé received research grant from Fujifilm, received consultancy fee from Norgine, speaker’s fee from Norgine, Olympus, Casen Recordati, Janssen and editorial fee from Thieme. Francesc Balaguer has endoscopic equipment on loan of Fujifilm, receives an honorarium for consultancy from Sysmex, and speaker’s fee from Norgine. Ignasi Puig has endoscopic equipment on loan of Fujifilm and Olympus. The rest of co-authors have no conflict of interest.

Acknowledgments

REDCap electronic data capture tools are hosted at the Asociación Española de Gastroenterología (AEG; http://www.aegastro.es). AEG is a non-profit scientific and medical society focused on gastroenterology, and it provided this service free of charge, with the sole aim of promoting independent investigator-driven research.

^* These authors contributed equally to this work.

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Corresponding author

Publication History

Received: 19 March 2020

Accepted after revision: 03 December 2020

Accepted Manuscript online:
03 December 2020

Article published online:
11 February 2021

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
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