Serrated colorectal neoplasia: detection, characterization … what next?

Prediction is very difficult, especially if it’s about the future

Niels Bohr

It has been 20 years since Emina Torlakovic and Dale Snover published their seminal description of “serrated adenomatous polyposis” [1]. Few could have foreseen at that time that the serrated pathway would emerge from relative obscurity to becoming one of the main actors in the field of colorectal neoplasia. The serrated class of colorectal lesions is distinct from conventional adenomas and includes hyperplastic polyps, sessile serrated polyps (SSPs), and traditional serrated adenomas (TSAs) [2]. The serrated pathway contributes significantly to the burden of colorectal cancer (CRC), particularly of right-sided interval cancers whose molecular signature (hypermethylation, microsatellite instability) often overlaps with that of serrated neoplasms [3] [4] [5]. SSPs and TSAs are considered premalignant (unlike hyperplastic polyps), although SSPs are arguably more relevant given the rarity of TSAs. SSPs are considered equivalent to conventional adenomas in screening and surveillance guidelines [6].

Despite the exponential growth in studies focused on serrated neoplasia, there remain major knowledge gaps and clinical challenges. SSPs are morphologically subtle lesions often located in the right colon, and are more difficult to detect endoscopically than conventional adenomas, leading to wide variability in endoscopic detection rates. The histopathological classification of serrated polyps, despite efforts at standardizing definitions, continues to be beset by high interobserver variability, particularly with respect to differentiating hyperplastic polyps from SSPs [7]. Until very recently, the real-time histologic diagnosis of diminutive polyps as part of “resect-and-discard” and “diagnose-and-leave” strategies has been focused on differentiating conventional adenomas from non-neoplastic polyps, and did not include SSPs. There are concerns regarding higher risk of incomplete endoscopic resection of SSPs compared with conventional adenomas, using standard polypectomy techniques [8]. Finally, there are few longitudinal data from high quality observational studies to inform appropriate surveillance after resection of serrated lesions.

In this issue of Endoscopy, two studies [9] [10] enrich the serrated neoplasia field and point the way for future research. The study by IJspeert et al. [9] aimed to determine the prevalence and colorectal distribution of SSPs, and to evaluate the association between SSPs and synchronous advanced neoplasia. The sample included 3364 patients who had undergone high quality colonoscopy by 25 endoscopists. The colonoscopy indication was diagnostic (evaluation of abdominal symptoms) in about two-thirds of patients. All lesions were reviewed by 5 experienced pathologists applying the World Health Organization (WHO) classification [2]. In addition, a random sample of 10 % of all SSPs and hyperplastic polyps < 10 mm was reviewed by an expert gastrointestinal (GI) pathologist, demonstrating good agreement (kappa 0.70) with the original diagnosis. The prevalence of SSPs was 8.2 % (9 % when excluding patients younger than 50 years), and SSPs with cytological dysplasia (SSP-CD) constituted 0.4 % of the overall sample and 3.8 % of all SSPs. There was no significant association between age and SSP prevalence in individuals aged > 50 years, and no association with gender. The prevalence of SSPs was significantly higher when the colonoscopy indication was surveillance (odds ratio [OR] 1.73, 95 % confidence interval [95 %CI] 1.20 – 2.49; P < 0.01) or familial CRC risk (OR 1.52, 95 %CI 1.05 – 2.22; P = 0.03), compared with symptomatic indications. An association with synchronous advanced neoplasia was shown by SSPs overall (OR 1.71, 95 %CI 1.25 – 2.34; P = 0.001) and by high risk SSPs (≥ 10 mm and/or SSP-CD) (OR 2.70, 95 %CI 1.56 – 4.67; P < 0.001).

The SSP prevalence rates found by IJspeert et al. can be compared to those reported by Abdeljawad et al. [11]. The rationale for the latter study was that the variability in reported SSP prevalence in the older literature was due to inconsistent pathological criteria and to reporting of aggregate detection rates among groups of endoscopists with wide individual variation in serrated lesion detection [12] [13]. To overcome these sources of heterogeneity, the study included 1910 average risk patients (≥ 50 years old) who had undergone screening colonoscopy by one endoscopist with high adenoma and serrated lesion detection rates, coupled with a review of all slides of serrated lesions proximal to the sigmoid colon and all rectal and sigmoid serrated lesions > 5 mm by one expert GI pathologist. The overall SSP prevalence was 8.1 %, and SSP-CD prevalence was 0.6 % (7.8 % of patients with SSP), remarkably similar to those of the study by IJspeert et al. Taken together, this suggests that SSP yield is less dependent on colonoscopy indication and patient demographic features than it is on the ability of endoscopists to reliably identify these lesions, for pathologists to consistently diagnose them, and for the two groups to agree on terminology.

The association with synchronous advanced neoplasia deserves additional comment. A meta-analysis [14] of 9 studies including 34 084 patients found that serrated polyps are associated with an approximately twofold increased risk of detection of synchronous advanced neoplasia, similarly to the study of IJspeert et al., with the highest risk in individuals with proximal and large serrated polyps. A practical implication for endoscopists is the need to conduct a meticulous examination looking for synchronous lesions whenever a suspected SSP is detected, particularly if it is large and in the proximal colon. This author’s practice is to routinely examine the right colon at least twice (in retroflexion or standard forward view), with additional passes when polyps are detected. Beyond their link with synchronous advanced neoplasia, and perhaps more importantly, SSPs are associated with increased risk of metachronous neoplasia. A recent follow-up study [15] to the Norwegian flexible sigmoidoscopy screening trial (NORCCAP) reported CRC rates in 81 individuals with large serrated polyps at baseline, after a median of 10.9 years. Compared with controls without polyps, the hazard ratio (HR) for CRC was 2.5 (95 %CI 0.8 – 7.8) comparable to that of patients with advanced adenomas at baseline (HR 2.0, 95 %CI 1.3 – 2.9). Interestingly, no CRCs developed among 23 large serrated polyps which had been left in situ for a median of 11 years. This suggests that the increased risk of metachronous advanced neoplasia associated with SSPs is not solely due to histologic progression of individual polyps, but also due to a neoplastic field effect.

The systematic review and meta-analysis by Parikh et al. [10] addresses the role of image-enhanced endoscopy to allow differentiation of SSPs from non-neoplastic lesions. A meticulous literature search yielded 13 studies which met inclusion criteria. The pooled sensitivities were 80 % for magnification-narrow band imaging (magnification-NBI), 60 % for NBI, 49 % for autofluorescence, and 47 % for flexible spectral imaging color enhancement. Only magnification-NBI and NBI had significantly better sensitivity than white-light endoscopy, exceeding 90 % in 4 of 10 studies. As expected, there was significant variability in study methodology, diagnostic criteria for SSP, and primary comparisons. This led to marked variability in performance characteristics and significant heterogeneity in meta-analyses, which could not allow recommendation of image-enhanced endoscopy as a diagnostic tool for SSPs. However, the findings are appropriately placed in the context of the recently developed Workgroup serrAted polypS and Polyposis (WASP) classification [16], which combines the NBI International Colorectal Endoscopic (NICE) algorithms with surface features associated with SSP (clouded surface, indistinctive border, irregular shape, and dark spots inside crypts). In the validation study, for high confidence diagnoses, the accuracy of NBI was 0.73 (95 %CI 0.64 – 0.82) which improved to 0.87 (95 %CI 0.80 – 0.95) after training, broadly similar to the findings of the meta-analysis. Ultimately, as stated by Parikh et al., the role of image-enhanced endoscopy in general (and NBI in particular, given the number of NBI studies and promising findings in the meta-analysis) for real-time diagnosis of SSP will be determined with carefully designed prospective studies employing validated classification algorithms such as WASP.

In the meantime, how should clinicians approach optical diagnosis of polyps while taking into account SSPs? As recommended by an expert panel [17], endoscopists who meet optical diagnosis thresholds can apply a resect-and-discard strategy for all diminutive polyps proximal to the sigmoid colon, and, in the rectum and sigmoid, resect-and-discard for suspected diminutive adenomas and diagnose-and-leave for suspected diminutive hyperplastic polyps. Potential SSP-related threats to these approaches are whether the prevalence of cytological dysplasia in diminutive SSPs proximal to the sigmoid is high, and whether significant proportions of diminutive, apparently hyperplastic, polyps in the rectum and sigmoid are in fact SSPs. These important issues are the subject of active study.

What next? It is now clear that SSPs are screening-relevant lesions: they have a higher prevalence than previously thought, the dwell time before progression to CRC in most cases is long enough to make them suitable screening targets (much like conventional adenomas), and they are associated with synchronous and metachronous advanced neoplasia. The field should now move from descriptive cross-sectional studies to longitudinal ones, to determine optimal polypectomy methods and appropriate surveillance intervals, and to provide direct evidence that detection and resection of SSPs independently decreases CRC incidence and mortality.

• References

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