What’s next for wide-area transepithelial sampling in Barrett’s esophagus management?

Abstract

Most patients with esophageal adenocarcinoma (EAC) present at an advanced stage, with a <20% 5-year survival.1Codipilly D.C. Sawas T. Dhaliwal L. et al.Epidemiology and outcomes of young-onset esophageal adenocarcinoma: an analysis from a population-based database.Cancer Epidemiol Biomarkers Prev. 2021; 30: 142-149Google Scholar, 2Siegel R.L. Miller K.D. Fuchs H.E. et al.Cancer Statistics, 2021.CA: A Cancer Journal for Clinicians. 2021; 71: 7-33Google Scholar, 3Hur C. Miller M. Kong C.Y. et al.Trends in esophageal adenocarcinoma incidence and mortality.Cancer. 2013; 119: 1149-1158Google Scholar Barrett’s esophagus (BE) is the only known precursor of EAC, and endoscopic treatment of dysplasia can reduce EAC incidence.4Shaheen N.J. Sharma P. Overholt B.F. et al.Radiofrequency ablation in Barrett's esophagus with dysplasia.N Engl J Med. 2009; 360: 2277-2288Google Scholar,5van Munster S, Nieuwenhuis E, Weusten B, et al. Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation ± endoscopic resection: results from the national Dutch database in a 10-year period. Gut. Epub 2021 Mar 22.Google Scholar As such, gastroenterological societies recommend endoscopic surveillance to detect dysplasia/EAC.6Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett's esophagus.Am J Gastroenterol. 2016; 111 (quiz 51): 30-50Google Scholar,7Qumseya B. Sultan S. Bain P. et al.ASGE Standards of Practice CommitteeASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359.e2Google Scholar Surveillance should involve meticulous examination of the BE segment, targeted samples from visible lesions, and biopsies performed per the Seattle protocol.8Levine D.S. Haggitt R.C. Blount P.L. et al.An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus.Gastroenterology. 1993; 105: 40-50Google Scholar It is associated with detection of EAC at earlier stages and a modest improvement in cancer-related mortality.9Codipilly D.C. Chandar A.K. Singh S. et al.The effect of endoscopic surveillance in patients with Barrett's esophagus: a systematic review and meta-analysis.Gastroenterology. 2018; 154: 2068-2086.e5Google Scholar Despite this, up to a third of EAC and high-grade dysplasia (HGD) is “missed.”10Visrodia K. Singh S. Krishnamoorthi R. et al.Magnitude of missed esophageal adenocarcinoma after Barrett's esophagus diagnosis: a systematic review and meta-analysis.Gastroenterology. 2016; 150: 599-607e7Google Scholar Although clinician noncompliance with biopsy recommendations plays a role in this, along with the inability to recognize subtle lesions with dysplasia/EAC, it is likely that sampling error contributes to this “miss” rate because wide swaths of BE mucosa are not sampled by protocol biopsies. Wide-area transepithelial sampling with 3-dimensional analysis (WATS-3D) (CDx Diagnostics, Suffern, New York, USA) uses a stiff endoscopic brush to sample the BE mucosa and hence may decrease sampling error by sampling a greater area of BE mucosa. Cytology samples are then analyzed by a proprietary neural network, and areas enriched with dysplasia are presented to pathologists, who can focus on these areas and assess for the presence and degree of dysplasia. WATS-3D brushings may obtain cells from “deeper” structures, such as the basal crypts, which would not be sampled by conventional brushings. WATS-3D is associated with an incremental yield of dysplasia (7.2% all dysplasia, 2.1% HGD/EAC) over those obtained by forceps biopsy (FB).11Vennalaganti P.R. Kaul V. Wang K.K. et al.Increased detection of Barrett’s esophagus–associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial.Gastrointest Endosc. 2018; 87: 348-355Google Scholar, 12Anandasabapathy S. Sontag S. Graham D.Y. et al.Computer-assisted brush-biopsy analysis for the detection of dysplasia in a high-risk Barrett's esophagus surveillance population.Dig Dis Sci. 2011; 56: 761-766Google Scholar, 13Codipilly D.C. Krishna Chandar A. Wang K.K. et al.Wide-area transepithelial sampling for dysplasia detection in Barrett's esophagus: a systematic review and meta-analysis.Gastrointest Endosc. 2022; 95: 51-59.e1Google Scholar Importantly, a miss rate of dysplasia by WATS-3D detected by endoscopic FB (62% of FB dysplasia not detected by WATS-3D) also exists, suggesting that it should be used an adjunct to FB to increase dysplasia yield. Although the ability to obtain more cells (and more data) is advantageous, there remain some unanswered questions regarding the clinical significance of WATS-3D−detected dysplasia. First, almost all WATS-3D samples in studies have been read by CDx-employed pathologists (except in 1 study), raising questions of generalizability of data to outside pathologists.11Vennalaganti P.R. Kaul V. Wang K.K. et al.Increased detection of Barrett’s esophagus–associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial.Gastrointest Endosc. 2018; 87: 348-355Google Scholar Indeed, in most published studies, the incremental WATS-3D dysplasia is not reconfirmed by histologic analysis of FB samples. Second, although the presence of cytologic atypia in the basal BE glands (“baseline atypia”) is recognized, endoscopic FB allow for visualization of the architecture of the entire gland with surface maturation, allowing interpretation of these data in context—a limitation that cannot be assessed in WATS-3D samples, which are predominantly cytologic. Indeed, WATS-3D frequently diagnoses crypt dysplasia (CD), which is rarely reported in FB samples; the true significance of this finding is unclear. Last, likely stemming from the differences in pathologic assessment, whether a WATS-3D dysplasia diagnosis carries the same progression risk as an FB-detected histologic dysplasia also remains unclear. For likely these reasons, despite the inclusion of WATS-3D in a recent American Society for Gastrointestinal Endoscopy BE management guideline7Qumseya B. Sultan S. Bain P. et al.ASGE Standards of Practice CommitteeASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359.e2Google Scholar (albeit at a conditional GRADE level), questions remain regarding the clinical significance of WATS-3D–only dysplasia and its impact on the clinical treatment of BE patients. In this current issue of Gastrointestinal Endoscopy, Shaheen et al14Shaheen N.J. Smith M.S. Odze R.D. Progression of Barrett's esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by wide-area transepithelial sampling with 3-dimensional computer-assisted analysis: a retrospective analysis.Gastrointest Endosc. 2022; 95: 410-418Google Scholar provide some clarity by assessing “progression or natural history” outcomes in patients with 2 WATS-3D samples obtained at least 12 months apart in those with baseline no dysplasia (nondysplastic BE), low-grade dysplasia (LGD), or CD on initial WATS3D samples.14Shaheen N.J. Smith M.S. Odze R.D. Progression of Barrett's esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by wide-area transepithelial sampling with 3-dimensional computer-assisted analysis: a retrospective analysis.Gastrointest Endosc. 2022; 95: 410-418Google Scholar In this retrospective review, the authors assessed the outcomes in 4545 patients (out of 38,759 in the entire database) with 2 consecutive WATS-3D assays during 1.97 mean years of follow-up. The primary outcome was the crude progression rate (proportion of patients per patient-year who demonstrated progression to HGD or EAC on FB samples) in patients with an initial WATS-3D diagnosis of NDBE, CD, and or LGD. Progression rates from WATS-3D–diagnosed HGD/EAC were also calculated, irrespective of FB results. Of the original 4545 patients, 15 progressors were confirmed by FB and 16 were detected by WATS-3D (Table 1).Table 1Progression rates based on initial WATS-3D diagnosisInitial WATS-3D diagnosisNProgression to HGD/EAC (N)Per patient year progression rate to HGD/EAC (95% CI)Forceps biopsies confirming progressionNDBE43747 (0.16%)0.08% (0.02-0.14)CD1283 (2.3%)1.42% (0.00-3.01)LGD435 (11.6%)5.79% (1.02-10.55)WATS-3D detecting progressionNDBE43749 (0.21%)0.10% (0.04-0.17)CD1284 (3.13%)1.89% (0.07-3.72)LGD433 (6.98%)3.47% (0.00-7.26)CD, Crypt dysplasia; CI, confidence interval; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; LGD, low-grade dysplasia; NDBE, nondysplastic Barrett’s esophagus; WATS-3D, wide area transepithelial sampling—3-dimensional.Adapted from Shaheen NJ, Smith MS, Odze RD. Progression of Barrett's esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by WATS3D: a retrospective analysis.Gastrointest Endosc. Epub 2021 Sep 16. Open table in a new tab CD, Crypt dysplasia; CI, confidence interval; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; LGD, low-grade dysplasia; NDBE, nondysplastic Barrett’s esophagus; WATS-3D, wide area transepithelial sampling—3-dimensional. Adapted from Shaheen NJ, Smith MS, Odze RD. Progression of Barrett's esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by WATS3D: a retrospective analysis. Gastrointest Endosc. Epub 2021 Sep 16. This study provides previously missing data to determine the significance of WATS-3D NDBE and LGD results. The confirmation of progression based on FB is a significant strength of this study because the clinical significance of WATS-3D−only LGD was previously unclear. Further, these results somewhat mirror previously published meta-analyses assessing progression rates in NDBE (pooled annual incidence: 0.33% [95% CI, 0.28%–0.38%]) and LGD (pooled annual incidence: 1.7% [95% CI, 1.0%–2.5%]), although direct comparison is limited by patient heterogeneity and differences in reported outcome measures, and also by the wide confidence intervals provided.15Desai T.K. Krishnan K. Samala N. et al.The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis.Gut. 2012; 61: 970-976Google Scholar,16Singh S. Manickam P. Amin A.V. et al.Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta-analysis.Gastrointest Endosc. 2014; 79 (quiz 983.e1, 983.e3): 897-909.e4Google Scholar These data are critical in understanding the overall significance of WATS-3D−based dysplasia diagnoses and their potential impact on the clinical treatment of BE patients. Notably, baseline FB histologic features were available in only 55% of the cohort (hence the true status of the baseline group is somewhat unclear and susceptible to missed prevalent dysplasia), and the diagnoses of LGD, HGD, or EAC on FB were not confirmed by expert GI pathologists. It also is important to note that that the analysis was based on a relatively small number of progressors. Patients with baseline WATS-3D NDBE (4374) had 7 progressors, those with baseline WATS-3D CD (128) had 3 progressors, and those with baseline WATS-3D LGD (43) had only 5 progressors (Table 1). This leads the confidence intervals of the progression estimates to be wide and to approach zero for CD. Similar to baseline dysplasia detection, there was not a complete overlap between the detection of progression by WATS-3D and FB, with not all WATS-3D progressors being confirmed by FB, again suggesting an adjunctive role for WATS-3D to FB. On follow-up endoscopy, 9 of 16 progressors on WATS-3D had no visible abnormalities reported. FB in these patients revealed HGD/EAC in only 11, raising the issue of the significance and follow-up care of those in whom WATS demonstrates progression but the result of histologic analysis is negative. In this cohort, WATS-3D missed 2 progressors identified by FB, yielding a miss rate of 13% (2/15 identified by FB) but found an extra 3 patients who were missed by FB—an additional yield of 20% (3/15 identified by FB). This is similar to data recently reported in a systematic review and meta-analysis.13Codipilly D.C. Krishna Chandar A. Wang K.K. et al.Wide-area transepithelial sampling for dysplasia detection in Barrett's esophagus: a systematic review and meta-analysis.Gastrointest Endosc. 2022; 95: 51-59.e1Google Scholar This finding further emphasizes the role of WATS-3D as an adjunctive test, to be used in conjunction with FB, not standalone. CD in BE is not widely reported, and its diagnostic criteria are not standardized. In a prior study, the interobserver agreement of 6 expert pathologists for CD was moderate (κ = .44).17Coco D.P. Goldblum J.R. Hornick J.L. et al.Interobserver variability in the diagnosis of crypt dysplasia in Barrett esophagus.Am J Surg Pathol. 2011; 35: 45-54Google Scholar There are no data on the natural history of CD in BE, either. In this article, the entity of CD on WATS brushings is reported. Challenges with a CD diagnosis on cytology specimens were mentioned earlier. Additionally, given the small number of progressors in the CD group leading to confidence intervals of the progression estimate reaching zero, further analysis of longitudinal outcomes is necessary to fully elucidate the role of WATS-3D CD for the prediction of dysplasia progression. Although this is the first comprehensive study on FB-confirmed WATS-3D outcomes, other limitations need to be acknowledged. Despite the inclusion of >4000 patients, the original WATS-3D cohort consisted of 38,759 patients with intestinal metaplasia (entered into a CDx commercial database), so the vast majority did not undergo a second round of WATS-3D biopsies. Whether this represents some form of selection bias, because patients with 2 WATS-3D biopsies appeared to have longer BE segments compared with those excluded and therefore may have been considered at higher risk by their treating clinician, is unclear, but this may have artificially increased progression rates. Baseline histologic features and final progression histologic features were also not confirmed by expert GI pathologists. Given the known substantial proportion of downgrading of community LGD diagnosis upon expert review, and the lack of consensus among pathologists on a diagnosis of CD, these estimates should be interpreted with caution. This study provides some of the critical missing data regarding the clinical significance of some WATS-3D histologic subtypes, acknowledging several limitations highlighted earlier. Used as an adjunct to traditional FBs, WATS-3D may identify progression that would otherwise be missed based on FB alone, with progression estimates of WATS-3D NDBE and LGD approximating or exceeding those of FB. Although prospective data on larger cohorts and the outcomes in those with WATS-3D-only LGD/HGD (with FB-negative histologic features) are urgently needed to fully elucidate the role of WATS-3D in BE surveillance, this study highlights some of the gaps that need to be filled for the firm inclusion of WATS-3D in the available treatment options for BE management. Dr Iyer is a consultant for, and a recipient of research funding from, Exact Sciences, Pentax Medical, and Cernostics and a consultant for Medtronic, Symple Surgical, and Ambu. The other author disclosed no financial relationships. Progression of Barrett’s esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by wide-area transepithelial sampling with 3-dimensional computer-assisted analysis: a retrospective analysisGastrointestinal EndoscopyVol. 95Issue 3PreviewWide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS3D) is used as an adjunct to forceps biopsy sampling in Barrett’s esophagus (BE). BE-associated crypt dysplasia (CD), which can be detected by WATS3D, involves crypts but not surface epithelium. The risk of neoplastic progression of CD has never been evaluated. The prognosis of WATS3D-diagnosed nondysplastic BE (NDBE) and low-grade dysplasia (LGD) is also unknown. We assessed the risk of progression of WATS3D-reported NDBE, CD, and LGD with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). Full-Text PDF