WATS3D (CDx Diagnostics, Suffern, NY)
Salvatore Docimo, DO1; Mazen Al-Mansour, MD2; Shawn Tsuda, MD3
1Division of Bariatric, Foregut, and Advanced GI Surgery, Stony Brook Medicine, Stony Brook, NY; 2Department of Surgery, University of Massachusetts Medical School/Baystate, Springfield, MA; 3VIP Surg, Las Vegas, NV
Acknowledgements:
SAGES Technology and Value Assessment Committee
Sharona Ross MD, Co-Chair
David Renton, MD, Co-Chair
SAGES Flexible Endoscopy Committee
Eric Pauli MD, Chair
Ryan Juza MD, Member
SAGES Foregut Task Force
Leena Khaitan MD, Chair
Marina Kurian MD, Co-Chair
SAGES Advocacy and Health Policy Committee
Ross Goldberg MD, Chair
John Roth MD, Co-Chair
Don Selzer MD, Member
Technology Overview
Wide-area trans-epithelial sampling of the esophagus with computer-assisted three-dimensional analysis (WATS3D , CDx Diagnostics, Suffern, NY) is an adjunctive technique to random biopsies for early detection of Barrett’s esophagus. The system is comprised of brush sampling that obtains trans-epithelial specimens covering a larger area of the BE segment compared to traditional forceps biopsy.(1) The system allows for evaluation of deeper glandular epithelium commonly found in Barrett’s esophagus through the full-thickness epithelial sample and 3-D computer analysis. The computer analysis uses a neural network, high-speed scanning system that identifies abnormal cells based on cellular morphology and molecular diagnostics.(2)
Forceps biopsy using the Seattle protocol has the potential to leave behind un-sampled tissue containing Barrett’s esophagus or other pathology. The Seattle protocol examines 4% of the esophageal area of concern, potentially yielding a low sensitivity.(3) Traditional histological techniques for sample evaluation of biopsy specimens may also have limitations. The standard technique is to mount a thin slice of the fixed biopsy specimen onto a glass slide, which is then examined by the pathologist with microscopy. WATS3D obtains trans-epithelial specimens, circumferentially from the lower esophagus via a stiff brush placed through working channel of the endoscope.(Figure 1).
Figure 1: Wide-area trans-epithelial sampling (WATS-3D) is performed by passing an abrasive brush through the working channel of the endoscope |
The brush is passed across the mucosa and rotated circumferentially until erythematous tissue or pinpoint bleeding at the biopsy site is noted.(4) The brush obtains samples down to the lamina propria, which are plated and stained, as 100 micron-thic tissue containing tissue fragments, individual cells, and cell clusters. The specimens are stained and examined at the CDx Diagnostics laboratory. All of the approximately 100,000 cells obtained through brushings are analyzed with a proprietary imaging and computer network that allows a three-dimensional view, resulting in a “3-D Micro-Biopsy.”(4) The approximate two hundred cells with suspicious characteristics such as goblet cells or dysplasia are then flagged for the pathologist as a starting point for analysis. Eighty of the most suspicious images are sent to the pathologist, who renders the final result following both the 3D, computer-assisted high-resolution images and manual microscopic examination of the slide.
Figure 2: WATS 3D system synthesizes multiple two-dimensional images into a single three-dimensional image to capture the en face view of the gland. |
Figure 3: A three-dimensional computer synthesized image of an in vivo, en face view of a gland to be evaluated by a pathologist. |
Technology Significance
Barrett’s esophagus is replacement of esophageal squamous mucosa by metaplastic columnar mucosa. As a precancerous process, BE is associated with a progression to esophageal adenocarcinoma, which carries a survival rate of only 15-20%.(5) Over the past several decades, the incidence of esophageal adenocarcinoma has increased by seven-fold, although for the last ten of those years, new esophageal cancer diagnoses have been falling by 1.2%.(6) The early detection of BE is of considerable importance in the optimal prevention of esophageal adenocarcinoma. Currently, four-quadrant biopsies obtained at 1 to 2 cm intervals is recommended for the detection of BE (The Seattle protocol). But, as stated earlier, this method of tissue sampling can have significant limitations.(7)
Some studies have questioned the sensitivity of endoscopic surveillance for the detection of dysplasia and therefore questioned the value of surveillance of BE.(8,9) A significant increase in sensitivity provided by an adjunctive modality like WATS3D has the potential to increase the value of routine screening and surveillance for BE.
Other alternative or adjunctive technologies to BE screening include narrow band imaging, autofluorescence imaging, confocal laser endomicroscopy, chromoendoscopy, diffuse reflectance and light scattering spectroscopy, optical coherence tomography, and volumetric endomicroscopy, all of which remain under clinical investigation.(10)
Clinical Evidence Summary
Clinical studies involving wide-area trans-epithelial sampling (WATS) of the esophagus with computer-assisted 3D analysis and were identified via a search of the PubMed/Medline databases (www.ncbi.nlm.nih.gov/pubmed) conducted in March of 2019. Keywords utilized in the search include: wide-area transepithelial sampling, three-dimensional (3D) computer-assisted analysis, WATS-3D, Barrett’s esophagus and WATS-3D, Barrett’s esophagus and wide-area transepithelial sampling with three-dimensional computer-assisted analysis, Barrett’s esophagus and emerging technology. Bibliographies of key references were searched for relevant studies not covered by the PubMed search. Case reports and small case series were excluded. The manufacturer’s website was also used to identify key references and instructions for use. The U.S. FDA Manufacturer And User facility and Device Experience (MAUDE) database was searched for reports regarding the device malfunction or injuries
Safety and Efficacy Data
Summary paragraph
Current studies compare WATS3D to the Seattle protocol, the current standard of care for BE screening. The American College of Gastroenterologists (ACG) guidelines state current biopsy sampling protocol accuracy to be in the range of 35% to 68%, suggesting the need for alternative or adjunctive diagnostic tools to improve accuracy.(11) Studies have demonstrated WATS3D increases the detection of Barrett’s esophagus or dysplasia by 39-425% compared to standard forcep biopsy.(12)
Currently, WATS3D alone is not recommended as a substitute for the Seattle protocol, but as an adjunctive diagnostic tool. Indications for WATS3D technology include patients undergoing endoscopic evaluation for upper gastrointestinal conditions including reflux disease, peptic ulcer disease, and screening or surveillance for Barrett’s esophagus. Contraindications mirror the contraindications for upper endoscopy, including known perforated viscus. Final conclusions regarding WATS-3D cannot be made until studies demonstrate its ability to solely increase the diagnosis of Barrett’s esophagus, esophageal dysplasia, and esophageal neoplasia beyond current protocols.
Publication Review
- Gross et al. performed a prospective, multi-center, community-based trial involving 25 sites conducted between 2012 and 2014.(2) Investigators were instructed to sample suspected BE from salmon-colored mucosa in the tubular esophagus. The investigators were trained in person or by videoconference and were also provided written instructions. Up to 6 cm of columnar lined mucosa was sampled with a single brush. Brush specimens were then transferred to a bar-coded glass slide for evaluation. The bristle portions were clipped off and enclosed in a vial for cellblock preparation. A second bristle sample was repeated. Immediately after obtaining the WATS3D specimens, a four-quadrant FB of the esophagus at 1cm and 2 cm intervals was performed at sites of abnormal mucosa. A total of 4203 patients were enrolled in the study with no documented complications. Barrett’s esophagus was diagnosed in 594 FB patients and in 799 WATS3D patients. Of the WATS3D patients, 493 had negative FB results. The addition of WATS3D to FB increased detection of BE by 83% (493/594; 95% CI 74-93%). The increased detection of BE by 12% resulted in a number needed to test (NNT) to detect one additional case of BE of 8.53 patients.
Low-grade dysplasia (LGD) was diagnosed in 26 patients by FB and 33 patients by WATS3D. Twenty-three of the 33 WATS3D patients had a negative FB. Addition of WATS3D to FB increased detection of LGD by 88.5% (23/26; 95% CI 48%–160%). The NNT to detect one additional case of dysplasia was 182. Of the 211 patients with known BE, LGD was diagnosed in three patients by FB and an additional 6 cases by WATS3D. Addition of WATS3D to FB increased the detection of LGD by 200%.
- ii. Vennalaganti et al. evaluated a total of 160 patients from May 2014 to January 2015.(13) Patients ≥ 18 years of age, with a history of BE, and willing to undergo FB and WATS3D were enrolled in the study. After any suspicious lesions were biopsied, patients were randomized into two groups: one group underwent biopsy sampling (4-quadrant FB at 1- to 2-cm intervals along the length of BE) follow by WATS3D and one group underwent WATS3D followed by FB using the same described protocol. Biopsy specimens were taken at 1-cm intervals in patients with a history of dysplasia and at 2-cm intervals in patients with non-dysplastic BE (NDBE).
The average age was 63.4 years (SD +/- 11), 122 (76.3%) were men, and most were Caucasian (n = 152; 95.0%). Of the 160 patients, 6% had a visible lesion (<10mm in size) and underwent target biopsy sampling before randomization. Seventy-six patients underwent FB followed by WATS3D and 84 underwent WATS3D follow by FB sampling. In cases were FB was negative for HGD/EAC, WATS3D led to an additional 23 cases of HGD/EAC (increase of 14% [23/160]; 95% CI 7.9%-19.3%). Of the 23 cases that WATS3D was positive in but biopsy sampling was negative, 11 were diagnosed as NDBE and 12 as indefinite for dysplasia or low-grade dysplasia. Results demonstrated a 4-fold higher detection of HGD/EAC with WATS3D compared to biopsy using the Seattle protocol. Also, the order of the procedure (FB then WATS3D vs. WATS3D then FB) did not alter the yield of HGD/EAC.
iii. Smith et al. evaluated patients undergoing screening for BE by 58 endoscopists at 21 sites from June 2013 to July 2015.(14) The endoscopists were instructed to use both WATS3D and FB to sample suspected BE only in patients with salmon-colored mucosa in the esophagus. Forceps biopsy were obtained using a 4-quadrant biopsy protocol at every 1cm and 2 cm. Any visually abnormal tissue (raised lesions, ulcerations) were biopsied with FB as well. WATS3D was used to evaluate additional areas of the BE segment that would not have been sampled by FB.
In total, 12,899 patients were included in the study with 61% females, mean age of 56 years (range of 18-93), and 14% with a known history of BE. Forceps biopsy identified 88 cases of ED and WATS3D detected an additional 213 cases missed by FB (5 LGD); 128 indefinite for dysplasia (IND); 10 high-grade dysplasia (HGD)/EAC) which represented an increased yielded from 0.68% to 2.33%. Adding WATS3D to FB increased the overall detection of ED by 242% (95% CI: 191-315%). Approximately 61 patients needed to be tested with WATS3D to identify an additional case of ED.
Forceps biopsy found 1,684 cases of BE (13.1%) and WATS3D detected 2,570 cases of BE missed by FB. Adding WATS3D to FB created a 19.9% absolute increase in the rate of detection from 13.1% to 33%, and increased the overall detection of BE by 153% (95% CI: 144-162%). The NNT with WATS3D to detect an additional case of BE was 5. Similar to previous studies, whether FB or WATS3D was completed first did not impact the results.
- Vennlalaganti et al. evaluated the inter-observer agreement of WATS3D.(15) They used WATS slides of varying degrees of BE or dysplasia which were randomly selected and distributed to four pathologists. The pathologists independently graded the degree of dysplasia to non-dysplastic, LGD, or HGD/EAC. A total of 149 slides were evaluated in a blinded fashion including 109 with no dysplasia and forty with LGD and HGD/EAC. The overall mean kappa value for all 3 diagnoses was 0.86 (95% CI 0.75-0.97). The kappa values for HGD/EAC, IND/LGD and no dysplasia were 0.95 (0.88-0.99), 0.74 (0.61-0.85) and 0.88 (0.81-0.94), respectively, indicating a high level of overall inter-observer agreement.
Technology Limitations
Currently, WATS3D is not recommended as a stand-alone substitute for cold forcep biopsies. Forcep biopsy still offers the ability to sample specific areas of concern within the esophagus. Because the WATS3D system samples larger sections of the esophagus (compared to specific locations offered by forcep biopsy), gastroenterologists or surgeons may find it difficult to identify where a biopsy specimen may have come from in relation to the gastroesophageal junction.(1) Most studies have utilized the proximal gastric folds as the landmark for the gastroesophageal junction, however, this structure is dynamic, changing position with respiration, gut motor activity, and distention of the stomach and esophagus. Some patients diagnosed with BE may have intestinal metaplasia of the cardia. These concerns are inherent in the learning curve of a new device. Further research into the use of the WATS3D system as an independent screening or diagnostic modality may be warranted.
Expert Panel Recommendation
With regards to safety:
- No significant morbidity or mortality was reported within the literature associated with the WATS3D
With regards to efficacy:
- WATS3D increases diagnostic yield by 38-150% for Barrett’s Esophagus, by 40-150% for Low Grade Dysplasia; and by 420% for High Grade Dysplasia; when compared to forceps biopsy alone.
- WATS3D technique has very high inter-observer agreement for the pathological diagnosis of non-dysplastic and dysplastic Barrett’s Esophagus.
With regards to value:
- Increased detection of pre-malignant diseases of the esophagus by the adjunctive use of WATS3D supports screening and surveillance by the adjunctive use of WATS3D during upper endoscopy in appropriate patients.
Conclusion
Wide-area trans-epithelial sampling with three-dimensional computer-assisted analysis (WATS3D, CDx Diagnostics) is a safe and effective adjunct to forcep biopsies in the evaluation of Barrett’s Esophagus, Low Grade Dysplasia, and High Grade Dysplasia.
Author Financial Disclosures/Conflict of Interest Statement
Salvatore Docimo: Consulting or received general payments from Boston Scientific Corporation, W. L. Gore & Associates, Inc., Gore, Intuitive Surgical Inc.
Mazen Al-Mansour: General payments from Intuitive Surgical, Inc.
Shawn Tsuda: Consulting, education honoraria, research support, and general payments from Allergan Inc., Intuitive Surgical Inc., Endo Pharmaceuticals Inc., and Covidien LP.
References
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- Gross SA, Smith MS, Kaul V, and the US Collaborative WATS3D Study Group. Increased detection of Barrett’s esophagus and esophageal dysplasia with adjunctive use of wide-area transepithelial sample with three-dimensional computer-assisted analysis (WATS) United European Gastroenterol J. 2018 May; 6(4): 529–535.
- Harrison R, Perry I, Haddadin W, McDonald S, Bryan R, Abrams K, Sampliner R, Talley NJ, Moayyedi P, Jankowski JA. Detection of intestinal metaplasia in Barrett’s esophagus: an observational comparator study suggests the need for a minimum of eight biopsies. Am J Gastroenterol. 2007;102:1154–1161.
- CDx Technology. (2019, June) Retrieved from http://www.cdxdiagnostics/our-technology.html.
- Statistics, Epidemiology, and End Results Program. Cancer Stat Facts: Esophageal Cancer. (2019, March) Retrieved from https://seer.cancer.gov/statfacts/html/esoph.html.
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- Harrison R, Perry I, Haddadin W, McDonald S, Bryan R, Abrams K, Sampliner R, Talley NJ, Moayyedi P, Jankowski JA. Detection of intestinal metaplasia in Barrett’s esophagus: an observational comparator study suggests the need for a minimum of eight biopsies. Am J Gastroenterol. 2007;102:1154–1161.
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- Sharma P. Review article: emerging techniques for screening and surveillance in Barrett’s oesophagus. Aliment Pharmacol Ther 2004; 20: 63–70; discussion 95–6.
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- Shaheen 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: pp. 30-50
- Vennalaganti PR, Kaul V, Wang KK, Falk GW, Shaheen NJ, Infantolino A6, Johnson DA, Eisen G, Gerson LB, Smith MS, Iyer PG, Lightdale CJ, Schnoll-Sussman F, Gupta N, Gross SA, Abrams J, Haber GB, Chuttani R, Pleskow DK, Kothari S, Goldblum JR, Zhang Y, Sharma P. Increased detection of Barrett’s esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial. Gastrointest Endosc. 2018 Feb;87(2):348-355.
- Smith MS, Ikonomi E, Bhuta R, Iorio N, Kataria RD, Kaul V, Gross SA; US Collaborative WATS Study Group. Wide-area transepithelial sampling with computer-assisted 3-dimensional analysis (WATS) markedly improves detection of esophageal dysplasia and Barrett’s esophagus: analysis from a prospective multicenter community-based study. Dis Esophagus. Dis Esophagus. 2019 Mar 1;32.
- Vennalaganti PR, Naag Kanakadandi V, Gross SA, Parasa S, Wang KK, Gupta N, Sharma P. Inter-bserver Agreement among Pathologists using Wide-Area Transepithelial Sampling With Computer-Assisted Analysis in Patients With Barrett’s Esophagus. Am J Gastroenterol. 2015 Sep;110(9):1257-1260.