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Adjunctive Techniques for Screening and Surveillance of Barrett Esophagus and Esophageal Dysplasia

Policy Number: MP-743

Latest Review Date: August 2023

Category: Medical                                                                

POLICY:

Wide-area transepithelial sampling with three-dimensional computer-assisted analysis (WATS3D) is considered investigational for all indications, including but not limited to the screening and surveillance of Barrett esophagus and esophageal dysplasia.

DESCRIPTION OF PROCEDURE OR SERVICE:

Barrett Esophagus

Barrett esophagus (BE) is a condition in which the squamous epithelium that normally lines the esophagus is replaced by specialized columnar-type epithelium known as intestinal metaplasia in response to irritation and injury caused by gastroesophageal reflux disease (GERD). Barrett esophagus occurs in the distal esophagus. It may involve any length of the esophagus, be focal or circumferential, and is visualized on endoscopy with a different color than background squamous mucosa. Confirmation of BE requires a biopsy of the columnar epithelium and microscopic identification of intestinal metaplasia. The prevalence of BE in the United States is estimated at 5.6%. Risk factors associated with the development of BE include GERD, male gender, central obesity, and age over 50 years. The diagnosis of GERD is associated with a 10% to 15% risk of BE. However, a population-based analysis from Sweden observed that 40% of the study cohort with esophageal cancer reported no prior history of GERD symptoms.

Cancer Risk and Management

Intestinal metaplasia is a precursor to esophageal adenocarcinoma, and patients with BE are at a 40-fold increased risk for developing this disease compared to the general population.

However, there are few data to guide recommendations about management and surveillance, and many issues are controversial. Guidelines from the American College of Gastroenterology (ACG) and a consensus statement from an international group of experts (Benign Barrett's and CAncer Taskforce) on the management of BE are published. The ACG recommendations for surveillance are stratified by the presence and grade of dysplasia.

When no dysplasia is detected, ACG has reported the estimated risk of progression to cancer ranges from 0.2% to 0.5% per year and endoscopic surveillance every 3 to 5 years is recommended. For low-grade dysplasia, the estimated risk of progression is 0.7% per year, and endoscopic therapy is preferred; however, endoscopic surveillance every 12 months is considered an acceptable alternative. It is recommended that both options are discussed with the patient. Precise estimates of cancer risk are not available for individuals with low-grade dysplasia due to large disparities among studies on its natural history. Interobserver variability in the diagnosis of low-grade dysplasia with standard biopsy may be responsible, with expert pathologists commonly downgrading initial diagnoses made by community pathologists.

The Benign Barrett's and CAncer Taskforce consensus group did not endorse routine surveillance for people without dysplasia and was unable to agree on surveillance intervals for low-grade dysplasia.

For high-grade dysplasia, the estimated risk of progression is about 7% per year, and ACG has recommended endoscopic eradication therapy, with the type of procedure dependent on patient age and life expectancy, comorbidities, the extent of dysplasia, local expertise in surgery and endoscopy, and patient preference. Approximately 40% of patients with high-grade dysplasia on biopsy are found to have associated carcinoma in the resection specimen.

For patients who are indefinite for dysplasia, a repeat endoscopy should be performed at 3 to 6 months following optimization of acid suppressive medications. A surveillance interval of 12 months is recommended if an indefinite for dysplasia reading is confirmed on repeat endoscopy in these individuals. Many patients who are indefinite for dysplasia show regression to nondysplastic BE with subsequent endoscopic evaluation. It is unclear whether some cases of regression are observed due to sampling error.

KEY POINTS:

This evidence review was created in August 2021 with a search of the PubMed database. The most recent literature update was performed through June 28, 2023.

Summary of Evidence

For individuals with a history of Barrett esophagus (BE) who receive standard surveillance with adjunctive WATS3D, the evidence includes a meta-analysis of studies of diagnostic yield, a randomized controlled trial, a physician impact study, a decision analytic model, and a retrospective analysis of the manufacturer database. Relevant outcomes are test validity, overall survival, disease-specific survival, change in disease status, and quality of life. A meta-analysis reported incremental diagnostic yields of 6.9% and 2.4% for any dysplasia or esophageal adenocarcinoma (EAC) or high-grade dysplasia (HGD)/EAC, respectively. These studies are limited by heterogeneity in classification and reporting of test results and selection bias stemming from the enrichment of patients with a prior history of dysplasia. It is also unclear to what extent results obtained from academic centers are generalizable to community-based settings, where adherence to endoscopic biopsy guidelines is poor. In discordant cases where BE or dysplasia were identified only by WATS3D, significant physician management changes included initiation of invasive treatments. Health outcomes stemming from management changes were not reported, and risks associated with overdiagnosis and overtreatment require elucidation. Follow-up data on disease progression in these patients are limited. A retrospective analysis of the manufacturer database found a disease progression rate of 5.79% per patient-year (95% confidence interval [CI], 1.02% to 10.55%) for baseline low-grade dysplasia diagnoses via WATS3D sampling; however, study interpretation is limited as only 16 cases (0.33%) of progression defined as high-grade dysplasia or esophageal adenocarcinoma on follow-up forceps biopsy were identified. A RCT enrolling patients with a recent history of dysplasia reported an absolute increase of 10% in the diagnostic yield of HGD/EAC but did not report on long-term disease progression or mortality outcomes. No direct evidence of clinical utility was identified. Because combined use of WATS3D with standard surveillance is intended to replace the current standard of care for guiding patient management decisions regarding initiation of treatment or surveillance, direct evidence of clinical utility is required. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals at increased risk of BE who undergo standard screening with adjunctive WATS3D, the evidence includes a meta-analysis of studies of diagnostic yield, a physician impact study, a decision analytic model, and a retrospective analysis of the manufacturer database. Relevant outcomes are test validity, overall survival, disease-specific survival, change in disease status, and quality of life. A meta-analysis reported incremental diagnostic yields of 7.2% and 2.1% for any dysplasia/EAC or HGD/EAC, respectively. However, available studies have incomplete descriptions of selection criteria, and it is unclear whether study patients are at increased risk as defined by guideline recommendations for screening. In fact, 2 studies were enriched with women in whom screening is generally not recommended by society guidelines. These studies also noted that detected cases of BE in short-segment patients may actually reflect intestinal metaplasia of the cardia, which is thought to carry a significantly lower risk of cancer development compared to traditional BE. In discordant cases where BE or dysplasia were identified only by WATS3D, significant physician management changes included initiation of invasive treatments. Health outcomes from management changes were not reported, and risks associated with overdiagnosis and overtreatment require elucidation. Follow-up data on disease progression in these patients are limited. A retrospective analysis of the manufacturer database found a disease progression rate of 5.79% per patient-year (95% CI, 1.02% to 10.55%) for baseline low-grade dysplasia diagnoses via WATS3D sampling; however, study interpretation is limited as only 16 cases (0.33%) of progression defined as high-grade dysplasia or esophageal adenocarcinoma on follow-up forceps biopsy were identified. No direct evidence of clinical utility was identified. Because combined use of WATS3D with standard screening is intended to replace the current standard of care for guiding patient management decisions regarding initiation of treatment or surveillance, direct evidence of clinical utility is required. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American College of Gastroenterology

In 2016, the American College of Gastroenterology (ACG) published clinical guidelines on the diagnosis and management of Barrett esophagus (BE) on the basis of a systematic literature review. Guidelines state that "in patients with suspected BE, at least 8 random biopsies should be obtained to maximize the yield of [intestinal metaplasia] on histology. In patients with short (1-2 cm) segments of suspected BE in whom 8 biopsies are unattainable, at least 4 biopsies per cm of circumferential BE, and 1 biopsy per cm in tongues of BE, should be taken (conditional recommendation, low level of evidence)." The guidelines also state that "the role of computer-assisted or wide-field 'brush biopsy' tissue acquisition for increasing the yield of dysplasia is currently under investigation."

In a 2022 guideline update, the ACG stated that they could not make a recommendation on the use of wide-area transepithelial sampling with three-dimensional computer-assisted analysis (WATS3D) and noted that "it is difficult to know how much of the incremental benefit is truly due to more complete sampling of the mucosa by WATS-3D or better detection of dysplasia by the analysis algorithm and how much might be due to overdiagnosis of dysplasia and false-positive examinations by WATS-3D." Limitations of the existing evidence base were summarized, including a lack of studies on adjunctive use for surveillance when forceps biopsies are guided both by white light and chromoendoscopy, a lack of studies reproducing results using pathologists not employed by the manufacturer, and limited stratification of results by grade of dysplasia.

American Gastroenterological Association

In 2022, the American Gastroenterological Association issued a clinical practice update addressing new technology and innovation for surveillance and screening in BE. Best practice advice statements were issued based on a review of existing literature and expert opinion. However, statements were not formally rated based on quality of evidence or strength of recommendation. The update states that WATS3D may be used as an adjunctive technique to sample the suspected or established BE segment in addition to the Seattle biopsy protocol.

American Society of Gastrointestinal Endoscopy

In 2019, the American Society of Gastrointestinal Endoscopy (ASGE) published guidelines addressing screening and surveillance of BE based on a systematic review and meta-analysis of the literature. Recommendations were drafted at a meeting of the Standards of Practice Committee. The guidelines state that "in patients with known or suspected BE, we suggest using WATS-3D in addition to [white-light endoscopy] with Seattle protocol biopsy sampling compared with [white-light endoscopy] with Seattle protocol biopsy sampling alone (conditional recommendation, low quality of evidence)." The certainty of the recommendation was downgraded due to risk of bias, inconsistency, and indirectness. Definitions of dysplasia varied across studies, and most studies were manufacturer-funded. The guidelines also note that no recommendation for WATS-3D was made at the initial face-to-face panel meeting. The conditional recommendation was issued following review of additional published literature and a phone conference.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines on esophageal and esophagogastric junction cancers (v.2.2023) state that while WATS3D may help increase the detection of esophageal dysplasia in patients with BE, the utility and accuracy of WATS3D for detecting high-grade dysplasia and adenocarcinoma in patients with BE needs to be evaluated in larger phase III randomized trials.

Society of American Gastrointestinal and Endoscopic Surgeons

The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Technology and Value Assessment Committee (TVAC) published expert panel recommendations following a safety and efficacy analysis of WATS3D in 2020. Expert panel statements regarding the safety, efficacy, and value of WATS3D included:

  • "No significant morbidity or mortality was reported within the literature associated with the WATS3D technology."
  • "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."
  • "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."

The committee also noted that "currently, WATS3D is not recommended as a stand-alone substitute for cold forcep biopsies," as the latter still offers the ability to sample specific areas of concern or visible lesions. Additionally," further research into the use of the WATS3D system as an independent screening or diagnostic modality may be warranted."

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force (USPSTF) recommendations for the screening or surveillance of BE and esophageal dysplasia were identified.

KEY WORDS:

Wide-area transepithelial sampling with three-dimensional computer-assisted analysis, WATS3D

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). The WATS3D (CDx Diagnostics), formerly known as EndoCDx, is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply.  Refer to member’s benefit plan.  

CURRENT CODING

CPT Codes:

88104

Cytopathology, fluids, washings or brushings, except cervical or vaginal; smears with interpretation

88305

Level IV - Surgical pathology, gross and microscopic examination

88312

Special stain including interpretation and report; Group I for microorganisms (eg, acid fast, methenamine silver)

88361

Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; using computer-assisted technology

 

REFERENCES:

  1. Agha YH, Srinivasan S, Hyder J, et al. WATS 3D versus forceps biopsy in screening for Barrett's esophagus: experience in community endoscopy centers. Ann Gastroenterol. 2021; 34(2): 164-168.
  2. Anandasabapathy S, Sontag S, Graham DY, et al. Computer-assisted brush-biopsy analysis for the detection of dysplasia in a high-risk Barrett's esophagus surveillance population. Dig Dis Sci. Mar 2011; 56(3): 761-6.
  3. Bennett C, Moayyedi P, Corley DA, et al. BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia. Am J Gastroenterol. May 2015; 110(5): 662-82; quiz 683.
  4. CDx Diagnostics. WATS3D. 2023; www.cdxdiagnostics.com/wats3d. 
  5. Codipilly DC, Krishna Chandar A, Wang KK, et al. Wide-area transepithelial sampling for dysplasia detection in Barrett's esophagus: a systematic review and meta-analysis. Gastrointest Endosc. Jan 2022; 95(1): 51-59.e7.
  6. Corbett FS, Odze RD, McKinley MJ. Utility of wide-area transepithelial sampling with 3-dimensional computer-assisted analysis as an adjunct to forceps biopsy sampling in the surveillance of patients with Barrett's esophagus after endoscopic eradication therapy. iGIE. December 2022; 1(1): 33-43. DOI: 10.1016/j.igie.2022.10.011.
  7. Curvers WL, ten Kate FJ, Krishnadath KK, et al. Low-grade dysplasia in Barrett's esophagus: overdiagnosed and underestimated. Am J Gastroenterol. Jul 2010; 105(7): 1523-30.
  8. DeMeester S, Smith C, Severson P, et al. Multicenter randomized controlled trial comparing forceps biopsy sampling with wide-area transepithelial sampling brush for detecting intestinal metaplasia and dysplasia during routine upper endoscopy. Gastrointest Endosc. Jun 2022; 95(6): 1101-1110.e2. 
  9. Docimo S, Al-Mansour M, Tsuda S. SAGES TAVAC safety and efficacy analysis WATS 3D (CDx Diagnostics, Suffern, NY). Surg Endosc. Sep 2020; 34(9): 3743-3747.
  10. Fayter D, Corbett M, Heirs M, et al. A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett's oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin. Health Technol Assess. Jul 2010; 14(37): 1-288.
  11. Gross SA, Smith MS, Kaul V. 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. May 2018; 6(4): 529-535.
  12. Hirota WK, Loughney TM, Lazas DJ, et al. Specialized intestinal metaplasia, dysplasia, and cancer of the esophagus and esophagogastric junction: prevalence and clinical data. Gastroenterology. Feb 1999; 116(2): 277-85.
  13. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  14. Johanson JF, Frakes J, Eisen D, et al. Computer-assisted analysis of abrasive transepithelial brush biopsies increases the effectiveness of esophageal screening: a multicenter prospective clinical trial by the EndoCDx Collaborative Group. Dig Dis Sci. Mar 2011; 56(3): 767-72.
  15. Kaul V, Gross S, Corbett FS, et al. Clinical utility of wide-area transepithelial sampling with three-dimensional computer-assisted analysis (WATS3D) in identifying Barrett's esophagus and associated neoplasia. Dis Esophagus. Dec 07 2020; 33(12).
  16. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. Mar 18 1999; 340(11): 825-31.
  17. Muthusamy VR, Wani S, Gyawali CP, et al. AGA Clinical Practice Update on New Technology and Innovation forSurveillance and Screening in Barrett's Esophagus: Expert Review. Clin Gastroenterol Hepatol. Dec 2022; 20(12): 2696-2706.e1.
  18. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers (v.2.2023). March 10, 2023; www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. 
  19. Qumseya B, Sultan S, Bain P, et al. ASGE guideline on screening and surveillance of Barrett's esophagus. Gastrointest Endosc. Sep 2019; 90(3): 335-359.e2.
  20. Shaheen NJ, Falk GW, Iyer PG, et al. ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. Am J Gastroenterol. Jan 2016; 111(1): 30-50; quiz 51.
  21. Shaheen NJ, Falk GW, Iyer PG, et al. Diagnosis and Management of Barrett's Esophagus: An Updated ACG Guideline. Am J Gastroenterol. Apr 01 2022; 117(4): 559-587.
  22. Shaheen NJ, Smith MS, Odze RD. 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. Mar 2022; 95(3): 410-418.e1.
  23. Singer ME, Smith MS. Wide Area Transepithelial Sampling with Computer-Assisted Analysis (WATS 3D ) Is Cost-Effective in Barrett's Esophagus Screening. Dig Dis Sci. May 2021; 66(5): 1572-1579.
  24. Sinh P, Anaparthy R, Young PE, et al. Clinical outcomes in patients with a diagnosis of "indefinite for dysplasia" in Barrett's esophagus: a multicenter cohort study. Endoscopy. Aug 2015; 47(8): 669-74.
  25. Smith MS, Ikonomi E, Bhuta R, et al. 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. Mar 01 2019; 32(3).
  26. Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology. Mar 2011; 140(3): 1084-91.
  27. Trindade AJ, Odze RD, Smith MS, et al. Benefit of Adjunctive Wide Area Transepithelial Sampling with 3-DimensionalComputer-Assisted Analysis Plus Forceps Biopsy Based on Barrett's Esophagus Segment Length. Gastrointest Endosc.Apr 04 2023.
  28. van Munster SN, Leclercq P, Haidry R, et al. Wide-area transepithelial sampling with computer-assisted analysis to detect high grade dysplasia and cancer in Barrett's esophagus: a multicenter randomized study. Endoscopy. Apr 2023; 55(4):303-310.
  29. Vennalaganti PR, Kaul V, Wang KK, et al. Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial. Gastrointest Endosc. Feb 2018; 87(2): 348-355.
  30. Vennalaganti PR, Naag Kanakadandi V, Gross SA, et al. Inter-Observer Agreement among Pathologists Using Wide-Area Transepithelial Sampling With Computer-Assisted Analysis in Patients With Barrett's Esophagus. Am J Gastroenterol. Sep 2015; 110(9): 1257-60.
  31. Yantiss RK. Diagnostic challenges in the pathologic evaluation of Barrett esophagus. Arch Pathol Lab Med. Nov 2010; 134(11): 1589-600.

POLICY HISTORY:

Medical Policy Panel, August 2021

Medical Policy Group, August 2021 (5): New Medical Policy. Available for comment September 29, 2021 through November 13, 2021.

Medical Policy Panel, August 2022

Medical Policy Group, August 2022 (5): Updates to Description, Key Points, Practice Guidelines and Position Statements, Approved by Governing Bodies, and References. No change to Policy Statement.

Medical Policy Panel, August 2023

Medical Policy Group, August 2023 (11): Updates to Key Points, Benefit Application, and References. No change to Policy Statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

 

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.