CurrentPremera BluecrossPolicy 7.01.596

Adjunctive Techniques for Screening, Surveillance, and Risk Classification of Barrett Esophagus and Esophageal Dysplasia

Defines coverage stance for adjunctive tests (WATS3D, TissueCypher, Esopredict) used with endoscopy/biopsy for screening, surveillance, or risk stratification of Barrett esophagus and esophageal dysplasia for Premera Bluecross members.

Policy Summary

PayerPremera Bluecross

PolicyAdjunctive Techniques for Screening, Surveillance, and Risk Classification of Barrett Esophagus and Esophageal Dysplasia

Policy CodePolicy 7.01.596

Change TypeNo material change

Effective DateFeb 1, 2026

Next Review DateJan 1, 2026

Key ActionWhen submitting claims or prior authorization requests for TissueCypher or Esopredict, include the listed CPT codes and CLIA laboratory identifiers and supporting documentation.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

3Adjunctive technologies evaluated

InvestigationalWATS3D stance

InvestigationalTissueCypher/Esopredict stance

2025Last literature update

CLIA LDTsRegulatory status

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Coverage Criteria

Investigational (Not Covered) technologies

Coverage stance as stated in policy coverage criteria

WATS3D Investigational: 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.

Policy states WATS3D investigational; evidence insufficient to show improvement in net health outcome.

TissueCypher Investigational: TissueCypher is considered investigational for assessing the risk of progression to high-grade dysplasia or esophageal adenocarcinoma in individuals with Barrett esophagus.

Clinical validity data exist but clinical utility and impact on health outcomes not demonstrated.

Esopredict Investigational: Esopredict is considered investigational for assessing the risk of progression to high-grade dysplasia or esophageal adenocarcinoma in individuals with Barrett esophagus.

Clinical validity data exist but no evidence of clinical utility; insufficient to demonstrate improvement in net health outcome.

Guideline and evidence summary

Summary of professional guidance and evidence relevant to coverage decisions

ACG (2016, 2022): 2016 ACG recommends random biopsy sampling (Seattle protocol) and states the role of wide-field/brush biopsy is under investigation; the 2022 update could not make a recommendation on WATS3D and noted concerns about overdiagnosis and limitations of the evidence base.

ACG: conditional/no recommendation

AGA (2022, 2025): 2022 AGA clinical practice update suggests WATS3D may be used as an adjunct and nonendoscopic cell-collection devices may be considered for screening; the 2025 AGA surveillance guideline made no recommendation for or against routine use of WATS3D or TissueCypher for surveillance or risk stratification.

AGA: permissive but inconclusive

ASGE (2019): ASGE suggests using WATS3D in addition to white-light endoscopy with Seattle protocol (conditional recommendation, low-quality evidence).

conditional recommendation

Investigational / Not medically necessary statements

Policy stance statements recorded in history entries:

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

From history entry 02/04/22

TissueCypher and Esopredict investigational for risk assessment: TissueCypher and Esopredict are considered investigational for assessing the risk of progression to high-grade dysplasia or esophageal adenocarcinoma in individuals with Barrett esophagus.

Added 04/06/25; referenced in history

WIDE-AREA TRANSEPITHELIAL SAMPLING WITH THREE-DIMENSIONAL COMPUTER-ASSISTED ANALYSIS (WATS3D), TissueCypher, and Esopredict are considered investigational for all indications related to the screening, surveillance, or risk assessment of Barrett esophagus and esophageal dysplasia. The policy notes that, although diagnostic and clinical-validity studies exist for these adjunctive tests (including meta-analyses, randomized trials, and physician-impact studies), there is insufficient direct evidence that use of these technologies improves net health outcomes or provides clinical utility beyond standard endoscopic biopsy-based care.

The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Technology and Value Assessment Committee (TVAC) reported that WATS3D increases diagnostic yield versus forceps biopsy and has high inter-observer agreement, but the committee explicitly stated that WATS3D is not recommended as a stand-alone substitute for cold forceps biopsies and that forceps biopsies remain necessary to sample specific areas of concern or visible lesions.

The policy considers WATS3D investigational for all indications, including screening and surveillance of Barrett esophagus and esophageal dysplasia. Similarly, TissueCypher and Esopredict are considered investigational for assessing risk of progression to high-grade dysplasia or esophageal adenocarcinoma in individuals with Barrett esophagus. Clinical-validity data exist for TissueCypher and Esopredict, and studies show increased diagnostic yield with WATS3D, but the available evidence lacks direct demonstration of improved long-term clinical outcomes or clinical utility to guide management decisions.

For prognostic assays, clinical-validity studies of TissueCypher report variable sensitivities and specificities and hazard ratios indicating higher progression risk for patients classified as high risk; however, studies assessing the effect of TissueCypher-informed management on long-term patient outcomes are lacking. Esopredict similarly has reported clinical-validity data but no evidence demonstrating that testing alters outcomes. Consequently, both assays are classified as investigational for risk assessment of progression to high-grade dysplasia or cancer.

Across technologies, the evidence is judged insufficient to show that routine use of WATS3D, TissueCypher, or Esopredict results in an improvement in net health outcome. Studies frequently report increased diagnostic yield or risk stratification metrics but are limited by heterogeneity, selection bias, lack of generalizability, absence of long-term outcome data, and limited or absent clinical-utility trials demonstrating that changes in management lead to better survival, reduced progression, or improved quality of life.

Professional society guidance reflects uncertainty about routine adoption of these adjunctive tests. The American College of Gastroenterology (ACG) in its 2022 update could not recommend routine use of TissueCypher for risk stratification and stated it could not make a recommendation on routine use of WATS3D due to concerns about overdiagnosis and limitations in the evidence. The American Gastroenterological Association (AGA) surveillance guideline (2025) likewise made no recommendation for or against routine use of WATS3D or TissueCypher, indicating that guideline panels find the current evidence insufficient to support routine implementation.

Because these techniques are designated investigational in the policy, they are not supported as covered services for the specified indications. Policy history entries document the investigational stance for WATS3D (policy effective 02/04/22) and the later addition of the investigational designation for TissueCypher and Esopredict (added 04/06/25); claims for these tests may therefore be denied as investigational when submitted for screening, surveillance, or risk classification of Barrett esophagus.

Coding

Listed CPT codesCPT

0108U	Gastroenterology (Barrett's esophagus), whole slide-digital imaging, including morphometric analysis, computer-assisted quantitative immunolabeling of 9 protein biomarkers (p16, AMACR, p53, CD68, COX-2, CD45RO, HIF1a, HER-2, K20) and morphology, formalin-fixed paraffin-embedded tissue, algorithm reported as risk of progression to high-grade dysplasia or cancer. (used to report TissueCypher Barrett's Esophagus Assay from Cernostics Lab).
0398U	Gastroenterology (Barrett esophagus), P16, RUNX3, HPP1, and FBN1 DNA methylation analysis using PCR, formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as risk score for progression to high-grade dysplasia or cancer (Esopredict Barrett's Esophagus Risk Classifier Assay).
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.
88361	Morphometric analysis, tumor immunohistochemistry, quantitative or semiquantitative, per specimen, each single antibody stain procedure; using computer-assisted technology.

Mentioned tests (no explicit billing codes in this excerpt)mixed

N/A	Document lists test names (TissueCypher, WATS3D, Esopredict) and notes CLIA-regulated LDT status; specific CPT/HCPCS codes not provided in this section.

Referenced CPT CodesCPT

0108U	TissueCypher (listed in policy history).
0398U	Esopredict (moved from policy 10.01.533 and listed in policy history).

Provider Actions and Billing Guidance

Prior Authorization

Prior Authorization and Test Lab Identification

Prior authorization is required for the listed CPT codes and for tests offered as laboratory-developed tests (LDTs). When submitting prior authorization requests, include the performing laboratory's CLIA number or other lab identifier (for LDTs) and documentation of the clinical indication and prior diagnostic procedures (for example, endoscopy with Seattle protocol biopsies when applicable).

Prior authorization required for CPT codes: 0108U, 0398U, 88104, 88305, 88312, 88361.
For LDTs (e.g., TissueCypher, WATS3D, Esopredict) include the laboratory CLIA certification number on requests and claims.

Prior Authorization

Prior Authorization for Listed CPT Codes

Prior authorization is required for services reported with the CPT codes listed in this policy. Ensure coding supports the clinical indication and that required documentation (procedure reports, pathology reports, prior biopsy results) is available upon request.

Affected CPT codes: 0108U, 0398U, 88104, 88305, 88312, 88361.

Background

Barrett esophagus (BE) is intestinal metaplasia of the distal esophagus, commonly associated with chronic gastroesophageal reflux disease (GERD), and is recognized as a precursor lesion for esophageal adenocarcinoma. Surveillance and management decisions are guided primarily by endoscopic inspection with targeted and systematic forceps biopsies (eg, Seattle protocol). Adjunctive technologies—including brush-based wide-area transepithelial sampling with three-dimensional computer-assisted analysis (WATS3D), tissue-systems pathology assays (TissueCypher), and methylation-based assays (Esopredict)—have been developed to augment detection or to risk-stratify patients, but the policy finds that their impact on long-term clinical outcomes remains unproven and therefore considers them investigational.

Definitions

WATS3D definition

TermWATS3D (wide-area transepithelial sampling with three-dimensional analysis)

MethodBrush-based wide-area transepithelial sampling performed during endoscopy with computer-assisted three-dimensional analysis of sampled tissue

Intended useAdjunctive sampling to standard four-quadrant forceps biopsies for detection of Barrett esophagus and dysplasia

Regulatory statusAvailable as a CLIA-regulated laboratory-developed test (offered by vendor under CLIA), FDA has not required regulatory review

Policy stanceConsidered investigational for all indications, including screening and surveillance of Barrett esophagus and esophageal dysplasia

TissueCypher definition

Policy Summary

PayerPremera Bluecross

PolicyAdjunctive Techniques for Screening, Surveillance, and Risk Classification of Barrett Esophagus and Esophageal Dysplasia

Policy CodePolicy 7.01.596

Change TypeNo material change

Effective DateFeb 1, 2026

Next Review DateJan 1, 2026

Key ActionWhen submitting claims or prior authorization requests for TissueCypher or Esopredict, include the listed CPT codes and CLIA laboratory identifiers and supporting documentation.

SourceLink

On This Page

NCCN (v.4.2025): NCCN notes WATS3D may increase detection but its utility for detecting high-grade dysplasia and adenocarcinoma requires larger phase III trials.

calls for more evidence

SAGES (TVAC 2020): SAGES expert panel reported increased diagnostic yield with WATS3D and stated it is not recommended as a stand-alone substitute for forceps biopsies.

expert panel statements

Claims lacking required supporting documentation may be denied or subject to retrospective review.

Denial Risk

Investigational Technologies May Be Denied

Tests and techniques that the policy considers investigational may be denied. WATS3D, TissueCypher, and Esopredict are identified in this policy as investigational for specified uses and are subject to medical necessity review and denial when billed for investigational indications.

WATS3D is considered investigational for all indications, including screening and surveillance of Barrett esophagus and esophageal dysplasia.
TissueCypher and Esopredict are considered investigational for assessing risk of progression to high-grade dysplasia or esophageal adenocarcinoma in individuals with Barrett esophagus.

Note

No Medicare National Coverage Determination

There is no Medicare national coverage determination for these tests or technologies. Providers should not rely on a Medicare NCD to establish coverage; local Medicare Administrative Contractor (MAC) rules and member benefit contracts may further affect coverage.

No Medicare national coverage determination exists for WATS3D, TissueCypher, or Esopredict.

Denial Risk

Investigational Technique and Prognostic Assay Denial Risk

Because the policy designates certain adjunctive techniques and prognostic assays as investigational, claims for these techniques are at elevated risk for denial. WATS3D (wide-area transepithelial sampling with three-dimensional computer-assisted analysis) is investigational for all indications. TissueCypher and Esopredict are investigational when used to assess progression risk in Barrett esophagus.

WATS3D investigational for all indications — denial risk for screening or surveillance use.
TissueCypher and Esopredict investigational for prognostic use — denial risk when billed to assess progression to high-grade dysplasia or esophageal adenocarcinoma.

Note

Professional Guidelines Describe Adjunctive Techniques as Adjunctive or Optional

Professional society guidance generally describes adjunctive techniques (for example, WATS3D) as adjunctive or optional to standard biopsy protocols (Seattle protocol) rather than replacements. Follow accepted professional guidelines and document adherence to standard-of-care sampling when using adjunctive tools.

ACG, AGA, and ASGE guidance describe adjunctive techniques as optional or adjunctive to the Seattle biopsy protocol.
Document that Seattle protocol biopsies were performed when adjunctive techniques are used in surveillance to support clinical necessity.

MethodTissue systems pathology assay using morphometric analysis and computer-assisted quantitative immunolabeling of multiple protein biomarkers on formalin-fixed paraffin-embedded (FFPE) tissue

Intended useReport an algorithm-derived risk of progression to high-grade dysplasia or esophageal adenocarcinoma in Barrett esophagus

CPT code0108U (described in policy as TissueCypher Barrett's Esophagus Assay)

Regulatory statusOffered as a CLIA-regulated laboratory-developed test; FDA has not required regulatory review

Esopredict definition

TermEsopredict

MethodDNA methylation PCR assay (p16, RUNX3, HPP1, FBN1) performed on FFPE tissue producing an algorithm-reported risk score for progression

Intended useAssess risk of progression to high-grade dysplasia or esophageal adenocarcinoma in patients with Barrett esophagus

CPT code0398U (described in policy as Esopredict Barrett's Esophagus Risk Classifier Assay)

Regulatory statusAvailable as a CLIA-regulated laboratory-developed test (Previse/Castle BioSciences); no FDA regulatory requirement to date

WATS3D (alternate reference)

TermWATS3D (alternate reference)

DescriptionComputer-assisted brush biopsy procedure performed during endoscopy as an adjunct to standard four-quadrant forceps biopsy to increase detection of Barrett esophagus and dysplasia

Guideline noteAGA and ASGE acknowledge WATS3D as an adjunctive technique; SAGES does not recommend it as a stand-alone substitute for forceps biopsies

Evidence noteClinical utility remains unproven; additional comparative studies to Seattle protocol are recommended

Nonendoscopic cell-collection devices

TermNonendoscopic cell-collection devices

ExamplesCytosponge, EsoCheck, EsophaCap (swallowable sponge or capsule-based devices)

MethodSwallowed capsule or sponge that collects esophageal cells for biomarker or DNA testing as a minimally invasive alternative to endoscopy

Guideline noteAGA suggests nonendoscopic devices may be considered as an option to screen for Barrett esophagus

TissueCypher (alternate reference)

TermTissueCypher (alternate reference)

Assay detailsWhole slide digital imaging with morphometric analysis and quantitative immunolabeling of 9 protein biomarkers on FFPE tissue; algorithm reports risk of progression to high-grade dysplasia or cancer

Documentation/CodingListed CPT code 0108U in policy; sample reports and vendor materials cited in references

Regulatory statusOffered as CLIA-regulated laboratory-developed test; laboratories must be CLIA-certified for high-complexity testing

Adjunctive techniques for Barrett esophagus (list)

Adjunctive techniques listedWATS3D; TissueCypher tissue-systems pathology; Esopredict (methylation assay); nonendoscopic methylated DNA/epigenetic assays (e.g., EsoGuard, EsoCheck)

Intended rolesIncrease detection of Barrett esophagus and dysplasia (WATS3D) or provide prognostic risk stratification for progression to high-grade dysplasia/cancer (TissueCypher, Esopredict)

Policy stance summaryThese adjunctive techniques are considered investigational for screening, surveillance, or risk assessment of Barrett esophagus and esophageal dysplasia

Guideline contextProfessional societies provide conditional or limited recommendations; larger phase III trials and evidence of clinical utility are needed