CurrentPremera BluecrossPolicy 7.01.167

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

This policy describes coverage stance for adjunctive tests (WATS3D, TissueCypher, Esopredict) used with endoscopy/biopsy for screening, surveillance, and risk stratification of Barrett esophagus and esophageal dysplasia for Premera Blue Cross members.

Policy Summary

PayerPremera Bluecross

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

Policy CodePolicy 7.01.167

Change TypeNo material change

Effective DateFeb 1, 2026

Next Review DateJan 1, 2026

Key ActionDocument clinical indication and rationale when using adjunctive tests and include CLIA certification and laboratory reports when billing.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

3adjunctive technologies evaluated

Investigationalcoverage stance (WATS3D)

Investigationalcoverage stance (TissueCypher/Esopredict)

2CPT code additions noted

Nov 6, 2025

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literature review through

Coverage Determinations

Investigational and not covered adjunctive tests

Covered when ALL of the following are met:

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.

Meta-analyses and an RCT report incremental diagnostic yield but there is no demonstrated clinical utility or improved net health outcomes; evidence insufficient to support coverage.

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

Clinical validity studies report variable sensitivity and specificity and physician impact data are limited to decision changes or simulated cases; no direct evidence of improved long-term health outcomes.

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

Clinical validity studies report variable sensitivity and specificity and no clinical utility studies demonstrating improved outcomes; evidence insufficient.

Professional society guidance (adjunctive techniques)

Summary of professional society positions (coverage-relevant guidance):

ACG 2016 & 2022: ACG (2016) recommends systematic forceps biopsies (Seattle protocol) and states WATS3D is under investigation; ACG (2022) could not make a recommendation for WATS3D and noted limitations in evidence; the ACG also conditionally supports nonendoscopic sponge devices as an alternative for screening in selected patients.

ACG cites concerns about potential overdiagnosis and lack of reproducibility outside manufacturer-associated studies.

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

AGA notes incremental yield for WATS3D but calls for further comparative studies; reports limited evidence for TissueCypher performance.

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

Investigational - Risk stratification assays

Policy-level determinations documented in history

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

Statement was added to the policy history; CPT codes for these assays (0108U, 0398U) were added to the policy record but investigational stance remains and may affect coverage decisions.

The policy considers WATS3D, TissueCypher, and Esopredict investigational for all indications. Specifically, WATS3D is investigational for screening and surveillance of Barrett esophagus and esophageal dysplasia, and TissueCypher and Esopredict are investigational for assessing risk of progression to high‑grade dysplasia or esophageal adenocarcinoma in individuals with Barrett esophagus.

Professional society review has emphasized that WATS3D should not be used as a stand‑alone substitute for cold forceps biopsies. Expert panels note that WATS3D may increase detection but lack the ability to sample targeted visible lesions the way forceps biopsies do, and therefore recommend its use only as an adjunct to, not a replacement for, standard biopsy protocols.

At the policy level, WATS3D is considered investigational for all indications, including but not limited to screening and surveillance. The policy history also documents that TissueCypher and Esopredict were added as investigational for assessing progression risk in individuals with Barrett esophagus.

The evidence base for adjunctive technologies shows improved diagnostic yield in some studies (meta‑analyses and clinical validity studies) but lacks direct evidence that adjunctive use leads to improved patient‑level outcomes. Limitations include heterogeneity among studies, selection bias, limited or absent long‑term follow‑up, and absence of trials demonstrating that changes in management based on these tests improve survival, disease progression, or quality of life. Consequently, available data are insufficient to demonstrate clinical utility.

Guideline panels from the ACG and AGA were unable to recommend routine use of TissueCypher or p53 immunohistochemistry for routine risk stratification due to limited sensitivity and specificity and insufficient evidence of benefit. The ACG (2022) could not make a recommendation for TissueCypher and noted the low sensitivity/specificity of available biomarkers; the AGA (2025) similarly made no recommendation for or against routine TissueCypher testing.

Policy history entries document the investigational determination for these adjunctive techniques across multiple updates. The original policy entry noted WATS3D as investigational for all indications, and later history records explicitly added the investigational status of TissueCypher and Esopredict for progression risk assessment, with CPT codes for those assays subsequently added to the policy record.

Billing Codes and Coding Details

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 (e.g., Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each

Codes referenced in this sectionmixed

N/A	No specific CPT/HCPCS/ICD-10 codes listed in these chunks

Referenced CPT-level test codes addedCPT

0108U	TissueCypher (added to policy)
0398U	Esopredict (added to policy)

Planned enrollment sizes in listed trials

Example planned enrollment125 (NCT05210049)

Example planned enrollment200 (NCT05056051)

Example planned enrollment90,000 (NCT04312633)

Example planned enrollment2,298 (NCT05530343)

Example planned enrollment416 (ongoing WATS study)

Example planned enrollment680 (ongoing cohort study)

Provider Billing and Documentation Actions

Billing Rule

Billing Codes for Listed Assays

Billing and coding guidance for assays and related pathology testing. Use the CPT codes listed below when billing for these assays and associated pathology services; ensure documentation supports use of adjunctive molecular or imaging assays in addition to standard biopsy protocols.

CPT 0108U — TissueCypher Barrett's Esophagus Assay (whole-slide digital imaging + morphometric analysis and 9 protein biomarkers).
CPT 0398U — Esopredict Barrett's Esophagus Risk Classifier Assay (DNA methylation analysis of P16, RUNX3, HPP1, FBN1).
Pathology CPTs commonly billed in association: 88104 (cytopathology smears), 88305 (surgical pathology level IV), 88312 (special stains), 88361 (morphometric analysis for tumor IHC).

Prior Authorization

Background and Scope

Barrett esophagus (BE) is intestinal metaplasia of the distal esophagus associated with gastroesophageal reflux disease and an increased risk of esophageal adenocarcinoma. Standard management consists of upper endoscopy with biopsy for screening and surveillance. Adjunctive tests and sampling techniques—such as WATS3D (wide‑area transepithelial brush sampling with computerized three‑dimensional analysis), TissueCypher (multimarker tissue‑systems pathology assay), and Esopredict (DNA methylation assay)—have been developed to improve detection or risk stratification, but current evidence does not demonstrate that their adjunctive use produces better long‑term clinical outcomes than standard endoscopy with forceps biopsy.

Key Terms and Test Descriptions

WATS3D — definition and method description

TermWATS3D (Wide-area transepithelial sampling with 3-dimensional computer-assisted analysis)

MethodBrush-sampling (wide-area transepithelial) performed during endoscopy as an adjunct to standard four-quadrant forceps biopsy

Analytic approachSpecimens analyzed using computerized 3-D algorithms/computer-assisted analysis to detect intestinal metaplasia and dysplasia

Regulatory statusAvailable as a CLIA laboratory-developed test; laboratories must be CLIA high-complexity certified

TissueCypher — definition and assay description

Test nameTissueCypher (tissue systems pathology test)

Policy History and Updates

2024-12-10policy_update

Policy added investigational statement: 'TissueCypher and Esopredict are considered investigational for assessing the risk of progression to high-grade dysplasia or esophageal adenocarcinoma in individuals with Barrett esophagus' and CPT code 0108U (TissueCypher) was added; CPT code 0398U for Esopredict was also added (moved from a different policy). Literature review through June 26, 2024 was included.

2025-04-06effective_date

Policy effective for dates of service on or after April 6, 2025 following 90-day provider notification related to the December 10, 2024 approval.

2026-01-01annual_review

Policy Summary

PayerPremera Bluecross

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

Policy CodePolicy 7.01.167

Change TypeNo material change

Effective DateFeb 1, 2026

Next Review DateJan 1, 2026

Key ActionDocument clinical indication and rationale when using adjunctive tests and include CLIA certification and laboratory reports when billing.

SourceLink

On This Page

Recommendation downgraded due to bias, inconsistency, and indirectness in studies.

NCCN 2025: NCCN (v.4.2025) acknowledges WATS3D may increase detection of dysplasia but states that larger phase III randomized trials are needed to evaluate utility and accuracy for detecting high-grade dysplasia and adenocarcinoma.

NCCN calls for further high-quality trials to establish clinical utility.

Prior authorization: none specified in this policy. Follow the standard Premera prior authorization processes when applicable under the member's benefit plan or when required by contract. Providers should verify PA requirements via normal Premera channels before performing testing.

No specific prior authorization requirement is listed in this policy for TissueCypher, Esopredict, or WATS3D.
When PA is required by the member's benefit plan, submit clinical documentation justifying the test, including indication, biopsy results, and why adjunctive testing is being considered.

Note

No Medicare National Coverage Determination

There is no Medicare national coverage determination (NCD) for these assays. Absence of an NCD may affect individual payer coverage decisions; providers should confirm coverage with the member's plan.

Medicare National Coverage: None — payers may apply their own coverage rules in the absence of an NCD.
Confirm member-specific coverage and benefit limitations prior to testing.

Denial Risk

Investigational Test Denial Risk

Investigational status may lead to claim denials. TissueCypher, Esopredict, and WATS3D are considered investigational for their stated indications in this policy; billing for these tests risks denial if coverage criteria are not met or if the test is considered investigational under the member's plan.

TissueCypher and Esopredict are considered investigational for assessing progression risk to high-grade dysplasia or esophageal adenocarcinoma in Barrett esophagus.
WATS3D is considered investigational for all indications, including screening and surveillance of Barrett esophagus and esophageal dysplasia.
Expect potential denial for tests billed for investigational indications; provide robust clinical rationale and supporting documentation if requesting coverage.

Assay descriptionDigital whole-slide imaging with morphometric analysis and computer-assisted quantitative immunolabeling of multiple protein biomarkers reported via an algorithm as a risk score for progression to high-grade dysplasia or cancer

Biomarkers/analytesMultiplex IHC including biomarkers such as p16, AMACR, p53, CD68, COX-2, CD45RO, HIF1a, HER-2, K20 (per CPT descriptor)

Regulatory statusOffered as a CLIA laboratory-developed test; CPT code 0108U was added to the policy

Esopredict — assay definition and markers

Test nameEsopredict (DNA methylation assay)

Assay descriptionPCR-based DNA methylation analysis of selected genes in FFPE tissue, reported as an algorithm-derived risk score for progression to high-grade dysplasia or cancer

Markers includedP16, RUNX3, HPP1, FBN1 (per CPT descriptor for 0398U)

Regulatory statusOffered as a CLIA laboratory-developed test; CPT code 0398U was added to the policy

WATS3D (alternate reference) — adjunctive brush-sampling with 3D computer assistance

Technique summaryAdjunctive brush-sampling (wide-area transepithelial) collected during endoscopy analyzed with computerized 3-D algorithms to augment detection of intestinal metaplasia and dysplasia

Use casePerformed in addition to standard four-quadrant (Seattle) forceps biopsies rather than as a stand-alone replacement

Evidence noteMeta-analyses and RCTs show incremental diagnostic yield but clinical utility and improved health outcomes are unproven

Regulatory statusAvailable under CLIA as a laboratory-developed test

TissueCypher (alternate reference) — CLIA LDT for risk stratification

Test descriptionCLIA laboratory-developed tissue-systems pathology assay using whole-slide digital imaging and multiplex protein biomarker quantification with algorithm-reported risk stratification

Intended useRisk-stratify patients with Barrett's esophagus for progression to high-grade dysplasia or esophageal adenocarcinoma

Key analytic featuresMorphometric analysis and computer-assisted quantitative immunolabeling of multiple protein biomarkers with algorithmic classification

Regulatory & codingAvailable as CLIA LDT; CPT code 0108U documents the assay in billing

Nonendoscopic cell-collection devices — Cytosponge, EsoCheck, EsophaCap

Device classNonendoscopic cell-collection devices (swallowable capsule or sponge-based) such as Cytosponge, EsoCheck, EsophaCap

ProcedurePatient swallows a capsule or sponge device that collects esophageal cells for biomarker analysis without endoscopy

Intended useMinimally invasive screening for Barrett's esophagus when combined with appropriate biomarkers

Guideline positionACG and AGA note these devices may be acceptable alternatives for screening in selected patients (conditional/recommended in guidance summaries)

Investigational — policy use of the term 'Investigational'

Policy termInvestigational (as used in policy history)

Meaning in this policyTechnologies classified as investigational are not supported by sufficient evidence of improved clinical outcomes and are considered not covered for the listed indications

Examples in this policyWATS3D, TissueCypher, and Esopredict are designated investigational for screening, surveillance, and risk stratification of Barrett esophagus

Coverage implicationClaims for tests labeled investigational may be denied depending on member benefits; providers should verify benefits and document rationale if used

Annual review approved December 8, 2025 updated the policy with literature review through November 6, 2025; policy statements remained unchanged.