CurrentBlue Cross Blue Shield - MassachusettsPolicy 249

Multimarker Serum Tests for Ovarian Adnexal Mass Assessment (OVA1, Overa, ROMA)

This policy governs coverage and prior authorization for use of the FDA‑cleared multimarker serum tests OVA1, Overa, and ROMA to assess likelihood of malignancy in women with adnexal masses and who have not yet been referred to a gynecologic oncologist. It applies to commercial members of Blue Cross Blue Shield of Massachusetts.

Policy Summary

PayerBlue Cross Blue Shield - Massachusetts

PolicyMultimarker Serum Tests for Ovarian Adnexal Mass Assessment (OVA1, Overa, ROMA)

Policy CodePolicy 249

Change TypeNo material change

Effective Date

Next Review Date

Key ActionObtain precertification/preauthorization when the procedures described in this policy are performed inpatient.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

3FDA‑cleared tests discussed

InvestigationalPolicy stance

RequiredPrecertification required (inpatient)

92–94%Reported sensitivity

42–67%

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Reported specificity

Coverage Determinations

Investigational — All Uses — Policy statement and rationale

Covered when ALL of the following are met:

Policy stance: All uses of the OVA1, Overa, and ROMA tests are investigational for Commercial Members, including but not limited to preoperative evaluation of adnexal masses to triage for malignancy; selecting individuals for surgery for an adnexal mass; screening for ovarian cancer; evaluation of individuals with clinical or radiologic evidence of malignancy; evaluation of individuals with nonspecific signs or symptoms suggesting possible malignancy; and postoperative testing and monitoring to assess surgical outcome or detect recurrent disease.

Policy statement: investigational for all uses as specified in the policy.

inv-02: Use supported by cited literature and guidelines — Evidence and guideline considerations

Evidence and guideline considerations supporting evaluation of multimarker biomarkers and algorithms:

Evidence sources: Multiple validation studies, diagnostic accuracy studies, meta-analyses, and professional guideline documents (e.g., studies validating OVA1/Overa/ROMA and guidance from FDA, ACOG, NCCN, and NICE) have evaluated multimarker tests and algorithms for risk stratification of adnexal masses.

See referenced studies and guidelines for technical performance and diagnostic accuracy (sensitivity/specificity) and for recommendations regarding specialist referral; cited references include Moore et al., Terlikowska et al., and FDA 510(k) documentation.

Diagnostic performance and limitations: While OVA1/Overa and ROMA have demonstrated high sensitivity (reported ~92–94% for OVA1/Overa; ROMA reported in some studies ~90% sensitivity) with variable specificity (reported ranges approx. 42–67%), no randomized controlled trials were identified demonstrating that use of these FDA‑cleared multimarker tests to guide referral to gynecologic oncology improves patient health outcomes.

Summary of evidence indicates insufficient direct evidence of clinical usefulness to show improved net health outcome when using test-directed referral decisions.

Guideline context: Professional guideline recommendations (e.g., NCCN, ACOG Committee Opinion No. 716, NICE) recommend evaluation by an experienced gynecologic oncologist for patients with suspected ovarian cancer; multimarker tests are intended as adjuncts to clinical and radiologic assessment, not replacements for specialist evaluation.

Guidelines inform clinical pathway and limit the standalone role of multimarker testing.

For Commercial members (Managed Care HMO and POS; and Indemnity), all uses of the OVA1, Overa, and ROMA multimarker serum tests are considered investigational. This includes, but is not limited to, use for preoperative evaluation of adnexal masses to triage for malignancy, selecting individuals for surgery, screening for ovarian cancer, evaluation of individuals with clinical or radiologic evidence of malignancy, postoperative testing or monitoring, and evaluation of nonspecific signs or symptoms. Additionally, outpatient use of these tests is explicitly not a covered service for Commercial Managed Care (HMO and POS) and for Commercial PPO and Indemnity plans; precertification/preauthorization is required when the procedures are performed inpatient.

No explicit exclusions beyond the investigational stance and outpatient noncoverage statements are listed in the referenced policy materials.

The evidence review found diagnostic accuracy data for OVA1/Overa/ROMA but no randomized or other direct comparative trials demonstrating that use of FDA‑cleared multimarker serum testing to guide referral decisions to gynecologic oncology improves patient health outcomes. Given guideline recommendations that patients with suspected ovarian cancer be evaluated by an experienced gynecologic oncologist, direct evidence showing that test‑directed referral changes outcomes is required but not available; therefore the evidence is considered insufficient to support clinical usefulness for that purpose.

The referenced document does not include any statements explicitly labeling the technology as "not medically necessary." The policy instead characterizes the tests as investigational based on insufficient evidence of improved health outcomes.

Coding and Identifiers

Investigational CPT/HCPCS codes for multimarker ovarian testsmixedNot Covered

81500	Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score
81503	Oncology (ovarian), biochemical assays of five proteins (CA-125, apoliproprotein A1, beta-2 microglobulin, transferrin and pre-albumin), utilizing serum, algorithm reported as a risk score
0003U	Oncology (ovarian) biochemical assays of five proteins (apolipoprotein A-1, CA 125 II, follicle stimulating hormone, human epididymis protein 4, transferrin), utilizing serum, algorithm reported as a likelihood score
0375U	Oncology (ovarian), biochemical assays of proteins (follicle stimulating hormone, human epididymis protein 4, apolipoprotein A-1, transferrin, beta-2 macroglobulin, prealbumin [ie, transthyretin] and cancer antigen 125), algorithm reported as ovarian cancer risk score

Regulatory identifier referencedmixed

K081754

FDA 510(k) substantial equivalence decision summary: OVA1 Test (reference to K081754)

Menopausal status — modifier/input used in ROMA algorithm (studies)

RoleMenopausal status is used as a modifier/input in the ROMA (Risk of Ovarian Malignancy Algorithm).

ApplicationApplied to classify women presenting with an adnexal mass as premenopausal or postmenopausal when calculating ROMA score.

RationaleSpecificity and positive predictive value of CA-125 (and combined algorithms) differ by menopausal status, justifying separate consideration in ROMA.

EvidenceMultiple validation studies and meta-analyses cited evaluate ROMA performance with menopausal-status stratification.

Provider Requirements and Authorization

Prior Authorization

Prior Authorization Required

Prior Authorization Required — Inpatient: For services described in this policy, precertification/preauthorization IS REQUIRED when the procedure is performed inpatient. Lack of required precertification for inpatient procedures may result in denial of payment.

Precertification/preauthorization required for inpatient procedures

Denial Risk

Outpatient Noncoverage — Verify Benefits

Outpatient Noncoverage Triggers — Commercial Managed Care (HMO and POS): outpatient use of the services described in this policy is not a covered benefit. Commercial PPO and Indemnity: outpatient use is not a covered benefit. Providers should verify member-specific benefits prior to ordering outpatient testing to avoid claim denials.

Commercial Managed Care (HMO and POS): outpatient = not a covered service

Clinical Background

Epithelial ovarian cancer is used as a collective term for high‑grade serous epithelial ovarian, fallopian tubal, and primary peritoneal carcinomas and is associated with high mortality. Most adnexal masses encountered in adult women are benign (an estimated ~68%); a small proportion represent malignancy. Because definitive diagnosis requires surgical evaluation, accurate preoperative risk stratification is clinically important to direct patients to appropriate surgical teams and to gynecologic oncology consultation when malignancy is suspected. Multimarker serum tests (OVA1, Overa, ROMA) have been developed to aid preoperative assessment by estimating the likelihood of malignancy, but they are intended as adjuncts to—not replacements for—clinical assessment and specialist referral.

Definitions and Test Descriptions

Epithelial ovarian cancer — definition and scope

DefinitionEpithelial ovarian cancer is a collective term for high-grade serous epithelial ovarian, fallopian tubal, and peritoneal carcinomas that share pathogenesis, presentation, and treatment.

Clinical contextMost adnexal masses are benign; about 22% are invasive malignant lesions and 3% metastatic disease; surgery is required for definitive diagnosis.

Referral implicationWomen with masses with high likelihood of malignancy should undergo surgical staging by a gynecologic oncologist; criteria differ for premenopausal and postmenopausal women.

Intended use of OVA1/Overa/ROMA — aid to assess likelihood of malignancy in patients with adnexal masses not yet referred to oncologist

Intended useAid to further assess whether malignancy is present in a patient with an ovarian adnexal mass who has not yet been referred to an oncologist, used in conjunction with clinical and radiologic evaluation.

Policy Summary

PayerBlue Cross Blue Shield - Massachusetts

PolicyMultimarker Serum Tests for Ovarian Adnexal Mass Assessment (OVA1, Overa, ROMA)

Policy CodePolicy 249

Change TypeNo material change

Effective Date

Next Review Date

Key ActionObtain precertification/preauthorization when the procedures described in this policy are performed inpatient.

SourceLink

On This Page

Commercial PPO and Indemnity: outpatient = not a covered service

Prior Authorization

Prior Authorization — FDA and Guideline Evidence

Prior Authorization Informed by FDA Clearance and Guidelines — Prior authorization decisions may be informed by FDA 510(k) determinations and relevant professional guidelines (e.g., ACOG, NCCN, NICE). Providers should include documentation of how FDA-cleared multimarker testing (and the supporting evidence or guidance) informs the requested service.

Reference FDA 510(k) summaries and device-specific guidance when applicable
Cite relevant professional guidelines (NCCN, ACOG, NICE) in authorization requests

Documentation Required

Clinical Pathway — Use as Adjunct to Assessment

Clinical Pathway Context — Multimarker serum tests (OVA1, Overa, ROMA) are intended as adjuncts to clinical assessment and not replacements for evaluation by a gynecologic oncologist. NCCN recommends evaluation by an experienced gynecologic oncologist for suspected ovarian cancer; documentation should reflect how test results will be used in the clinical pathway (e.g., to inform referral decisions).

Document clinical assessment and rationale for how multimarker testing will influence referral or surgical planning
Confirm whether patient will be evaluated by or referred to a gynecologic oncologist as recommended

Billing Rule

Coding and Documentation Requirements

Coding and Documentation — Providers should report all services using the most up-to-date procedure, revenue, and diagnosis codes, and include modifiers and clinical rationale supporting medical necessity. Inclusion or exclusion of specific codes in policy materials is informational only and does not by itself determine coverage.

Report services with current CPT/HCPCS/ICD-10 codes and appropriate modifiers
Include clinical notes showing how test results will affect management

Note

Operational Gaps — Contact Payer If Unclear

Operational Notes / Unspecified Rules — Some prior authorization or denial triggers and step-therapy rules are not fully specified in the reference materials provided. When requirements are not explicitly stated here, follow payer-specific prior authorization procedures and request clarification from the plan as needed.

No step therapy rules specified in these reference chunks
Prior authorization/denial triggers not fully specified — contact plan for operational details

Documentation Required

Cite Professional Guidelines in Authorization Requests

Reference Professional Guidelines — When documenting clinical rationale for authorization or medical necessity, providers should reference applicable professional guidelines (ACOG, NCCN, NICE) and relevant peer-reviewed evidence supporting use in the specific clinical scenario.

Cite relevant guideline recommendations and category levels when available
Attach key references or summaries that support clinical use for the member

Use caseIntended for preoperative triage of patients with adnexal masses to help identify those who may benefit from referral to a gynecologic oncologist.

LimitationsNot intended as a stand-alone diagnostic test; developed and evaluated only in patients with adnexal masses and planned surgery; not validated for screening or monitoring.

OVA1 multi-marker blood test — FDA 510(k) cleared multivariate assay for adnexal mass assessment

Regulatory statusOVA1 is a multimarker blood test that has been cleared by the U.S. Food and Drug Administration (FDA 510(k)).

Test descriptionMultivariate assay integrating multiple serum protein analytes and reporting an algorithm-derived risk score to predict malignancy in adnexal masses.

Intended populationDeveloped and evaluated in women with adnexal masses who have planned surgery; positive results may prompt referral to gynecologic oncology.

ROMA — Risk of Ovarian Malignancy Algorithm combining HE4 and CA125 with menopausal status

DescriptionROMA is the Risk of Ovarian Malignancy Algorithm that combines serum HE4 and CA-125 concentrations with menopausal status to stratify risk of malignancy.

PurposeDesigned to aid, in conjunction with clinical assessment, in classifying women with adnexal masses as having high or low likelihood of malignancy prior to referral or surgery.

Evidence basePerformance of ROMA has been evaluated in multiple studies and meta-analyses comparing ROMA to CA-125 and HE4 individually and to other indices.

Serum biomarkers used (HE4 and CA-125)

BiomarkersHE4 (human epididymis protein 4) and CA-125 (cancer antigen 125) are the primary serum biomarkers used individually or in combination for ovarian cancer detection and are inputs to ROMA.

Use in panelsThese biomarkers are used either alone or combined in multimarker panels (e.g., OVA1/Overa include additional proteins) to derive algorithmic risk scores.

Clinical notePerformance characteristics differ by biomarker and by menopausal status; combined algorithms aim to improve sensitivity and specificity over single markers.