ModifiedHealthfirstPolicy PO-RE-041v5

Serum Tumor Markers for Malignancies

This policy governs when measurement of serum tumor markers is considered covered or not covered for diagnosis, workup, monitoring, surveillance, and follow-up of various malignancies for Healthfirst members in North Carolina.

Policy Summary

PayerHealthfirst

PolicySerum Tumor Markers for Malignancies

Policy CodePolicy PO-RE-041v5

Change TypeRevised coverage indicationsadded CPT 0558U/0559U

Effective DateOct 15, 2025

Next Review DateN/A

Key ActionDocument test indication and frequency on the claim and use new CPT codes 0558U/0559U for applicable proprietary assays beginning 7/1/2025.

SourceLink

POLICY UPDATE CHANGES

Adjusted terminology from 'serum tumor markers' to 'serum biomarkers' to broaden the definition.

Added and removed multiple specific indications across biomarkers (e.g., ALP, CA 19-9, CA-125, HE4, inhibin, beta-2 microglobulin, serum free light chains) including additions for occult primary workup and monitoring/follow-up for various ovarian and other cancers.

Added CPT codes 0558U and 0559U effective 7/1/2025.

Added CPT codes 0558U and 0559U (effective date 7/1/2025).

Expanded ovarian cancer indications across multiple tumor markers (AFP, CA-125, CA 19-9) to include specific histologies such as carcinosarcoma, clear cell carcinoma, grade 1 endometrioid carcinoma, mucinous neoplasms, and low-grade serous carcinoma for monitoring/follow-up.

Added indications for tumor markers (e.g., CA 15-3/27.29, CA 19-9) for occult primary cancers for prognosis assessment and monitoring/follow-up.

Removed the Lactate dehydrogenase (LDH) section from serum tumor biomarker designation.

Inhibin (INHA) section: removed 'adrenocortical carcinoma' and added 'occult primary (unknown primary cancer)' indication for additional workup.

Added 'Castleman disease' as an indication under Serum free light chains with 'workup' and 'follow-up' to multiple myeloma.

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2new CPT codes added

multiplebiomarkers with updated indications

Severalproteomic/proprietary tests mentioned

~20+distinct codes listed

quarterlydefault monitoring frequency

Coverage Criteria for Serum Tumor Biomarkers

Covered tumor marker indications

Measurement of the following serum biomarkers meets coverage criteria when performed for the specific listed indications and frequencies:

Covered markers and indications (selection examples): ALP: workup for bone neoplasms and uveal melanoma; AFP: HCC—screening, workup, surveillance (every 3–6 months for 2 years, then every 6 months), intrahepatic cholangiocarcinoma workup, occult primary workup, ovarian cancer initial workup/during primary chemotherapy/monitoring and follow-up (including expanded ovarian histologies), germ cell tumor surveillance with specified frequencies; B2M: workup for lymphoid malignancies and multiple myeloma; BNP/NT-proBNP: initial diagnostic workup in multiple myeloma; Calcitonin: medullary thyroid cancer—workup, post-surgical evaluation and surveillance (2–3 months postoperative, then every 6–12 months) and MEN2 evaluation; CA15-3/CA27.29: monitoring metastatic breast cancer; CA19-9: baseline and monitoring for pancreatic, ampullary, biliary, gallbladder, intrahepatic cholangiocarcinoma and ovarian indications with surveillance cadences noted; CA-125: baseline and monitoring for ovarian/fallopian tube/primary peritoneal cancer, endometrial carcinoma, Lynch syndrome surveillance, appendiceal adenocarcinoma, peritoneal mesothelioma and uterine neoplasms; CEA: baseline and surveillance for appendiceal, colon, rectal, and other indicated cancers; CGB3 (beta-hCG): gestational trophoblastic neoplasia—initial workup, during/post treatment (no more than weekly during treatment; monthly for 12 months post-treatment), testicular cancer surveillance (no more than every 2 months); HE4 and Inhibin: ovarian cancer initial workup and monitoring; Serum free light chains: multiple myeloma—initial diagnostic workup and surveillance (up to once per month), Castleman disease workup, systemic light-chain amyloidosis initial workup; Troponin T: systemic light-chain amyloidosis initial workup; Tryptase: systemic mastocytosis diagnosis; uPA/uPAR: prognostic contexts in breast cancer per ASCO guidance.

This node aggregates the multiple per‑marker indication statements as listed in the document.

Not medically necessary / Not covered

Not covered or experimental

Not covered categories: Use of the biomarkers listed above for cancer indications not discussed in this policy does not meet coverage criteria; all other serum tumor markers not addressed above do not meet coverage criteria; analysis of proteomic patterns in serum for the screening and detection of cancer does not meet coverage criteria; routine use of nonspecific tumor markers (e.g., for population screening) or use of unlisted/unspecified chemistry procedures without clear indication may be considered unsupported.

Direct policy exclusions from the document.

Hepatocellular carcinoma biomarkers

Evidence-based utility and limitations summarized by biomarker:

AFP/AFP-L3/DCP for HCC: AFP is commonly used for HCC detection and surveillance but has limitations: AFP-L3% and DCP (PIVKA-II) have insufficient sensitivity alone for early-stage HCC. Combined models (e.g., GALAD: AFP, AFP-L3%, DCP) showed sensitivity ~65% and specificity ~82% in a phase III study. In individual studies AFP alone had AUC 0.751 versus cirrhosis; AFP-L3 measured by uTASWako showed AUC 0.867 (sensitivity 0.849, specificity 0.886). Addition of AFP-L3 to AFP+PIVKA-II did not consistently improve discrimination in some analyses.see thresholds

Multiple studies show mixed incremental benefit of AFP-L3; further validation needed.

B2M (hematologic prognostic marker)

Prognostic biomarker for hematologic malignancies:

Beta-2 microglobulin (B2M): Elevated B2M is associated with worse survival in diffuse large B‑cell lymphoma; one study used a cutoff of 22.5 mg/L and found significantly lower 5‑year and overall survival in patients above this threshold.22.5 mg/L

Used as a prognostic indicator.

Serum free light chains

Serum free light chains in plasma cell and related disorders:

Serum free light chains: Measurement of kappa and lambda free light chains and the kappa/lambda ratio aids diagnosis, prognosis, and monitoring of multiple myeloma, Waldenstrom's macroglobulinemia, Castleman disease, and light-chain (immunoglobulin) amyloidosis. Both absolute values and the kappa/lambda ratio should be considered because absolute elevations may occur with a preserved ratio. Surveillance frequency for multiple myeloma follow-up is permitted up to once per month.kappa/lambda ~0.58 reference in healthy individuals; surveillance up to once per month

Assay variability and potential over/under‑estimation exist between tests.

Cardiac biomarkers

Cardiac biomarkers for cardiac involvement in systemic disease:

BNP/NT-proBNP and troponin: BNP or NT‑proBNP and cardiac troponins are useful markers of cardiac dysfunction and are applied in assessing cardiac involvement in systemic light‑chain amyloidosis and multiple myeloma. Persistently elevated troponins often indicate cardiac amyloid infiltration and inform staging and management decisions in amyloidosis contexts.not specified

Used for staging and management decisions in amyloidosis contexts.

Cancer antigen panels

Tumor-associated antigens for various solid tumors:

CA markers and CEA: CA 19‑9, CA‑125, CA 15‑3/27.29, CEA, HE4, and other cancer‑associated antigens are used as diagnostic, prognostic, and monitoring adjuncts across gastrointestinal, ovarian, breast, lung, and biliary/gallbladder cancers. Individual studies report variable sensitivity and specificity; combining markers (for example HE4+CA‑125 or biomarker panels) can improve diagnostic performance in some contexts. Specific study cutoffs vary by tumor type and assay.study-specific cutoffs reported (e.g., theoretical CA19‑9 252.31 U/mL; CA‑125 92.19 U/mL in gallbladder study)

Marker performance varies by tumor type and assay; interpret in clinical context.

Chromogranin A

Neuroendocrine tumor marker:

Chromogranin A (CgA): Chromogranin A is the most sensitive chromogranin for neuroendocrine tumors with pooled sensitivity ~0.73 and specificity ~0.95 in a meta‑analysis. Correlation of CgA changes with treatment response is weak and the marker is affected by confounders (e.g., PPI use, atrophic gastritis, renal insufficiency). One study used a cutoff of 46.2 ng/mL.46.2 ng/mL used in one study

Marker subject to confounders and assay variability; not routinely treatment‑informing.

Inhibins

Inhibins for ovarian granulosa cell tumors:

Inhibin A/B: Inhibin A and B are produced by ovarian granulosa cells; inhibin B generally shows higher sensitivity than inhibin A for granulosa cell tumors. Measurement of inhibin B (and anti‑Mullerian hormone in combination) improved detection in studies (inhibin B AUC ~0.94 in one series).not specified

Inhibin levels may vary with the menstrual cycle and should be interpreted accordingly.

Tryptase/systemic mastocytosis

Mast cell disease marker:

Tryptase: Serum tryptase is an accepted diagnostic criterion for systemic mastocytosis and may be measured to assess mast cell activation disorders in conjunction with clinical and pathological criteria.not specified

Used as part of diagnostic evaluation for systemic mastocytosis.

uPA (invasion/metastasis marker)

Invasion/metastasis biomarker:

uPA/UPAR: Urokinase plasminogen activator (uPA) is involved in tumor invasion and metastasis; high levels have been associated with shorter survival in breast cancer. ASCO guidance outlines clinical situations where uPA measurement may have utility.not specified

May have prognostic utility in select breast cancer contexts per guideline.

Guideline-based clinical coverage considerations

Coverage and clinical-use statements summarized from cited professional guidelines:

NCCN on ovarian adnexal mass biomarkers: NCCN notes FDA‑approved use of ROMA, OVA1, and OVERA to estimate risk for ovarian cancer in patients with an adnexal mass for which surgery is planned, but the Panel does not recommend these tests for determining status of an undiagnosed adnexal/pelvic mass routinely; evaluation by an experienced gynecologic oncologist prior to surgery is recommended.

Captures guidance tension: FDA approval vs NCCN cautious stance.

ASCO on germ cell tumor markers: ASCO recommends against serum tumor markers for screening germ cell tumors but advises measuring AFP and hCG before orchiectomy, shortly after orchiectomy, before chemotherapy when indicated, at the start of each chemotherapy cycle, and during surveillance (up to 10 years) for NSGCTs; biomarkers should not guide the decision to perform orchiectomy.surveillance up to 10 years

Documented recommended intervals and uses.

ADLM recommendations: ADLM endorses AFP measurement for HCC management and surveillance (6‑month intervals in high‑risk patients) and indicates AFP concentrations above 20 µg/L should prompt further investigation even if ultrasound is negative; ADLM supports pretreatment measurement of AFP, hCG and LDH for suspected testicular cancer and their use in monitoring.

Updated coverage criteria (summary)

Coverage is defined per biomarker with specific clinical indications (initial workup, monitoring/follow-up, prognosis, and occult primary workup) as updated in the revision history.

Policy update summary: Multiple biomarkers had indications added, removed, or clarified: examples include addition of HE4 and expanded ovarian indications; addition of Castleman disease and follow‑up for multiple myeloma to serum free light chain indications; updated B2M entries for prognostic/therapy determination in CLL/SLL; removal of LDH from the serum biomarker designation; and addition of new CPT codes (0558U, 0559U) effective 7/1/2025.

Detailed per‑marker tables are present elsewhere in the policy.

Revised Coverage Indications for Serum Tumor Biomarkers

Revisions to indications and monitoring/follow-up coverage for multiple serum tumor biomarkers as aligned with compendium guidance.

Ovarian cancer histology expansions: For AFP, CA‑125, CA 19‑9 and other markers, indications were expanded to include carcinosarcoma (malignant mixed Müllerian tumors), clear cell carcinoma, grade 1 endometrioid carcinoma, mucinous neoplasms, and low‑grade serous carcinoma for monitoring and follow‑up; 'less common' designations were removed from some ovarian rows.

Operational change to ovarian marker indications.

Occult primary indications: Markers including CA 15‑3/27.29, CA 19‑9, calcitonin, CEA, INHA and others had indications added for occult primary (unknown primary cancer) to support additional workup and prognosis assessment; Inhibin (INHA) had adrenocortical carcinoma removed and occult primary added.

Expanded use for occult primary evaluation.

Serum free light chains: Added Castleman disease as an indication for serum free light chains (workup) and added 'follow‑up' to multiple myeloma indications (surveillance permitted up to once per month).

Proteomic pattern analysis of serum (proteomics-based screening assays that analyze global protein expression or signatures) for the purpose of cancer screening or detection does not meet coverage criteria.

Serum calcitonin is the primary tumor marker for medullary thyroid carcinoma, and its concentration often correlates with tumor burden. However, the American Thyroid Association has stated there is a lack of agreement on routine measurement of calcitonin for screening thyroid nodules, and a small study of patients with thyroid nodules recommended against routine screening due to low diagnostic yield.

Guideline panels generally advise against routine use of nonspecific tumor markers for screening. Tests such as chromogranin A, pancreastatin, CA 15-3/CA 27.29, and CA 19-9 are not recommended for routine screening because they are nonspecific, subject to confounding factors, and infrequently alter management.

The policy removed the Lactate dehydrogenase (LDH) section from the serum tumor biomarker designation; LDH is no longer included in the serum tumor biomarker table.

LDH was removed from the serum tumor biomarker designation because it is considered a broad, non-specific marker that extends beyond the scope of this serum tumor biomarker classification and therefore is not maintained in the policy's tumor marker list.

Use of tumor markers or panels that are not discussed in this policy, or serum tumor markers not specifically addressed by the policy, do not meet coverage criteria and may be considered unsupported if submitted for cancer indications not covered by the document.

A small study evaluating serum calcitonin in patients presenting with thyroid nodules reported few medullary thyroid carcinoma cases and instances of initially elevated calcitonin that became undetectable; the authors recommended against routine calcitonin screening for nodules because of low diagnostic yield.

Although FDA-cleared proprietary multianalyte assays (e.g., ROMA, OVA1, OVERA) exist for assessing adnexal masses prior to surgery, the NCCN Panel does not recommend these tests for routinely determining the status of an undiagnosed adnexal/pelvic mass; ordering them outside recommended indications may not be supported.

Professional guidance cautions against routine use of nonspecific or multi-biomarker assays to direct management in many settings. For adnexal masses, NCCN emphasizes specialist evaluation and does not endorse multibiomarker assays as a routine determinant of adnexal mass status; for neuroendocrine tumors, NANETS notes that nonspecific markers such as CgA and pancreastatin are not routinely treatment-informing and should not be used routinely outside research.

Procedure and Test Codes

Biomarker assay codes (not specified in text)mixed

No codes listed

Proprietary multianalyte assay CPT codesCPT

81479	Unlisted molecular pathology procedure.
81500	Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4) with algorithm reported as a risk score (ROMA).
81503	Oncology (ovarian), biochemical assays of five proteins (OVA1).
81538	Oncology (lung), mass spectrometric 8-protein signature (VeriStrat).

Individual tumor marker CPT/chemistry codesCPTCovered

81599	Unlisted multianalyte assay with algorithmic analysis.
82105	Alpha-fetoprotein (AFP); serum.
82107	Alpha-fetoprotein (AFP) isoform AFP-L3 and total AFP (including ratio).
82232	Beta-2 microglobulin.
82308	Calcitonin.
82378	Carcinoembryonic antigen (CEA).
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, NOS.
83521	Each (unit) for immunoassays.
83789	Mass spectrometry and tandem mass spectrometry.
83880	Natriuretic peptide.

1–10 of 26

1/3

Proprietary multianalyte HCPCS/U codesHCPCS

0003U	Oncology (ovarian) biochemical assays of five proteins, Overa (OVA1 Next Generation).
0092U	Oncology (lung), three protein biomarkers using magnetic nanosensor technology (REVEAL Lung Nodule Characterization).
0163U	Oncology (colorectal) screening, ELISA of 3 plasma/serum proteins with demographic data (BeScreened CRC).
0404U	Oncology (breast), semiquantitative thymidine kinase activity (Divitum Tka).
0558U	Oncology (colorectal), ELISA for BF7 antigen (IGoCheck).

Procedure and laboratory CPT/HCPCS/U-codesmixed

84704	Gonadotropin, chorionic (hCG); free beta chain
84999	Unlisted chemistry procedure
86300	Immunoassay for tumor antigen, quantitative; CA 15-3 (27.29)
86301	Immunoassay for tumor antigen, quantitative; CA 19-9
86304	Immunoassay for tumor antigen, quantitative; CA 125
86305	Human epididymis protein 4 (HE4)
86316	Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each
86336	Inhibin A
0003U	Oncology (ovarian) biochemical assays of five proteins

Proprietary/other oncology biomarker codesmixed

0092U	Oncology (lung) three protein biomarkers, immunoassay using magnetic nanosensor technology; REVEAL Lung Nodule Characterization
0163U	Oncology (colorectal) screening, ELISA of 3 plasma or serum proteins; BeScreened-CRC
0404U	Oncology (breast) semiquantitative measurement of thymidine kinase activity by immunoassay; Divitum Tka
0558U	Oncology (colorectal) quantitative ELISA for BF7 antigen (IGoCheck)
0559U	Oncology (breast) quantitative ELISA for BF9 antigen (Haystack MRD Baseline)
G0327	Colorectal cancer screening; blood-based biomarker

Added CPT CodesCPT

0558U	CPT code added (effective 7/1/2025)
0559U	CPT code added (effective 7/1/2025)

AFP — > 200 ng/mL associated with higher risk of HCC recurrence after transplant

AFP recurrence association>200 ng/mL associated with a higher risk of hepatocellular carcinoma (HCC) recurrence after liver transplant (3.32x increased probability in Santos Schraiber et al., 2016)

AFP clinical usesUsed for HCC screening, workup, and surveillance; also used for intrahepatic cholangiocarcinoma workup and select ovarian cancer indications

AFP role in prognosticationSustained or markedly elevated AFP correlates with lower survival and higher recurrence risk post-resection/transplant

Serum free light chains frequency — up to once per month

Maximum surveillance frequency

Provider Actions, Authorization, and Documentation

Documentation Required

Coverage contingent on benefit and indication

Coverage is contingent on the member's benefit plan and the documented clinical indication. Prior authorization requirements are dictated by applicable benefit coverage and state/federal regulations; providers must verify member eligibility and benefit limits at time of request. Quarterly measurement of designated serum biomarkers is permitted for follow-up, monitoring, and surveillance only where supported by benefits and clinical indication.

Coverage is contingent on benefit and indicated use — verify member benefits and applicable state/federal rules before ordering.
Quarterly biomarker monitoring allowed when supported by clinical indication and benefits.

Prior Authorization

Prior authorization not specified

This policy does not specify routine prior authorization requirements for standard serum tumor marker tests, but it does not preclude prior authorization where required by the member's plan or state/federal mandates. Providers should check payer-specific prior authorization rules and any claim-edit requirements before submitting services.

Background and Definitions

Circulating tumor biomarkers are proteins or other substances detectable in body fluids that can be used to detect, diagnose, stage, prognosticate, predict therapy response, and monitor for recurrence in patients with cancer. Their analytic and clinical performance vary by marker, assay, and clinical context, and interpretation should consider disease prevalence and intended use.

Biomarker definitions (diagnostic, prognostic, predictive, companion)

Diagnostic biomarkerA marker that aids in diagnosis or subclassification and results in different disease management.

Prognostic biomarkerA marker associated with clinical outcomes (e.g., overall survival) independent of treatment.

Predictive biomarkerA marker that predicts response to a specific therapy and guides treatment decisions.

Companion biomarkerA biomarker used to identify patients for whom a therapy has shown benefit; usually linked to a specific therapy.

Intended Line(s) of Therapy / Use

Biomarker-specific Requirements and Thresholds

AFP / AFP-L3 — >200 ng/mL associated with higher recurrence risk after transplant (study cited)

AFP / AFP-L3 threshold — transplant recurrence>200 ng/mL associated with higher recurrence risk after transplant (study cited)

AFP-L3 roleAFP-L3% discussed as part of risk stratification and included in combined models (e.g., GALAD) though sensitivity for early HCC is limited when used alone.

Policy placementAFP and AFP-L3 retained as biomarkers for HCC screening, workup, and surveillance per policy criteria.

CA-125, HE4, Inhibin, Ova1/Overa/Ova1Plus — listed tumor markers and multi-marker tests

Tumor marker panel examplesCA-125, HE4, Inhibin, and multianalyte tests (OVA1/OVERA/Ova1Plus) are listed with intended uses for ovarian adnexal mass evaluation and monitoring

Proprietary tests

Policy Revision History

2025-06-04policy_revision

Reviewed and updated background, guidelines, and evidence; adjusted terminology from 'serum tumor markers' to 'serum biomarkers' to broaden the definition and changed table title accordingly; modified ALP indications including addition of 'Melanoma (uveal)'.

2025-06-04coverage_update

Multiple marker-specific edits: clarified testicular nonseminoma wording, reorganized BNP/NT-proBNP and troponin sections, and updated CA 19-9 and CA-125 ovarian indications and monitoring/follow-up entries.

2025-06-04coverage_update

Policy Summary

PayerHealthfirst

PolicySerum Tumor Markers for Malignancies

Policy CodePolicy PO-RE-041v5

Change TypeRevised coverage indicationsadded CPT 0558U/0559U

Effective DateOct 15, 2025

Next Review DateN/A

Key ActionDocument test indication and frequency on the claim and use new CPT codes 0558U/0559U for applicable proprietary assays beginning 7/1/2025.

SourceLink

On This Page

AFP >20 µg/L prompts investigation

Specific screening/monitoring guidance noted.

NANETS and NET markers: NANETS does not recommend routine use of nonspecific markers (CgA, pancreastatin) to guide treatment for PNETs because results rarely influence management; elevated baseline CgA may be prognostic but optimal thresholds are unclear.

Advises limited use outside research.

AASLD on HCC biomarkers: AASLD notes AFP‑L3% and DCP are promising but insufficiently validated for routine surveillance alone; AFP may be used for screening but diagnosis of HCC should rely on imaging or pathology rather than biomarkers alone.

AFP permitted for screening but not diagnostic alone.

Revision reflected in coverage tables.

Serum free light chains: surveillance/follow-up frequency up to once per month (multiple myeloma and related disorders)

Clinical contextsUsed for diagnosis, prognosis, and monitoring of multiple myeloma, Waldenstrom's macroglobulinemia, Castleman disease, and light-chain amyloidosis

Interpretation noteConsider both absolute kappa and lambda values and the kappa/lambda ratio (healthy reference ratio ~0.58); absolute elevations may occur with preserved ratio

Germ cell tumor surveillance frequency

Germ cell tumor surveillance cadenceNo more than every 2 months for the first 2 years; every 4 months in years 3–5; then annually after year 5

Peri-treatment timingMeasure AFP and hCG before orchiectomy, before chemotherapy for mediastinal/retroperitoneal NSGCTs, at start of each chemotherapy cycle, and during surveillance up to 10 years as recommended by ASCO

Treatment monitoringDuring and post-treatment for gestational trophoblastic neoplasia: markers may be measured up to weekly during treatment and monthly for 12 months post-treatment

AFP recurrence threshold — >200 ng/mL

AFP recurrence threshold>200 ng/mL

Evidence sourceSantos Schraiber et al. (2016) found AFP >200 ng/mL was the only risk factor for recurrence after liver transplant (associated with a 3.32x higher probability)

Clinical implicationAFP >200 ng/mL signals higher post-transplant recurrence risk and correlates with lower survival

B2M prognostic cutoff — 22.5 mg/L

B2M prognostic cutoff22.5 mg/L

Prognostic findingSeo et al. (2016) reported significantly worse 5-year and overall survival in diffuse large B-cell lymphoma patients with B2M ≥22.5 mg/L

Clinical usesB2M used for workup in lymphoid malignancies, prognostic assessment in DLBCL, and therapy determination in CLL/SLL contexts

CgA study cutoff — 46.2 ng/mL

CgA study cutoff46.2 ng/mL

Study performanceTian et al. reported a CgA cutoff of 46.2 ng/mL with sensitivity 78.8% and specificity 73.8% in one study; meta-analysis pooled sensitivity 0.73 and specificity 0.95

LimitationsCgA levels are affected by proton pump inhibitors, atrophic gastritis, and renal insufficiency; correlation with treatment response is weak

AFP surveillance threshold (ADLM guidance)

ADLM/ADLM guidance thresholdAFP concentrations above 20 µg/L should prompt further investigation even if ultrasound is negative

Surveillance roleADLM recommends AFP measurement at 6‑month intervals in high‑risk patients; sustained increases may be used with ultrasound to inform detection and management

Unit clarificationThreshold expressed as 20 µg/L in ADLM guidance (equivalent to 20 ng/mL) and should prompt further workup

Effective date for new U-codes — 0558U and 0559U effective 7/1/2025

New U-code effective dateCPT/HCPCS U-codes 0558U and 0559U effective 7/1/2025

Policy actionPolicy revision added CPT codes 0558U and 0559U to the applicable code list; providers should use these codes for the indicated proprietary tests beginning 7/1/2025

Codes listed in applicable sections0558U described as IGoCheck (BF7 antigen ELISA); 0559U listed alongside other newly added proprietary codes in the revision history

No explicit, blanket prior authorization stated for standard covered biomarkers.
Verify plan- or state-specific authorization triggers at point of care.

Prior Authorization

Prior authorization for proprietary/multianalyte assays

Proprietary and multianalyte assays (including FDA-cleared or laboratory-developed multi-marker tests) may require additional review or authorization. These specialized tests have emerging clinical validity and utility and are subject to medical review to confirm the intended use aligns with policy-covered indications.

Proprietary and specialized tumor marker/proteomic tests may require pre-approval or medical review.
Examples include OVA1/OVERA, ROMA, VeriStrat, BeScreened-CRC and other branded multianalyte assays.

Billing Rule

Proprietary U-code authorization

Certain proprietary tests are reported with new HCPCS/CPT U-codes or require specific billing representation. When a proprietary U-code is available for a test, submit claims using the designated U-code and include any authorization identifier or documentation as required by the payer.

Ensure claims for proprietary biomarker tests use the assigned U-code when applicable (e.g., 0003U, 0092U, 0163U, 0404U, 0558U, 0559U) and include supporting clinical indication.
Claims using unlisted codes (81479, 81599, 84999, 81479) may trigger additional review if a specific U-code exists.

Billing Rule

Use of New CPT Codes (0558U, 0559U)

For newly introduced CPT/HCPCS codes (for example 0558U and 0559U effective 7/1/2025), providers should bill using these codes for the indicated services and ensure any prior authorization or claims reflect the new codes. Added codes should be accompanied by clinical documentation linking the test to a covered indication.

Use new CPT/U-codes (e.g., 0558U, 0559U) for the corresponding proprietary tests effective dates as published.
Update prior authorizations and claims to reference the new codes to avoid claim delays.

Note

No explicit authorization or denial trigger

This policy does not enumerate explicit authorization or denial triggers for every scenario. Absence of a listed trigger does not guarantee coverage; tests ordered outside the policy's covered indications or with improper coding are subject to denial or recoupment.

No specific universal authorization/denial triggers listed — verify coverage against documented indications and member benefits.
Tests for indications not addressed in policy may be denied.

Denial Risk

Guideline-inconsistent ordering risk

Ordering multibiomarker proprietary assays for adnexal mass evaluation or other indications inconsistent with accepted guidelines may be subject to additional review and possible denial. Providers should follow guideline-recommended evaluation pathways (e.g., referral to a gynecologic oncologist for adnexal masses) and use proprietary tests as intended.

Guideline-inconsistent ordering (e.g., substituting multibiomarker assays for recommended clinical evaluation or specialist referral) increases risk of claim denial.
Use proprietary multi-marker tests only for their defined intended uses (preoperative risk stratification when surgery is planned, reflex strategies, etc.).

Denial Risk

Coding / claim risk

Use of unlisted chemistry procedure codes or proprietary U-codes without matching clinical indications, or failure to include specific test names and indications on claims, may trigger claim review, denial, or recoupment. Follow national and state coding standards and Healthfirst's claim edit expectations.

Include specific test name and clinical indication on claims to support medical necessity.
Avoid using 81479/81599/84999 when a specific U-code or CPT exists; improper coding may trigger additional review or denial.

Documentation Required

Support clinical indication and frequency

Document the clinical indication, intended use, and how test results will inform management decisions. For surveillance and monitoring, document the frequency and clinical rationale (e.g., quarterly surveillance, monthly for multiple myeloma as clinically indicated).

Support clinical indication and frequency in the medical record (initial workup, monitoring, surveillance cadence).
Specify how test results will alter treatment or follow-up plans.

Documentation Required

Serum free light chain documentation

When ordering serum free light chain assays, document both the absolute kappa and lambda values and the kappa:lambda ratio. Consider reporting absolute values and the ratio together, since changes in absolute values may occur with a preserved ratio.

Document absolute kappa and lambda concentrations and the kappa:lambda ratio.
Indications include multiple myeloma (diagnostic workup, follow-up, surveillance up to monthly), systemic light-chain amyloidosis, and Castleman disease.

Documentation Required

Clinical indication and intended use

For all biomarker testing, document the diagnosis, clinical indication, and intended clinical use (diagnosis, prognosis, monitoring, surveillance). Include specific test names, brand/proprietary assay identifiers, and how results will guide patient management.

Clinical indication and intended use must be clearly linked to the ordered test on the requisition and claim.
Include brand name or proprietary test identifier when applicable (e.g., OVA1, OVERA, ROMA, VeriStrat).

Billing Rule

Required Coding and Billing Practices

Providers must follow national and state coding/billing standards and Healthfirst reimbursement policies. Claims are subject to Healthfirst's claim edits, NCCI rules, NCD/LCDs, and state-specific billing policies. Failure to adhere to coding and billing guidelines may result in denial or recoupment.

Follow AMA/CPT, HCPCS, ICD-10, NCCI, and New York State-specific billing rules where applicable.
Ensure appropriate modifier use, global surgery rules, and multiple procedure reductions are applied.

Documentation Required

Proprietary test use expectations

Proprietary multi-marker tests have defined intended uses and reflex strategies (for example, OVA1 is performed first with OVERA reflex for intermediate-risk results). Use of these proprietary tests should align with their specified indications and reflex algorithms.

Adhere to proprietary test intended use and reflex strategies when ordering (e.g., OVA1 then OVERA reflex).
Do not use proprietary assays outside their validated or intended clinical pathways.

Step Therapy

No step therapy requirements described

No step therapy requirements are described for biomarker testing in this policy excerpt. Providers should nonetheless follow any plan-specific step edits or prior authorization sequences imposed by the member's benefit plan.

No explicit step therapy or required sequencing described in this policy.
Verify plan-level step therapy or utilization management rules prior to ordering.

AFP-L3 definitionAn AFP isoform with high reactivity to Lens culinaris agglutinin; theorized to be more specific to hepatocellular carcinoma and associated with tumor dedifferentiation.

Clinical contextAFP-L3% is FDA-cleared for risk stratification but has insufficient sensitivity for surveillance when used alone.

Role in modelsIncluded in combined models (e.g., GALAD) with AFP and DCP for improved discrimination in some studies

Serum free light chains

Serum free light chains definitionQuantitative measures of unbound kappa and lambda immunoglobulin light chains used to assess monoclonal plasma cell disorders; the kappa/lambda ratio aids diagnosis and monitoring.

Clinical considerationsBoth absolute free light chain values and the kappa/lambda ratio should be considered because absolute elevations can occur with a preserved ratio.

Reference ratioHealthy reference kappa/lambda ratio approximately 0.58

Tryptase

Tryptase definitionA mast cell protease measured in tissue or serum; elevated serum tryptase is an accepted diagnostic criterion for systemic mastocytosis.

Clinical useMeasured to assess mast cell activation disorders and to support diagnosis of systemic mastocytosis alongside clinical/pathologic criteria.

SpecimenCan be measured in tissue or serum; interpretation requires clinical correlation

Tryptase (duplicate) — diagnostic criterion

Tryptase (diagnostic criterion)Elevated serum tryptase is an accepted diagnostic criterion for systemic mastocytosis.

Measurement contextUsed with clinical and pathological findings to establish diagnosis of mast cell disorders.

Analytic noteLevels may vary with timing and acute mast cell activation events; interpret in clinical context.

Urokinase plasminogen activator (uPA)

uPA definitionUrokinase plasminogen activator (uPA): a serine protease involved in tumor invasion and metastasis with prognostic associations, particularly in breast cancer.

Clinical relevanceHigh uPA levels have been associated with shorter survival in breast cancer and ASCO provides guidance on clinical situations where uPA measurement may be helpful.

MechanismuPA bound to uPAR converts plasminogen to plasmin, mediating extracellular matrix degradation during tumor invasion.

Proteomics

Proteomics definitionQualitative and quantitative assessment of proteins in a biological sample (e.g., via PAGE or MALDI); investigational for cancer biomarker discovery and diagnostic use.

Research statusProteomic methods are still under investigation for clinical application in cancer detection and characterization.

Example findingsPublished proteomic studies have identified panels of upregulated/downregulated proteins that may have diagnostic potential in specific cancers.

Occult primary (unknown primary cancer)

Occult primary definitionOccult primary (unknown primary cancer): an indication added for multiple biomarkers to support additional workup and prognosis assessment.

Policy changeRevision history added occult primary indications across several markers (e.g., CEA, CA 19-9, INHA) to aid workup of adenocarcinoma or carcinoma not otherwise specified.

Clinical useMarkers may be used to help identify likely tissue of origin or guide prognosis when a primary is not identified by imaging/pathology.

ROMA, OVA1, and OVERA are FDA‑approved for estimating ovarian malignancy risk in patients with an adnexal mass for which surgery is planned (per NCCN/Applicability sections)

Clinical roleThese markers/panels are intended for initial workup, during primary chemotherapy, and monitoring/follow-up when clinically indicated

beta-hCG (CGB3)

beta-hCG (CGB3) usesGestational trophoblastic neoplasia: initial workup; during and post treatment (no more than weekly during treatment; monthly for 12 months post-treatment); testicular cancer surveillance (no more than every 2 months)

Measurement specificsMeasure AFP and hCG before orchiectomy and at the start of each chemotherapy cycle for NSGCTs as recommended by ASCO

Occult primary rolehCG (CGB3) may be used for additional workup in selected occult primary presentations (mediastinal or retroperitoneal masses)

Serum free light chains — plasma cell disorder marker

Serum free light chains (marker)Used for plasma cell disorder evaluation including multiple myeloma, Castleman disease, and amyloidosis; supports diagnosis and monitoring

Surveillance frequency notePolicy permits follow-up/surveillance of serum free light chains up to once per month when clinically indicated

Interpretation guidanceAlways consider kappa/lambda ratio and absolute values; assays vary and clinical context is required for interpretation

AFP / AFP-L3 / DCP (PIVKA-II)

AFP / AFP-L3 / DCP summaryAFP >200 ng/mL associated with recurrence risk after transplant; AFP-L3% thresholds are variable and adding AFP-L3 to AFP+PIVKA-II did not consistently improve discrimination in some studies

Combined model performanceGALAD model (AFP, AFP-L3%, DCP) showed sensitivity 65% and specificity 82% in a phase III study; further validation needed

Clinical cautionAFP-L3 and DCP have insufficient sensitivity to detect early-stage HCC when used alone; use in combination with imaging and clinical context

Serum free light chains (kappa/lambda) — reference

Free light chain reference ratioReference kappa/lambda ratio approximately 0.58 in healthy individuals

Assay variabilityStudy-specific abnormal cutoffs are not universally provided; assay variability can affect absolute values and ratios

Clinical interpretationConsider both ratio and absolute free light chain values when evaluating plasma cell disorders

BNP / NT-proBNP and troponin — cardiac biomarkers referenced

Cardiac biomarkers referencedBNP / NT-proBNP and troponins are cited for evaluation of cardiac involvement in systemic light chain amyloidosis and multiple myeloma

Clinical rolePersistently elevated troponins often indicate cardiac amyloid infiltration and inform staging/management

Policy placementBNP/NT-proBNP and troponin included as initial diagnostic workup markers in relevant sections

Chromogranin A (CgA) — 46.2 ng/mL used in one study

Chromogranin A (CgA) study value46.2 ng/mL used as a cutoff in one study (sensitivity 78.8%, specificity 73.8%)

Meta-analysis performancePooled sensitivity 0.73 and specificity 0.95 for CgA in NETs (Yang et al. meta-analysis)

LimitationsCgA is affected by PPIs, atrophic gastritis, and renal insufficiency; correlation with treatment response is weak

CA-125 / HE4 (ROMA)

CA-125 / HE4 (ROMA) contextROMA (CA-125 + HE4) and proprietary tests (OVA1, OVERA) are used to estimate ovarian malignancy risk in patients with an adnexal mass for which surgery is planned

FDA and guideline contextFDA-approved for this indication; NCCN notes these tests but does not recommend routine use to determine status of undiagnosed adnexal masses

Intended usesInitial workup, during primary chemotherapy, and monitoring/follow-up for complete response as clinically indicated

AFP (ADLM) — AFP >20 µg/L prompts further investigation

ADLM AFP surveillance triggerAFP >20 µg/L should prompt further investigation even if ultrasound is negative (ADLM guidance)

Surveillance frequencyADLM recommends AFP measurement at 6‑month intervals in high‑risk patients for HCC surveillance

Combination with imagingSustained AFP increases may be used in combination with ultrasound to inform detection and management

hCG — marker referenced in requirements

hCG (clinical uses)Measured before orchiectomy, before chemotherapy for mediastinal/retroperitoneal NSGCTs, at start of each chemotherapy cycle, and during surveillance (up to every 2 months as indicated)

Gestational trophoblastic neoplasiahCG measured up to weekly during treatment and monthly for 12 months post-treatment

Occult primary rolehCG (CGB3) may be used in occult primary workup for select presentations

Chromogranin A (CgA) — referenced again

CgA policy noteCgA is referenced for NET evaluation but not routinely recommended to guide treatment; confounders and limited treatment-informing value noted

GuidanceNANETS cautions against routine use of nonspecific markers like CgA for PNETs as results rarely influence treatment

Assay variabilityCgA interpretation requires attention to medications (PPIs) and comorbid conditions

HE4 — referenced in updated indications

HE4 added indicationsHE4 added for ovarian/fallopian tube/primary peritoneal cancer: initial workup; during primary chemotherapy; monitoring/follow-up for complete response as clinically indicated

Policy revisionRevision history documents addition of HE4 section and associated ovarian cancer indications

Use with CA-125HE4 may be combined with CA-125 (ROMA) to estimate risk preoperatively

CA-125 — referenced in updated indications

CA-125 additionsCA-125 indications expanded to include initial workup, monitoring during chemotherapy, and monitoring/follow-up for several ovarian subtypes and for occult primary workup

Revision historyPolicy revision added CA-125 indications for uterine neoplasms and expanded ovarian subtype monitoring/follow-up

Surveillance noteIf initially elevated, CA-125 may be monitored at each visit; otherwise follow standard surveillance cadences indicated elsewhere in policy

CA 19-9 — referenced in updated indications

CA 19-9 indicationsCA 19-9 used for baseline and monitoring in pancreatic, ampullary, biliary, gallbladder, and select ovarian cancer indications; policy additions include occult primary uses

Surveillance cadencePost-resection surveillance examples: every 3–6 months for 2 years, then every 6–12 months as clinically indicated

Study cutoffsStudy-specific CA19-9 cutoffs reported in literature (e.g., theoretical/ study values) but not universally adopted in policy

Serum free light chains — additional references

Serum free light chains repeated referenceSerum free light chains are repeatedly referenced for multiple myeloma workup and surveillance and for Castleman disease workup

Policy additionsRevision history added 'follow-up' to multiple myeloma indications and explicitly added Castleman disease as an indication for workup

Documentation guidanceClinicians should document how results will inform management and include specific test names on claims

Beta-2 microglobulin (B2M) — referenced in updated indications

B2M reference in updatesBeta-2 microglobulin (B2M) retained as a prognostic marker in hematologic malignancies; policy revisions added prognostic/therapy determination indications in CLL/SLL

Clinical evidenceSeo et al. (2016) identified a prognostic cutoff of 22.5 mg/L linked to worse survival in DLBCL

Use casesB2M used for workup in multiple myeloma, CLL/SLL, Castleman disease, and other lymphoid neoplasms per policy tables

CA-125, CA 19-9, AFP, CA 15-3/27.29 and others — expanded indications

Expanded marker setPolicy expanded indications for CA-125, CA 19-9, AFP, CA 15-3/27.29 and others across monitoring/follow-up and occult primary workup

Coverage implicationMarkers may be covered for initial workup, monitoring, surveillance, or occult primary evaluation depending on the specific tumor type and documented indication

Provider actionsDocumentation should support intended use and specific test names/codes should be included on claims to demonstrate medical necessity

Serum free light chains — repeated requirement references

Serum free light chains (requirement context)Repeated references emphasize use in multiple myeloma workup and surveillance, Castleman disease workup, and amyloidosis evaluation

Interpretation reminderConsider both absolute free light chain values and kappa/lambda ratio; assay variability and preserved ratios despite absolute elevations are noted

Policy placementIncluded in biomarker requirements and coverage criteria tables with surveillance frequency guidance (up to monthly)

Added new HE4 section and expanded ovarian cancer histology indications (including carcinosarcoma, clear cell, grade 1 endometrioid, mucinous neoplasms, low-grade serous carcinoma) for monitoring/follow-up; removed LDH section as outside serum biomarker designation.

2025-06-04coverage_update

Added 'Castleman disease' as an indication under serum free light chains and added 'follow-up' indication for multiple myeloma.

2025-06-04coding_update

Added CPT codes 0558U and 0559U to the policy code list (effective 2025-07-01).

2024-09-04policy_revision

Prior reviewed and updated background, guidelines, and references with additions and removals across AFP, B2M, calcitonin, CA 15-3/27.29, CA 19-9 and other markers to align with compendium guidance.