Serum Tumor Markers for Malignancies
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Defines coverage indications, limitations, and CPT/HCPCS codes for serum tumor marker tests used in diagnosis, staging, monitoring, and surveillance of malignancies for BlueCross BlueShield of Tennessee members.
Adjusted terminology from 'serum tumor markers' to 'serum biomarkers' to broaden definition.
Updated indications for multiple specific biomarkers (ALP, Beta-2 microglobulin, BNP/NT-proBNP, CA19-9, CA-125, CEA, HE4, Inhibin, serum free light chains) including additions, removals, and reorganization of indications.
Removed the entire Lactate dehydrogenase (LDH) section from the serum tumor biomarker table.
Added CPT codes 0558U and 0559U (effective 7/1/2025) and removed CPT code 83615.
Coverage Criteria for Serum Biomarkers
Coverage Criteria — Included Serum Biomarkers
Covered indications (selected examples) — measurement of specified serum biomarkers meets coverage criteria for the listed indications when used for diagnostic workup, monitoring, surveillance, or follow-up as noted. Except where otherwise specified, quarterly measurement is permitted for follow-up, monitoring, and/or surveillance.
ANY of the following
- Alkaline phosphatase (ALP): meets coverage criteria for workup of bone neoplasms and for workup of melanoma (uveal).
- Alpha fetoprotein (AFP): meets coverage criteria for initial diagnostic workup of systemic light chain amyloidosis; workup for intrahepatic cholangiocarcinoma for isolated intrahepatic mass; additional workup for occult primary (localized adenocarcinoma or carcinoma not otherwise specified; liver, mediastinum, or retroperitoneal mass); ovarian cancer/fallopian tube cancer/primary peritoneal cancer — initial workup, during primary chemotherapy, and monitoring/follow-up for complete response as clinically indicated; multiple ovarian cancer subtypes for monitoring/follow-up (carcinosarcoma, clear cell, grade 1 endometrioid, mucinous neoplasms, low-grade serous); ovarian borderline and germ cell tumor surveillance per specified frequencies; testicular cancer (nonseminoma and pure seminoma) for workup, risk classification, and surveillance per specified frequencies.
- Beta-2 microglobulin (B2M): meets coverage criteria for workup and prognostic/therapy determination in chronic lymphocytic leukemia/small lymphocytic lymphoma; for multiple myeloma initial diagnostic workup and follow-up/surveillance as needed for solitary plasmacytoma; for systemic light chain amyloidosis initial diagnostic workup; for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma workup; Castleman disease — workup (added).
- BNP or NT-proBNP: meets coverage criteria for indicated cardiac-related assessments and specific hematologic indications per policy (note: systemic light chain amyloidosis indication moved to Troponin T section during revision).
- Calcitonin (CALCA): meets coverage criteria for workup of adenocarcinoma and anaplastic/undifferentiated epithelial tumors; medullary thyroid carcinoma — additional workup, post-surgical evaluation, monitoring, and surveillance (2–3 months postoperative, then every 6–12 months); multiple endocrine neoplasia type 2 — clinical evaluation at diagnosis; occult primary — workup.
- Cancer antigen 15-3 and 27.29 (CA 15-3 and 27.29): meets coverage criteria for monitoring metastatic breast cancer.
- Cancer antigen 19-9 (CA 19-9): meets coverage criteria for workup and baseline/monitoring/surveillance for ampullary adenocarcinoma, appendiceal adenocarcinoma (baseline), extrahepatic cholangiocarcinoma (baseline/monitoring), gallbladder cancer (baseline/monitoring/post-resection surveillance as clinically indicated), intrahepatic cholangiocarcinoma (baseline/monitoring), pancreatic adenocarcinoma (baseline/monitoring/post-op and post-adjuvant surveillance per schedule), and select occult primary indications to establish baseline.
- Cancer antigen 125 (CA-125): meets coverage criteria for workup and baseline in appendiceal adenocarcinoma; initial evaluation/workup for occult primary when uterus and/or ovaries present; ovarian/fallopian tube/primary peritoneal cancer — initial workup, during primary chemotherapy, monitoring/follow-up for complete response as clinically indicated; uterine neoplasms — additional workup/surveillance.
- Carcinoembryonic antigen (CEA): meets coverage criteria for baseline/monitoring/post-treatment surveillance in appendiceal adenocarcinoma; monitoring metastatic breast cancer; colon cancer — baseline/monitoring and surveillance schedule (every 3–6 months for 2 years, then every 6 months for total of 5 years); extrahepatic cholangiocarcinoma baseline/monitoring; intrahepatic cholangiocarcinoma baseline; medullary carcinoma — diagnosis and additional workup, monitoring, and post-surgical surveillance (2–3 months postoperative, then every 6–12 months); occult primary — workup for adenocarcinoma or carcinoma not otherwise specified.
- Human epididymis protein 4 (HE4): meets coverage criteria for ovarian/fallopian tube/primary peritoneal cancer — initial workup, during primary chemotherapy, and monitoring/follow-up for complete response as clinically indicated; monitoring/follow-up indications for various less common ovarian cancer subtypes and borderline/malignant germ cell/sex cord stromal tumors per specified frequencies and indications.
- Inhibin (INHA): meets coverage criteria for occult primary (additional workup for adenocarcinoma or carcinoma not otherwise specified) and for ovarian/fallopian tube/primary peritoneal cancer — initial workup, during primary chemotherapy, monitoring/follow-up for complete response as clinically indicated; applicable monitoring for specified ovarian subtypes and surveillance schedules.
- Serum free light chains (sFLC): meets coverage criteria for Castleman disease workup; multiple myeloma — initial diagnostic workup, follow-up, and surveillance (up to once per month); systemic light chain amyloidosis — initial diagnostic workup.
- Troponin T: meets coverage criteria for initial diagnostic workup of systemic light chain amyloidosis.
- Tryptase: meets coverage criteria for initial diagnosis of systemic mastocytosis.
Coverage Criteria — Revisions
Revised biomarker coverage and indications — coverage and indications updated for specific biomarkers; changes are additive/clarifying to prior table entries.
ANY of the following
- Adjusted terminology: 'serum tumor markers' broadened to 'serum biomarkers' to reflect some serum-related markers more accurately described as biomarkers rather than tumor markers.
- ALP: removed 'during treatment, surveillance' from indications for bone neoplasms; added 'Melanoma (uveal)' as an indication for workup.
- Beta-2 microglobulin: Castleman disease indication moved/clarified as a separate entry for workup.
- Chorionic gonadotropin beta polypeptide (CGB3): renamed from Beta‑human chorionic gonadotropin (beta‑hCG); modified occult primary language to 'mediastinum or' under occult primary designation.
- BNP/NT‑proBNP: systemic light chain amyloidosis initial diagnostic workup indication removed and moved to Troponin T section.
- CA 19‑9, CA‑125, CEA, HE4, Inhibin, and Serum free light chains: updated indications and added monitoring/follow-up or initial workup language, consolidation of ovarian cancer subtypes, and added Castleman disease to sFLC.
- LDH: removed entirely from the table; LDH is excluded as a covered serum biomarker.
Coverage Criteria — Marker-specific Examples
Many tumor markers are covered for specified cancer types and clinical scenarios — marker-by-marker indications consolidated below (examples).
ANY of the following
- AFP: see Covered indications; multiple testicular and ovarian tumor subtypes and surveillance schedules outlined in the policy.
- CA‑125 and HE4: used for ovarian/fallopian tube/primary peritoneal cancer initial workup, monitoring during chemotherapy, and monitoring/follow-up for complete response as clinically indicated; applicable to several less common ovarian histologies and surveillance schedules.
- CA 19‑9: baseline and monitoring for biliary, pancreatic, ampullary, gallbladder, and intrahepatic cholangiocarcinoma; post-operative and surveillance schedules where specified.
- CEA: baseline, monitoring, and surveillance for colorectal cancer and other indicated GI and medullary thyroid malignancies; monitoring metastatic breast cancer.
- Calcitonin: diagnosis and surveillance for medullary thyroid carcinoma and related indications.
- Serum free light chains and immunoglobulin free light chains (CPT 83521): diagnostic and monitoring role in multiple myeloma, systemic light chain amyloidosis, Waldenström, and Castleman disease; testing frequency guidance included.
- Troponin T: diagnostic workup for systemic light chain amyloidosis.
Coverage Criteria — Use and Operational Notes
Diagnostic, prognostic, and monitoring uses of serum tumor markers and related assays across oncology, hematology, and cardiology contexts are supported only when aligned with the specific indications listed in this policy and when clinical documentation supports their medical necessity.
ALL of the following
- Use of biomarkers for cancer screening or for indications not specifically listed in this policy does not meet coverage criteria (see Not Medically Necessary/Not Covered below).
- When a biomarker is performed for monitoring or surveillance, frequency should follow the schedules specified in this policy (e.g., malignant germ cell tumor surveillance: no more than every 2 months for first 2 years, every 4 months in years 3–5, then annually after year 5; colon cancer surveillance: every 3–6 months for 2 years, then every 6 months to complete 5 years), or be clinically justified in documentation.
Not Medically Necessary / Not Covered
Not medically necessary / Not covered
ALL of the following
- Analysis of proteomic patterns in serum for the screening and detection of cancer does not meet coverage criteria.
- For all other cancer indications not discussed above, use of the listed biomarkers (alone or in a panel of serum tumor markers) does not meet coverage criteria.
- All other serum tumor markers not addressed above (alone or in a panel of serum tumor markers) do not meet coverage criteria.
- Lactate dehydrogenase (LDH) is explicitly excluded and does not meet coverage criteria as a covered serum biomarker under this policy.
Covered Indications and Marker-Specific Uses
Workup, initial evaluation, monitoring/follow-up, and surveillance (updated per biomarker rows)
Workup, initial evaluation, monitoring/follow-up, and surveillance are permitted for specific cancers according to the updated biomarker table entries and marker-specific recommendations.
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Marker-by-marker coverage examples and scenarios
Marker-by-marker examples and typical clinical scenarios for diagnostic workup, baseline establishment, monitoring, surveillance, and post-treatment follow-up are listed below.
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Use across oncology, hematology, cardiology (examples & references)
Examples of how these biomarkers are applied across oncology, hematology, and cardiology contexts, with supporting references cited in the policy.
See bibliographic references in policy for evidence support
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Procedure and Proprietary Test Codes
| 81479 | Unlisted molecular pathology procedure. |
| 81599 | Unlisted multianalyte assay with algorithmic analysis. |
| 82105 | Alpha-fetoprotein (AFP); serum. |
| 82107 | Alpha-fetoprotein (AFP); AFP-L3 fraction isoform 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, not otherwise specified. |
| 83521 | Immunoglobulin light chains (ie, kappa, lambda), free, each. |
| 83789 | Mass spectrometry and tandem mass spectrometry (eg, MS, MS/MS, MALDI, MS- TOF, QTOF), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen. |
| 83880 | Natriuretic peptide. |
| 83950 | Oncoprotein; HER-2/neu. |
| 83951 | Oncoprotein; des-gamma-carboxy-prothrombin (DCP). |
| 84075 | Phosphatase, alkaline. |
| 84078 | Phosphatase, alkaline; heat stable (total not included). |
| 84080 | Phosphatase, alkaline; isoenzymes. |
| 84484 | Troponin, quantitative. |
| 84702 | Gonadotropin, chorionic (hCG); quantitative. |
| 0003U | Oncology (ovarian) biochemical assays of five proteins with algorithm reported as a likelihood score (OVA1 Next Generation). |
| 0092U | Oncology (lung), three protein biomarkers with algorithm reported as risk score (REVEAL Lung Nodule Characterization). |
| 0163U | Oncology (colorectal) screening, ELISA of 3 plasma/serum proteins with proprietary algorithm (BeScreened - CRC). |
| 0404U | Oncology (breast), semiquantitative thymidine kinase activity by immunoassay, reported as risk of disease progression (Divitum Tka). |
| G0327 | Colorectal cancer screening; blood-based biomarker. |
| 83521 | Immunoglobulin light chains (ie, kappa, lambda), free, each. |
| 83789 | Mass spectrometry and tandem mass spectrometry (eg, MS, MS/MS, MALDI, MS- TOF, QTOF), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen. |
| 83880 | Natriuretic peptide. |
| 83950 | Oncoprotein; HER-2/neu. |
| 83951 | Oncoprotein; des-gamma-carboxy-prothrombin (DCP). |
| 84075 | Phosphatase, alkaline. |
| 84078 | Phosphatase, alkaline; heat stable (total not included). |
| 84080 | Phosphatase, alkaline; isoenzymes. |
| 84484 | Troponin, quantitative. |
| 84702 | Gonadotropin, chorionic (hCG); quantitative. |
| 0092U | Oncology (lung), three protein biomarkers, immunoassay using magnetic nanosensor technology, algorithm reported as risk score for likelihood of malignancy (Proprietary test: REVEAL Lung Nodule Characterization). |
| 0163U | Oncology (colorectal) screening, biochemical ELISA of 3 plasma or serum proteins with demographic data using a proprietary algorithm reported as likelihood of CRC or advanced adenomas (Proprietary test: BeScreened™ -CRC). |
| 0404U | Oncology (breast), semiquantitative measurement of thymidine kinase activity by immunoassay, serum, results reported as risk of disease progression (Proprietary test: Divitum®Tka). |
| G0327 | Colorectal cancer screening; blood-based biomarker. |
Testing Frequency and Surveillance Intervals
Provider Actions, Billing, and Documentation
Procedure codes and billing guidance
Use the listed CPT/HCPCS procedure codes on claims. Submit the appropriate code(s) that correspond to the tests performed and the proprietary assays referenced in the policy. Procedure codes included in the Medical Policy are provided as a general reference and may not be all-inclusive; providers should verify current code sets and payer-specific billing guidance prior to submission.
- Procedure codes listed in policy are for general reference and may not be exhaustive.
- Verify payer-specific prior authorization requirements for listed laboratory and proprietary oncology panel codes before ordering.
- Effective 07/01/2025: CPT codes 0558U and 0559U were added; CPT 83615 was removed. Ensure prior authorization and billing reflect these updates.
Denial risk and documentation requirements
Testing performed outside the policy's specified and updated indications may be denied. Claims should be supported by clinical documentation that justifies the use of the specific serum biomarker for the indicated purpose (e.g., initial workup, monitoring/follow-up, surveillance). Providers should be aware that removal of certain tests (for example LDH) from the serum biomarker table indicates they are out-of-scope for coverage under this policy and may increase denial risk if billed for those indications.
- Tests performed for cancer indications not discussed in the policy do NOT meet coverage criteria and are at risk for claim denial.
- All claims must include documentation supporting the precise updated indication used for each serum biomarker (workup, monitoring/follow-up, initial evaluation).
- Quarterly measurement is permitted for follow-up/monitoring/surveillance only where specified in the policy.
Regulatory and documentation note
Documentation must support the medical necessity and the specific indication for each serum biomarker ordered. Government (Medicare/Medicaid) coverage rules supersede this policy where conflicts exist. Laboratory-developed tests (LDTs) and proprietary panels should be clearly identified in the record, including the test name, performing laboratory, and algorithm or components when applicable.
- Include the reason for testing (e.g., workup, initial evaluation, monitoring/follow-up) in the medical record.
- For proprietary tests (e.g., Overa™, REVEAL, BeScreened™, Divitum®Tka), document the test name and laboratory.
- Verify and follow any payer-specific prior authorization processes before ordering tests that require it.
Ordering and Prior Authorization Requirements
Government policy supersedes this policy when conflicting
When Medicare or Medicaid (LCD/NCD or state Medicaid) policy conflicts with this policy for a member, follow the applicable government coverage determination.
- Consult the Medicare Coverage Database or the applicable state Medicaid website for the controlling policy.
- Government determinations will be used to adjudicate coverage for impacted members.
Ordering requirements note — no provider-type restrictions in excerpt
No specific ordering provider restrictions are stated in this excerpt; follow standard ordering practices and payer requirements.
- The policy excerpt does not impose practitioner-type ordering limitations.
- Verify any payer-specific ordering provider requirements separately.
Ordering must align with updated indications per biomarker
Ensure each order aligns with the policy's updated biomarker indications (workup, initial evaluation, monitoring/follow-up, surveillance) as specified in the revised table entries.
- Order tests only when the clinical indication matches the biomarker-specific coverage in the policy.
- No specific practitioner-type ordering restrictions are provided in this excerpt.
Not Covered / Exclusions
Analysis of proteomic patterns in serum for screening and detection of cancer does not meet coverage criteria. This statement reinforces that proteomic pattern assays for cancer screening or detection lack sufficient published evidence to support coverage under this policy.
No explicit additional 'not covered' tests are listed in this excerpt beyond the general exclusions already stated in the policy. Procedure codes included in the document are provided as a reference and may not be all-inclusive; coverage determinations depend on the specific test and indication billed.
LDH has been removed from the serum biomarker table and is not a covered tumor biomarker under this policy. This operational change means LDH should not be used or billed as a serum tumor marker for covered oncology indications within the scope of this policy.
Background and Scope
Circulating tumor biomarkers are substances detected in body fluids that are produced by a tumor or in response to a tumor and can assist with detection, diagnosis, staging, and management because levels are often elevated in individuals with tumors. The policy aligns with current guideline sources (for example, the NCCN Biomarkers Compendium) and describes biomarker use across clinical scenarios including diagnostic workup, baseline assessment, monitoring of therapy response, and surveillance.
Definitions
Policy Revision History and Material Changes
Policy terminology was broadened from 'Serum Tumor Markers' to 'Serum Biomarkers' and multiple biomarker indications and table entries were revised (ALP, B2M, CGB3/beta-hCG, CA19-9, CA-125, CEA, HE4 and others).
The Lactate dehydrogenase (LDH) section was removed from the serum biomarker table because LDH was deemed too broad for serum tumor biomarker designation.
CPT codes 0558U and 0559U were added (effective 2025-07-01) and CPT code 83615 was removed to align coding with updated tests.
This policy defines coverage indications, limitations, and applicable CPT/HCPCS procedure codes for serum tumor marker tests used in diagnosis, staging, monitoring, and surveillance for BlueCross BlueShield of Tennessee members. Specific markers (for example, AFP, CA-125, CA 19-9, CEA, HE4, inhibin, serum free light chains, troponin T) are listed with permitted clinical scenarios and, where specified, surveillance frequencies. Providers must use the listed procedure codes when submitting claims and verify payer-specific prior authorization requirements for proprietary or multi-analyte assays. Note that coding updates were made (CPT codes 0558U and 0559U were added and CPT 83615 was removed) and that LDH was removed from the biomarker table and is not covered as a tumor biomarker under this policy.
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