Modifiedblue cross blue shield - louisianaPolicy AHS - G2124 - Serum Tumor Markers for Malignancies, 1

Serum Tumor Markers for Malignancies

Policy governing coverage and limitations for measurement of serum tumor markers for cancer detection, diagnosis, monitoring, and surveillance for Blue Cross and Blue Shield of Louisiana members; applies to laboratory orders for serum biomarkers.

Policy Summary

Payerblue cross blue shield - louisiana

PolicySerum Tumor Markers for Malignancies

Policy CodePolicy AHS - G2124 - Serum Tumor Markers for Malignancies, 1

Change TypeRevisions to marker indications, frequencies and coding updates

Effective DateMay 15, 2022

Next Review Date

Key ActionExcept where otherwise specified, quarterly measurement of designated serum biomarkers is permitted for follow-up, monitoring, and surveillance; follow marker-specific frequency limits where stated and include documentation to support clinical indication.

SourceLink

POLICY UPDATE CHANGES

Multiple specific marker indications were added, removed, or clarified (examples: ALP, B2M, BNP/NT-proBNP, CA19-9, CA-125, HE4, inhibin, serum free light chains).

Removed CPT code 83615; CPT codes 0558U and 0559U were added (07/01/2025); CPT 0404U was previously added 10/01/2023.

Policy terminology changed from 'serum tumor markers' to 'Serum Biomarkers' and coverage table titles/definitions were adjusted.

BNP/NT-proBNP and serum free light chains were added or clarified for coverage in systemic light chain amyloidosis, multiple myeloma, and related disorders.

05/15/2022initial policy implementation date

11/15/2025most recent revision date

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

quarterlyquarterly allowance

6-moAFP HCC surveillance

3-moCEA CRC surveillance

Coverage Criteria — Serum Biomarkers

Revised and added tumor marker coverage criteria

Revisions and additions to marker-specific coverage criteria were made during periodic policy updates. The following summarizes marker-level changes and examples of revised, added, or removed indications and operational edits that affect coverage determinations.

Alkaline phosphatase (ALP): For bone neoplasms, indications were revised to include measurement during treatment and surveillance in addition to workup; an indication for uveal melanoma (melanoma, uveal) was added for workup. (See revision history for dates.)

Alpha fetoprotein (AFP): Frequency and indication clarifications were made for ovarian-related indications (borderline ovarian epithelial tumors: monitoring frequency changed to 'every visit if initially elevated'); for occult primary cancers the wording was changed from 'initial diagnostic evaluation' to 'additional workup'; HCC indications were clarified for screening, workup, and surveillance with specified surveillance intervals (every 3-6 months for 2 years, then every 6 months).

Beta-2 microglobulin (B2M): Castleman disease was moved to a separate indication row (workup). For Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, prognostication language was modified. Revisions removed certain prognostication indications at treatment initiation.

Chorionic gonadotropin beta polypeptide (CGB3 / beta-hCG): Title standardized to Chorionic gonadotropin beta polypeptide (CGB3). For gestational trophoblastic neoplasia, added or clarified intensive monitoring schedules (initial workup; during and post treatment no more than weekly; follow-up/surveillance no more than monthly for 12 months). Occult primary specification changed from initial diagnostic evaluation to additional workup.

BNP / NT-proBNP and Troponin T / Cardiac markers: BNP/NT-proBNP indication for multiple myeloma was adjusted (added for initial diagnostic workup in a revision that moved some cardiac biomarker indications between sections); troponin T was repositioned with systemic light chain amyloidosis workup in a later revision.

Cancer antigen 19-9 (CA 19-9): Multiple changes — added workup and surveillance indications for ampullary adenocarcinoma (surveillance intervals specified: every 3-6 months for 2 years, then every 6-12 months for up to 5 years as clinically indicated); added baseline/workup indications for appendiceal adenocarcinoma with note to trend abnormal measurements; added monitoring indications for extrahepatic cholangiocarcinoma, gallbladder cancer, and intrahepatic cholangiocarcinoma; removed HCC initial diagnostic evaluation. Ovarian-related subtypes had monitoring/follow-up indications added or clarified (carcinosarcoma, clear cell, grade 1 endometrioid, low-grade serous, mucinous neoplasms) and frequency edits (borderline tumors: every visit if initially elevated).

Cancer antigen 125 (CA-125): Added baseline workup for appendiceal adenocarcinoma; added Lynch syndrome surveillance; added initial evaluation/workup for occult primary; uterine neoplasms received additional workup/surveillance indications; ovarian-related subtypes received monitoring/follow-up additions and frequency edits (borderline tumors: every visit if initially elevated).

Carcinoembryonic antigen (CEA): Added occult primary indication for workup of adenocarcinoma or carcinoma not otherwise specified; added monitoring indications for colon cancer, extrahepatic cholangiocarcinoma, gallbladder cancer, intrahepatic cholangiocarcinoma, and medullary carcinoma; appendiceal adenocarcinoma received baseline, monitoring, and post-treatment surveillance indications; ovarian borderline tumor frequency updated to every visit if initially elevated.

Human epididymis protein 4 (HE4): New marker added to the coverage table. Indications include ovarian/fallopian tube/primary peritoneal cancer — initial workup, during primary chemotherapy, and monitoring/follow-up for complete response as clinically indicated. Ovarian histologic subtypes also listed for monitoring/follow-up with similar frequency/usage language.

Inhibin (INHA): For ovarian indications, monitoring/follow-up frequency for borderline epithelial tumors updated to every visit if initially elevated. Adrenocortical carcinoma indication was adjusted in revisions (see history).

Lactate dehydrogenase (LDH): Several initial diagnostic evaluation indications for hematologic and other conditions were removed in revision (e.g., ALL, pediatric ALL, Hodgkin lymphoma, MDS, AML); other indications and ovarian-related frequency edits were made. LDH was reviewed for removal of broad, non-specific LDH uses in later edits.

Serum free light chains (sFLC): Surveillance frequency for multiple myeloma was standardized to once per month in revision; indications for Castleman disease, multiple myeloma, systemic light chain (AL) amyloidosis, and Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma were clarified and moved into discrete rows.

Tryptase and other specialty markers: For systemic mastocytosis and select myeloid/lymphoid neoplasms updates were made removing some monitoring or initial diagnostic indications where evidence was insufficient.

Tests removed from the list / market withdrawal: Certain proprietary/commercial tests were removed from the coverage list when they were withdrawn from the market (examples: OvaSure, Coloprint).

Coding and operational changes: New and removed CPT codes were reflected in revisions (examples: Addition of CPT 0404U and 83521, 83880; removal of CPT 82397, 0067U, 83883).

Policy formatting and organizational changes: The layout of CC1 was reformatted from condition-based listing to marker-based listing for ease of reference; terminology was adjusted (e.g., 'serum tumor markers' to broader 'serum biomarkers') and numerous editorial clarifications were made for consistency with NCCN Biomarkers Compendium guidance.

Marker- and Disease-specific Covered Indications

Numerous marker-specific covered indications (AFP, CA-125, CA19-9, CEA, serum free light chains, hCGβ, etc.) with frequency limits

Numerous marker-specific covered indications (examples include AFP, CA‑125, CA19‑9, CEA, serum free light chains, hCGβ) with frequency limits where specified

AFP — summary: Covered for HCC screening/workup/surveillance and multiple gynecologic and testicular indications; surveillance frequency examples and per‑tumor limits provided in policy (e.g., HCC: every 3–6 months then every 6 months; ovarian borderline: every visit if initially elevated; testicular nonseminoma: no more than every 2 months)

See full AFP entry for complete per‑tumor frequencies

CA‑125 — summary: Covered for ovarian/fallopian tube/primary peritoneal cancers (initial workup, during chemo, monitoring), appendiceal adenocarcinoma baseline workup, endometrial carcinoma additional workup and surveillance if initially elevated, Lynch syndrome surveillance, and peritoneal mesothelioma/uterine neoplasms as indicated

Borderline ovarian tumors: monitoring every visit if initially elevated

Procedure Codes and Coding Updates

Applicable CPT/HCPCS procedure codesmixed

No codes listed

Proprietary multi-analyte algorithm codesCPT

81500	Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4), algorithm reported as a risk score (ROMA™)
81503	Oncology (ovarian), biochemical assays of five proteins (OVA1™), algorithm reported as a risk score
81538	Oncology (lung), mass spectrometric 8-protein signature, prognostic/predictive algorithm

Individual analyte and assay CPT codesCPT

82105	Proprietary test: VeriStrat®
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 antigen; quantitative, NOS
83521	Immunoglobulin light chains (kappa, lambda), free, each
83789	Mass spectrometry and tandem mass spectrometry, non-drug analyte(s)
83880	Natriuretic peptide
83950	Oncoprotein; HER-2/neu

1–10 of 18

1/2

Additional proprietary and test-specific codesCPT | HCPCS

86316	Inhibin A
86336	Oncology (ovarian) biochemical assays of five proteins, algorithm reported as a likelihood score
0092U	Proprietary test: REVEAL Lung Nodule Characterization
0404U	Oncology (breast), semiquantitative measurement of thymidine kinase activity (Divitum®Tka)
0558U	Oncology (colorectal), quantitative ELISA for BF7 antigen (IGoCheck™)
0559U	Oncology (breast), quantitative ELISA for BF9 antigen (Haystack MRDTM)
G0327	Colorectal cancer screening; blood-based biomarker

Added CPT CodesCPT

0558U	newly added CPT-level I/II code referenced in revision history
0559U	newly added CPT-level I/II code referenced in revision history

Removed CPT CodesCPTNot Covered

83615

previous CPT code removed

Policy CPT code updatesCPT

0404U	CPT added 10/01/2023
83521	CPT added
83880	CPT added
82397	CPT removed
0067U	CPT removed
83883	CPT removed

Surveillance frequency examples

AFPSurveillance examples include every 3–6 months for 2 years, then every 6 months

CA19-9Post‑resection surveillance every 3–6 months for 2 years, then every 6–12 months up to 5 years

CEASurveillance every 3–6 months for 2 years, then every 6 months up to 5 years (marker‑dependent)

hCGβ (CGB3)Surveillance for ovarian/germ cell tumors per disease: e.g., malignant germ cell tumors surveillance no more than every 2 months initially

AFP level associated with recurrence risk after liver transplant

Provider Actions, Documentation, and Authorization Notes

Note

Assay authorization context

Biomarker assay authorization context: FDA-cleared assays (eg, ROMA, Ova1, Overa) are noted in the policy as approved options for evaluating adnexal/ovarian masses when surgery is planned and an oncologic referral has not yet occurred. Proprietary/commercial laboratory-developed tests (LDTs) such as OvaWatch, BeScreened-CRC, VeriStrat, Divitum®Tka, IGoCheck™, and others are described with their intended use and evidence summaries; coverage depends on demonstrated analytic/clinical validity and clinical utility for the requested indication.

FDA-approved assays (ROMA, Ova1, Overa) are recognized for adnexal mass evaluation prior to oncologist referral.
Proprietary/commercial tests and LDTs are discussed and require documentation of validity and utility for coverage.

Billing Rule

Coding and prior authorization note

Coding and prior authorization: Procedure codes listed in the policy (CPT/HCPCS codes in the Applicable Codes section) are used for billing and coverage determinations. Providers should verify the applicability of listed codes for the ordered test and confirm whether prior authorization is required by the member's benefit plan or payer rules at time of request.

Surveillance and Monitoring Frequency Limits

Marker‑specific frequency limits (examples)

AFPEvery 3–6 months for 2 years, then every 6 months (HCC surveillance and various ovarian indications)

CA19‑9Every 3–6 months for 2 years, then every 6–12 months up to 5 years (post‑resection surveillance for pancreatic/ampullary/ biliary cancers)

CA‑125Monitoring/follow‑up for ovarian and related cancers; for borderline ovarian epithelial tumors, frequency updated to 'every visit if initially elevated'

CEAEvery 3 months in stage II/III CRC (if candidate for surgery/systemic therapy); generally every 3–6 months then less frequent

Serum free light chainsMultiple myeloma surveillance up to once per month

hCGβ (CGB3)No more than weekly during/post treatment; monthly follow‑up for up to 12 months

Ordering and Documentation Requirements

Documentation Required

Ordering must match specified clinical scenarios

Ordering should be tied to the specific clinical scenarios described in the policy (for example, indeterminate adnexal mass for ovarian risk assays or CRC screening context for BeScreened™‑CRC); confirm the clinical scenario in documentation.

Documentation Required

Adnexal mass ordering — follow NCCN referral guidance

When ordering biomarker tests for adnexal masses, follow guideline context: NCCN recommends gynecologic oncologist evaluation prior to surgery and notes biomarker tests are adjunctive rather than a substitute for referral.

Documentation Required

LDTs — ensure CLIA high‑complexity lab and validation

LDTs are permissible when performed in CLIA‑certified high‑complexity laboratories and when validated; orders should follow the laboratory's instructions for use and the policy's requirement for validated LDTs.

Not Covered — Exclusions and Unvalidated Tests

All other serum tumor markers not specifically addressed in this policy and proteomic pattern analyses in serum for cancer screening or detection are not covered.

Biomarker tests that lack established analytic validity, clinical validity, or demonstrated clinical utility for the intended use do not meet coverage criteria and are not covered.

Routine use of multiple biomarkers that professional groups do not recommend (for example Glypican‑3 for liver, and various proposed markers for bladder, cervical, or gastric cancers) is not covered because guideline panels have not supported their routine clinical application.

Numerous unvalidated biomarkers and noninvasive biospecimen‑based tests proposed for early detection or to guide therapy (for example some proteomic panels, nonspecific NET markers, bladder markers like NMP22) lack sufficient evidence and are therefore not covered.

Lactate dehydrogenase (LDH) has been removed from the biomarker designation in this policy and is no longer managed under the serum biomarker policy; LDH is therefore treated as outside the scope of covered serum tumor marker testing.

Specific tests removed from the coverage list because they are no longer marketed — for example OvaSure and Coloprint — are not covered under this policy.

Background — Circulating Tumor Biomarkers

Circulating tumor biomarkers are substances detectable in blood, urine, or other body fluids that are produced by tumors or in response to tumors and can assist with detection, diagnosis, staging, prognostication, treatment monitoring, and surveillance. This policy focuses on laboratory‑measured serum biomarkers and aligns coverage with guideline recommendations and evidence of clinical validity and utility.

Definitions and Terms

Circulating tumor biomarkers — definition

Circulating tumor biomarkers (definition)Substances detected in blood, urine, or other body fluids produced by a tumor or in response to its presence; used to detect, diagnose, stage, and manage some cancers

Serum biomarker termPolicy focuses on laboratory‑measured proteins or peptides in serum used across diagnosis, prognostication, treatment monitoring, and surveillance

Policy basisBuilt from NCCN Biomarkers Compendium recommendations

LDT — definition and regulation

LDT (Laboratory‑developed test)A test developed and validated by a laboratory; regulated under CLIA as a high‑complexity test and not FDA‑approved for clinical use

Validation requirement

Revision History and Policy Changes

2025-11-15policy_reviewLatest

Comprehensive review and update: background, guidelines, evidence references revised; terminology changed from 'serum tumor markers' to 'Serum Biomarkers'; multiple per‑marker indication edits and table title changes implemented.

2023-10-01coding_update

Added CPT code 0404U to the policy effective 10/01/2023.

2023-01-01policy_revision

Policy Summary

Payerblue cross blue shield - louisiana

PolicySerum Tumor Markers for Malignancies

Policy CodePolicy AHS - G2124 - Serum Tumor Markers for Malignancies, 1

Change TypeRevisions to marker indications, frequencies and coding updates

Effective DateMay 15, 2022

Next Review Date

SourceLink

On This Page

CA 19‑9 — summary:

Covered for pancreatic adenocarcinoma baseline/monitoring/post‑operative surveillance and for ampullary, appendiceal, cholangiocarcinoma, gallbladder cancer and selected ovarian cancers with specified surveillance intervals (e.g., resected ampullary cancer: every 3–6 months for 2 years then every 6–12 months up to 5 years)

Abnormal values should be trended

CEA — summary: Covered for colorectal cancer baseline/monitoring/surveillance (every 3–6 months then every 6 months up to 5 years), appendiceal adenocarcinoma, breast metastatic monitoring, cholangiocarcinoma/gallbladder monitoring, and medullary thyroid carcinoma follow‑up

ADLM recommends CEA every 3 months in stage II/III when candidate for further therapy

Serum free light chains — summary: Covered for Castleman disease workup, multiple myeloma initial diagnostic workup and surveillance (up to once per month), and systemic light chain amyloidosis initial diagnostic workupup to once per month for multiple myeloma

ADLM recommends use with SPEP and immunofixation

Proprietary tests used for risk assessment/refinement (BeScreened™-CRC, Ova1Plus®, OvaWatch SM) — intended contexts

Proprietary tests used for risk assessment/refinement (BeScreened™‑CRC, Ova1Plus®, OvaWatch SM) — intended contexts

BeScreened™‑CRC: Described as a blood‑based colorectal cancer screening aid that reports 'negative' or 'positive' for likely presence of CRC; reported by developer to have 94% accuracy and is not intended to replace colonoscopy

Screening aid (not diagnostic replacement)

Ova1Plus® (Ova1® → Overa® reflex): Intended to assess ovarian malignancy risk in women with pelvic masses scheduled for surgery; Ova1® is performed first and Overa® reflexively performed if Ova1® is intermediate risk to improve sensitivity and reduce false positives

FDA‑cleared components; reflex workflow described

OvaWatch SM: May be considered for adnexal masses not planned for surgery when initial assessment is indeterminate or benign; combines seven biomarkers plus age and menopausal status to provide a risk score with reported NPV of 99%

Intended for risk refinement when surgery not planned

AFP measurement for HCC surveillance in high-risk patients per ADLM guidance

AFP measurement for HCC surveillance in high‑risk patients per ADLM guidance

AFP for HCC surveillance: Measure AFP at 6‑month intervals in patients at high risk of hepatocellular carcinoma; sustained AFP concentrations >20 μg/L should prompt further investigation even if ultrasound is negativeAFP every 6 months; >20 μg/L

ADLM practice guideline recommendation

Measurement of AFP, hCG, and LDH in nonseminomatous germ cell tumors — peri-treatment and surveillance use

Measurement of AFP, hCG, and LDH in nonseminomatous germ cell tumors — peri‑treatment and surveillance use

Germ cell tumor biomarkers (ASCO): ASCO recommends measuring serum AFP and hCG before orchiectomy to establish baseline and measuring AFP, hCG, and LDH shortly after orchiectomy, before chemotherapy, at each chemotherapy cycle, at end of chemotherapy, and during surveillance; surveillance durations up to 10 years recommended in ASCO guidance depending on histology

ASCO clinical practice guideline

HCC surveillance using AFP at 6-month intervals; threshold prompting investigation

HCC surveillance using AFP at 6‑month intervals; threshold prompting investigation

AFP surveillance frequency and alert level: ADLM recommends AFP measurement every 6 months in high‑risk patients for HCC; sustained AFP concentrations above 20 μg/L should prompt further diagnostic evaluation; some combination analyses reference AFP >10 ng/mL and other cutoffs in research contextsAFP every 6 months; alert >20 μg/L

See policy thresholds for research cutoffs (AFP‑L3, DCP) used in combination models

Serial CEA for colorectal cancer surveillance — every 3 months in stage II/III when candidate for further treatment

Serial CEA for colorectal cancer surveillance

CEA surveillance in CRC: ADLM recommends serial CEA measurement every 3 months in stage II or III colorectal cancer when the patient is a candidate for surgery or systemic therapy; CEA is used in pre‑operative planning and to monitor for recurrenceCEA every 3 months

Surveillance intervals may vary; policy gives examples of 3–6 month schedules

ER/PR/HER2 testing policies for breast cancer — baseline and invasive disease indications

Breast cancer receptor testing: ER and PR should be measured in all breast cancer patients; HER2 should be measured in all invasive breast cancer specimens to guide systemic therapy decisions

ASCO/ADLM guideline recommendations

AFP/LDH/hCG testing in suspected testicular cancer — pretreatment determination and monitoring

Testicular cancer biomarker requirements: Pretreatment determination of AFP, LDH, and hCG is mandatory if testicular cancer is suspected; these biomarkers are recommended for monitoring and risk stratification per society guidance

ASCO and ADLM recommendations

Multiple marker-specific indications updated across malignancies (examples)

Multiple marker-specific indications updated across malignancies (additions/removals/frequency changes)

Examples of marker updates: Policy revisions added and clarified indications for CA‑125, HE4, inhibin, serum free light chains and others across ovarian, hematologic, and hepatobiliary indications; several initial diagnostic indications were removed for select markers (see revision history)

Refer to per‑marker table entries in the policy

Tumor- and disease-specific indication updates (ALP, BNP/NT-proBNP, CA19-9 examples) — refer to individual marker entries for exact per-cancer indications and surveillance intervals

Tumor- and disease-specific indication updates (examples include ALP, BNP/NT-proBNP, CA19-9) — see individual marker entries for details

ALP and bone neoplasms: ALP indicated for bone neoplasms workup; revisions adjusted indications for measurement during treatment and surveillance in some updates

See revision history for exact edits

BNP/NT‑proBNP for amyloidosis: BNP/NT‑proBNP was added for initial diagnostic evaluation of systemic light chain (AL) amyloidosis in policy updates

Revision entries dated 01/01/2023 and later

CA19‑9 monitoring examples: CA19‑9 surveillance schedules for resected ampullary cancer and other hepatobiliary tumors were added or clarified (e.g., every 3–6 months for 2 years then every 6–12 months up to 5 years)

Per‑tumor surveillance intervals specified in policy

AFP level linked to transplant recurrence risk>200 ng/mL (AFP >200 ng/mL associated with increased probability of HCC recurrence)

Study sourceSantos Schraiber et al. (2016) multivariate analysis identifying AFP >200 ng/mL as risk

Clinical implicationSustained high AFP correlates with lower survival and higher recurrence probability after liver transplant

AFP‑L3 and DCP cutoffs in combination analyses

AFP cutoff used in combination analysesAFP >10 ng/mL (combined with PIVKA-II >40 mAU/mL gave highest AUC in Park et al.)

AFP‑L3 cutoffAFP‑L3 >10% referenced in combination analyses

DCP / PIVKA‑II cutoffPIVKA‑II (DCP) >40 mAU/mL referenced in combination analyses

AFP threshold for HCC investigation

Operational AFP threshold prompting further workupAFP >20 μg/L prompts further investigation for HCC even if ultrasound is negative

Guideline sourceADLM practice guidance recommends AFP measurement every 6 months in high‑risk patients and flags >20 μg/L for further workup

Use contextSustained increases may be used with ultrasound to inform detection and management

AFP alert level

AFP alert levelConcentrations above 20 μg/L should prompt further investigation (alert threshold)

Frequency contextMeasured every 6 months in high‑risk patients for surveillance per ADLM

Clinical noteAFP >20 μg/L may have diagnostic and prognostic implications and warrants follow‑up testing/imaging

CEA surveillance interval

CEA surveillance interval (stage II/III CRC)Every 3 months when patient is a candidate for surgery or systemic therapy

Use casePre‑operative and serial CEA measurements may inform surgical planning and monitoring

Guideline sourceADLM recommendation for CRC surveillance

AFP surveillance frequency

AFP surveillance frequency (high‑risk HCC)Measure AFP at 6‑month intervals in patients at high risk of HCC

Guideline sourceADLM practice guidance recommends AFP every 6 months for surveillance

Action on elevationSustained elevations >20 μg/L prompt further investigation

beta‑HCG monitoring frequency

beta‑hCG monitoring frequency (treatment period)No more than weekly during and post treatment

beta‑hCG follow‑up frequencyMonthly follow‑up surveillance for up to 12 months after treatment

Clinical contextsUsed for gestational trophoblastic neoplasia and selected germ cell/ovarian indications per ADLM/ASCO guidance

CA19‑9 surveillance (resected ampullary cancer)

CA19‑9 surveillance schedule (resected ampullary cancer)Every 3–6 months for 2 years, then every 6–12 months up to 5 years

Use casePost‑resection surveillance for stage I–III ampullary adenocarcinoma; abnormal measurements should be trended

Guideline sourcePolicy revision notes cite ADLM/NCCN‑aligned guidance for this schedule

Periodic monitoring allowance

Quarterly monitoring allowanceExcept where otherwise specified, quarterly measurement of designated serum biomarkers is permitted for follow‑up, monitoring, and/or surveillance

LimitationMarkers with specific frequency guidance (e.g., AFP every 6 months; beta‑hCG weekly during treatment) override the quarterly allowance

Denial riskTests ordered more frequently than specified intervals may be denied

Verify CPT/HCPCS code applicability before submission.
Confirm prior authorization requirements with plan-specific rules and benefits verification.

Billing Rule

New CPT codes / coding changes

New and changed CPT codes: The policy notes recent additions and removals to the code set. CPT 0404U was added effective 10/01/2023. CPT 0558U and 0559U were added (effective 07/01/2025 entry). CPT 83615 was removed. Providers must use the current, accurate CPT when submitting claims and check authorization requirements for any new codes.

CPT 0404U added effective 10/01/2023.
CPT 0558U and 0559U added per recent revision history.
CPT 83615 removed — verify not to use.

Denial Risk

Frequency limits and exceedance risk

Frequency exceedance and measurement limits: Except where otherwise specified in coverage criteria, quarterly measurement of designated serum biomarkers is permitted for follow-up, monitoring, and surveillance. Some markers and indications in the policy have explicit frequency limits (for example beta-hCG, CA19-9 and other tumor-specific entries); requests that exceed specified intervals may be denied unless clinical documentation justifies more frequent testing.

Quarterly measurement is permitted by default unless criteria specify otherwise.
If policy-specified frequency limits exist for a marker/indication, documentation must support any request to exceed those limits.

Documentation Required

Validity and clinical utility

Validity and clinical utility requirement: Tests (including LDTs and proprietary multi-marker assays) must have established analytic validity, clinical validity, and demonstrated clinical utility relevant to the requested clinical scenario. Tests lacking adequate validation or evidence of improved clinical decision-making or outcomes may be denied.

Analytic and clinical validity and clinical utility must be documented for coverage.
LDTs are regulated under CLIA as high-complexity tests and require laboratory validation; FDA approval is not required for clinical use but may be noted when present.

Prior Authorization

Prior authorization — not explicitly specified

No explicit universal prior-authorization requirement specified in this fragment: The policy excerpt does not list a single, plan-wide prior authorization mandate for serum tumor markers. However, coverage is conditional on member benefits and payer rules at time of request, and some proprietary tests may require additional documentation or prior authorization per payer or contract.

Confirm member-specific benefit coverage and payer prior-auth rules.
Provide clinical justification and intended use documentation when submitting proprietary or novel assays.

Note

Government policy supersedes commercial policy when applicable

Conflict with government policy: When government policies (e.g., Medicare LCDs or NCDs, or state Medicaid rules) apply to a member, those policies supersede this commercial policy and will be used to make determinations. Providers should check applicable federal or state coverage rules for the member before ordering.

Government (LCD/NCD/Medicaid) policies override this policy where applicable.
Refer to CMS Medicare Coverage Database and state Medicaid sites for current rules.

Documentation Required

Required clinical documentation for proprietary tests

Clinical indication and test-specific documentation: For proprietary tests and LDTs, documentation should explicitly support the clinical indication, prior testing performed, and how the test result will alter management. For example, documentation for ovarian mass biomarker testing should include surgical planning status, menopausal status, and whether referral to gynecologic oncology has occurred or is planned.

Document the clinical indication and intended management impact for proprietary assays.
For Ova1Plus® reflex workflow, record initial Ova1® result and rationale for reflex to Overa® (intermediate-risk result).

Note

Guidelines and evidence summaries

Guideline context and evidence summaries: The policy references guideline sources (eg, NCCN Biomarkers Compendium, ASCO guidance) and evidence summaries to inform coverage decisions. NCCN supports specific biomarker assays for preoperative assessment of adnexal masses but does not universally recommend multi-biomarker tests to determine management; ASCO provides marker-specific timing and surveillance recommendations for germ cell tumors and other conditions. Providers should align testing and frequency with guideline recommendations where provided.

NCCN Biomarkers Compendium is a primary guidance source for coverage.
ASCO guidelines give specific timing/frequency recommendations for some markers (eg, AFP, hCG surveillance schedules).

Documentation Required

Laboratory-developed tests (LDTs) — validation and regulation

LDT validation and regulation: Laboratory-developed tests are performed and validated by individual laboratories and are regulated under CLIA as high-complexity tests; they are not FDA-approved/cleared by default. LDTs may be covered if the laboratory validation and clinical utility for the intended indication are documented.

LDTs must be validated under CLIA '88 as high-complexity tests.
FDA clearance/approval is not required for clinical use of LDTs, but documented validation and utility are necessary for coverage.

Documentation Required

Documentation to support requested frequency or updated indication

Frequency and documentation notes to support updated indications/frequencies: Where the policy updates indicate specific monitoring intervals or changes (eg, surveillance intervals for beta-hCG, CA19-9, CA-125, serum free light chains), providers must document prior elevation/status, clinical rationale, and intended surveillance plan. Requests to modify frequency from policy defaults must include supporting clinical evidence or rationale.

Document baseline/previous values and clinical rationale for altered surveillance frequency.
Follow policy-specified intervals unless justified otherwise with clinical documentation.

Note

Reflex testing — Ova1Plus® workflow

Reflex testing workflow (Ova1Plus®): The Ova1Plus® workflow performs Ova1® first and reflexes to Overa® when the Ova1® result falls into an intermediate-risk category. When ordering or submitting for Ova1Plus®, include documentation of the initial Ova1® result and the reflex rationale per the manufacturer's algorithm.

Ova1® is performed first; Overa® is reflexed for intermediate-risk results to improve sensitivity and reduce false positives.
Include initial Ova1® result and reflex justification in documentation/submission.

Step Therapy

Step therapy — not specified

Step therapy and utilization management: No step therapy requirements are specified in this policy fragment. However, utilization rules (frequency limits, documentation requirements, and plan prior-authorization processes) may apply per member benefits and payer processes.

No explicit step therapy required for serum tumor markers in this excerpt.
Verify utilization management or plan-specific requirements with the payer.

OvaWatch SM — frequency/context reference

OvaWatch SM contextConsidered for ovarian cancer risk refinement in individuals with adnexal mass not planned for surgery when initial assessment is indeterminate or benign; reported NPV 99%

Test compositionUses seven tumor biomarkers plus age and menopausal status to produce a single risk score

Clinical noteIntended for risk refinement, not a substitute for diagnostic evaluation or oncologic referral when indicated

AFP — surveillance frequency summary

AFP (surveillance summary)Measure AFP every 6 months in patients at high risk for HCC; sustained AFP >20 μg/L should prompt investigation

Clinical useAFP used for screening, surveillance, workup, and monitoring in HCC and selected other indications per marker entry

Related guidanceADLM and AASLD support AFP measurement in surveillance though biomarkers alone are inadequate for diagnosis

AFP — surveillance frequency (details)

AFP (surveillance frequency)Every 6 months in high‑risk HCC patients (ADLM recommendation)

Alert thresholdConcentrations above 20 μg/L should prompt further investigation even if ultrasound negative

Monitoring roleSustained increases can be trended with imaging for detection/management

CEA — surveillance frequency example

CEA example frequencyEvery 3 months in stage II/III colorectal cancer if patient is a candidate for surgery or systemic therapy

Surveillance windowUsed for pre‑operative planning and serial monitoring during systemic therapy

Guideline sourceADLM clinical practice guidance

Calcitonin; CEA; TFTs; TSH — medullary thyroid carcinoma follow‑up

Medullary thyroid carcinoma follow‑up markersCalcitonin, CEA, TFTs, and TSH: every 6–12 months for post‑operative follow‑up

Clinical roleSerum calcitonin plays an important role in management after thyroidectomy though ATA cannot recommend routine calcitonin screening for nodules

SourceATA guidance referenced in policy (management after thyroidectomy)

beta‑HCG (CGB3) — monitoring frequency

Beta‑hCG (CGB3) treatment monitoring frequencyNo more than weekly during and post treatment

Beta‑hCG follow‑up surveillanceMonthly follow‑up for up to 12 months after treatment

IndicationsUse in gestational trophoblastic neoplasia and occult primary workup in select patients; measure free β‑subunit when assessing hCG

CA19‑9 surveillance schedule for resected ampullary cancer

CA19‑9 surveillance schedule (ampullary cancer)Every 3–6 months for 2 years, then every 6–12 months up to 5 years for resected ampullary cancer (stage I–III)

Trend abnormal valuesAbnormal CA19‑9 measurements should be trended over time

ApplicabilityAlso used for pancreatic, biliary, and related cancer monitoring per marker entries

Borderline ovarian epithelial tumors monitoring guidance

Borderline ovarian epithelial tumors monitoring frequencyUpdated guidance: 'every visit if initially elevated' replaces prior fixed interval guidance

Affected markersApplies to AFP, CA‑125, CA19‑9, and beta‑HCG for borderline ovarian epithelial tumors

Clinical implicationFlexibility to monitor at each clinical visit when marker initially elevated rather than adhere to a fixed schedule

General allowance for periodic serum tumor marker monitoring

General quarterly allowanceExcept where otherwise specified, quarterly measurement of designated serum tumor markers is permitted for follow‑up, monitoring, and/or surveillance

Override rulesSpecific marker frequency guidance (e.g., AFP every 6 months; beta‑hCG weekly during treatment) supersedes the quarterly allowance

Denial riskOrders exceeding specified surveillance intervals may be subject to denial

ORDERING REQUIREMENTS — coverage and ordering context

Coverage depends on member benefits and contextApplication of coverage criteria is dependent on the individual's benefit coverage at time of request; verify applicable Medicare/Medicaid rules

Ordering clinician contextOrdering should align with intended clinical use and documentation supporting indication; no specific provider‑type restriction listed

LDT regulation noteLDTs must be validated and are regulated under CLIA as high‑complexity tests; FDA approval not required for clinical use

Confirm the performing lab is CLIA‑certified for high‑complexity testing
Retain validation information as available

Note

Ordering clinician requirements not specified

The excerpt does not specify which clinician types may order these tests; follow standard clinical practice and payer-specific ordering rules as applicable.

Documentation Required

Align ordering with updated indications/frequencies

Ensure orders align with the policy's updated indications and frequencies; include documentation supporting any revised indication or nonstandard frequency.

If policy lists 'every visit if initially elevated,' document the initial elevation
If requesting more frequent surveillance than listed, provide clinical rationale

LDTs must be validated by the performing laboratory and comply with CLIA regulations

Coverage noteProprietary tests and LDTs require evidence of intended clinical use to meet coverage criteria

Companion biomarker — definition

Companion biomarker (definition)A marker used to identify a subgroup of patients for whom a therapy has shown benefit; may overlap with predictive biomarkers

PurposeUsed to select patients likely to benefit from a specific therapy rather than to broadly screen populations

CA 19‑9 — definition

CA 19‑9 (definition)Carbohydrate antigen 19‑9 (sialyl Lewis A), often elevated in adenocarcinomas including pancreatic and biliary tumors

Clinical useUsed for baseline workup, monitoring, and post‑resection surveillance with specified intervals

CEA — definition

CEA (definition)Carcinoembryonic antigen, a fetal protein often elevated in several malignancies; levels affected by nonmalignant conditions such as smoking or liver disease

Clinical useUsed for baseline workup, monitoring, and serial surveillance in colorectal and other cancers per guideline intervals

CgA — definition

Chromogranin A (CgA) (definition)Protein from neurosecretory vesicles; most sensitive of chromogranins for neuroendocrine tumors but variable in performance

LimitationsCgA is confounded by proton pump inhibitor use and comorbidities; routine use not universally recommended

Serum free light chains — definition and surveillance frequency

Serum free light chains (definition)Kappa and lambda free light chains measured to detect monoclonal light chain production in plasma cell disorders; kappa/lambda ratio used diagnostically

Clinical roleUsed in diagnosis and monitoring of multiple myeloma, systemic light chain amyloidosis, and Castleman disease

Surveillance frequencyMultiple myeloma surveillance: up to once per month as specified in policy revisions

LDT (CLIA/regulation note)

LDT regulatory note (CLIA)LDTs are regulated under CLIA as high‑complexity tests and must be validated by the performing laboratory

FDA statusLDTs are not FDA‑approved; FDA clearance/approval not required for clinical use per policy text

Serum Biomarkers — term definition

Serum Biomarkers (term)Laboratory‑measured proteins or peptides in serum used for cancer diagnosis, prognostication, treatment monitoring, or surveillance; policy broadened terminology from 'serum tumor markers' to 'Serum Biomarkers'

ScopeCovers dozens of markers with marker‑specific indications and frequency limits

Updated surveillance frequency example

Updated surveillance phrasing example'Every visit if initially elevated' replaces prior fixed‑interval guidance for select ovarian tumor markers (e.g., borderline epithelial tumors)

Markers affectedAFP, CA‑125, CA19‑9, beta‑hCG among those updated to 'every visit if initially elevated' for borderline ovarian tumors

Added general frequency note permitting quarterly measurement of designated serum tumor markers unless otherwise specified and added BNP/NT‑proBNP and serum free light chain biomarkers for specific hematologic indications.

2024-??-??per_marker_edits

Multiple marker-specific edits across 2024–2025 including additions/removals and frequency changes for ALP, AFP, B2M, BNP/NT‑proBNP, CA19‑9, CA‑125, HE4, inhibin, serum free light chains and others (per revision history entries).

2025-07-01coding_update

CPT codes 0558U and 0559U were added and CPT 83615 was removed (coding table update reflected in revisions).

2022-05-15initial_implementation

Initial policy implementation date.

Revision note: coding table updates and other editorial changes are summarized in the revision history; see the coding section for details.

Coding update: CPT codes 0558U and 0559U were added in recent revisions, and CPT 83615 was removed; verify current coding when submitting claims or authorizations.

Effective 10/01/2023, CPT code 0404U was added to the policy; include this code where applicable for authorization and billing.