CurrentCentenePolicy N/A

Genetic Testing for Oncology Cytogentic Testing (PDF)

Defines medical necessity criteria for cytogenetic and related tumor molecular/protein analyses (FISH, CISH, IHC, PCR, targeted fusion panels) across multiple tumor types (e.g., ALK, RET, ROS1, ERBB2/HER2, PD-L1, NTRK, PML/RARA, FOLR1, multiple myeloma, CLL/SLL, bladder urine FISH). Applies to tests and CPT codes listed as examples.

Policy Summary

PayerCentene

PolicyGenetic Testing for Oncology Cytogentic Testing (PDF)

Policy CodePolicy N/A

Change TypeRevisions: added RET content, expanded tumor types, coding updates, wording/terminology clarifications

Effective Date

Next Review Date

Key ActionProviders must document the member's diagnosis/stage and that testing meets the specific tumor-type criteria to support medical necessity.

SourceLink

POLICY UPDATE CHANGES

Throughout policy: replaced 'coverage criteria' with 'criteria'; minor edits to overview and reference table.

Added Tumor Specific RET Gene Rearrangement (FISH) and related content to the policy reference table and criteria.

Replaced phrase 'coverage criteria' with 'criteria' throughout the policy and updated overview wording.

Expanded tumor type coverage for Tumor Specific ROS1 Gene Rearrangement to be consistent with updated NCCN guidelines (added several tumor types).

Changed Bladder Cancer Diagnostic and Recurrence FISH Tests from non-covered to covered based on LCD guidelines.

Added CPT codes 81315 and 81316 to PML/RARA Gene Rearrangement testing.

13Tumor-specific tests with explicit criteria included in this part

Coverage Summary

Defines medical necessity criteria for cytogenetic and related tumor molecular/protein analyses including FISH, CISH, IHC, PCR, and targeted fusion panels across multiple tumor types (examples: ALK, RET, ROS1, ERBB2/HER2, PD‑L1, NTRK, PML/RARA, FOLR1, multiple myeloma, CLL/SLL, bladder urine FISH). Applies to the tests and illustrative CPT codes listed in the policy reference table. Related Centene policies for circulating tumor DNA (ctDNA)/circulating tumor cells (liquid biopsy), hereditary cancer susceptibility genetic testing, and broader molecular testing are referenced and should be consulted when applicable.

Selected policy statistics

Tumor-specific tests with explicit criteria included in this part13

Bladder FISH investigational screening indication1

NCCN guideline versions citedNCCN v2.2024 - v1.2025

Review cadenceSemi-annual

Medical Necessity Criteria (by test/panel)

Tumor Specific ALK Gene Rearrangement (Qualitative FISH and PCR) Tests

Render criteria for Tumor Specific ALK Gene Rearrangement (Qualitative FISH and PCR) Tests as presented in the source policy.

Somatic ALK rearrangement analysis (88271, 88274) in solid tumors is considered medically necessary when:

ALL of the following:

- The member/enrollee has a diagnosis of or is in the initial work up stage for one of the following:

1. Stage IB or higher lung adenocarcinoma

2. Stage IB or higher large cell lung carcinoma

3. Stage IB or higher squamous cell lung carcinoma

Coding (policy reference groups)

ALK common CPT codes (examples)CPTCovered

88271	Cytogenetic analysis, FISH, probe interpretation (example used for ALK)
88274	Cytogenetic analysis, FISH, probe testing (example used for ALK)

Bladder FISH CPT codesCPTCovered

88120	Cytogenetic analysis, urine FISH (UroVysion example)
88121	Cytogenetic analysis, urine FISH interpretation (example)

CLL/SLL FISH panel CPT codesCPTCovered

88271	FISH probe interpretation
88274	FISH probe testing
88275	FISH panel (example)
88291	Microarray/other cytogenetic analysis (example)

ERBB2/HER2 CPT codesCPTCovered

88360	Immunohistochemistry (IHC) with interpretation (HER2 example)
88377	In situ hybridization (FISH/CISH) for HER2

Multiple Myeloma FISH CPT codesCPTCovered

88237	Karyotype, chromosomal analysis (example)
88271	FISH probe interpretation
88275	FISH panel testing
88291	Chromosome analysis/microarray (example)

NTRK fusion panel CPT codesCPTCovered

81191	NGS multi-gene panel; fusions (example NTRK)
81192	NGS - additional
81193	NGS - additional
81194	NGS - additional

PD-L1 IHC CPT codesCPTCovered

88341	Immunohistochemistry single or initial stain
88342	Immunohistochemistry additional stain
88360	IHC with interpretation (listed also under HER2/FOLR1)
88361	IHC interpretation, each additional antibody

FOLR1 IHC CPT codeCPTCovered

88360

IHC with interpretation (FOLR1 example)

PML/RARA FISH and PCR CPT codesCPTCovered

81315	Molecular pathology procedure, PML/RARA (example)
81316	Molecular pathology procedure, PML/RARA (additional)
88271	FISH probe interpretation
88274	FISH probe testing
88275	FISH panel testing
88291	Chromosome analysis/microarray (example)

RET FISH CPT codesCPTCovered

88374	In situ hybridization, probe interpretation (RET example)
88377	In situ hybridization, probe testing (RET example)
88271	FISH probe interpretation
88275	FISH panel testing
88291	Chromosome analysis/microarray (example)

ROS1 FISH CPT codesCPTCovered

88271	FISH probe interpretation (ROS1 example)
88274	FISH probe testing (ROS1 example)

Codes removed from Policy Reference Table (historical)CPT

88275	Code removed from policy reference table (historical mention)
88291	Code removed from policy reference table (historical mention)

Codes added (historical mentions)CPT

81315	Added to PML/RARA Gene Rearrangement (Qualitative FISH and PCR) in revision notes
81316	Added to PML/RARA Gene Rearrangement (Qualitative FISH and PCR) in revision notes

Provider Actions & Billing Rules

Documentation Required

Diagnostic documentation required

Providers must document the member's diagnosis and disease stage and attest that the requested testing meets the specific tumor‑type criteria (for example: stage, recurrent/metastatic status, or initial diagnostic workup) described in the policy to support medical necessity.

Document member diagnosis and stage
Document that testing meets the tumor‑specific criteria (stage, recurrent/metastatic status, initial diagnostic workup)
Include relevant supporting clinical information in the record to justify medical necessity

Billing Rule

Frequency limits for bladder tumor marker FISH

Bladder tumor marker FISH testing (CPT 88120, 88121) is limited by the policy to the following frequencies when used for surveillance after bladder cancer treatment: up to 4 studies per year in years 1–2 after diagnosis; up to 3 studies in year 3; up to 2 studies in year 4; and up to 1 study annually for up to 15 years after diagnosis. Per CMS guidance, generally no more than one repeat FISH is considered reasonable within 1 year following a comprehensive negative workup for high‑risk persistent hematuria.

Background, Evidence & Definitions

Cytogenetic analysis (FISH, CISH), PCR, IHC, and targeted fusion/NGS panels are used to classify tumors, identify somatic 'driver' mutations that inform targeted therapy selection, prognosis, and diagnosis for solid tumors and hematologic malignancies. The document notes that tests, example CPT codes, and ICD codes are illustrative and not exhaustive; a comprehensive register of registered tests is available on the Concert Platform. See Other Related Policies for guidance on ctDNA/liquid biopsy, molecular analysis of tumors, and hereditary cancer susceptibility testing.

Source	Note
NCCN guidance citations
Multiple NCCN guideline recommendations (various 2023-2025 versions) referenced supporting testing indications per tumor type (see policy references).
CMS LCD
CMS local coverage determination for bladder/urothelial tumor markers cited for utilization and coverage limitations of UroVysion (MolDX L33420).
NCCN NSCLC
NCCN NSCLC v7.2024 - recommends ROS1 (and other) testing for specified advanced/stage IB+ lung cancer histologies per policy.
NCCN Gastric
NCCN Gastric v2.2024 - recommends biomarker testing for locally advanced, recurrent or metastatic gastric cancer; lists RET gene fusion as a targeted biomarker.

Advanced cancer: Cancer that is unlikely to be cured or controlled with treatment; it may have spread to nearby tissue, lymph nodes, or distant sites. Treatment in this context may be palliative, intended to shrink tumors, slow growth, or relieve symptoms.

Medicare Determinations & Local Coverage Articles

Name	Number	Type	Effective Date
MolDX: Lab: Bladder/Urothelial Tumor Markers
L33420
LCD

MolDX: Billing and Coding: Lab: Bladder/Urothelial Tumor Markers
A53095
Billing Article

Lab: Bladder/Urothelial Tumor Markers

LCD

Revision History

03/23revision_note

Revision Date noted as 03/23: replaced 'coverage criteria' with 'criteria' throughout; removed codes 88275 and 88291 from policy reference table; added Tumor Specific RET Gene Rearrangement (FISH) and related content. No clinical policy statement changes detected in provided part. Material: false

10/23revision_note

Revision Date 10/23: reference table, background and references updated; replaced 'Advanced or metastatic' with stage language for some ALK criteria; added Tumor Specific FOLR1 Protein Analysis; added 81315/81316 to PML/RARA in later notes; added RET gene rearrangement criteria. Material: true (added RET content and new criteria additions)

04/24revision_note

Policy Summary

PayerCentene

PolicyGenetic Testing for Oncology Cytogentic Testing (PDF)

Policy CodePolicy N/A

Change TypeRevisions: added RET content, expanded tumor types, coding updates, wording/terminology clarifications

Effective Date

Next Review Date

Key ActionProviders must document the member's diagnosis/stage and that testing meets the specific tumor-type criteria to support medical necessity.

SourceLink

On This Page

Bladder Cancer Diagnostic and Recurrence FISH Tests

Render criteria for Bladder Cancer Diagnostic and Recurrence FISH Tests including diagnostic evaluation for hematuria, surveillance after treatment with frequency limits, and investigational exclusions.

Bladder cancer diagnostic and recurrence FISH tests (88120, 88121) for diagnosing, and monitoring bladder cancer are considered medically necessary when:

ONE of the following branches must be met:

A. Diagnostic evaluation for hematuria:

ALL of the following:

- The member/enrollee has hematuria, AND

- Diagnostic studies have failed to identify the etiology of the hematuria, AND

- A bladder cancer diagnostic and recurrence FISH test has not been ordered more than 1 time in the past 12 months

B. Surveillance after treatment for bladder cancer:

ALL of the following:

- The member/enrollee has been treated for bladder cancer, AND

- The bladder cancer diagnostic and recurrence FISH tests are ordered with the following frequency limits:

a) No more than 4 bladder tumor marker studies per year for years 1-2 after diagnosis

b) No more than 3 bladder tumor marker studies per year during year 3 after diagnosis

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) FISH Panel Analysis

Render criteria for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) FISH Panel Analysis including required loci and initial workup condition.

FISH panel analysis for CLL/SLL (common CPTs: 88271, 88274, 88275, 88291) is considered medically necessary when:

ALL of the following:

- The testing is part of the initial diagnostic workup for suspected or confirmed chronic lymphocytic leukemia / small lymphocytic lymphoma, AND

- The panel includes probes for the loci commonly required for CLL/SLL assessment (for example: 13q deletion, 11q22 (ATM), 17p13 (TP53), trisomy 12)

- Results will be used to inform prognosis and treatment planning

Tumor Specific ERBB2 (HER2) Deletion/Duplication (FISH and CISH)

Render criteria for Tumor Specific ERBB2 (HER2) Deletion/Duplication (FISH and CISH) including listed tumor types and stages.

ERBB2 (HER2) deletion/duplication testing by FISH or CISH (e.g., 88360, 88377) is considered medically necessary for tumor types where HER2 status guides therapy or prognosis. Applicable tumor types include, but are not limited to:

- Tumors of the breast (C50)

- Tumors of the stomach and gastroesophageal junction (e.g., C16, C17)

- Selected other solid tumors where guideline-recommended (e.g., select colorectal, esophageal, and other sites) and where HER2-directed therapy is being considered or is guideline-supported

- Stage and clinical context consistent with guideline-directed HER2 testing

Multiple Myeloma FISH Panel Analysis

Render criteria for Multiple Myeloma FISH Panel Analysis including required loci and initial diagnostic workup condition.

Multiple myeloma FISH panel analysis (common CPTs: 88237, 88271, 88275, 88291) is considered medically necessary when:

ALL of the following:

- The testing is performed as part of the initial diagnostic workup or for risk stratification of confirmed multiple myeloma (C90), AND

- The panel includes probes for loci relevant to multiple myeloma prognostication (for example: del(17p), t(4;14), t(14;16), 1q gain, del(13q)), AND

- Results will inform prognosis, staging, transplantation candidacy, or therapy selection

NTRK Fusion Analysis Panel

Render criteria for NTRK Fusion Analysis Panel including A (initial diagnostic workup/advanced disease) and B (specific diagnoses at any stage) branches.

NTRK fusion analysis panels (common CPTs: 81191-81194) are considered medically necessary when ANY of the following are met:

A. Initial diagnostic workup or advanced/metastatic disease where detection of an NTRK fusion would alter therapy (e.g., consideration of TRK inhibitors)

B. Tumor histologies with a high pretest probability or guideline recommendation for NTRK testing at any stage (examples include select sarcomas, secretory carcinomas, infantile fibrosarcoma, and certain rare tumors)

Tumor Specific PD-L1 Protein Analysis

Render criteria for Tumor Specific PD-L1 Protein Analysis including listed tumor types/stages.

PD-L1 immunohistochemistry (IHC) with interpretation (e.g., 88341, 88342, 88360, 88361) is considered medically necessary when PD-L1 expression is required to determine eligibility for approved immune checkpoint inhibitor therapies or per guideline recommendations. Applicable tumor types/stages include, but are not limited to:

- Non-small cell lung cancer (selected stages as per guidelines)

- Head and neck squamous cell carcinoma

- Urothelial carcinoma

- Selected other solid tumors where PD-L1 testing is indicated by treatment guidelines

Tumor Specific FOLR1 Protein Analysis

Render criteria for Tumor Specific FOLR1 Protein Analysis including criteria linking to treatment consideration (Elahere).

FOLR1 (folate receptor alpha) immunohistochemistry testing (e.g., 88360) is considered medically necessary when:

ALL of the following:

- The tumor is of a histology for which FOLR1-directed therapy (e.g., Elahere) is being considered, AND

- Testing results will be used to determine treatment eligibility per the companion diagnostic or guideline-directed thresholds

Tumor Specific PML/RARA Gene Rearrangement (Qualitative FISH and PCR)

Render criteria for Tumor Specific PML/RARA Gene Rearrangement (Qualitative FISH and PCR) including initial diagnostic workup for AML.

PML/RARA (t(15;17)) qualitative FISH and PCR testing (e.g., 81315, 81316, 88271, 88274, 88275, 88291) is considered medically necessary when:

ALL of the following:

- The testing is part of the initial diagnostic workup for suspected acute promyelocytic leukemia (APL) or acute myeloid leukemia with clinical suspicion for PML/RARA rearrangement, AND

- Results will guide immediate treatment decisions (e.g., initiation of ATRA/arsenic regimens)

Tumor Specific RET Gene Rearrangement Tests (FISH)

Render criteria for Tumor Specific RET Gene Rearrangement Tests (FISH) including medullary thyroid cancer branch (with germline testing note) and expanded tumor list/stages for testing.

RET gene rearrangement testing by FISH (common CPTs include 81315, 81316, 88271, 88274, 88275, 88291) is considered medically necessary when ANY of the following are met:

- Medullary thyroid carcinoma: testing may be performed in the context of medullary thyroid cancer; note that consideration of germline RET testing is indicated for medullary thyroid cancer given hereditary implications

- Other tumor types and clinical contexts where RET rearrangement testing is guideline-recommended or would alter therapy, including select lung cancers and thyroid cancers (locally advanced, recurrent, or metastatic disease)

- Testing is performed where results will inform targeted therapy selection or prognosis

Tumor Specific ROS1 Gene Rearrangement

Render criteria for Tumor Specific ROS1 Gene Rearrangement including listed tumor types and pediatric glioma indication.

ROS1 gene rearrangement testing (FISH or other validated assays; common CPTs include 88271, 88274, 88291, 88374, 88377) is considered medically necessary when ANY of the following are met:

- Non-small cell lung cancer where ROS1 status would guide targeted therapy selection (e.g., advanced/metastatic NSCLC)

- Selected other solid tumors where testing is guideline-supported and would affect management

- Pediatric gliomas with clinical scenarios or histologies where ROS1 fusions are implicated and where results would guide therapy

Guideline-based indications referenced for ROS1 and RET gene rearrangement testing

Guideline-based indications referenced for ROS1 and RET gene rearrangement testing (list of cited guideline references).

NCCN Guidelines for Non-Small Cell Lung Cancer (relevant years cited in source)

NCCN Guidelines for Thyroid Carcinoma (relevant years cited in source)

Other referenced society guidelines and peer-reviewed sources as cited in the policy document

Policy revision and criteria modifications (summary)

Policy revision and criteria modifications — summary of changes across revisions. Consolidated, non-duplicative summary of edits and updates to criteria in this section.

- Updated and clarified indications for ALK rearrangement testing to specify staging thresholds (Stage IB or higher for listed lung histologies) and inclusion of anaplastic thyroid carcinoma.

- Added explicit frequency limits and surveillance intervals for bladder cancer diagnostic and recurrence FISH testing (limits per year for years 1-3 after diagnosis) and clarified diagnostic hematuria pathway with prior diagnostic evaluation requirement.

- Consolidated and standardized FISH panel expectations for hematologic malignancies: specified required loci/examples for CLL/SLL and multiple myeloma panels and emphasized use in initial diagnostic workup and treatment planning.

- Included tumor-specific guidance for ERBB2 (HER2) testing across multiple tumor types where HER2 status impacts therapy; aligned wording to guideline-directed testing.

- Added NTRK fusion panel criteria distinguishing initial/advanced disease contexts and tumor-histology-specific indications where testing is appropriate at any stage.

- Specified PD-L1 and FOLR1 protein IHC criteria tied to therapy eligibility (PD-1/PD-L1 inhibitors and FOLR1-directed therapy respectively).

- Reinforced that PML/RARA (t(15;17)) testing is required in initial workup for suspected APL due to immediate treatment implications.

- Clarified RET and ROS1 rearrangement testing indications, included note about germline RET testing consideration in medullary thyroid carcinoma, and expanded tumor lists/stages consistent with guideline references.

- Harmonized CPT and ICD code examples and reference citations across criteria items for coding consistency (codes provided as examples; not exhaustive).

- Administrative/formatting: reorganized criteria groups for clarity and added cross-references to related policies (e.g., circulating tumor DNA, hereditary cancer testing).

Documentation Required

Panel composition requirement

For CLL/SLL and multiple myeloma FISH panels, the panel composition must include the enumerated loci/abnormalities specified in the policy. For CLL/SLL panels this includes testing for +12, del(11q), del(13q), and del(17p). For multiple myeloma panels this includes del(13), del(17p13), t(4;14), t(11;14), t(14;16), t(14;20), 1q21 gain/amplification, and del(1p).

Affected codes: 88271
Affected codes: 88274
Affected codes: 88275
Affected codes: 88291
Affected codes: 88237

Documentation Required

Use guideline-based indications for testing

Follow NCCN guideline‑based indications when ordering ROS1 or RET rearrangement testing. Orders should document the tumor type and disease stage (for example: advanced/metastatic or specified stages/tumor types per NCCN) to demonstrate that testing meets the policy's guideline‑referenced indications.

Document tumor type and disease stage per NCCN referenced in policy

Billing Rule

Refer to updated policy reference table for coding

Use the updated policy reference table and current coding guidance when submitting claims. The policy notes that some CPT codes were removed and others added in revisions; follow plan/LCD/MolDX guidance (for example, MolDX/LCD L33420 and associated billing article) when selecting codes for submission.

Affected codes: 88275
Affected codes: 88291
Affected codes: 81315
Affected codes: 81316

11/24revision_note

Revision Date 11/24: semi-annual review documenting multiple updates — added additional cancer types for coverage (including esophageal/esophagogastric, gastric, vaginal cancers), updated NCCN references and versions; Bladder Cancer Diagnostic and Recurrence FISH Tests coverage changed from non-covered to covered based on MolDX/LCD L33420. Material: true (coverage change for bladder FISH and expanded tumor lists)

ongoing_updatesLatest

Ongoing editorial and coding updates over multiple revisions (including adding CPT codes 81315 and 81316 to PML/RARA; removal/addition of various CPT codes in reference table; terminology standardization). Some edits are non-material (terminology and wording); others are material (tumor type expansions, RET addition, bladder FISH coverage alignment with MolDX/LCD L33420). Material: mixed

Summary of recent changes: the policy documents revisions (e.g., Revision Date 03/23 and subsequent updates) note expansions in covered tumor types for RET and ROS1 gene rearrangement testing, coding table updates (added CPT 81315 and 81316 for PML/RARA; historical removal of codes 88275 and 88291 from the reference table), and alignment with MolDX/LCD L33420 and its billing article for bladder/urothelial tumor marker guidance. The policy is maintained on a semi‑annual review cadence per the revision history.