Immunohistochemistry
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Defines coding, coverage limitations, terminology, scientific background, and analytic validation expectations for immunohistochemistry and multiplex IHC used in diagnostic pathology; applies to providers submitting IHC testing for Medical Mutual - Ohio members.
Coverage Criteria and Validation Requirements
Analytic Validation and Guideline-based Testing
Laboratory analytic validation, quality control, and guideline-based testing recommendations (apply as noted):
CAP recommendation for predictive markers
CAP guidance; document rationale if fewer than recommended
CAP lists specific changes that trigger confirmation or revalidation
CAP requirement when antibody clone is changed
Laboratory medical director responsibility per CAP; maintain records for audits
ASCO/CAP recommendations affirmed through 2023
NCCN endorses CAP/ASCO protocols; ESMO supports IHC for cancers of unknown primary
The policy notes that there is no specific, generally accepted guidance on the selection or number of antibodies to use for most immunohistochemistry evaluations. As written, the document does not establish explicit coverage exclusions based on antibody selection or panel size; instead, it references that IHC use and antibody choices are informed by multiple specialty society recommendations and by individual clinical context.
If a conflict exists between this policy and an applicable government policy (for example, Medicare Local Coverage Determinations or National Coverage Determinations, or state Medicaid policies), the government policy governs determinations. Providers should consult the CMS coverage database and relevant state Medicaid resources for the most current authoritative guidance.
The policy was reviewed on 12/03/2025. The literature review performed at that time did not require any modifications to the existing coverage criteria.
Indications and Accepted Uses
Diagnostic evaluation of tumors, tissue/cell origin, benign vs malignant differentiation, infectious organism identification, and targeted therapy selection
Diagnostic evaluation of tumors, tissue/cell origin, benign vs malignant differentiation, infectious organism identification, and selection of targeted therapies — common marker panels include:
Diagnostic, prognostic, and predictive biomarker testing in cancers (guideline-supported)
Diagnostic, prognostic, and predictive biomarker testing in cancers (guideline-backed examples):
Procedure Coding and Validation Metrics
| 88342 | First single antibody procedure; reimbursed at one unit per specimen, up to four specimens per date of service |
| 88341 | Each additional single antibody per specimen; reimbursed up to a maximum of 13 units per date of service |
| 88344 | Each multiplex antibody per specimen; reimbursed up to six specimens per date of service |
| 88341 | Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure. |
| 88342 | Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain. |
| 88344 | Immunohistochemistry or immunocytochemistry, per specimen; each multiplex antibody stain procedure. |
Billing, Documentation, and Laboratory Responsibilities
CPT coding and unit limits
Use CPT codes 88342, 88341, and 88344 with the stated per-specimen and per-date-of-service unit limits; ensure units billed match the number of specimens and antibody type (single vs multiplex). Code 88342 is for the first single antibody per specimen (one unit per specimen, up to four specimens per date of service); 88341 is for each additional single antibody per specimen (reimbursed up to 13 units per date of service); 88344 is for each multiplex antibody per specimen (up to six specimens per date of service).
- Bill 88342 once per specimen for the initial single-antibody stain (max 4 specimens/ date of service).
- Bill 88341 for each additional single-antibody stain per specimen (aggregate limit 13 units/date of service).
- Bill 88344 per specimen for each multiplex antibody stain (max 6 specimens/date of service).
Procedure coding guidance for 88342 / 88341 / 88344
When billing IHC procedures, designate 88342 for the initial single-antibody stain per specimen and 88341 for each additional single-antibody stain; use 88344 for multiplex antibody stains—apply these code definitions per specimen as described in the CPT listings.
Match coding to specimen counts
Ensure coding and documentation reflect the exact specimen count and antibody type; misalignment between specimen counts and units billed risks denial or reimbursement adjustment.
Defer to applicable government policies
Confirm that determinations for coverage or reimbursement will follow applicable government policies (LCDs/NCDs/Medicaid); when a conflict exists, the government policy governs the determination.
- Defer to LCDs, NCDs, and state Medicaid policy where applicable.
Maintain analytic validation and verification records
Maintain complete analytic validation and verification documentation for all laboratory-developed tests (LDTs) and for verification of FDA-cleared IHC assays, including concordance testing and counts of positive and negative validation tissues as described by CAP guidance.
- Retain documentation showing >=90% overall concordance for initial validation/verification where applicable.
- Document counts of positive and negative tissues used in validation per CAP recommendations.
Document validation case counts and rationale for fewer cases
Document the number of validation cases and the laboratory medical director's rationale whenever fewer than the CAP-recommended minimum cases are used (for example, when fewer than 10 positive/10 negative cases are used for cytologic validations or fewer than 20/20 for predictive assays).
- If fewer than 10 positive and 10 negative cytologic cases are used, record the rationale in the validation file.
- If the laboratory medical director accepts fewer than 20/20 (or 40 when specified) for predictive markers, document the justification.
Government policy controls in conflicts
When this policy conflicts with any relevant government policy (LCD/NCD/Medicaid), determinations will be made in accordance with the government policy rather than this policy.
- Review applicable LCDs, NCDs, and state Medicaid rules for members before final determination.
Who Should Order and Ordering Constraints
No specific ordering restrictions in this policy
No specific ordering restrictions are stated in this policy; ordering and coverage depend on the member’s benefits and applicable state/federal regulations.
Expected ordering by treating pathology/laboratory personnel per guidance
Testing is expected to be ordered by treating pathology or laboratory personnel in accordance with professional guidance (eg, NCCN, ASCO/CAP); follow those guideline-based ordering practices.
- Order IHC and/or MSI for universal CRC screening per NCCN recommendations
- Follow ASCO/CAP protocols for HER2, HR testing and other guideline‑recommended assays
Limitations and Non-covered Items
Laboratory-developed tests (LDTs) used for IHC are not currently required to have FDA clearance or approval for clinical use; however, they are regulated under CLIA as high-complexity tests and must be validated and performed in-house in accordance with applicable regulatory and accreditation standards.
Scientific Background and Technology Overview
Immunohistochemistry (IHC) is a staining technique that uses labeled antibodies to detect specific antigens in cells or tissue sections. IHC is applied across diagnostic pathology to differentiate benign from malignant lesions, determine tumor origin or subtype, identify infectious organisms, and inform targeted therapy selection based on marker expression. Multiplex IHC (mIHC) extends these capabilities by allowing detection of multiple targets simultaneously in a single tissue section, which can assist in characterizing the tumor microenvironment and in immunotherapy stratification.
Key Terms and Definitions
Policy Review and Revision Timeline
Literature review and policy update: background, guidelines/recommendations, and evidence-base updated; literature review did not require changes to coverage criteria.
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