Summary & Overview

CPT 88366: In Situ Hybridization Multiplex Probe Stain with Interpretation

CPT code 88366 covers a diagnostic anatomic pathology service in which a lab analyst applies a single in situ hybridization multiplex probe stain to slide(s) from a single patient specimen and a qualified provider, typically a pathologist, performs qualitative interpretation to produce a pathologic diagnosis. This code is nationally relevant for pathology practices, oncology programs, and diagnostic laboratories that rely on molecular tissue testing to guide clinical care and treatment selection.

Key payers included in the review are Aetna, Blue Cross Blue Shield, Cigna Health, UnitedHealthcare, and Medicare. The analysis explains coverage patterns and billing considerations across major commercial payers and the federal program to help providers understand payer expectations and documentation requirements.

Readers will learn what the code represents clinically, where the service is typically performed, and which stakeholders commonly reimburse this service. The publication also summarizes benchmarks and policy-relevant updates affecting molecular pathology billing, clarifies common billing scenarios for single-probe in situ hybridization multiplex staining with qualitative interpretation, and identifies areas where documentation supports appropriate use. Data not available in the input for specific payor rates, taxonomies, ICD-10 pairings, and related codes.

AetnaBlue Cross Blue ShieldCigna HealthUnitedHealthcareMedicareCPT 88366in situ hybridizationmolecular pathologyanatomic pathologypathology billingdiagnostic laboratoryslide interpretationoncology diagnostics

Billing Code Overview

CPT code 88366 describes a pathology service in which a laboratory analyst performs a single in situ hybridization multiplex probe stain on slide(s) prepared from a single patient specimen, such as tumor tissue. A qualified provider, typically a pathologist, then qualitatively interprets the stained slide(s) to provide a pathologic diagnosis.

Service type: Diagnostic anatomic pathology laboratory procedure with qualitative interpretation
Typical site of service: Hospital pathology laboratory, independent diagnostic laboratory, or outpatient surgical pathology setting

Clinical & Coding Specifications

Clinical Context

A 62-year-old patient presents with a newly diagnosed lung mass on imaging. A core needle biopsy of the tumor is obtained and processed to formalin-fixed, paraffin-embedded (FFPE) tissue. The laboratory technologist performs a single in situ hybridization multiplex probe stain on representative tissue sections to detect gene rearrangements or copy-number alterations relevant to targeted therapy. A board-certified pathologist reviews the stained slides, qualitatively interprets probe signals, and issues a pathology report that integrates morphologic findings with the in situ hybridization result to guide oncologic treatment planning. Typical workflow steps include specimen accessioning, slide preparation, probe hybridization and staining by a lab analyst, slide interpretation and reporting by a pathologist, and result transmission to the treating oncologist. Typical documentation includes the diagnosis, test performed (88366), probe target(s), interpretation (positive/negative/indeterminate), and any technical limitations.

Coding Specifications

Modifier	Description	When to Use
`26`	Professional component	Use when reporting only the pathologist’s interpretation component separate from the technical staining service.
`TC`	Technical component	Use when billing only the laboratory staining and technical processing component.
`59`	Distinct procedural service	Use when this test is distinct from other services on the same day (e.g., separate from immunohistochemistry or FISH panels) and not normally billed together.
`76`	Repeat procedure by same physician	Use when the in situ hybridization stain is repeated by the same payer of record for the same patient on the same day.
`77`	Repeat procedure by another physician	Use when a repeat stain is performed by a different laboratory or pathologist.
`90`	Reference (outside) laboratory	Use when the testing was performed by an outside reference laboratory and only the report is transmitted.
`91`	Repeat clinical diagnostic test	Use for repeat testing when indicated to confirm prior indeterminate or discordant results (lab-level repeat).
`52`	Reduced services	Use when a portion of the test was not performed or only a partial panel was completed.
`53`	Discontinued procedure	Use when the staining procedure was started but discontinued due to specimen quality or technical failure.
`22`	Increased procedural services	Use when the service required substantially greater resources or time than typical.
`59`	Distinct procedural service	Use when this ISH is distinct from other concurrently reported pathology procedures (listed again here as commonly applied).
`90`	Reference (outside) laboratory	Use when send-out testing performed elsewhere (listed again as commonly applied).

Taxonomy Code	Specialty	Notes
207K00000X	Anatomic Pathology	Pathologists who interpret in situ hybridization studies and issue diagnostic reports.
207KR0500X	Hematopathology	Specialists interpreting ISH for hematologic malignancies and rearrangements.
207L00000X	Molecular Genetic Pathology	Pathologists or laboratorians focused on molecular and cytogenetic testing, including ISH.
2080P0005X	Clinical Laboratory Director	Laboratory directors overseeing technical staining and assay validation.

Related Diagnoses

ICD-10 Code	Description	Clinical Relevance
`C34.90`	Malignant neoplasm of unspecified part of unspecified bronchus or lung	Primary lung tumor specimen commonly evaluated with ISH for driver alterations.
`C50.919`	Malignant neoplasm of unspecified site of unspecified female breast	Breast carcinoma specimens frequently undergo ISH for HER2 gene amplification.
`C71.9`	Malignant neoplasm of brain, unspecified	Central nervous system tumors may be evaluated with ISH for diagnostic or prognostic markers.
`C22.9`	Malignant neoplasm of liver, not specified as primary or secondary	Hepatic tumors may require ISH to detect viral/integrated sequences or copy-number changes.
`C91.10`	Chronic lymphocytic leukemia of the blood, not having achieved remission	Hematologic malignancies use ISH for chromosomal rearrangements or deletions relevant to prognosis.

Related CPT Codes

CPT Code	Description	Relationship to This Procedure
`88342`	Immunohistochemistry or immunocytochemistry, per single antibody stain; each additional single antibody stain	Often performed on adjacent sections to characterize protein expression complementary to ISH results.
`88365`	In situ hybridization (e.g., FISH), non-multiplex probe, each probe	Reported for single-probe ISH assays; `88366` describes a multiplex probe stain — `88365` may be used for single-probe studies in the same workflow.
`88367`	In situ hybridization (e.g., FISH), each additional probe beyond initial probe multiplex	Used when multiple separate probes beyond the primary multiplex are interpreted on the specimen.
`88325`	Consultation and review of slides when performed remotely (pathology consultation)	Used when a second pathologist review or consultation is obtained for interpretation of ISH results.
`88321`	Cytopathology, slide interpretation and report	May be used earlier in the workflow if a cytology specimen (rather than tissue block) was submitted and ISH is performed on cytology slides.