Description:
The purpose of this policy is to outline when it is appropriate to allow reimbursement for the physician component of certain clinical pathology services. This policy also addresses the processing of automated laboratory tests.

Policy Statement:
Professional Clinical Laboratory
It has been customary to recognize the physician component of certain clinical pathology services for separate reimbursement when it is inappropriate for the physician to bill the global service because the technical component was rendered by a technician or another physician who performed the technical component of the service only. The technical component represents the facility charge for administering a service: machinery, technicians and supplies required to perform the procedure. The professional component represents the physician’s charge for direct involvement in performing or interpreting the procedure performed. Examples of professional components that are appropriate for reimbursement would include:

• Interpretation and report of a clinical pathology examination rendered by a physician who has no association with the laboratory that prepared the specimen. 

The factors necessary for the recognition of such services for reimbursement would include:

• The interpretation and report must be necessary for the appropriate evaluation and treatment of the patient (medically necessary).
• The interpretation and report must have been requested by the attending physician (a request for consultation).
• The interpretation and report must be based on the physician’s personal evaluation of the pathological specimen or the specific laboratory findings. The physician must provide a written report signed by the physician that documents the interpretation or opinion.

Professional components are not recognized for routine clinical pathology services when those services involve testing of clinical specimens by automated machinery when the machine generates the test result without the necessity for physician interpretations.

A professional component of a technical service can be recognized as appropriate for reimbursement under the following guidelines:

• The interpretation of the result and a written report is medically necessary for the appropriate evaluation and treatment of the patient.
• The interpretation and report has been requested by the attending physician.
• The interpretation in the report is based on the physician’s personal evaluation of the pathological specimen or the specific technical findings.
• The reporting physician creates a report that is specific to the individual patient’s technical findings and signs and dates that report.

Table of Terminology

Rationale/Background
Immunohistochemistry (IHC) is used to identify certain components of tissues or cells (also known as immunocytochemistry) via use of specific antibodies that can be visualized through a staining technique. The premise behind IHC is that distinct tissues and cells contain a unique set of antigens that allows them to be identified and differentiated. The selection of antibodies used for the evaluation of a specimen varies by the source of the specimen, the question to be answered, and the pathologist performing the test.

Importantly, an entirely sensitive and specific IHC marker rarely exists, and therefore, determinations are typically based on a pattern of positive and negative stains for a panel of several antibodies. The four most common IHC staining patterns include nuclear staining, cytoplasmic staining, membrane staining, and extracellular staining (Tuffaha et al., 2018). A single IHC marker approach (other than for pathogens such as cytomegalovirus or BK virus) is strongly discouraged since aberrant expression of a highly specific IHC marker can rarely occur. However, aberrant expression of the entire panel of highly specific IHC markers is nearly statistically impossible (Lin & Chen, 2014).

Multiplex immunohistochemistry (mIHC) is a particular IHC technique that allows multiple targets in a single tissue to be detected simultaneously; this approach is able to characterize “the tumor microenvironment including vascular architecture and hypoxia, cellular proliferation, cell death as well as drug distribution” (Kalra & Baker, 2017). Hence, mIHC can assist in the development of parameter tumor maps. Other researchers have utilized mIHC for its novel ability to provide quantitative data on different types of tumor-infiltrating immune cells within a single tissue; this may improve cancer patient immunotherapy stratification (Hofman et al., 2019).

Clinical Utility and Validity
Immunohistochemistry can be used for a variety of purposes including: differentiation of benign from malignant tissue, differentiation among several types of cancer, selection of therapy, identification of the origin of a metastatic cancer, and identification of infectious organisms (Shah et al., 2012). IHC has many uses in the realm of tumor identification, and it has even been clinically used to pinpoint various breast cancer-specific markers, such as progesterone and

estrogen receptors, gross cystic duct fluid protein, and mammaglobin (Hainsworth & Greco, 2023). Further, overexpression of the HER2 oncogene, a predicative breast cancer biomarker, is often identified via IHC (Yamauchi & Bleiweiss, 2023). In regards to tumor identification, a specific type of IHC, known as pan-Trk IHC, has been shown to positively identify inflammatory myofibroblastic tumors with a nuclear and cytoplasmic staining pattern that may assist in targeted therapy (Yamamoto et al., 2019).

Antibodies for use in IHC are available as single antibody reagents or in mixtures of a combination of antibodies. More than 200 diagnostic antibodies are generally available in a large clinical IHC laboratory, and hundreds of antibodies are usually available in research laboratories. The list of new antibodies is growing rapidly with the discovery of new biomarkers by molecular methodologies (Lizotte et al., 2016). Several studies have shown that a relatively low number of antibodies are capable of accurately diagnosing specific cancers and identifying the primary source of a metastasis (Le Stang et al., 2019; Lizotte et al., 2016; Prok & Prayson, 2006).

Guidelines are lacking regarding the selection and number of antibodies that should be used for most immunohistochemistry evaluations. However, IHC is broadly used for conditions such as cancers, which are mentioned across many different societies. The below section is not a comprehensive list of guidance for immunohistochemistry.

College of American Pathologists (CAP)
The College of American Pathologists has published several reviews in Archives of Pathology & Laboratory Medicine that detail the quality control measures for IHC; further, CAP has also published more than 100 small IHC panels to address the frequently asked questions in diagnosis and differential diagnosis of specific entities. These diagnostic panels are based on literature, IHC data, and personal experience. A single IHC marker approach (other than for pathogens such as cytomegalovirus or BK virus) is strongly discouraged since aberrant expression of a highly specific IHC marker can rarely occur. However, aberrant expression of the entire panel of highly specific IHC markers is nearly statistically impossible (Lin & Chen, 2014; Lin & Liu, 2014).

In 2024, CAP published an update to their guidelines on the principles of analytic validation of immunohistochemical assays. The guidelines include the following recommendations (Goldsmith et al., 2024):

1. “Laboratories must analytically validate all laboratory developed IHC assays and verify all FDA-cleared IHC assays before reporting results on patient tissues.
2. For initial analytic validation or verification of every assay used clinically, laboratories should achieve at least 90% overall concordance between the new assay and the comparator assay or expected results.
3. For initial analytic validation of nonpredictive laboratory-developed assays, laboratories should test a minimum of 10 positive and 10 negative tissues. When the laboratory medical director determines that fewer than 20 validation cases are sufficient for a specific marker (e.g., rare antigen), the rationale for that decision needs to be documented.
4. For initial analytic validation of all laboratory-developed predictive marker assays, laboratories should test a minimum of 20 positive and 20 negative tissues. When the laboratory medical director determines that fewer than 40 validation tissues are sufficient for a specific marker, the rationale for that decision needs to be documented.
5. For initial analytic verification of all unmodified FDA-approved predictive marker assays, laboratories should follow the specific instructions provided by the manufacturer. If the package insert does not delineate specific instructions for assay verification, the laboratory should test a minimum of 20 positive and 20 negative tissues. When the laboratory medical director determines that fewer than 40 verification tissues are sufficient for a specific marker, the rationale for that decision needs to be documented.
6. For initial analytic validation of laboratory-developed assays and verification of FDA-approved or cleared predictive immunohistochemical assays with distinct scoring schemes (e.g., HER2, PD-L1), laboratories should separately validate or verify each assay-scoring system combination with a minimum of 20 positive and 20 negative tissues. The set should include challenges based on the intended clinical use of the assay.
7. For laboratory-developed assays with both predictive and nonpredictive applications using the same scoring criteria, laboratories should treat these assays as predictive markers and test a minimum of 20 positive and 20 negative cases.
8. Laboratories should use validation tissues that have been processed using the same fixative and processing methods as cases that will be tested clinically, when possible.
9. For analytic validation of IHC performed on cytologic specimens that are not fixed in the same manner as the tissues used for initial assay validation, laboratories should perform separate validations for every new analyte and corresponding fixation method before placing them into clinical service.
10. A minimum of 10 positive and 10 negative cases is recommended for each validation performed on cytologic specimens, if possible. The laboratory medical director should consider increasing the number of cases if predictive markers are being validated. If the minimum of 10 positive and 10 negative cases is not feasible, the rationale for using fewer cases should be documented.
11. If IHC is regularly done on decalcified tissues, laboratories should test a sufficient number of such tissues to ensure that assays consistently achieve expected results. The laboratory medical director is responsible for determining the number of positive and negative tissues and the number of predictive and nonpredictive markers to test.
12. Laboratories should confirm assay performance with at least 1 known positive and 1 known negative tissue when a new antibody lot is placed into clinical service for an existing validated assay (a control tissue with known positive and negative cells is sufficient for this purpose).
13. Laboratories should confirm assay performance with at least 2 known positive and 2 known negative tissues when an existing validated assay has changed in any one of the following ways: 1. Antibody dilution 2. Antibody vendor (same clone) 3. Incubation or retrieval times (same method).
14. Laboratories should confirm assay performance by testing a sufficient number of tissues to ensure that assays consistently achieve expected results when any of the following have changed: 1. Fixative type 2. Antigen retrieval method (eg, change in pH, different buffer, different heat platform) 3. Detection system 4. Tissue processing equipment 5. Automated testing platform 6. Environmental conditions of testing (eg, laboratory relocation, laboratory water supply) The laboratory medical director is responsible for determining how many predictive and nonpredictive markers and how many positive and negative tissues to test.
15. Laboratories should run a full revalidation (equivalent to initial analytic validation) when the antibody clone is changed for an existing validated assay.”

The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP)
The American Society of Clinical Oncology and the College of American Pathologists currently recommend that “all newly diagnosed patients with breast cancer must have a HER2 test performed” (Wolff et al., 2013). Also, for those who develop metastatic disease, a HER2 test must be done on tissue from the metastatic site, if available. In less common HER2 breast cancer patterns, as observed in approximately 5% of cases by dual-probe in situ hybridization (ISH) assays, new recommendations have been made to make a final determination of positive or negative HER2 tissue. This new “diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups… to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays;” further, “The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results” (Wolff et al., 2018).

The 2018 update included the following changes from the prior 2013 update, particularly focusing on infrequent HER2 test results that were of “uncertain biologic or clinical significance”:

• “Revision of the definition of IHC 2+ (equivocal) to the original FDA-approved criteria.
• Repeat HER2 testing on a surgical specimen if the initially tested core biopsy is negative is no longer stated as mandatory. A new HER2 test may (no longer should) be ordered on the excision specimen on the basis of some criteria (such as tumor grade 3).
• A more rigorous interpretation criteria of the less common patterns that can be seen in about 5% of all cases when HER2 status in breast cancer is evaluated using a dual-probe ISH testing. These cases, described as ISH groups 2 to 4, should now be assessed using a diagnostic approach that includes a concomitant review of the IHC test, which will help the pathologist make a final determination of the tumor specimen as HER2 positive or negative.

The Expert Panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, but it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world” (Wolff et al., 2018). The 2018 recommendations were affirmed in 2023 (Wolff et al., 2023).

The National Cancer Coalition Network
The NCCN has made numerous recommendations for use of IHC to diagnose and manage various types of cancer. Cancers with clinically useful IHC applications include breast, cervical, various leukemias, and colorectal cancer.

The NCCN states that the determination of estrogen receptor, progesterone receptor, and HER2 status for breast cancer is recommended and may be determined by IHC (NCCN, 2024). Specifically, the guidelines state that “the NCCN Panel endorses the CAP protocol for pathology reporting and endorses the ASCO CAP recommendations for quality control performance of HER2 testing and interpretation of IHC and ISH results.” They also specifically endorse the

ASCO/CAP HER2 testing guideline “Principles of HER2 testing,” and state “HR testing (ER and PR) by IHC should be performed on any new primary or newly metastatic breast cancer using methodology outlined in the latest ASCO/CAP HR testing guideline.” Additionally, “PR testing by IHC on invasive cancers can aid in the prognostic classification of cancers and serve as a control for possible false negative ER results. Patients with ER-negative, PR-positive cancers may be considered for endocrine therapies, but the data on this group are noted to be limited” (NCCN, 2024).

Further, the NCCN recommendations concerning genetic testing for colorectal cancer state, “The panel recommends that for patients or families where colorectal or endometrial tumor is available, one of three options should be considered for workup: 1) tumor testing with IHC or MSI; 2) comprehensive NGS panel (that includes, at minimum, the four MMR genes and EPCAM, BRAF, MSI, and other known familial cancer genes); or 3) germline multi-gene testing that includes the four MMR genes and EPCAM. The panel recommends tumor testing with IHC and/or MSI be used as the primary approach for pathology-lab-based universal screening” (NCCN, 2023). More recently, the NCCN has made additional recommendations to individuals diagnosed with any type of hereditary colorectal cancer (CRC) syndrome; these recommendations state that “all individuals newly diagnosed with CRC have either MSI or immunohistochemistry (IHC) testing for absence of 1 of the 4 DNA MMR proteins” (NCCN, 2023).

The European Society of Medical Oncology (ESMO)
The ESMO recommends that for cancers of an unknown primary site, “histology and IHC on good quality tissue specimens are required [III, A]” (Krämer et al., 2023). Particularly in the context for gastrointestinal carcinomas, ESMO states “Immunohistochemical loss of BRCA1-associated protein 1 (BAP1) or AT-rich interactive domain-containing protein 1A (ARID1A) can support the diagnosis but the final decision can only be made in conjunction with clinical and radiological findings.” Other mentions of IHC in their updated 2023 guidelines did not result in any other updated recommendations (Krämer et al., 2023).

References

1. Fitzgibbons, P. L., Bradley, L. A., Fatheree, L. A., Alsabeh, R., Fulton, R. S., Goldsmith, J. D., Haas, T. S., Karabakhtsian, R. G., Loykasek, P. A., Marolt, M. J., Shen, S. S., Smith, A. T., & Swanson, P. E. (2014). Principles of analytic validation of immunohistochemical assays: Guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med, 138(11), 1432-1443. https://doi.org/10.5858/arpa.2013-0610-CP
2. Goldsmith, J. D., Troxell, M. L., Roy-Chowdhuri, S., Colasacco, C. F., Edgerton, M. E., Fitzgibbons, P. L., Fulton, R., Haas, T., Kandalaft, P. L., Kalicanin, T., Lacchetti, C., Loykasek, P., Thomas, N. E., Swanson, P. E., & Bellizzi, A. M. (2024). Principles of Analytic Validation of Immunohistochemical Assays: Guideline Update. Arch Pathol Lab Med, 148(6), e111-e153. https://doi.org/10.5858/arpa.2023-0483-CP
3. Hainsworth, J., & Greco, F. (2023, January 20). Overview of the classification and management of cancers of unknown primary site. https://www.uptodate.com/contents/overview-of-the-classification-and-management-of-cancers-of-unknown-primary-site
4. Hofman, P., Badoual, C., Henderson, F., Berland, L., Hamila, M., Long-Mira, E., Lassalle, S., Roussel, H., Hofman, V., Tartour, E., & Ilie, M. (2019). Multiplexed Immunohistochemistry for Molecular and Immune Profiling in Lung Cancer-Just About Ready for Prime-Time? Cancers (Basel), 11(3). https://doi.org/10.3390/cancers11030283
5. Kalra, J., & Baker, J. (2017). Multiplex Immunohistochemistry for Mapping the Tumor Microenvironment. Methods Mol Biol, 1554, 237-251. https://doi.org/10.1007/978-1-4939-6759-9_17
6. Khoury, J. D., Wang, W. L., Prieto, V. G., Medeiros, L. J., Kalhor, N., Hameed, M., Broaddus, R., & Hamilton, S. R. (2018). Validation of Immunohistochemical Assays for Integral Biomarkers in the NCI-MATCH EAY131 Clinical Trial. Clin Cancer Res, 24(3), 521-531. https://doi.org/10.1158/1078-0432.Ccr-17-1597
7. Krämer, A., Bochtler, T., Pauli, C., Baciarello, G., Delorme, S., Hemminki, K., Mileshkin, L., Moch, H., Oien, K., Olivier, T., Patrikidou, A., Wasan, H., Zarkavelis, G., Pentheroudakis, G., & Fizazi, K. (2023). Cancer of unknown primary: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol, 34(3), 228-246. https://doi.org/10.1016/j.annonc.2022.11.013
8. Le Stang, N., Burke, L., Blaizot, G., Gibbs, A. R., Lebailly, P., Clin, B., Girard, N., & Galateau-Salle, F. (2019). Differential Diagnosis of Epithelioid Malignant Mesothelioma With Lung and Breast Pleural Metastasis: A Systematic Review Compared With a Standardized Panel of Antibodies-A New Proposal That May Influence Pathologic Practice. Arch Pathol Lab Med. https://doi.org/10.5858/arpa.2018-0457-OA
9. Lin, F., & Chen, Z. (2014). Standardization of diagnostic immunohistochemistry: literature review and geisinger experience. Arch Pathol Lab Med, 138(12), 1564-1577. https://doi.org/10.5858/arpa.2014-0074-RA
10. Lin, F., & Liu, H. (2014). Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med, 138(12), 1583-1610. https://doi.org/10.5858/arpa.2014-0061-RA
11. Lizotte, P. H., Ivanova, E. V., Awad, M. M., Jones, R. E., Keogh, L., Liu, H., Dries, R., Almonte, C., Herter-Sprie, G. S., Santos, A., Feeney, N. B., Paweletz, C. P., Kulkarni, M. M., Bass, A. J., Rustgi, A. K., Yuan, G. C., Kufe, D. W., Janne, P. A., Hammerman, P. S., . . . Wong, K. K. (2016). Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes. JCI Insight, 1(14), e89014. https://doi.org/10.1172/jci.insight.89014
12. NCCN. (2023, May 30). NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
13. NCCN. (2024, March 23). NCCN Guidelines Version 4.2024 Invasive Breast Cancer. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
14. Prok, A. L., & Prayson, R. A. (2006). Thyroid transcription factor–1 staining is useful in identifying brain metastases of pulmonary origin. Annals of Diagnostic Pathology, 10(2), 67-71. https://doi.org/10.1016/j.anndiagpath.2005.07.013
15. Shah, A. A., Frierson, H. F., & Cathro, H. P. (2012). Analysis of Immunohistochemical Stain Usage in Different Pathology Practice Settings. https://doi.org/10.1309/AJCPAGVTCKDXKK0X
16. Tuffaha, M. S. A., Guski, H., & Kristiansen, G. (2018). Immunohistochemistry in Tumor Diagnostics. In M. S. A. Tuffaha, H. Guski, & G. Kristiansen (Eds.), Immunohistochemistry in Tumor Diagnostics (pp. 1-9). Springer International Publishing. https://doi.org/10.1007/978-3-319-53577-7_1
17. Wolff, A. C., Hammond, M. E., Hicks, D. G., Dowsett, M., McShane, L. M., Allison, K. H., Allred, D. C., Bartlett, J. M., Bilous, M., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Mangu, P. B., Paik, S., Perez, E. A., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., & Hayes, D. F. (2013). Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol, 31(31), 3997-4013. https://doi.org/10.1200/jco.2013.50.9984
18. Wolff, A. C., Hammond, M. E. H., Allison, K. H., Harvey, B. E., Mangu, P. B., Bartlett, J. M. S., Bilous, M., Ellis, I. O., Fitzgibbons, P., Hanna, W., Jenkins, R. B., Press, M. F., Spears, P. A., Vance, G. H., Viale, G., McShane, L. M., & Dowsett, M. (2018). Human Epidermal
19. Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol, 36(20), 2105-2122. https://doi.org/10.1200/jco.2018.77.8738
20. Wolff, A. C., Somerfield, M. R., Dowsett, M., Hammond, M. E. H., Hayes, D. F., McShane, L. M., Saphner, T. J., Spears, P. A., & Allison, K. H. (2023). Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO–College of American Pathologists Guideline Update. Journal of Clinical Oncology, 41(22), 3867-3872. https://doi.org/10.1200/JCO.22.02864
21. Yamamoto, H., Nozaki, Y., Kohashi, K., Kinoshita, I., & Oda, Y. (2019). Diagnostic utility of pan-Trk immunohistochemistry for inflammatory myofibroblastic tumors. Histopathology. https://doi.org/10.1111/his.14010
22. Yamauchi, H., & Bleiweiss, I. (2023, August 25). HER2 and predicting response to therapy in breast cancer. https://www.uptodate.com/contents/her2-and-predicting-response-to-therapy-in-breast-cance

Coding Section
A professional component is recognized for codes CMS designates as appropriate for a separate professional interpretation. See the codes listed below:

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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