Immunohistochemistry for Microscopic Evaluation of Breast Cancer

POLICY NUMBER

L.2.04.435

DESCRIPTION

Breast cancer is a disease that occurs with a wide age spectrum and requires the services of many physicians in different specialties. Routine hematoxylin and eosin (H&E) staining is the basis of tissue-based microscopic diagnosis. Some breast cancer detection services (breast and lymph node biopsies) require specific special histochemical stains (special stains) and/or immunohistochemical (IHC) stains that are used in the differential diagnosis of tissues or neoplasms.

As noted above, H&E staining is the first stain in tissue-based microscopic diagnosis. Thin sections of tissue are stained with H&E to visualize the tissue morphology. Hematoxylin dye stains the cell nuclei blue and the eosin dye stains other structures pink/red. H&E staining provides excellent detail required for tissue-based diagnosis.

Immunohistochemistry

IHC is a powerful tool for identifying substances and cells in tissue sections using the specificity of antigen-antibody reactions, where the antibody is linked to a colored indicator (stain) that can be seen with a microscope. More than 400 distinct antibody targets are currently available with varying sensitivity and specificity for a given target. A major use of IHC is to identify poorly differentiated malignant neoplasms (tumors) such as carcinoma, lymphoma, melanoma and sarcoma. Some IHC stains are useful in determining the primary site of a metastatic neoplasm, and others are used to guide specific therapies (e.g., Her2 IHC to determine potential response to trastuzumab).

The clinical care of patients with breast cancer depends upon the accurate diagnosis and the assessment of biomarkers. Hormone receptor assays and Her2 testing are recommended on all primary invasive breast cancers, and on recurrent or metastatic cancers. At the current time, there is no recommendation for Her2 testing on in situ breast lesions outside of a clinical trial.

Estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2) are well-established prognostic markers in invasive breast cancer management. The triple negative breast carcinoma subtype (ER-/PR-/Her2-) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women.

While there are a number of promising additional biomarkers, such as Ki-67 and PI3K, the College of American Pathologists (CAP), the American Society of Clinical Oncologists (ASCO) and the National Comprehensive Cancer Network (NCCN) have not recognized these markers in patient treatment pathways.

Ki-67 expression is a biomarker for proliferation and has been associated with response to therapy, but methods of measurement are controversial. In December 2013, the CAP reported that there is “a lack of consensus on scoring, definition of low versus high expression, an appropriate cut point for positivity, or which part of the tumor should be scored (e.g., leading edge, hot spots, overall average). There is also paucity of data on the effects of pre-analytical variables (e.g., ischemic time, length of fixation, antigen retrieval) on Ki-67 staining. For these reasons, routine testing of breast cancers for Ki-67 expression is not currently recommended by either ASCO or the NCCN.”

The clinical utility of testing for hormone receptors in in-situ breast cancer differs from those of invasive disease. Guidelines and the peer reviewed literature support only the use of ER testing for ductal in-situ breast cancer. Clinical guidelines have not been established for the use of Her2 or other biomarkers in patients with non-invasive breast neoplasia.

POLICY

IHC stains for estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2) may be considered medically necessary in the management of all primary invasive breast cancers (CPT codes 88342 and 88341 x 2, or 88360 x 3, or 88361 x 3).

IHC stain for estrogen receptor (ER) may be considered medically necessary in the management of ductal in-situ (non-invasive) breast cancer (one unit of CPT code 88342, 88360, or 88361).

IHC stain for progesterone receptor (PR) may be considered medically necessary in the management of ductal in-situ (non-invasive) breast cancer only in cases where an estrogen receptor (ER) stain was performed AND the estrogen receptor (ER) stain was negative.

IHC stain for progesterone receptor (PR) is considered not medically necessary in the management of ductal in-situ (non-invasive) breast cancer where the estrogen receptor (ER) stain was positive.

IHC stain for epidermal growth factor receptor 2 (Her2) is considered not medically necessary in the management of ductal in-situ (non-invasive) breast cancer.

In cases where the diagnosis is an invasive breast cancer, additional stains may be medically necessary and would be reimbursable under the policy.

IHC stains are considered not medically necessary when performed as reflex templates or pre-orders prior to review of routine H&E stains by the pathologist.

IHC stains without clinical evidence that the stain is actionable or provides the treating physician with information that changes patient management are considered not medically necessary.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Refer to the Immunohistochemistry Services Coding Guidelines which outline how each service must be selected and reported based on specific clinical indications.

Exceptions do exist and are recognized standards of care in the practice of pathology. In certain clearly defined circumstances, it may be reasonable to perform some IHC on sentinel lymph nodes when the frozen sections and permanent sections show they are free of tumors.

Other IHC may be indicated in the examination of breast biopsies and resections to determine whether the lesion is hyperplasia versus neoplasia and whether there is invasion in an in situ lesion as well as to determine whether a lesion may represent a sarcoma or secondary neoplasm.  These IHC stains may include - 

• CK5

• E-cadherin

• P27

• Cytokeratin

• P63

• Smooth muscle myosin

• Vimentin

• MPO

• CD markers for lymphoma

• Mart1

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which the Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

06/15/2017: New policy added. Effective 07/15/2017.

11/08/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

10/31/2023: Policy reviewed; no changes.

12/06/2024: Policy reviewed; no changes.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes C50.A0, C50.A1, and C50.A2.

SOURCE(S)

1. Allred DC, et al. NCCN Task Force Report: Estrogen Receptor and Progesterone Receptor Testing in Breast Cancer by Immunohistochemistry. JNCCN 2009;7[Suppl 6]:S1-S21)

2. CAP Cancer Biomarker Reporting Templates ( http://www.cap.org ).

3. Fitzgibbons PL, et al: Template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. Arch Pathol Lab Med 2014; 138(5):595-601.

4. NCCN Guidelines, 2017.

5. VandenBussche CJ, Cimino-Mathews A, Park BH, Emens LA, Tsangaris TN, Argani P (2015) Reflex estrogen receptor (ER) and progesterone receptor (PR) analysis ductal carcinoma in situ (DCIS) in breast needle core biopsies. Am J Surg Pathol 40:1090-1099, 2016.

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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