Immunohistochemistry for Microscopic Evaluation of Prostate Biopsy

POLICY NUMBER

L.2.04.434

DESCRIPTION

Prostate cancer affects many men and the incidence rises with age. The exact cause of prostate cancer is unknown, though it is known that heredity and environmental factors play a role in its development. Prostate cancer screening involves close attention to the clinical history, correlation with the patient’s age, digital rectal exam, and, sometimes, prostate specific antigen (PSA) analysis.

The diagnosis of prostate cancer is made by biopsy. The prostate specimens are placed in a fixative (formalin) and sent to a pathology laboratory for analysis. Sometimes only a few cores of tissue are taken from one or both sides of the gland, and sometimes a “sextant” (12) series of cores of tissue are taken. Rarely, a “saturation” biopsy may be needed when the first biopsy or biopsies are not completely diagnostic.

Hematoxylin and eosin (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

The accuracy of the pathologic diagnosis of prostate cancer is critical for optimal patient care. The diagnosis can usually be made on morphologic features such as growth pattern, nuclear atypia and the absence of basal cells. However, it may be difficult to reach a firm diagnosis by routine H&E stain for small foci of cancer in needle biopsies because many benign conditions can mimic prostate cancer.

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.

The immunohistochemical diagnosis of prostate cancer largely depends on panels of markers because no absolutely specific and sensitive marker for prostate cancer has yet been identified. These panels usually include at least one basal cell marker, such as high-molecular-weight cytokeratin (HMWCK) or p63, and the prostate cancer-specific marker, alpha-methyl-CoA-Racemase (AMACR). Although AMACR is considered a useful IHC marker for prostate cancer, because of non-standardized immunostaining protocols, interpretation criteria and heterogeneous staining pattern, there is wide variation in the sensitivity and specificity of AMACR immunoreactivity in prostate biopsies. Furthermore, because AMACR expression has been demonstrated in high-grade PIN, atypical adenomatous hyperplasia/adenosis and nephrogenic adenoma, it is recommended that AMACR is best restricted to the evaluation of morphologically highly suspicious foci in which negative immunoreactivity of basal cell markers alone is insufficient to establish a diagnosis of cancer.

PTEN and MYC may provide some prognostic information, but neither is part of any standard treatment protocol and neither should be routinely performed. ERG is another IHC that is more likely to be positive in cancer than in benign tissue, but it does not add information to conventional PIN4 testing. Similarly, neuroendocrine markers, such as IHC for synaptophysin, may be indicated in cases of recurrent/metastatic prostate carcinoma that have undergone small cell transformation after hormone therapy. The latter marker is only necessary for high grade, undifferentiated tumors and should not be used routinely.

PIN4 is an IHC cocktail of CK5/14, p63 and P504S that is used primarily to differentiate normal and neoplastic epithelial tissues. In prostate tissue, CK5 and CK14 are detected in basal cells of normal glands and prostatic intraepithelial neoplasia (PIN) which is a precursor lesion to prostatic adenocarcinoma. However, expression of CK5 and CK14 is not identified in invasive prostatic adenocarcinoma. P63 is detected in nuclei of basal epithelium in normal prostate glands, but is not expressed in malignant prostate tumors. Because P504S (aka AMACR) is not specific for prostatic adenocarcinoma, the use of PIN4 is best restricted to evaluation of morphologically highly suspicious foci.

The International Society of Pathology (ISUP) recommendations state that at the current time, there are no prognostic IHC or molecular studies that are recommended to be routinely performed on biopsy or resection specimens.

POLICY

Immunohistochemical (IHC) stains may be considered medically necessary in the diagnosis of prostate cancer when the hematoxylin and eosin (H&E) stains are suspicious but not diagnostic of cancer, when the diagnosis is uncertain as to the primary site of origin, and when the nature of the tumor (e.g., sarcoma) is in the microscopic differential diagnosis.

IHC stains may be considered medically necessary in the diagnosis of prostate cancer for one or more of the following indications:

• Indeterminate/suspicious focus and no other cores are positive for cancer;

• Single worrisome core;

• Worrisome core(s) contralateral to a positive core(s);

  • In a multi-part biopsy with Gleason 3+3=6 cancer in 1 part, and atypical small acinar proliferation (ASAP) suspicious for Gleason 3+3=6 cancer in other part(s): the number of positive biopsy sites and % core involvement of these sites can affect therapeutic choices for active surveillance (AS), focal therapy or surgery;

  • In a multi-part biopsy with 4+3=7 or 4+4=8 cancer in 1 part, and ASAP suspicious for the same grade cancer in other part(s): workup is justified since the extent of high grade cancer affects treatments.

• Identify tumor invasion of adjacent structures;

• Determine origin of undifferentiated/poorly differentiated neoplasm, such as bladder vs prostate

Prostate cases when IHC workup is Not Reasonable and Necessary include the following:

• In a multi-part biopsy with Gleason 3+4=7 cancer in 1 part, and ASAP suspicious for 3+3=6 cancer in other part(s), because stains are unlikely to change treatment; or

• In a multi-part biopsy with Gleason 4+3=7 cancer in 1 part, and “atypical cribriform lesson” (ACL) suspicious for intra-ductal carcinoma versus invasive, Gleason pattern 4 cancer in other part(s), because intra-ductal carcinoma is almost always closely associated with invasive high-grade cancer.

IHC testing (either single antibody or antibody cocktails) on cases with morphologically negative cores is considered not medically necessary.

IHC testing in a negative or a suspicious core biopsy when obvious prostate cancer is present in other cores is considered not medically necessary, unless the additional diagnosis changes the patient’s stage or treatment.

IHC stains when they are performed as reflex templates or pre-orders prior to review of the routine H&E stain by the Pathologist is 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.

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 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.

05/30/2018: Reference link updated in Sources section.

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." Sources updated to remove invalid link and source.

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

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

SOURCE(S)

1. Epstein JL, et al: Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol 2014;38(8):e6-e19.

2. Lotan TL, Gurel B, Sutcliffe S, et al., PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011;17:6563-73.

3. Morais C, Han JS, Gordetsky J, et al. Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN and intraductal carcinoma of the prostate on needle biopsy. Am J Surg Pathol 2014;Dec 16. Epub.

4. Shah RB. Clinical applications of novel EGR immunohistochemistry in prostate cancer diagnosis and management. Adv Anat Pathol 2013;20:117-24.

5. Varma M, Jasani B. Diagnostic utility of immunohistochemistry in morphologically difficult prostate cancer: review of current literature. Histopathol. 2005:47:1-16.

6. Bostwick DG and Kahane H: Adequate histologic sectioning of prostate needle biopsies. Annals of Diagnostic Pathology 17 (2013) 357-360.

7. Bostwick DG, Day CE, Meiers I: Optimizing prostate specimen handling for diagnosis and prognosis. Methods Mol Biol 2014; 1180:337-352.

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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