Response to Comments: Lab: Special Histochemical Stains and Immunohistochemical Stains

The following comment was submitted to Palmetto GBA, CGS and WPS:

We appreciate the opportunity to comment on the proposed LCD - Special Histochemical Stains and Immunohistochemical Stains (hereinafter referred to as “Special Stains”). As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, we serve patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.

We want to thank the Medicare Administrative Contractors (MACs) for their proposed updates to the LCD, these include:

• Recognizing that Lynch Syndrome tumor screening for microsatellite instability is medically necessary for individuals with newly diagnosed colorectal cancer or endometrial cancer, per the current NCCN Clinical Practice Guideline in Oncology.
• Removing the age limit for Lynch Syndrome tumor screening for microsatellite instability (MSI)/DNA mismatch repair by qualitative IHC for individuals with newly diagnosed colorectal and endometrial cancer, per current NCCN Guidelines. We also want to express appreciation to the MACs for their efforts to clarify the Coverage Guidance areas of the LCD. The proposed changes to the language have clarified coverage for special histochemical and immunohistochemical stains.

We also want to express appreciation for acknowledging that the nuclear protein Ki67 is an established prognostic and predictive indicator for the management and grading of neuroendocrine tumors.

We continue to have concerns regarding the ‘Coverage Guidance’ and the ‘Summary of Evidence’ areas of the LCD that we believe require further revision. We have identified additional areas of the LCD on Special Stains and/or IHC for the Prostate Pathology section that we believe require further revision. Specifically, we ask that (1) the LCD language be amended to allow for coverage for IHC staining of any suspicious core biopsy, irrespective of carcinoma in other cores; (2) Allow for further IHC workup, as needed, to assist with risk stratification; (3) Language be amended to support coverage for AMACR; and (4) Remove specified language from the final LCD related to utilization of stains for GI pathology.

A review by subject experts in the various subspecialties within pathology covered by the draft LCD were able to identify several examples of published literature that directly contradict the content of the LCD. The examples are described and referenced below, and we respectfully ask that MACs consider the evidence and following recommendations.

I. Coverage Guidance

1. IHC for Breast Pathology

LCD Statement:

PharmDx Ki-67 (MIB-1) by Agilent Technologies has prognostic value in the population of lymph node positive high risk breast cancer for use of the Cyclin-dependent 4 and 6 (CDK 4/6) inhibitor abermaciclib (Eli Lilly and Company) as adjuvant therapy in addition to endocrine therapy. Outside of this exception, Ki-67 is not considered reasonable and necessary for breast cancer and consequently will not be covered by Medicare.

More recent evidence identifies the use of the PharmDx Ki-67 (MIB-1) by Agilent Technologies as a companion diagnostic test shown to define a high-risk population along with high risk clinicopathologic features (i.e., nodal status, tumor size, and grade). This is used to identify patients with an even greater risk of recurrence and thus has prognostic value in the population of patients with ER+, HER2- lymph node positive high risk breast cancer for use of the Cyclin-dependent 4 and 6 (CDK 4/6) inhibitor abermaciclib (Eli Lilly and Company) as adjuvant therapy in addition to endocrine therapy.

Our Comment:

We agree that Ki-67 has prognostic value in the population of patients with ER+, HER2-lymph node positive high risk breast cancer. We also agree that Ki-67 testing is reasonable and necessary for both prognosis and therapy. We note that the FDA has removed the requirement for the PharmDx Ki-67 clone.

There is no evidence that the specific clone (Dako) used in the PharmDx test is superior to other Ki67 clones. Further, there is no evidence that the methodology of interpretation of the results is superior with this clone. Limiting coverage of Ki-67 testing to this single test would limit access to care for patients as many institutions may not carry this particular clone and use other equally efficient Ki-67 clones.

Our Request: Ki-67 has clinical utility in helping to determine the prognosis of Stage I and II breast cancer and we request the MACs not preclude its coverage. In particular, the Dako PharmDX clone is no longer specified by the FDA in the algorithm for treatment with abemaciclib and therefore we request the removal of any reference to the specific clone in the LCD.

2. Special Stains and/or IHC for Prostate Pathology

We are concerned that the MACs understanding of special stains and IHC for prostate is incomplete. Following are examples of discordant LCD statements and how the number of core biopsies inform risk stratification.

A. Discordant Statements

The 2 LCD statements below appear to be contradictory. We agree with the second LCD statement that the number of positive biopsy sites and percentage of core involvement of the sites CAN affect therapeutic choices. However, the first LCD statement contradicts the second by stating it is not reasonable and necessary to perform IHC testing on cases with morphologically suspicious cores when prostate cancer is present in other cores because it provides no additional actionable information to the treating physician.

LCD Statement #1:

It is not reasonable and necessary to perform IHC testing (either single antibody or antibody cocktails) on cases with morphologically negative cores. It is not reasonable and necessary to perform IHC testing in a negative or a suspicious core biopsy when obvious prostate cancer is present in other cores. While the pathologist may choose to confirm a suspicious focus in 1 or more cores in a case where the diagnosis of cancer has already been made, it is not a Medicare covered service because it provides no additional actionable information to the treating physician.

LCD Statement #2:

Prostate cases that may require reasonable and necessary IHC staining include but are not limited to the following:

• 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.

Our Comment:

The LCD’s position that volume, multifocality, or additional findings in lower-grade tumor- positive biopsies do not influence treatment, prognosis, or have other clinical implications is inaccurate. It is reasonable and necessary to perform IHC on a suspicious core biopsy even if carcinoma is obviously present in other cores. The number of involved biopsy cores provides actionable information on risk stratification to the treating physician which, in turn, can have a significant impact on patient management, per the NCCN Guidelines Version 1.2023 Prostate Cancer. Various treatment therapies can include:

• Active surveillance
• Brachytherapy
• External beam radiation therapy
• External beam radiation therapy + brachytherapy
• External beam radiation therapy + brachytherapy + androgen deprivation
• Pre-treatment bone imaging
• Radical prostatectomy
• Radical prostatectomy + lymph node dissection

Suspicious focus may prove to be of higher grade than that which is present in the other cores: management of a low-grade carcinoma (Gleason pattern 3) may consist of active surveillance, but if an atypical focus in another core is shown to be high grade carcinoma (patterns 4 or 5), surgery or radiation would likely be recommended. In such a case, IHC testing to confirm malignancy of those foci would have a major impact on patient management, so for pathologists and patients it is of great importance to determine the number and fraction of cores involved.

The following examples help demonstrate how the number of cores with tumor informs risk stratification and that each risk group carries designated therapies.

Example #1 - how the number of cores demonstrate risk group:

• 3+3=6 cancer in 2 of 13 cores = very low risk group
• 3+3=6 cancer in 3 of 13 cores = low risk group
• 3+4=7 cancer in 6 of 13 cores = favorable intermediate risk group
• 3+4=7 cancer in 7 of 13 cores = unfavorable intermediate risk group

Example #2 - how laterality (right/left) of cores with tumor can change risk group:

• 3+3=6 cancer in 3 cores (3 right) = low risk group
• 3+3=6 cancer in 4 cores (3 right, 1 left) = favorable intermediate risk group

Our Request: We request the LCD language be amended to allow coverage for IHC staining of SUSPICIOUS core biopsies, irrespective of carcinoma in other cores.

B. Risk Stratification

While we agree with MACs that the use of stains should be conducted in a judicious manner, risk stratification is an important factor in determining prognosis and treatment therapies. Following are additional LCD statements that inaccurately assert when stains are not likely to change treatment. The accompanying examples further demonstrate how biopsy workup determine risk stratification, which CAN influence patient treatment.

LCD Statement #3:

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

• In a multi-part biopsy with =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.

Example #3 - how the number of IHC workups can influence treatment therapies:

• 3+4=7 cancer in 6 of 13 cores = favorable intermediate risk group
• 3+4=7 cancer in 6 of 13 cores and 3+3=6 in 1 core = unfavorable intermediate risk group

LCD Statement #4:

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

• In a multi-part biopsy with =4+3=7 cancer in 1 part, and atypical cribriform glands that include a differential of Intraductal Carcinoma of Prostate (ICD-P) "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 and the results will not change the overall highest Gleason grade/Grade group for the case and may not change treatment.

Example #4 - how a change in risk stratification changes patient management:

• 4+3=7 cancer in 1 core and intraductal carcinoma in 1 core = favorable intermediate risk group
• 4+3=7 cancer in 1 core and 4+4=8 in 1 core = high risk group

Our Request: Clinical practice amongst urologists and acceptance of active surveillance varies so small differences in the number of positive cores or whether there is associated intraductal cancer can significantly impact clinical management in some cases. Therefore, we request MACs remove LCD statements #3 and #4 and related bullet points or otherwise amend them to allow additional workup to provide necessary risk stratification.

3. Special Stains and /or IHC for Lung Cancer

LCD Statement:

The diagnostic challenge of a lung biopsy can often prompt the need for additional stains to define the neoplasm. Two important considerations need to be considered in this regard:

• The diagnosis of squamous cell cancer can often be made without the use of any special stains, and
• The diagnosis of non-small cell carcinoma often requires additional stains, but it is essential that tumor tissue be carefully triaged to allow the patient’s sample to be tested for molecular markers (i.e., EGFR, ALK, and others) when clinically indicated.

Our Request: We recommend MACs delete the first bullet as this statement lacks any scientific validation and used in this context seems at odds with the statement that a lung biopsy often prompts the need for additional stains.

4. IHC for Cervical/Gyn/Bladder/Kidney Tumors

LCD Statement:

A variety of IHC stains have found limited use in cervical, gynecologic, and urologic tumor settings. In unusual cases of cervical dysplasia, markers or surrogate markers for HPV may be useful where the diagnosis on conventional H&E stain cannot be made with certainty. These markers are clearly not reasonable and necessary on all biopsies.

Similarly, it is rare to need stains to prove that an endometrial or ovarian cancer is a serous cancer or that a kidney neoplasm is an oncocytoma, an eosinophilic or chromophobic renal cell cancer.

Our Comment:

Immunohistochemistry is of paramount importance in accurate classification of renal neoplasms, both on core biopsy and on resection. Core biopsies are often performed in patients for whom surgery is not an acceptable option due to known comorbidities and other potential risks/complications, or for tumors that may need treatment prior to surgery and therefore accurate diagnosis on biopsy is crucial. Renal neoplasia entities or groups of entities are increasingly characterized by specific molecular features, often associated with either recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to more accurate prognosis, potential clinical management with targeted therapies and may identify hereditary or systemic associations.

There are few morphologic features that are diagnostic of a certain histologic type of tumor and similar growth pattern or cytologic feature can be seen in a variety of tumor types. IHC staining is indispensable in many situations in resolving differential diagnoses.

Additionally, a published survey of academic genitourinary pathologists on the use of immunohistochemistry in the evaluation of potential oncocytomas showed the following usage.

• Only when a specific differential diagnosis is considered: 41%
• Usually in most cases: 29%
• In all cases: 24%
• Rarely or never: 6%

Our Request: We recommend MACs delete both statements under this section as they are anecdotal and not based on scientific evidence as described in the Medicare Program Integrity Manual Chapter 13 – Local Coverage Determinations. Section 13.5.3, describes the evidentiary content of proposed and final LCDs, which requires MACs to summarize the evidence that supports coverage, limited coverage, maintenance of existing coverage or non-coverage and, at a minimum, the summary should include a narrative that describes the scientific evidence supporting the clinical indications for the item or service.

II. Summary of Evidence

1. Special Stains and/or IHC for Gastrointestinal (GI) Pathology

The medical necessity and utilization of special stains for GI biopsy cases in the LCD imposes a predetermined numerical utilization threshold on providers utilizing special stains in gastric biopsies and threatens enforcement action against providers who use specials stains in excess of this threshold.

LCD Statement #1:

Scientific data demonstrates that the combined number of gastric biopsies requiring special stains or IHC is roughly 20% of biopsies received and examined in a pathology practice. GI specialty practices with a large GI referral base or GI consultant pathologists may sometimes exceed this relative number of special stains/IHC, but one would not expect to see routine high utilization of special stains or IHC. To check utilization, we encourage providers to perform a self-audit on the number of separate gastric biopsies as compared to ancillary stains. The ancillary stain group should be less than 20% of the total gastric biopsies submitted. Providers that exceed the 20% criteria may be subject to additional action.

Our Comment:

The medical necessity and utilization of special stains for GI biopsy cases in the LCD imposes a predetermined numerical utilization threshold on providers utilizing special stains in gastric biopsies and threatens enforcement action against providers who use specials stains in excess of this threshold. The predetermined threshold is arbitrary and not supported by evidence or consensus of the pathology community. The dLCD appears to derive this standard from a single 2006 study whose results have never been demonstrated to be generalizable and do not suggest or support an across-the-board application to every provider regardless of the circumstances. The threshold does not capture the impact of the quantity and types of procedures and diagnostic tools used by the given practice, hospital or laboratory, or the variety of practice settings or populations served.

Further, the threat of unspecified "additional action” against providers utilizing special stains in excess of the threshold was first used in an “educational” posting by MACs on their websites in 2014. We expressed strong concerns regarding the language in a June 25, 2014, letter to CMS and CMS deemed the language inappropriate and consequently the language was rescinded. We observe that this same language has now resurfaced, and believes it is still inappropriate in a Medicare local coverage policy.

Our Request: We recommend that the MACs strike this entire paragraph from the final LCD. Alternatively, a more general statement emphasizing compliance with the LCD coverage parameters may be expressed, such as: "Compliance with the limitations provisions of this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits."

LCD Statement #2:

LS tumor screening for microsatellite instability (MSI)/deoxyribonucleic acid (DNA) mismatch repair (MLH1, MSH2, MSH6 and PMS2) by qualitative IHC is considered medically necessary and covered by Medicare for individuals with newly diagnosed colorectal cancer or endometrial cancer.

If IHC is normal and there is clinical evidence to consider additional testing, MMR gene mutation testing may be warranted. IHC testing for LS is qualitative and does not require the use of tumor morphometry for evaluation.

Our Comment:

MMR/MSI (mismatch repair/microsatellite instability) status in carcinoma is evaluated for multiple purposes including diagnosing patients for LS and for predicting response to therapies including PD-1 axis inhibition. MMR tumor screening is a rapidly changing field and can inform several cancer types other than colorectal and endometrial cancers.

As stated in the College of American Pathologists Guideline and endorsed by the American Society of Clinical Oncology (ASCO), providers use results of this testing to help select immune check point inhibitor therapy. The guideline addresses multiple issues around such testing across multiple cancer types. ASCO has published guidelines recommending testing for MMR for breast, ovarian, gastroesophageal, and small bowel cancer. In general, MMR testing should be permitted for patients with gastroesophageal and small bowel cancer, being considered for immune check point inhibitor therapy.

Our Request: We request expansion of coverage for MMR/MSI testing beyond colorectal cancer and endometrial cancers to include patients with gastroesophageal junction cancer, small bowel cancer and other solid tumors that are being considered for immune checkpoint inhibitor therapy.

2. Special Stains and/or IHC for Prostate Pathology

We continue to stress that AMACR should not be restricted to the evaluation of morphologically highly suspicious foci in which negative basal cell markers are insufficient for a diagnosis of cancer.

LCD Statement:

The immunohistochemical diagnosis of prostate cancer 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 1 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 prostatic intraepithelial neoplasia (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.

Our Request: We request that the language (above) be amended to support coverage for AMACR in all specimens suspicious for carcinoma which cannot be confirmed or excluded by morphology alone. Alternatively, we request the edits below:

• The immunohistochemical diagnosis of prostate cancer 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 1 basal cell marker, such as high-molecular-weight cytokeratin (HMWCK) or p63, and alpha-methyl-CoA-Racemase (AMACR), a prostate cancer-specific marker. Although AMACR is considered a useful IHC marker for prostate cancer, due to heterogeneous staining, protocol used and interpretation criteria, there is wide variation in the sensitivity and specificity of AMACR in diagnosing prostate cancer. Furthermore, because AMACR expression has been demonstrated in high-grade prostatic intraepithelial neoplasia (PIN), atypical adenomatous hyperplasia/adenosis and nephrogenic adenoma, it is recommended that AMACR is best used together with basal cell markers in work up of morphologically highly suspicious foci.

3. IHC for Skin & Cutaneous/Soft Tissue/Central Nervous System (CNS) & Peripheral Nervous System (PNS) Lesions

LCD Statement #1:

It is well recognized that most skin lesions are diagnosed with routine H&E slides. That is the case for most melanomas and other pigmented lesions as well. Soft tissue masses may require stains (e.g., smooth muscle differentiation in a malignant mass) but the most do not.

LCD Statement #2:

The primary role of IHC for CNS and PNS lesions is to differentiate primary from metastatic lesions.

Our Request: We request MACs remove the first statement from the final LCD as it is not based on any available scientific evidence. We also request that MACs amend the second statement to include other uses of IHC including classifying CNS tumors and for prognosis and therapy.

Thank you for the opportunity to comment on this proposed LCD and for your consideration of our requests.

References were provided for review.

Thank you for your comments. We appreciate CAPs comments and thank them for their review. We have changed the LCD in several areas where updated evidence is provided and have modified it accordingly.

The following comment was submitted to Palmetto GBA and WPS:

We are pleased to submit our written comments on the Draft Local Coverage Determination entitled “Special Histochemical Stains and Immunohistochemical Stains,” hereafter referred to as the dLCD. We are the national trade association representing leading laboratories that deliver essential diagnostic health information to patients and providers by advocating for policies that expand access to the highest quality clinical laboratory services, improve patient outcomes, and advance the next generation of personalized care.

We would like to thank you for developing a new dLCD following reconsideration requests on the current policy of the same name. Following our review of the new draft policy, we offer the following comments and recommendations:

IHC for Breast Pathology

We appreciate that Palmetto and WPS acknowledges that in at least 1 instance, testing for Ki-67 has prognostic value for breast cancer testing. However, we are concerned that the restriction of coverage for only the PharmDx Ki-67 (MIB-1) for the use of Cyclin-dependent 4 and 6 (CDK 4/6) inhibitor abermaciclib in addition to endocrine therapy will prevent patient access to clinically relevant testing for other approved treatments.

Reflecting the current use of Ki-67 testing in breast cancer, the College for American Pathologists’ (CAP) Template for Reporting Results of Biomarker Testing of Specimens From Patients With Carcinoma of the Breast (2020) includes reporting for Ki-67 while noting that routine testing of Ki-67 is not currently recommended for all carcinomas. Testing for particular biomarkers such as Ki-67 is medically necessary in particular cases, however, and it is the pathologist’s responsibility to make that determination and to document such medical necessity in the pathology report and/or medical record.

In light of our concerns, we recommend the following edits to the language in the “Coverage Indications, Limitations, and/or Medical Necessity” section for “IHC for Breast Pathology”:

PharmDx Ki-67 (MIB-1) by Agilent Technologies has prognostic value in the population of patients with ER+, HER2- lymph node positive high risk breast cancer for use of the Cyclin-dependent 4 and 6 (CDK 4/6) inhibitor abermaciclib (Eli Lilly and Company) as adjuvant therapy in addition to endocrine therapy. Beyond this exception, Ki-67 is considered reasonable and necessary for breast cancer and consequently will be covered by Medicare only when ordered to directly inform treatment of the patient.

Special Stains and/or IHC for Gastrointestinal (GI) Pathology

Requirement for H&E Stain Prior to Ordering of Special Stains

While we agree that the review of routine H&E stain is performed prior to the ordering of special stains or IHC stains, there are many instances where it is unreasonable to wait for the result of an H&E stain to be performed and reviewed. We are concerned that not only will this requirement impose unnecessary lengthy delays for diagnosis and treatment decision for patients, but that this requirement also will restrict the ability of the ordering provider to practice medicine. We do not believe that an ordering provider should be barred from ordering a special stain or IHC for a patient if they have significant clinical suspicion and need the results of these tests to manage the patients care in a timely manner.

To remedy both of these concerns, we recommend the following edits to the language in the “Coverage Indications, Limitations, and/or Medical Necessity” section for “Special Stains and/or IHC for Gastrointestinal (GI) Pathology":

Ordering special stains or IHC stains on every specimen prior to review of the routine H&E stain is not reasonable and necessary.

Threshold for “Reasonable" Stains Ordered

Similar to our comments in 2014, we remain concerned about the following language in the “Summary of Evidence":

Scientific data demonstrates that the combined number of gastric biopsies requiring special stains or IHC is roughly 20% of biopsies received and examined in a pathology practice. GI specialty practices with a large GI referral base or GI consultant pathologists may sometimes exceed this relative number of special stains/IHC, but one would not expect to see routine high utilization of special stains or IHC. To check utilization, we encourage providers to perform a self-audit on the number of separate gastric biopsies as compared to ancillary stains. The ancillary stain group should be less than 20% of the total gastric biopsies submitted. Providers that exceed the 20% criteria may be subject to additional action.

Section 1869(f)(2)(B) of the Social Security Act defines a local coverage determination as a determination by a fiscal intermediary or a Medicare Administrative Contractor “respecting whether or not a particular item or service is covered on an intermediary- or carrier-wide basis” under Medicare Part A or Part B. The Social Security Act does not authorize Medicare contractors to establish in an LCD the expected frequency of an item or service across a population of Medicare beneficiaries. Medicare coverage of an item or service is not determined based on the frequency with which a health care provider or practitioner furnishes an item or service. Palmetto expects a qualified pathologist to determine the reasonableness and medical necessity of each special stain and IHC on a case-by-case basis, and the suggestion that there is a set threshold that a pathology practice should not exceed is the antithesis of the concept of a case-by-case determination.

Further, this threshold has the potential to limit the ability of the pathologist to practice medicine – by potentially restricting them from ordering a medically necessary test for a patient to be in compliance with the 20% threshold – with downstream access issues for Medicare beneficiaries. The 20% threshold is applied across all laboratories and does not consider the existence of laboratories that specialize in IHC testing for GI and can be expected to routinely go over that threshold due to ordering providers seeking them out for this service. Finally, medical centers that specialize in treating GI cancers will have a skewed patient population that will have implications for this threshold when tests are performed at affiliated laboratories.

While we appreciate that MACs have added language specifying that this information is to be used by providers as a self-audit, we still anticipate that this arbitrary threshold in the LCD could be misunderstood by a Medicare auditor as a high water mark. MACs make its position about the potential for overutilization of special stains and IHC staining procedures clear in other places in the Draft LCD. We believe the above language is not suitable for inclusion in an LCD and that it is not necessary. We recommend removing the paragraph entirely from the “Summary of Evidence."

Special Stains and/or IHC for Prostate Pathology

We are concerned by the blanket non-coverage determination for IHC testing on cases with morphologically negative cores and/or IHC testing in a negative or suspicious core biopsy when obvious prostate cancer is present in other cores. IHC testing is medically necessary in particular negative or suspicious cases and it is the pathologist’s responsibility to make that determination and to document such medical necessity in the pathology report and/or medical record.

To address our concerns, we recommend the following edits to the “Coverage Indications, Limitations, and/or Medical Necessity” section for the “Special Stains and/or IHC for Prostate Pathology":

While the pathologist may choose to confirm a suspicious focus in 1 or more cores in a case where the diagnosis of cancer has already been made, it is only a Medicare covered service if it provides additional actionable information to the treating physician.

Additionally, the LCD includes the following sentence in the “Summary of Evidence” section:

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.

We disagree that ERG never provides a pathologist with additional actionable information. Both basal cell markers and the prostate-specific marker alpha-methyl-CoA-Racemace (AMACR) offer high sensitivity but low specificity for prostate cancer detection. In contrast, ERG has low sensitivity but high specificity for prostate cancer detection. Where a high-grade prostatic intraepithelial neoplasia is ruled out, ERG positivity in small, atypical glands can be used to confirm a prostate cancer diagnosis. We recommend that the sentence above be removed to allow patient access to medically necessary testing.

IHC for Skin & Cutaneous/Soft Tissue/Central Nervous System (CNS) & Peripheral Nervous System (PNS) Lesions

We appreciate the MACs acknowledge there are some types of skin and skin appendage lesions that require immunohistochemical stains, including the 3 examples listed in the LCD, as well as others not specifically listed. We would like to highlight that lesion involving the nail unit, while often not requiring IHC evaluation, may need such differential diagnostic work-up due to the nature of the anatomic location and the relative difficulties in obtaining diagnostic material. Additionally, as with any other anatomic specimen, clinical samples obtained from the skin/skin appendages, soft tissue, and bone may not always show clearly diagnostic features on H&E alone, necessitating the use of IHC staining to provide an accurate diagnosis to the ordering physician. Beyond H&E and IHC stains, histochemical stains have diagnostic utility in certain circumstances, including Fontana-Masson in cases of onychodystrophy where melanin deposition, potentially due to a subclinical melanocytic process, may be influencing the clinical appearance of the nail.

The use of IHC morphometric analyses for skin lesions is reasonable and necessary in certain clinical indications. Specifically, in the case of small fiber peripheral neuropathy (SFPN), intra-epidermal nerve fiber density (ENFD) testing, the diagnostic gold standard, requires morphometric evaluation of a skin biopsy to render an intra-epidermal nerve density and therefore a diagnosis. In order to ensure that the standard of care is available for patients with lesions of these types, we recommend the following edits to the language in the “Coverage Indications, Limitations, and/or Medical Necessity” section for “IHC for Skin & Cutaneous/Soft Tissue/Central Nervous System (CNS) & Peripheral Nervous System (PNS) Lesions":

Most skin lesions are diagnosed with routine H&E slides. A minority of skin lesions require immunostains (e.g., atypical fibroxanthomas, Merkel cell lesions, lymphomas, as well as others). Most common skin lesions (e.g., seborrheic keratosis) do not require IHC stains. Use of IHC morphometric codes for skin lesions, outside of the diagnosis of small fiber peripheral neuropathy, is not reasonable and necessary.

Similarly, most routine soft tissue lesions do not require IHC stains or other "special" stains.

Many CNS and PNS lesions are readily diagnosed with routine stains. It is unusual for a meningioma to require an IHC.

Thank you for your consideration of our comments and recommendations. We appreciate that Palmetto and WPS are revisiting the Special Histochemical Stains and IHC Stains Local Coverage Determination and we welcome the opportunity to work collaboratively on this draft policy.

References were provided for review.

Thank you for your comment. We appreciate the comments from ACLA and thank them for their review. We have addressed several issues and have added the specific instance for morphometric evaluation of distal leg biopsies for small fiber neuropathy (SFN). We note that the literature only validates a specific immunoperoxidase stain along with the use of strict reporting criteria using controls which should be part of the interpretation to establish this diagnosis after other possible etiologies are investigated.

The following comment was submitted to CGS:

We appreciate the opportunity to comment on the Proposed Local Coverage Determination (LCD) Special Histochemical Stains and Immunohistochemical Stains as it relates to our mission of improving and facilitating, quality, effective, equitable, and accessible cancer care so all patients can live better lives. We are pleased to provide information and resources and will focus on the portions of the LCD with reference to NCCN Guidelines as well as the role of clinical practice guidelines and the NCCN Biomarker Compendium as a tool for establishing appropriate care.

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The NCCN Biomarkers Compendium^® is intended to be a resource for payers, providers, and health care entities navigating the rapidly changing evidence-base for medically necessary biomarker testing in oncology. The NCCN Biomarkers Compendium^® contains information derived directly from the NCCN Guidelines to support decision-making around the use of biomarker testing in patients with cancer. The NCCN Biomarkers Compendium is updated continuously in conjunction with the NCCN guidelines to stay evergreen. The goal of the NCCN Biomarkers Compendium is to provide essential details for testing methodologies which have been approved by NCCN Guideline Panels and are recommended within the NCCN Guidelines. Included in the Biomarkers Compendium are testing methodologies that measure changes in genes or gene products and used for the purposes of diagnosis, screening, monitoring, surveillance, prediction, and prognostication.

Launched in 2012 and updated in 2021 to have shared data fields with other Compendia in the Library, the information within the Biomarkers Compendium is extracted directly from Guideline algorithms, principles pages, and footnotes, and all entries are reviewed and approved by the Guideline Panel pathologist or other panel member with expertise in the area. Information within the Biomarkers Compendium focuses on the biology or abnormality being measured rather than on commercially available tests or test kits, with methodologic information provided only if included in the parent Clinical Practice Guideline.

The Biomarkers Compendium is intended to be user friendly in an easy to navigate format for payers and providers alike. The displayed fields can be customized to the user and include links to the Guideline Page on which the biomarker is addressed. Compendium entries can be printed, providing the summary of the recommendations with details regarding each field within the Compendium, in a format that is concise and easy to read. With this resource, the NCCN Biomarkers Compendium aims to ensure that patients have coverage and access to appropriate biomarker testing based on the evaluations and recommendations of NCCN Panel Members.

NCCN Guidelines and Compendia as a Tool to Keep Coverage Determinations Evergreen

Recognizing the value of continuously updated evidence-based guidelines, numerous Medicare Administrative Contractors (MACs) have cited NCCN Guidelines within their proposed and final coverage policies as a mechanism to evergreen coverage regarding drug and biologic coverage. These policies include Local Coverage Article: Billing and Coding: Chemotherapy and Local Coverage Determinations: Luteinizing Hormone-Releasing Hormone (LHRH) Analogs, Chemotherapy Drugs and their Adjuncts, and Genomic Sequence Analysis Panels in the Treatment of Solid Organ Neoplasms, among others. We are pleased to offer these guidelines and related compendia products as a resource for coverage mechanism within this would ensure the LCD stays evergreen while also significantly reducing administrative burden.

NCCN Guideline References within the LCD and Areas for Clarification

We thank you for referencing NCCN content within the proposed LCD. We are pleased to be able to provide additional background information on these references and seeks clarification on several areas within the LCD. Specifically, we note:

• The Proposed LCD states: "While there are a number of promising additional biomarkers, such as Ki-67, PJ3K and gene expression assays, 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.” NCCN respectfully notes that this aforementioned specific statement is not aligned with our guidelines. As is accurately discussed further in the LCD, the NCCN Guidelines for Breast Cancer^® note on page BINV-1 that a Ki-67 test must be performed if considering adjuvant abemaciclib. PCR-based PI3KCA-mutation testing and gene expression assays are not the subject of this LCD, but determination of such biomarkers in exceptional circumstances are noted in the NCCN Guidelines to identify candidates for alpelisib­ containing regimen or to aid in prediction of response to adjuvant cytotoxic chemotherapy. We respectfully request that the above italicized statement remove the NCCN reference in the above citation and include statements to accurately reflect NCCN Guidelines recommendations as noted here.
• The LCD also states: "Claims data indicate combinations of gram stain, PAS, Ki-67, pl 6 and ProExC stains on all cervical biopsies from select pathology practices, and combinations ofp53, Ky [Ki]-67, and CD20 and CD44 on bladder biopsies from select pathology practices." with a reference to the 2014 version 3 of the NCCN Guidelines for Ovarian Cancer. NCCN respectfully notes that this content is not found in either the 2014 v.3 or current (2023 v.1) NCCN Guidelines for Ovarian Cancer^®. As such, we request this reference be removed.
• The LCD updates coverage criteria for IHC to state "LS tumor screening for microsatellite instability (MSI)/DNA mismatch repair (MLHJ, MSH2, MSH6 and PMS2) by qualitative IHC is considered medically necessary and covered by Medicare for individuals with newly diagnosed colorectal cancer or endometrial cancer.", thus removing previous age requirements. This coverage aligns with the NCCN Clinical Practice Guidelines for Genetic/Familial High-Risk Assessment: Colorectal^®.
• NCCN would like to further note several outdated versions are cited within this LCD. The NCCN Guidelines are updated on a continual basis, with a minimum of 1 update annually, though more frequent updates commonly occur as the science evolves. NCCN notes that the most frequent versions across our library of clinical practice guidelines can always be found online, free of charge, at NCCN.org.

We again thank you for including NCCN Guidelines content within the proposed LCD. We appreciate the opportunity to comment on the Proposed Local Coverage Determination (LCD) Special Histochemical Stains and Immunohistochemical Stains. We are happy to serve as a resource and look forward to working together to advance access to high-quality cancer care for your beneficiary population.

Thank you for your comment. We appreciate the NCCNs contribution to cancer care for our beneficiaries and all patients with this disease. We have modified the LCD as requested and removed the NCCN reference to our claims data. We appreciate your agreement on the updated Lynch Syndrome recommendations and the utility of Ki-67 in a specific population of Breast Cancer patients. We have updated our NCCN versions where appropriate.

The following comment was submitted to WPS:

Thank you for the opportunity to submit comments in response to the Proposed Local Coverage Determination: Lab: Special Histochemical Stains and Immunohistochemical Stains. Our organization comprises clinical diagnostic laboratories and manufacturers involved with the delivery of high quality in vitro diagnostic physician pathology services that help inform important therapeutic management decisions for Medicare beneficiaries.

For many years, we have worked with the Centers for Medicare & Medicaid Services (CMS) and the Medicare Administrative Contractors (MACs) on the development and implementation of policies intended to facilitate appropriate Medicare coverage and payment for high-quality physician pathology services. We appreciate periodically reviewing and evaluating LCDs and responding to the recent reconsideration request from the College of American Pathologists.

We appreciate the updates proposed to the draft LCD including broadening coverage for the Lynch Syndrome tumor screening for microsatellite instability (MSI)/DNA mismatch repair by qualitative IHC by removing the age limitation. In addition, we support the expansion of coverage in IHC for Breast Pathology to include Ki-67 though we ask to apply this position to all Ki-67 clones and not limit it to a single test.

We remain concerned with some language in the draft LCD for the reasons outlined below:

I. Use of conclusory, uncited, opinion as basis for coverage determination rather than peer-reviewed scientific/clinical evidence

The 21st Century Cures Act implemented changes to the LCD process and established additional evidentiary requirements for LCD. Section 13.5.3 in Chapter 13 of the Program Integrity Manual states the following:

In every proposed and final LCD, the MAC must summarize the evidence that supports coverage, limited coverage, maintenance of existing coverage in cases of LCD reconsideration or noncoverage.

At a minimum, the summary should include the following:

• a complete description of the item or service under review;
• a narrative that describes the scientific evidence supporting the clinical indications for the item or service;
• the target Medicare population; and
• whether the item or service is intended for use by health care providers or beneficiaries.

There are a few sections in the draft LCD where a coverage position has been taken that appears to be conclusory and based upon uncited opinion rather than scientific evidence. Coverage policy that is not based upon evidence but rather on uncited opinions do not meet CMS-prescribed LCD requirements. The 3 specific examples are detailed below:

IHC for Cervical / Gyn / Bladder / Kidney Tumors

A variety of IHC stains have found limited use in cervical, gynecologic, and urologic tumor settings. In unusual cases of cervical dysplasia, markers or surrogate markers for HPV may be useful where the diagnosis on conventional H&E stain cannot be made with certainty. These markers are clearly not reasonable and necessary on all biopsies.

Similarly, it is rare to need stains to prove that an endometrial or ovarian cancer is a serous cancer or that a kidney neoplasm is an oncocytoma, an eosinophilic or chromophobic renal cell cancer.

IHC for Skin & Cutaneous / Soft Tissue / CNS & PNS Lesions

It is well recognized that most skin lesions are diagnosed with routine H&E slides. That is the case for most melanomas and other pigmented lesions as well. Soft tissue masses may require stains (e.g., smooth muscle differentiation in a malignant mass) but most do not.

Special Stains and/or IHC for Lung Cancer

The diagnosis of squamous cell cancer can often be made without the use of any special stains.

As these statements appear to be statements of opinion rather than scientific or clinical fact based upon evidence, these statements are in conflict with LCD requirements, and we ask that this language be removed from the final LCD. Specific to the statement regarding special stains and/or IHC for lung cancer, this statement not only conflicts with LCD requirements but also the previous sentence in the LCD which states, “The diagnostic challenge of a lung biopsy can often prompt the need for additional stains to define the neoplasm."

II. Establishment of arbitrary utilization target is inappropriate.

The section on Special Stains and/or IHC for GI Pathology has the following language:

Scientific data demonstrates that the combined number of gastric biopsies requiring special stains or IHC is roughly 20% of biopsies received and examined in a pathology practice. GI specialty practices with a large GI referral base or GI consultant pathologists may sometimes exceed this relative number of special stains/IHC, but one would not expect to see routine high utilization of special stains or IHC. To check utilization, we encourage providers to perform a self-audit on the number of separate gastric biopsies as compared to ancillary stains. The ancillary stain group should be less than 20% of the total gastric biopsies submitted. Providers that exceed the 20% criteria may be subject to additional action.

As noted in the comment letter from the College of American Pathologists (CAP), this language establishes a pre-determined utilization requirement and threatens punitive action on providers that exceed this percentage. The draft LCD notes that this commentary is based upon “scientific data,” however, this threshold requirement is arbitrary, not supported by the clinical evidence cited in the LCD or any guidelines/guidance issued by the broader pathology community. Furthermore, this threat of “additional action” has been previously deemed to be inappropriate by CMS. Therefore, the continued use of this language is not only inconsistent with the LCD requirements but also in conflict with a position taken by CMS central office. As such, we strongly request this entire paragraph be removed from the Final LCD.

We support a more general statement emphasizing compliance with the LCD coverage parameters as suggested by CAP:

Compliance with the limitations provisions of this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits.

Thank you for your comment. We have reviewed your comments and have made changes where there is provided evidence. We have added the suggested CAP comment to the LCD as you have suggested.

The following comment was submitted to Palmetto GBA:

I’m a pathologist in Jurisdiction J. It is troubling to me to see the detailed and in some cases ill guided attack on the use of immunohistochemical stains. I humbly ask you to reconsider this direction as an accurate diagnosis is critical for patient care and very expensive treatment decisions.

We thank you for your comment. It is not our intention to attack IHC stains but rather to provide some guardrails so that their use continues to be reasonable and necessary based on evidence.

The following comment was submitted to WPS:

I agree with most of CAP's letter. I am afraid I must respectfully disagree with the statement that 'any implication that pathologic diagnosis should be limited based on the pathologist's presumption of the subsequent course of treatment is an unwarranted extension of the scope of pathology practice and impingement upon that of the treating physician.' As patient care team members, pathologists have to ensure that their work product is clinically actionable. To suggest that the end goal is a diagnosis for the sake of diagnosis undermines the 'medically necessity' clause of healthcare. The clinician can request that the pathologist perform additional IHC in the rare case where it is clinically necessary. However, allowing additional testing for the sake of 'complete part-by-part' diagnosis, without consideration of clinical impact, results in waste and harm to the patient.

Thank you for your comment. We agree with your statement.