Response to Comments: MolDX: Molecular Testing for Risk Stratification of Thyroid Nodules

The following comment was submitted to Palmetto GBA, CGS, and WPS and was received from multiple stakeholders:

Clarification on whether the testing of a second indeterminate nodule is considered reasonable and necessary.

Per current ATA guidelines (reference 16), recommendation 21(A) states that patients with multiple nodules ≥ 1 cm, should be evaluated the same as patients with one nodule. Therefore, if a patient has more than one indeterminate nodule, it may be reasonable and necessary to assess nodules beyond the index if the test results will alter surgical decisions. For example, if a patient has multiple indeterminate nodules in the same lobe and a lobectomy is indicated based on the result of the index nodule, testing of additional nodules is not necessary. However, if the index nodule is classified as benign, testing of additional indeterminate nodules in the same lobe may be reasonable and necessary. If a patient has concurrent bilateral indeterminate nodules and test results will aid in deciding between a lobectomy and total thyroidectomy it may be reasonable and necessary to test both nodules concurrently. The coverage criteria have been modified to differentiate between index and multiple nodule testing scenarios.

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

Thank you for the opportunity to review and comment on proposed coverage policy for Molecular Testing for Risk Stratification of Thyroid Nodules. As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.

As a general matter, the CAP supports the proposed coverage policy for molecular diagnostic testing to evaluate indeterminate or suspicious thyroid nodules. Providing the most accurate assessment of malignancy risk is critical for determining appropriate treatment and preventing unnecessary surgery. However, we request to consider the following clarification or addition to the final LCD to ensure that additional molecular testing will be covered for patients with multiple concurrent indeterminate nodules or who develop a new, changing or clinically concerning nodule over time.

Coverage Indications, Limitations, and/or Medical Necessity

Currently, the draft LCD states that “will cover molecular diagnostic tests for use in a beneficiary with an indeterminate or suspicious thyroid nodule” when all the following criteria are met:

• The patient:
  • Has not been tested with the same or similar assay for the same clinical indication AND:
    • Has an indeterminate thyroid nodule as defined by Bethesda categories III-I OR
    • Has a Bethesda category V nodule for which molecular testing may aid in further stratifying the type of malignancy.

CAP Comment: The bullet above limits coverage to patients who have not been tested with the same or similar assay for the “same clinical indication.” Yet, patients with multiple concurrent indeterminate nodules or who develop new nodules over time require repeat evaluation. Further, given the long-term follow up time frames for patients, nodules can accumulate additional potentially oncogenic mutations over time, thus it is possible that even the same nodule may require retesting. Therefore we request that the final LCD clarify that additional molecular testing be covered for patients with multiple concurrent indeterminate nodules or who develop a new, changing or clinically concerning nodule over time.

As pathologists, we know that the right test at the right time can make all the difference in a patient's diagnosis, treatment, and outcome. We appreciate your consideration of our request to ensure that Medicare patients have access to appropriate testing.

Thank you again for the opportunity to review and comment on this proposed policy.

Thank you for your thoughtful comments. We have addressed your comments and concerns in Response 1 listed above.

The following comment was submitted to Palmetto GBA:

As a board-certified endocrinologist who has been in practice for more than 25 years, I want to make it known that I am in full support of Proposed LCD. I find it extremely valuable to utilize molecular testing to support surgical planning when cytology is classified as Bethesda categories Ill, IV and V. I have utilized molecular testing as a diagnostic and prognostic tool for patients with Bethesda Ill¬ VI nodules and I am very pleased with MolDX's decision to include coverage of molecular testing as a prognostic tool for patients with Bethesda V nodules.

While I appreciate MolDX's thorough review of the most recent literature and the change in coverage for Bethesda V nodules, however, I am concerned the current language will deny coverage for molecular testing on more than one nodule with indeterminate cytology. On the occasion when a patient has more than one thyroid nodule that meets criteria for thyroid fine needle aspiration (FNA), molecular testing on any Bethesda Ill-VI nodule could change the optimal treatment choice. Take for example a patient with a dominant index nodule that is molecularly benign whereas molecular testing of a secondary nodule leads to a positive result for Medullary Thyroid Cancer (MTC.) In this case, if the index nodule were only tested, the patient would be sent for observation and have a missed cancer. If both nodules were to be tested, the patient would likely be referred directly to a total thyroidectomy and central neck dissection.

Relevant to this discussion is also our published research on the subject, widely referenced in national and international guidelines (Frates, et al JCEM 2006;91:3411- PMID: 16835280). This analysis of 1,985 consecutive patients (3,483 nodules) evaluated for multinodular disease clearly showed that the largest nodule is not representative of the malignancy risk in a multinodular goiter. Multiple nodules within a multinodular gland must be aspirated with cytologic/molecular assessment to define the extent of clinically relevant thyroid cancer in the gland. Without such, malignancy will be missed. Others have support this finding as well (Haugen et al. Thyroid 2016;26:1-133 - PMCID: PMC4739132)

Because of the demonstrated clinical utility, I respectfully ask that MolDX continue to cover testing of multiple thyroid nodules when medically necessary.

Thank you for taking into consideration the most recent NCCN guideline updates and changes in the Bethesda category when determining coverage for molecular testing. I appreciate your decision and hope to see coverage of secondary thyroid nodules as well, as this is in the best interest of patient care.

Thank you for your thoughtful comments. We have addressed your comments and concerns in Response 1 listed above.

The following comment was submitted to Palmetto GBA:

Veracyte, Inc. appreciates the opportunity to provide public comment in support of Palmetto GBA’s Proposed Local Coverage Determination (LCD). As a leading genomic diagnostics company, Veracyte has been a pioneer of multiple advanced molecular diagnostic tests, including but not limited to the Afirma Genomic Sequencing Classifier (GSC) for use in thyroid nodule diagnosis. Afirma has been covered by Medicare under LCDs and articles since March 2012.

Veracyte strongly supports the Proposed LCD, which maintains existing coverage of Afirma GSC and confirms coverage for thyroid nodules classified as Bethesda category V. Veracyte appreciates MolDX’s efforts to establish a clear framework of coverage criteria for this important area of risk stratification testing. We do respectfully request certain modifications to the Proposed LCD. In particular, we urge MolDX to clarify that testing of second, unrelated nodules will remain covered.

Support Proposed LCD

Veracyte wishes to express its strong support for the expeditious finalization. We applaud MolDX’s thorough review of the evidence for the Proposed LCD and MolDX’s commitment to establishing a clear coverage framework for risk stratification testing for thyroid nodules. Veracyte agrees with MolDX’s conclusion that:

“…molecular tests that aid in medical decision making for thyroid nodules of Bethesda Categories III-V are reasonable and necessary. Specifically, [MolDX] recognizes improved outcomes by safely precluding unnecessary surgical procedures with these services as well as better selecting patients who may benefit from such procedures.”

We agree with MolDX’s inclusion of Bethesda category V thyroid nodules as a covered indication in light of recent updates to The Bethesda System for Reporting Thyroid Cytopathology. As published in Thyroid 2023, these updates now recommend molecular testing as part of usual clinical management for Bethesda category V nodules. Furthermore, the most recent NCCN Guidelines address the need for better MTC diagnosis and state the following in v4 2023:

“Molecular diagnostics specifically for medullary thyroid cancer across Bethesda III-VI nodules may identify these specific carcinomas given the challenges of cytology to explicitly identify them (category 2A).”

Veracyte notes that these guidelines are indicative of growing evidence to support molecular testing in Bethesda VI, malignant thyroid nodules, to identify specific types of thyroid cancer and better guide treatment. We believe that Bethesda VI should ultimately become an indication covered by Medicare. Therefore, Veracyte will continue to invest in studies that evaluate the utility of molecular testing in this indication, and we look forward to future engagement with MolDX regarding coverage of Bethesda VI nodules.

Recommended Modifications to Proposed LCD

While we strongly support finalizing this Proposed LCD as soon as possible, we respectfully request a few revisions to improve the accuracy and clarity of the Proposed LCD.

1. Request clarification that testing of second thyroid nodules will remain a covered indication

   Most importantly, Veracyte is concerned with the language in the coverage criteria section of the Proposed LCD that states coverage will be afforded when the patient “has not been tested with the same or similar assay for the same clinical indication.” Our understanding is that this will be interpreted consistent with current Afirma Billing and Coding Article, which states that “[s]hould the unlikely situation of a second, unrelated thyroid nodule with indeterminate pathology occur, coverage may be considered upon appeal with support documentation.”

   Claims for Afirma testing of second, unrelated nodules are generally paid on appeal when they include evidence that supports coverage of an Afirma test as if the second nodule was the only nodule. If a patient has more than one indeterminate nodule, molecular testing will aid in the decision of a thyroid lobectomy versus total thyroidectomy as illustrated in the below recommendations from the 2015 American Thyroid Association (ATA) Thyroid Nodule and Cancer Guidelines supporting evaluation of two or more thyroid nodules:

   1) Recommendation 21 of the ATA guidelines states, “Patients with multiple thyroid nodules > 1cm should be evaluated in the same fashion as patients with a solitary nodule > 1cm, expecting that each nodule > 1 cm carries an independent risk of malignancy and therefore multiple nodules may require FNA” (Strong Recommendation, Moderate-Quality Evidence).

   2) Recommendations 15 and 16 in the ATA guidelines recommend that physicians may consider the use of molecular testing (e.g. Afirma) for both AUS/FLUS and FN/SFN cytology. This recommendation for the use of molecular tests is not limited to the number of nodules per patient but rather only to nodules with indeterminate cytopathology results.

   Supporting the ATA guideline recommendations to evaluate each nodule in the same fashion are clinical data demonstrating that the likelihood of thyroid cancer is independent of the number of thyroid nodules and the malignancy rate is not influenced by the distribution of the nodules or their size. ⁽¹⁾⁽²⁾

   Veracyte respectfully suggests edits to the coverage criteria to clarify that second nodules would continue to be a covered indication.

   This interpretation of coverage for second nodules would also align with CMS’ coverage approach in NCD 90.2 for next-generation sequencing for cancer, which prohibits coverage of the same test “for the same cancer genetic content.” Applying this standard, an unrelated nodule would represent distinct cancer genetic content.

   Lastly, we note that Veracyte recommends the above modifications to the coverage criteria in order to create a defined rule for coverage of second, unrelated thyroid nodules so as not to require a laborious, case-by-case review of each individual unrelated nodule on appeal. At a minimum, however, we respectfully request that the coverage criteria in the Final LCD reflect the current coverage rule that allows for payment to be made for Afirma testing on second, unrelated thyroid nodules based on documentation submitted on appeal. The use of Afirma testing in second nodules is engrained in clinical practice and has provided valuable diagnostic information for Medicare beneficiaries for over a decade. It is imperative that MolDX clarify that this will continue to be a covered indication.

2. Request that Table 1, summarizing the diagnostic categories of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), be updated to reflect the most recent version published in Thyroid 2023

   Below is the new table from TBSRTC with updated risk of malignancy (ROM) by Bethesda category. These minor changes in ROM have no impact on the coverage criteria of this Proposed LCD; however, Veracyte believes it is beneficial to have the most updated version of this table in the Final LCD.

3. Request that the Analysis of Evidence section be updated to reflect the value of molecular testing in helping surgeons determine the need for lymph node resection

   When medullary thyroid cancer (MTC) is diagnosed pre-operatively, the 2015 ATA MTC guidelines recommend prophylactic lymph node dissection:

   “Recommendation 24 - Patients with MTC and no evidence of neck lymph node metastases by US examination and no evidence of distant metastases should have a total thyroidectomy and dissection of the lymph nodes in the central compartment (level VI).”

   We believe this point should be specifically mentioned in the Analysis of Evidence (Rationale for Determination) section of the Proposed LCD. Veracyte suggests the following language:

   “Key decisions that must be made in the care of patients with suspicious thyroid nodules include whether to surgically intervene, the extent of surgery (such as a full vs. partial thyroidectomy), the need for lymph node resection (as in the case of an MTC diagnosis) and the selection of therapeutic intervention.”

4. Request updating the description of Afirma GSC under the “Second Generation Tests” section to more accurately describe the various components of this assay

   Veracyte respectfully requests the modification of the Afirma GSC test description.

Conclusion

Veracyte strongly supports finalizing Proposed LCD. We respectfully request that MolDX update the Final LCD to ensure that Afirma GSC testing may continue to be covered for second, unrelated thyroid nodules, consistent with MolDX’s current coverage of Afirma. Veracyte also recommends the technical modifications to the Proposed LCD referenced in this letter.

We appreciate MolDX’s consideration of our comments.

Redline draft, tables and references were provided for review.

Thank you for your thoughtful comments. We have addressed your first comment in Response 1 listed above. We have also updated the table and language in the policy as suggested in comments 2-4.

The following comment was submitted to Palmetto GBA:

As a practicing endocrinologist who uses molecular testing as a diagnostic and prognostic tool in thyroid nodule patients, I fully support Palmetto GBA’s Proposed Local Coverage Determination (LCD).

It is often clinically important to consider molecular test results to support surgical decision-making when thyroid nodule cytology is classified as Bethesda categories III, IV and V. I routinely use molecular testing as a diagnostic and prognostic tool for patients with Bethesda III-V (and occasionally Bethesda VI) nodules. Consequently, I am very pleased with MolDX’s decision to include coverage of molecular testing as a prognostic tool for patients with Bethesda V nodules.

I am concerned, however, that the current determination language may deny coverage for molecular testing of more than one nodule. When a patient has more than one thyroid nodule meeting criteria for thyroid fine needle aspiration, molecular testing of any Bethesda III-V nodule could influence the optimal treatment choice. For example, a patient with an index nodule that is cytologically indeterminate and molecularly benign, but also has a second cytologically indeterminate nodule that yields a molecular classification as a medullary thyroid cancer. In such a case, molecular testing of only the index nodule might lead to a recommendation of observation with failure to diagnose malignancy in the second nodule missed. In contrast, if both nodules were tested molecularly, the patient would likely be referred for total thyroidectomy and central neck dissection. Consequently, I respectfully ask that MolDX be explicit about continuing to cover testing of multiple thyroid nodules when medically necessary.

Thank you for taking into consideration the most updated NCCN guideline and Bethesda classification refinements in determining coverage for molecular testing of thyroid nodule. I applaud your decision and hope to see coverage of multiple thyroid nodules when appropriate.

Thank you for your thoughtful comments. We have addressed your comments and concerns in Response 1 listed above.

The following comment was submitted to Palmetto GBA:

Sonic Healthcare USA is submitting this request for reexamination of the coding decisions in regards to MolDX: Molecular Testing for Risk Stratification of Thyroid Nodules, and the accompanying Billing and Coding Article. We appreciate the opportunity to comment on this pair of documents.

We agree with the evidence review in the draft LCD, which focuses on the Afirma and ThyroSeq GC tests. We appreciate that the conclusion of the evidence review was not limited to these two tests but was more broadly stated that molecular tests that aid in medical decision-making for thyroid nodules with specific cytology results are reasonable and necessary. This is in line with the current NCCN guidelines for Thyroid Carcinoma, which does not recommend a specific test to aid in reclassification of Bethesda III or IV nodules, but instead recommends molecular diagnostics in general¹. However, the accompanying draft LCA indicates that the only two CPT codes that are medically necessary are 81546 (which is a MAAA code limited to the Afirma test), and 81479 (which is an unlisted molecular pathology procedure). The omission of the PLA code 0026U for ThyroSeq GC from the LCA is striking, given that ThyroSeq GC was included in the evidence review, and the LCD’s conclusion did not indicate that ThyroSeq GC was not considered medically necessary. However, in order to be covered ThyroSeq GC would need to be billed with 81479. This is not in alignment with Medicare’s NCCI coding manual, which advises the use of 81479 only if no CPT code accurately describes the procedure performed². The PLA codes are the most specific descriptions of these tests and should be used for billing the specified tests, so the LCA should include 0026U in the Group 1 codes.

Additionally, we would like to clarify the first criteria that “the patient has not been tested with the same or similar assay for the same clinical indication.” A patient may present with multiple thyroid nodules that each meet criteria for FNA based on size and ultrasound features, and have cytology results of Bethesda III, IV or V. In these cases, according to the American Thyroid Association’s guidelines, each nodule carries an independent risk of malignancy³ so molecular testing is appropriate for each nodule. We suggest that the first criteria be amended to “the nodule has not been tested with the same or similar assay for the same clinical indication.”

We appreciate your attention to this matter.

References were provided for review.

Thank you for your thoughtful comments. We have addressed your comments and concerns on testing multiple nodules in Response 1 listed above.

As a MolDX policy, the coverage criteria and CPT/PLA codes are relevant to services in the following jurisdictions: JM, JJ, JE, JF, J5, J8 and J15.