Response to Comments: MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma

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

Requesting physicians other than dermatopathologists be permitted to order molecular assays for the diagnosis of cutaneous melanoma.

Thank you for your comments. We have reviewed them all and have found that many of them concerned permitting physicians other than dermatopathologists to order molecular assays for the diagnosis of cutaneous melanoma. However, evidence from the medical literature to support this routine practice was not provided. Rather, the commenters offered supporting reasons as being things like not restricting ‘access’ to care and ease of ‘practice workflows.’

There is a significant body of literature that supports the need for a second opinion by a trained dermatopathologist in ambiguous and complex melanoma cases. As explicitly noted in the draft policy, “subspecialty training and experience in dermatopathology is associated with improved diagnostic accuracy and subsequent clinical management of patients with challenging melanocytic lesions”.^1-4

The referenced publications include a study of 1521 cases from an academic melanoma referral center that reported numerous major and minor discrepancies between the histopathologic diagnoses by the referring institutions and the subspecialist dermatopathologists. Guideline non-adherence was also observed for many of the diagnoses and reports rendered by the referring physicians. The authors conclude that the study “highlights the importance of referral of melanocytic lesions for review by trained dermatopathologists with ample experience in the subject. Such review resulted in significant changes in staging and recommended management”.¹ Additional studies have also found that second opinions improve the diagnostic accuracy and reliability of melanocytic lesion diagnoses^2,3 and that diagnostic reproducibility and accuracy is highest among pathologists with board certification and/or fellowship training in dermatopathology.⁴

Further, it is standard clinical practice to refer for expert opinion in ambiguous cases and the tests described in this policy are intended to be used for the explicit purpose of resolving diagnostically ambiguous cases. Therefore, sending a case for expert review (and further diagnostic testing, if necessary) provides the patient with the most accurate final diagnosis. Importantly, sending a case for consultation does not require the patient to make an appointment with the dermatopathologist or to travel. Only the specimens/slides of the lesion are sent by either the referring dermatologist or pathologist. Rapid/express mail delivery services exist throughout the country and do not require the patient, the dermatologist, or the pathologist to be in proximity to the expert dermatopathologist in order for a consultation to be provided and for a determination of whether a gene expression profile (GEP) test is even necessary. Interestingly, some of the commenters specifically acknowledged that good communication with dermatopathologists is a valuable aspect of the care they provide. This communication is important for patient care and does not result in any substantial delay in care. It can occur by telephone, email, and other modalities. In all, this process allows patients greater access to specialty care regardless of where they live.

Finally, some of the comments referred to the ‘retention’ of the ability to order the relevant tests. We note that such statements are incorrect because the policy that the present one is superseding (myPath Melanoma Assay) also required that the test be ordered by a board-certified dermatopathologist. In fact, the current policy has been slightly broadened and now also includes those who are board-eligible in dermatopathology.

For all of the reasons stated, we retain the requirement that a trained dermatopathologist be the physician to order molecular tests for the diagnosis of cutaneous melanoma in diagnostically challenging primary cutaneous melanocytic neoplasms.

References:

1. Ronen S, Al-Rohil RN, Keiser E, et al. Discordance in diagnosis of melanocytic lesions and its impact on clinical management. Arch Pathol Lab Med. 2021;145(12):1505-1515.
2. Piepkorn MW, Longton GM, Reisch LM, et al. Assessment of second-opinion strategies for diagnoses of cutaneous melanocytic lesions. JAMA Netw Open. 2019;2(10):e1912597.
3. Tosteson ANA, Tapp S, Titus LJ, et al. Association of second-opinion strategies in the histopathologic diagnosis of cutaneous melanocytic lesions with diagnostic accuracy and population-level costs. JAMA Dermatol. 2021;157(9):1102-1106.
4. Elder DE, Piepkorn MW, Barnhill RL, et al. Pathologist characteristics associated with accuracy and reproducibility of melanocytic skin lesion interpretation. J Am Acad Dermatol. 2018;79(1):52-59.e5.

The following comment was submitted to Palmetto GBA and Noridian:

Thank you for the opportunity to submit my supportive comments on the proposed draft LCD for use of molecular diagnostics/genetic testing for the improved accuracy of diagnosis in melanocytic lesions with equivocal histopathology (MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma). I am a board-certified dermatologist and Mohs surgeon with deep experience in the use of gene expression profile (GEP) tests as part of my clinical work-up and management of cutaneous neoplasms.

Despite advances in histopathology and multiple diagnostic ancillary tests, there remain times when I submit a biopsy from my dermatology practice and I receive a final pathology report that does not provide a clear benign or malignant diagnosis for a concerning pigmented lesion. The clinical significance of this scenario is that a melanoma may not be confirmed nor ruled out definitively in a lesion where I have a high level of clinical concern. While it is sometimes appropriate to simply perform a wide local excision out of an abundance of caution – meaning to simply treat the lesion as if it was the worst case scenario in the differential diagnosis – this approach is less than ideal for some patients which can depend on the specific clinical scenario and can result in the over treatment of truly benign nevi or under-treatment of truly malignant melanoma.

For these reasons, the ability for dermatologists to order the 23-GEP or 35-GEP tests is important, after a pathology report is returned which demonstrates that a lesion has substantial diagnostic uncertainty and in instances where the patient may be subjected to additional interventions. Further, I would argue that it is the treating dermatologists who see and manage these clinical lesions day in and day out, and based on our relevant training, expertise, and personal understanding of the patient’s specific clinical scenario we know which patients are appropriate for testing and which are not. For example, if there was a case that arose where the diagnosing pathologist was not able to order a diagnostic ancillary GEP test, the patient would be routed back to a dermatologist with a diagnostically equivocal melanocytic neoplasm without a GEP test result. In such a scenario, it is very helpful to allow the treating dermatologist to articulate the need for additional diagnostic clarity to guide patient care and be able to have their GEP order for either 23-GEP or 35-GEP be covered for their patients with Medicare.

I think it is important to recognize that, just like with other ancillary diagnostic tests, GEP tests are only ordered by clinicians who know when it is appropriate, and who know how to interpret and integrate the results into their management plans. Physicians do not, on a fundamental level, order tools that they do not have the intention or skill to integrate into management decisions. In the diagnosis and management of equivocal/uncertain melanocytic neoplasms, pathologists are not the only clinicians who diagnose and manage these patients. As a result, there are additional subspecialists - dermatologists AND pathologists - who are capable of determining which patients will benefit from ancillary diagnostic testing and when the test is medically reasonable and necessary for a particular patient.

In summary, it is appropriate and necessary to allow the treating pathologist or dermatologist involved in the diagnosis and management of a patient to access or order these important GEP tests. To reduce access to either specialty creates unnecessary lag in arriving at the correct diagnosis and unnecessary burden to existing workflows to accommodate these restrictions. As such, I believe the draft policy should be amended to include both dermatologists and pathologists as ordering physicians in the final LCD.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

Overall, diagnostic GEP testing has had a positive impact on my patients through objective results and has helped inform patient management (even if it does not change final diagnosis).

As a clinical dermatologist and practicing dermatopathologist, I am in favor of efforts to obtain Medicare coverage for the diagnostic 35-GEP test, DiffDx Melanoma, and continue coverage for the diagnostic 23-GEP test, MyPath Melanoma. As the primary clinician tasked with patient treatment and follow-up, I find a clear and confident diagnosis to be vital in making sure that my patient receives the best possible care. Melanocytic neoplasms can be of great concern and therefore can warrant additional information such as additional testing procedures in addition to the standard histopathology review and immunohistochemical stains. The 23-GEP and 35-GEP tests are objective tests which sets them apart from other ancillary tools available to me for testing; most tests in dermatopathology are subjective in nature which can lead to variation in regard to histopathological impressions. Both the 23-GEP and 35-GEP tests provide a benign or malignant result in the vast majority of cases, which limits the number of cases where an ambiguous diagnosis is given based on an intermediate test result. The patients that I treat clearly benefit when the pathologist orders a diagnostic GEP test (or other diagnostic ancillary test) that increases the diagnostic clarity of the pathology report and helps to inform the treatment plan based on solid clinicopathologic correlation. Even in scenarios where the final diagnosis made by the dermatopathologist is not changed by the test result, there is clinical utility for me in integrating the genetic malignant potential of the lesion with the reported histopathologic findings to help adjust my management approach for patients moving forward.

The 23-GEP and 35-GEP diagnostic tests have brought about important shifts in my patients’ care through the clinical utility of the benign or malignant result. As a dermatologist, I would ask that the availability of the test include treating clinicians like myself who see value in this objective test result.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

As a board-certified dermatologist and expert in non-invasive imaging of melanocytic neoplasms with dermoscopy and reflectance confocal microscopy, I appreciated the opportunity to participate in the recent open meeting with MolDX medical directors. I wanted to submit my public comment to accompany my recent presentation to formally support the proposed draft LCD - MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma. I fundamentally agree with the position that both diagnostic GEP tests (23-GEP and 35-GEP tests, commercially known as MyPath and DecisionDx-DiffDx) should be available for Medicare beneficiaries under a foundational LCD. I think that this proposed draft policy establishes appropriate coverage for these two diagnostic GEP tests broadly; I only have a single refinement or recommended suggestion that I believe MolDx should consider as the proposed draft policy moves to a final LCD.

I believe that dermatologists are inadvertently left out of the current wording of the draft policy and, from my perspective, this is a mistake as dermatologists are the primary point of care and responsible for the treatment of melanocytic neoplasms. I am not advocating that every dermatologist should be required to order these diagnostics GEP tests, but I believe that dermatologists interpreting their own biopsy specimens under the microscope, and dermatologists who have specialty focus on managing patients with challenging melanocytic neoplasms should be allowed to order these diagnostic GEP tests when appropriate. For example, dermoscopy and/or reflectance confocal microscopy can be used by dermatologists to evaluate a lesion before the decision to biopsy has been made. The use of these pre-biopsy diagnostic modalities mandates expertise in identifying when to use these tools for a particular patient and dermatologists are able to appropriately use these tools for Medicare beneficiaries today. There is broad consensus that advanced non-invasive imaging can benefit biopsy decision making in lesions with equivocal or uncertain clinical diagnostic criteria and, as a dermatologist, I am trained to know when these ancillary clinical decision-making tools are appropriate and when they are not.

After the biopsy is done and the specimen is sent to pathology, the 23-GEP or 35-GEP tests can be ordered to guide the correct diagnosis of melanoma vs. nevus by the interpreting pathologist/dermatopathologist. Moreover, there are dermatologists who read their own slides and can bill the professional component of the diagnosis for this clinical work. When the treating dermatologist is acting in the capacity of a pathologist/dermatopathologist and interpreting biopsy specimens under the microscope, they are able to order other relevant ancillary diagnostic tests as appropriate (e.g., IHC, FISH). Therefore, it stands to reason that they should be able to order other diagnostic ancillary tests. Specifically, these dermatologists should not be restricted from ordering diagnostic GEP ancillary tests.

I believe that even if the test is not ordered by the interpreting pathologist/dermatopathologist, the need for these GEP tests can be appropriately identified by the dermatology treating clinician after an equivocal or uncertain biopsy report is finalized and received to inform subsequent management decisions. My position regarding appropriate ordering subspecialties is supported by the published clinical utility for both dermatologists and dermatopathologists which demonstrates that both clinicians have a role in reduction of unnecessary re-excisions in diagnostically challenging lesions with benign GEP. Specifically, dermatopathologists reduce recommendations to excise lesions with benign GEP and dermatologists reduce re-excisions performed on equivocal melanocytic neoplasms that received a benign GEP test result.

Medicare already entrusts dermatologists to appropriately select clinical diagnostic tests before the biopsy. I believe that dermatologists can therefore be trusted to identify appropriate lesions for ancillary diagnostic GEP tests after the biopsy report is made as well, in circumstances where there is a critical mismatch between the pathologic diagnosis and available clinical information. To ensure appropriate testing, the LCD should keep the existing draft language regarding covered GEP tests and sets out appropriate guardrails to define the types of lesions where GEP testing:

• The specimen is a primary (non-metastatic, non-re-excision specimen) cutaneous melanocytic neoplasm for which the diagnosis is equivocal/uncertain (i.e., clear distinction between benign or malignant cannot be achieved using clinical and/or histopathological features alone) despite the performance of standard-of-care test procedures and relevant ancillary tests (i.e., immunohistochemical stains)
• The specimen includes an area representative of the lesion or portion of the lesion that is suspicious for malignancy
• The patient may be subjected to additional intervention, such as re-excision and/or sentinel lymph node biopsy, as a result of the diagnostic uncertainty
• The patient has not been tested with the same or similar assay for the same clinical indication

In conclusion, I support the Draft LCD as it appropriately covers both 23 and 35-GEP tests for Medicare beneficiaries based on the published clinical validity and clinical utility data. The use of these GEP tests aligns with the ordering flow at my academic institution and the draft foundational policy supports access to GEP tests that are clearly beneficial for Medicare patients; this includes my own patients for whom I use GEP to help correctly diagnose and manage cutaneous melanocytic neoplasms with equivocal/uncertain diagnoses. I therefore advocate to include dermatologists with pathologists and dermatopathologists in the final LCD, as all of these physicians are specialists trained to identify lesions that meet the criteria set out by the proposed LCD. Patient access to diagnostic GEP tests should not be limited by specialty restriction to BC/BE dermatopathologists as other highly trained treating clinicians can also identify lesions appropriate for diagnostic GEP testing.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA:

Dermatopathologists rely on a combination of different ancillary tests for coming to a final diagnosis for ambiguous melanocytic lesions. For example, when faced with a case that is difficult to classify as either a benign or malignant melanocytic lesion, steps such as obtaining deeper levels into the block, performing immunohistochemical studies (such as Sox-10/PRAME), FISH, or second opinion consultation are often taken. Since their clinical availability, the 23- and 35-GEP tests (commercially called myPath and DiffDx) have also been included in the types of diagnostic ancillary tests that dermatopathologists can turn to in order to obtain more diagnostic certainty and confidence when reviewing and signing out these cases.

As a result, I believe the 23- and 35-GEP tests should be fully supported for our Medicare patients in difficult melanocytic lesions.

Thank you for your support of the policy.

The following comment was submitted to Palmetto GBA and Noridian:

I am a board-certified dermatologist, a pigmented lesion expert and Clinical Associate Professor of Dermatology at an academic medical center. I am submitting a comment in support of LCD coverage of Castle’s Diff and myPath diagnostic tests. The myPath test has had long-standing coverage from MolDX, and I am glad to see the expansion of this coverage to include the new Diff test in addition to retaining coverage for the myPath test. Recently, I have received Diff test results along with the final pathology report. Either of these tests provides information that is helpful to me in determining how best to manage my patients. The use of these diagnostic tests has decreased the number of conflicting pathology reports I receive (e.g., the lesion is diagnosed as benign but there is a recommendation to excise).

I am supportive of dermatologists being able to order the test if it is not currently the practice of their respective pathology groups because it gives validated, clinically useful information that can be used to guide patient management, regardless of its formal inclusion in the diagnosis rendered from the dermatopathologist. I work closely with the team of dermatopathologists who interpret the skin biopsies that I take from my clinic, and they are keenly aware that I use gene expression profiling for melanocytic lesions with equivocal histology. After our conversations around my preferences, they order the test for my patients when they encounter equivocal melanocytic lesions where the definitive diagnosis of melanoma or a benign nevus cannot be made using just histology. I understand that in a university/academic setting this process is seamless, but it would not be as streamlined a process in a community dermatology setting where treating clinicians may not have such a strong relationship with pathology colleagues or have colleagues who are aware of the range of molecular diagnostic tests that can benefit challenging cases. Since community dermatologists don’t often have an in-house pathology department or even one pathologist they use routinely, I could see the need for expert clinical dermatologists like myself to have access to GEP testing when appropriate for an equivocal melanocytic lesion.

Ancillary diagnostic GEP test results are easy to understand and I get an answer of benign or malignant GEP almost every time the test is ordered. I would like to have the option to order the test myself as it has provided helpful information. I urge you to support this highly accurate and useful test and ensure both dermatopathologists and dermatologists can order this test.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

I am a board-certified dermatologist and dermatologic surgeon who specializes in the diagnosis and management of malignant and pre-malignant cutaneous neoplasms. In my practice I encounter problematic pigmented/melanocytic lesions. These are lesions that, after biopsy, the pathologic diagnosis is equivocal or uncertain as to the tumor’s malignant potential. This uncertainty makes determining the appropriate treatment of these lesions especially challenging. The consequences of under-treating a malignant pigmented neoplasm are significant and can include death from melanoma. Conversely, over-treating non-malignant lesions leads to greater cost and morbidity for the patient. Obtaining a firm diagnosis of malignant or non-malignant is the key to proper patient management.

I strongly support Medicare coverage for diagnostic genetic profiling tests, including both Mypath-Melanoma and DiffDx-Melanoma test under this policy. While the policy correctly identifies the correct intended use and patient population, I believe there is an oversight in not allowing board certified dermatologists, as primary treating clinicians, to order this necessary and clinically valuable test.

The best clinical decision making is between the patient and the treating physician in a shared decision-making manner. In the past, the requirement that myPath-Melanoma be ordered only by board-certified dermatopathologists has been restrictive for me and my patients. Simply put, the dermatopathologist is not directly involved in the patient’s care and does not know all the factors involved in the patients care or when having diagnostic certainty is most important. I need to have the ability to obtain the diagnostic genetic profiling on a case-by-case basis. Sometimes, the definitive difference between a malignant neoplasm and atypical neoplasm does not change management, but many times it will. The pathologist has no way to know when this is the case.

Given that my practice now includes the use of diagnostic GEP for equivocal melanocytic neoplasms where increased clarity significantly benefits my patients, I do not think that my patients should lose access to these diagnostic ancillary tests. I can combine clinical factors, histopathologic factors and genetic profiling to determine the most appropriate level of care and minimize the risk of over-treating or under-treating a patient’s tumor. This decision may range from determining the extensiveness of a surgical intervention to choosing to monitor a lesion based upon the additional information that I receive from the myPath-Melanoma or DiffDx-Melanoma tests.

Flexibility for me to order myPath Melanoma or DiffDx-Melanoma when medically reasonable and necessary without express permission from each individual pathologist/dermatopathologist who may interpret my specimens would be beneficial to the care of the Medicare patients whom I treat today and will continue to treat in the future.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

I am writing in support of the LCD for the diagnostic GEP testing from Castle Biosciences, and to enthusiastically support the maintenance of coverage for myPath Melanoma and extension of coverage to include DecisionDx DiffDx-Melanoma, as both are ancillary diagnostic tests with solid evidentiary evidence.

A diagnosis of melanoma triggers many important decisions in the management of the patient, so a precise and accurate diagnosis is essential for good patient care. However, there are many lesions that are not clearly benign or malignant by only a histopathological review, and ancillary testing is routinely used in the diagnostic process to resolve this uncertainty. I have used diagnostic GEP in my practice to achieve this end. Strong data supports the extension of coverage to include DiffDx-Melanoma. Of critical importance, more than 96% of cases are generate a DiffDx-Melanoma report that is suggestive of benign or suggestive of malignant, meaning that the results I get are actionable and clear [1]. This is an objective result based on the gene expression profile increases the confidence in my diagnosis by giving me diagnostic information not otherwise available to me.

Published studies on the utility of DiffDx-Melanoma echo the findings previously reported and covered in the prior MyPath Melanoma LCD showing that diagnostic confidence among dermatopathologists was increased by 51% when the GEP test result was considered when making a diagnosis of a melanocytic lesion [2,3,4]. This is also consistent with my own clinical experience. I strongly endorse the Medicare coverage of these innovative and essential diagnostic tools for patients with these difficult to diagnosis melanocytic lesions.

References were provided for review.

Thank you for your support of the policy.

The following comment was submitted to Palmetto GBA and Noridian:

Thank you for the opportunity to present at the recent open meeting and for reviewing public comments regarding MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma. As a board-certified dermatologist, dermatopathologist and past president of the American Academy of Dermatology, it is important that Medicare MACs provide pathways for evidence review to enable coverage for innovative tests that can directly benefit the patients for whom we provide care. I am submitting my comments to MolDX to support their continued coverage of both MyPath Melanoma (0089U) and DecisionDx DiffDx-Melanoma (0314U) tests as they provide valuable information to Medicare beneficiaries today.

Melanocytic neoplasms with uncertain or equivocal histopathology pose a well-documented clinical problem for clinicians. When malignancy cannot be excluded from the diagnosis, physicians typically recommend and follow a treatment plan for melanoma which may result in over-treatment including surgical procedures or sentinel lymph node biopsy and can also result in the potential for undertreatment including missing a diagnosis of melanoma. At a basic level, melanocytic lesions require a definitive diagnosis to avoid both overtreatment of benign lesions by unnecessary re-excision and undertreatment of truly malignant lesions to avoid a missed melanoma diagnosis.

Ancillary diagnostic GEP testing is an established tool, and both diagnostic GEP tests - MyPath and DiffDx - have robust analytical validity, clinical validity and clinical utility supporting their use. Other diagnostic ancillary tests, including consultation with colleagues, IHC studies, and FISH testing, are limited by high levels of discordance, variable accuracy, and subjectivity. In contrast, GEP tests are objective and complement the subjectivity inherent to histopathology, providing greater analytic validity, accuracy, and therapeutic clarity. MyPath Melanoma demonstrated highly accurate classification of lesions as benign or malignant in multiple independent validation studies totaling 1,300 tested cases. For example, MyPath demonstrated 94% sensitivity in cases with proven distant metastases and 96% specificity in cases with no evidence of disease progression (>6 years median follow-up) (Ko 2017). The DiffDx-Melanoma test demonstrated highly accurate classification of lesions as benign or malignant in an independent validation of 503 primary cutaneous melanocytic neoplasms. Technical success was achieved in 97% of specimens. The test had sensitivity of 99% and specificity of 94% in patients of all ages (Estrada 2020). Importantly, in addition to the strong validation data, MyPath Melanoma and DiffDx test results have demonstrated clinical utility for both dermatopathologists and dermatologists (Cockerell 2016; Cockerell 2017; Farberg 2020; Tschen 2021). For lesions with ambiguous histopathology and benign GEP results, both GEP tests have been shown to reduce dermatopathologist re-excision recommendations and that upon receiving this information, dermatologists perform fewer re-excisions for these lesions.

Based on this strong evidence, GEP testing is also referenced by multiple guidelines such as NCCN and AAD cutaneous melanoma guidelines. These guidelines state that diagnostic ancillary testing, including GEP, may facilitate more definitive diagnoses and guide treatment decisions for equivocal or uncertain melanocytic neoplasms. The American Society of Dermatopathology’s Appropriate Use Criteria Committee has designated key clinical scenarios ‘Majority Usually Appropriate’ for GEP testing ancillary testing. (Fung et al. 2021) Importantly these scenarios align with the intended use of both assays where, “Distinction of nevus from primary melanoma in an adult patient when the morphologic findings are ambiguous by light microscopic parameters.” Of note, this scenario overlaps entirely with the intended use population for both MyPath and DiffDx. It is important to emphasize that guideline inclusion is not a requirement for medical reasonableness and necessity as these guidelines are consensus-based, and not strictly evidence-based, and are considered to be broad suggestions - not strict rulebooks to be followed to the letter.

While dermatopathologists are the most frequent users of these tests, they are not the only clinicians who appropriately order and use these assays. In some cases, a BC/BE dermatopathologist may not be available, due to regional or practice pattern restrictions. BC/BE surgical pathologists with expertise in melanocytic neoplasia routinely interpret melanocytic neoplasms and currently use these and other diagnostic ancillary tests. It is inappropriate to limit access of any clinician who routinely interprets skin biopsies and orders ancillary diagnostic tests from also appropriately ordering and using GEP tests. The determining factor in who is included as an ordering provider for these tests should be determined by what is best for patient care, not their training background. Importantly, allowing other treating clinicians to access these tests will not lead to overutilization; these lesions represent a small fraction of melanocytic neoplasms and the clinical expertise required to incorporate test results into the diagnostic process is self-limiting to which physicians will order. Removing the dermatopathology specialty restriction benefits patients and does not remove the requirement for the test to be ordered by experts who diagnose and manage these lesions.

By offering both MyPath and DiffDx diagnostic GEP tests, Castle Biosciences has increased the actionable output of diagnostic GEP. In the event either test returns a failed result, physicians can obtain a second GEP test with the assurance that only one GEP test will be billed and reported to the ordering clinician. I believe that Castle’s offering of both MyPath and DiffDx as standalone tests provides the treating clinician with the greatest chance to obtain actionable GEP results for equivocal melanocytic lesions appropriately submitted for testing; further, the billing of a single GEP test results in appropriate billing for the molecular testing provided to patients.

In closing, I fully support the proposed MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma for difficult-to-diagnose melanocytic neoplasms with uncertain malignant potential, for BC/BE dermatopathologists and BC/BE pathologists who face the challenge of providing a clear and accurate diagnosis and BC/BE dermatologists who need a clear diagnosis to support treatment and patient management decisions.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

I am a board certified anatomic/clinical pathologist and dermatopathologist and have been involved in basic science and translational research for over 8 years. A significant focus of my investigational work has centered on the application of molecular diagnostics to the practice of dermatopathology and I have significant experience studying gene expression profiling (GEP) approaches for both diagnostic and prognostic applications. In addition, I have 5 years of experience of the clinical application of these GEP technologies where I have been able to incorporate advances in precision medicine into my work-up of equivocal melanocytic neoplasms and integrate molecular findings with histopathologic findings into my final pathology reports that I return to my dermatology colleagues.

During my fellowship training, I was involved in the developmental research of the myPath Melanoma GEP test, and, more recently, I was involved in early validation research of the DecisionDx DiffDx-Melanoma test that are now both clinically offered by Castle Biosciences. In addition, I have experience with the clinical use and application of both assays in my dermatopathology practice as well as other diagnostic ancillary tests such as IHC, FISH, NGS and second opinion consultations. I am also in dialogue with dermatopathologists and dermatologists about how these tests can improve patient care by reducing diagnostic uncertainty for melanocytic neoplasms where the distinction between a benign nevus and malignant melanoma cannot be made with routine histologic approaches.

I am submitting my comment to MolDx because I firmly believe that based on the strength of the published evidence that both GEP tests have met the Medicare criteria for coverage and agree with the draft LCD that proposed to consider both MyPath and DiffDx as covered tests for lesions appropriate for this testing.

Diagnostic GEP tests provide important information and based on strong evidence have already been recognized by multiple guideline organizations as an acceptable ancillary test for equivocal melanocytic neoplasms. Of particular interest, The American Society of Dermatopathology Appropriate Use Criteria committee has recognized GEP as being majority usually appropriate in key clinical scenarios in their latest update (Fung, J Cutan Pathol, 2021). I believe that GEP tests are an important tool for dermatopathologists to access when they encounter melanocytic neoplasms that are challenging to correctly classify as a benign nevus or malignant melanoma; instead of issuing vague or ambiguous reports to dermatology colleagues these tests can inform more definitive and confident diagnoses based on the gene expression of the tumor that can provide diagnostic clarity to inform appropriate management decisions in the clinic. One caveat to the proposed policy is that as a pathology trained dermatopathologist, I believe that my pathology trained colleagues (specifically those who have significant expertise in signing out skin biopsies and melanocytic lesions in particular, but who have not pursued formal fellowship training) could also identify lesions appropriate for testing.

Overall, I would encourage MolDx medical policy writers to finalize the draft LCD that approves Medicare coverage for both MyPath and DiffDx to ensure that pathologists and the patients whose lesions they sign out will have continued access to this important type of ancillary diagnostic testing.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

I am sending this letter in support of Castle Biosciences’ ancillary diagnostic tests and the recently released draft LCD that positively covers DiffDx and MyPath-Melanoma. I am a board-certified dermatologist and dermatologic surgeon with extensive expertise in pre-biopsy diagnostic tools - dermoscopy and confocal microscopy - and lecture nationally and internationally about how to incorporate these pre-biopsy clinical diagnostic tools appropriately in the dermatology clinic. As a result of this differentiating expertise, my clinical practice has focused on cutaneous oncology and my clinic is now a referral destination for difficult to diagnose melanocytic neoplasms. Furthermore, I have participated in initiatives that bring these pre-biopsy diagnostic tools to underserved rural areas where I have also focused my education efforts in an attempt to identify malignant melanoma at earlier time points when these lesions are most amenable to treatment with curative surgery.

I have followed with great interest the diagnostic ancillary tests that have been developed and are in clinical use for melanocytic lesions that remain ambiguous even AFTER the biopsy has undergone dermato-pathology review. Receipt of diagnostic pathology reports that fail to establish a definitive diagnosis of a benign nevus or of a malignant melanoma, present significant management challenges to the dermatology treatment team – not the least of whom is the dermatologic surgeon faced with the decision about how large of a surgery would be appropriate for such a case. Diagnostic clarity clearly benefits the patients whose pathology reports are moved from equivocal to unequivocal and the published evidence for myPath Melanoma and DecisionDx DiffDx-Melanoma has demonstrated that GEP testing can aid in differentiating benign from malignant melanocytic neoplasms with very high levels of accuracy and that clinicians are able to use this information to inform management decisions.

I can confirm from my own clinical practice that integration of these GEP tests improves the diagnostic clarity of equivocal melanocytic neoplasms and leads to improved patient care for my patients who receive these tests. I am fortunate to have an outstanding personal and professional relationship with my dermatopathologist who interprets the vast majority of the biopsies and excisional specimens that I take in the clinic and have had conversations with him about my interpretation of the evidence supporting GEP and the types of cases where I believe these tests are appropriate. As such, we have a collaborative approach to ordering GEP tests where either my dermatopathologist will initiate ordering in cases where he has identified the clinical need to additional diagnostic ancillary testing, or he will order in cases where I flag the need for additional diagnostic clarity based on the impactful clinical decisions facing a patient in the setting of an equivocal diagnosis. It is clear from my practice that both dermatopathologists and treating dermatologists are able to correctly identify cases appropriate for these GEP tests as both specialists are deeply involved in the care of patients with these lesions.

Access to either MyPath Melanoma and DiffDx-Melanoma tests is critical for my patients as these GEP tests allow me and my dermatopathology colleagues to obtain more definitive diagnoses and more accurate treatment plans. I am supportive of Medicare’s draft LCD that puts forward coverage for both MyPath and DiffDx-Melanoma for patients with equivocal diagnoses of their melanocytic neoplasms. I would suggest, based on my clinical experience, to allow both dermatologists providing care to the patient and the interpreting dermatopathologist the ability to order each of these tests. GEP tests results are ordered by clinicians with each patient’s best interest in mind - to appropriately guide their care and management moving forward.

Thank you for your comment. See Response #1.

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

In response to the proposed LCD MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma, Castle Biosciences is submitting the following public comment for your consideration. We appreciate the thoughtful LCD draft that clearly articulates the clinical need and utility for both MyPath Melanoma (0090U; MyPath) and DecisionDx DiffDx-Melanoma (0314U; DiffDx) gene expression profile (GEP) tests. Castle Biosciences fundamentally agrees with the MolDX designation of both MyPath and DiffDx as GEP tests that have met the threshold of medical reasonableness and necessity for Medicare and the determination that both are considered covered tests under this policy. The limitations in the policy of billing one GEP test for a single lesion is consistent with Castle Biosciences’ billing policy, and as stated in prior communication with MolDX medical directors, Castle Biosciences is committed to submission of a single GEP test for a lesion. Further, the coverage guidance is appropriately limited to specimens of uncertain malignant potential and clinical scenarios when GEP results will influence important clinical management interventions.

Diagnostic GEP Tests Address a Critical Unmet Need for Objective Diagnostic Clarity in Melanocytic Neoplasms with Equivocal Histopathology

As the current draft LCD clearly articulates, accurate diagnosis of melanoma versus non-melanoma in melanocytic neoplasms of uncertain malignant potential with equivocal histopathology pose a significant clinical challenge.^1–6 Briefly, in approximately 15% of biopsies being evaluated for possible malignant melanoma, a definitive diagnosis cannot be made by H&E visualization alone, and in these cases, ancillary molecular testing and/or referral for expert second dermatopathology opinion is often employed to resolve diagnostic ambiguity.^7–13 The persistence of diagnostic discordance between dermatopathologists and the difficulty in making treatment decisions for these patients by dermatologists has resulted in the development of ancillary molecular testing tools to aid in the diagnosis of melanocytic neoplasms with uncertain malignant potential.^25,27–35 Importantly, melanocytic neoplasms of uncertain malignant potential are commonly treated as the worst-case possibility in the differential diagnosis by the treating clinician, resulting in unnecessary re-excisions, performance of a sentinel lymph node biopsy, advanced imaging and increased clinical follow-up.^14–16 Thus, arriving at a definitive, accurate diagnosis of malignant melanoma versus benign nevus has significant clinical utility for guiding appropriate patient management.^17–21

The draft LCD has appropriately reviewed and cited the published evidence supporting the clinical validity and clinical utility of these assays and highlights how GEP testing provides a much-needed objective ancillary diagnostic test that can complement the other subjective tools available to pathologists such as immunohistochemistry (IHC), FISH or second opinion consultation. DiffDx and MyPath are ancillary diagnostic GEP tests intended for use in melanocytic neoplasms with equivocal histopathology or uncertain malignant potential that aid in arrival at the correct diagnosis of melanoma versus nonmelanoma when interpreted in the context of other clinical, laboratory, and histopathologic information. In validation studies, both tests have demonstrated high accuracy in classification of lesions as benign nevi or malignant melanoma by their gene expression profile.^25,33,38 The clinical utility of gene expression profiling in improving accuracy of diagnosis has been well-established in the literature, including the impact on improving dermatopathologist diagnosis of melanoma versus non-melanoma as well as impact on the dermatologists’ patient management.^39–41 For dermatopathologists, the tests have been demonstrated to increase definitive diagnoses, change final diagnosis, and impact recommendations for 2 patient management. For dermatologists, utility has been demonstrated by change in patient management and reduction of re-excisions in lesions classified as benign with no adverse patient outcomes.⁴² Taken together, these studies suggest that Medicare beneficiaries with diagnostically challenging primary cutaneous melanocytic neoplasms, for whom GEP is used to establish a definitive diagnosis, may have improved outcomes by comparison to untested patients, as defined by an increase in accurate diagnoses and reduction in burdensome and unnecessary treatments.

Recommendations for Additional Treating Clinicians as Covered Providers for Diagnostic GEP Testing

As mentioned during the Castle Biosciences presentation at the open meeting, we recommend modifying the coverage guidance to include other select subspecialists who are highly trained, involved in diagnosis, management and forming treatment decisions for patients with primary cutaneous melanocytic neoplasms with equivocal/uncertain malignant potential; specifically we recommended that the final LCD consider board-certified/board-eligible (BC/BE) dermatopathologists, pathologists and dermatologists as treating clinicians who should have access to both tests to improve diagnosis and management decisions for Medicare beneficiaries.

Dermatopathologists are not operating alone in their role to diagnose and develop appropriate treatment plans for challenging melanocytic neoplasms. Today, there are anatomic pathologists who routinely receive and diagnose skin biopsies – functioning as dermatopathologists in their scope of practice, although they are not BC/BE dermatopathologists. Additionally, dermatologists as treating clinicians routinely integrate pathology reports into patient management plans and in some instances also function as dermatopathologists. Today, both of these specialties are able to and do order other diagnostic ancillary tests. Castle Biosciences believes, therefore, that allowing these clinicians to order ancillary diagnostic GEP tests for appropriate patients is consistent with clinical practice standards and current practice.

BC/BE dermatopathologists, pathologists and dermatologists can all meet the Medicare definition of a ‘treating clinician’ for patients with an equivocal or uncertain melanocytic neoplasm. Each of these subspecialists can be involved in establishing clinicopathologic correlation (CPC) for these melanocytic neoplasms, essentially consolidating the treating pathologist’s and treating dermatologist’s impression of the lesion into a clinical diagnosis and treatment plan (Figure 1). Establishing CPC, in turn, ensures that the final pathology report is consistent with the clinical context of the patient being treated. There is clear collaboration between the clinician treating the patient at the bedside and the pathologist interpreting the patient’s skin biopsy to arrive at CPC that ultimately informs patient management decisions, such as additional surgeries and/or SLNB.

Establishing CPC highlights two points in a patient’s journey where diagnostic GEP tests aid in achieving CPC and accurate diagnosis: (i) in the interpretation of equivocal/uncertain histopathology by the pathologist reviewing the slides under a microscope, and (ii) in rendering a clinical diagnosis as the treating clinician incorporates the histologic diagnosis with other clinical information to establish the patient management plans that follow, including additional surgeries or SLNB.

Anatomic Pathologists Are the Diagnosing Clinicians for Some Patients with Melanocytic Neoplasms and Should Have Equal Access to Diagnostic GEP Tests

While the majority of skin biopsies are interpreted by dermatopathologists, across the country there are pathologists who, based upon local practice patterns and staffing realities, regularly interpret skin biopsies and can order other relevant ancillary tests such as IHC, FISH, etc. Thus, today some anatomic pathologists do function as a Medicare beneficiary’s dermatopathologist by interpreting skin biopsies and ordering diagnostic ancillary testing for equivocal melanocytic neoplasms. However, the draft LCD doesn’t fully reflect this real-world practice scenario due to the fact that pathologists are not listed as covered ordering clinicians. It is important to note that many Medicare beneficiaries, particularly those in rural areas, may not have access to specialty physicians and restricting coverage to specialty physicians does restrict or prejudice access to care from which beneficiaries in urban settings benefit.

The published clinical utility of GEP in uncertain melanocytic lesions for dermatopathologists applies to a pathologist working in the same capacity as a dermatopathologist within established clinical practice patterns for their region. In this context, it is difficult to understand the logic to deny GEP testing as an option for anatomic pathologists when they do and can order subjective ancillary tools that are reimbursed by Medicare, such as IHC, FISH and CGH, especially considering the known limitations of these subjective tests. These limitations include high frequency of non-conclusive results, subjectivity of analysis due to significant inter-observer variability and large tissue volume requirements which limit access to testing.^{27–29,30–32,36,37} Given the shared role of reviewing and interpreting skin biopsies, Castle Biosciences supports the addition of BC/BE anatomic pathologists as ordering clinicians for GEP testing in the final LCD.

Dermatologists are Responsible for Integrating Pathology Reports into Clinical Diagnoses that Inform Management Decisions and Should Have Access to Diagnostic GEP Tests.

The treating dermatologist is ultimately responsible for the clinical diagnosis and the treatment decision to perform or forgo re-excision for a particular melanocytic lesion with equivocal/uncertain diagnosis or uncertain malignant potential. As such, the treating dermatologists is trained to and required to interpret the pathology report, integrate the information with their clinical impression of the melanocytic lesion and determine the best treatment course for their patient.

The treatment intensity of any melanocytic neoplasm (e.g., observation vs. surgical re-excision vs. SLNB) depends on the malignant potential of the lesion. The benefit to the Medicare beneficiary of diagnostic GEP testing ordered by a treating dermatologist is high. Multiple peer-reviewed publications show treating clinicians can and do safely perform fewer re-excisions when an equivocal/uncertain melanocytic neoplasm receives a benign GEP result which demonstrates direct clinical utility of these tests for dermatologists for the benefit of patient care. These studies are currently cited in the draft LCD.^39-41 Requiring dermatologists to order only through their dermatopathologists has unintended consequences, including potential delays in diagnosis and treatment of melanoma, unnecessary excision recommendations or significant potential for missed melanoma and potential unnecessary subjective consultations if referral patterns are shifted based on provider inability to submit covered tests. Thus, given well-established clinical utility of the tests to treating clinicians, we request coverage for GEP tests ordered by treating dermatologists as they are qualified experts involved in establishing the correct diagnosis of melanoma versus non-melanoma when examining skin biopsies and/or informing subsequent management decisions.

In addition, dermatologists are also trained to be able to read and interpret their own skin biopsies, and many still read and bill for the professional component of these services. It is possible that a treating dermatologist would therefore be in a position to complete a pathology report for a particular melanocytic lesion and order other ancillary tests to best characterize the lesion as melanoma vs. non-melanoma. When dermatologists are essentially functioning as dermatopathologists, we believe that they should also be able to have GEP orders covered by Medicare as well.

In account of the dermatologists’ role as treating clinicians involved in the diagnosis and/or specific treatment decisions for equivocal/uncertain melanocytic neoplasms, Castle Biosciences supports the addition of BC/BE dermatologists as ordering clinicians for GEP testing in the final LCD.

Subspecialty Restrictions in LCDs from Other Disease States May Inform Revision to Ordering Provider Language

As stated during the open meeting, we completed a review of existing MolDX LCDs and only found a few examples from other disease states that restrict coverage of tests to specific subspecialties. Additionally, these LCDs also included less narrow restrictions on the ordering subspecialty to improve access to tests with proven clinical utility to physicians who need them while simultaneously limiting access to ordering to those that specialize in management of disease. Specifically, LCD for Prostate cancer identifies that a test can be ordered by a “physician specialist in the management of prostate cancer, such as a urologist or oncologist”. The LCD goes on to state, “exceptions may be made in geographic locations where the specialist(s) cannot be reasonably reached by the beneficiary or ordering provider is located closer to the beneficiary place of residence than the nearest specialist”. This LCD acknowledges the reality that different specialties do manage patients with prostate cancer who may be the appropriate clinician to order a prostate cancer test and also acknowledges the reality of limited access to specialty physicians in rural areas and allow for or enables equal care access regardless of where a patient lives. Similarly, LCD for non-small cell lung cancer includes that, “the test is ordered by a physician who is treating the patient for NSCLC (generally a medical oncologist, surgeon, or radiation oncologist) to help in the decision of whether or not to recommend adjuvant chemotherapy.”

The language in these LCDs can be seen as instructive guideposts to allow for the entire team of physicians treating patients with these equivocal or uncertain melanocytic neoplasms, and can be used to guide appropriate inclusion of dermatopathologists, pathologists and treating dermatologists to be able to order diagnostic GEP tests.

Conclusions

Dermatopathologists, dermatologists, and pathologists are all members of the treating clinical team tasked with interpretation of skin biopsy reports to inform management decisions for patients with melanocytic lesions with equivocal histopathology or for which malignant potential is uncertain. Limiting access to molecular ancillary diagnostic testing to only BC/BE dermatopathologists does not reflect current practice patterns and inappropriately restricts the ability of clinicians in their treatment plan decisions - potentially impeding their ability to arrive at timely diagnoses and impacting the quality of patient care delivered to Medicare beneficiaries. Fundamentally, if a Medicare beneficiary has a lesion interpreted by a non-dermatopathologist, that patient should not be restricted from covered GEP testing, particularly as other ancillary diagnostic tools are available and reimbursed by Medicare in this clinical scenario.

Castle Biosciences believes that the draft LCD contains the correct clinical requirements for lesions appropriate for diagnostic ancillary testing and that these would serve to promote appropriate orders. While we can appreciate concerns about non-dermatopathologists ordering GEP testing, it is important to emphasize that the draft LCD stipulates that GEP tests are only ordered for a “cutaneous melanocytic neoplasm for which the diagnosis is equivocal/uncertain." This criterion can be identified by dermatopathologists, pathologists and dermatologists alike based on their substantial training in drafting and interpreting pathology reports for melanocytic neoplasms. Through their role in direct patient care, these clinicians can all identify a case where a “clear distinction between benign or malignant cannot be achieved using clinical and/or histopathological features alone.”

As such, adding pathologists and dermatologists to the LCD is beneficial for patients and will support appropriate testing. Ancillary diagnostic testing should be available to all diagnosing clinicians seeking additional information to aid in the diagnostic accuracy so long as they intended to use the results to guide management of the melanocytic neoplasm undergoing GEP testing.

Castle Biosciences is Supportive of the LCD and Requests One Minor Revision to the Draft LCD

Overall, we support the draft LCD that establishes a foundational LCD where both MyPath and DiffDx have met coverage criteria according to the policy. The draft LCD is based on a comprehensive literature review and high level of published evidence supporting these objective diagnostic tests. The draft LCD’s limitations of billing one GEP test for a single lesion are consistent with Castle Biosciences’ billing policy, and coverage guidance appropriately limits testing to specimens of uncertain malignant potential and clinical scenarios when GEP results will influence important clinical management interventions. As an important aside, the coverage criteria align with the clinical ordering criteria that Castle Biosciences places on all clinicians who order myPath or DiffDx today. The primary modification proposed in this comment is the addition of BC/BE pathologists and dermatologists as treating clinicians who can also order covered GEP tests when examining skin biopsies and/or informing subsequent management decisions in addition to the currently listed BC/BE dermatopathologists.

Castle Biosciences believes that the inclusion of these two additional subspecialties will ensure equal access to Medicare beneficiaries. This change, combined with the clinical coverage limitations already in the draft LCD will support appropriate testing without prejudicing Medicare beneficiaries who lack access to a BC/BE dermatopathologist. Our suggested adjustment to the proposed LCD language is included as “Appendix-Suggested LCD Language”. The proposed language is consistent with how these tests are used clinically today in the appropriate management of Medicare beneficiaries with a cutaneous melanocytic neoplasm for which the diagnosis is equivocal/uncertain.

Figure, appendix, and references were provided for review.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

As a practicing, board-certified dermatologist, I face a difficult clinical scenario when I receive a diagnosis the relays ambiguity in malignant potential. In most scenarios like this, I take a necessarily but potentially over-conservative approach and will re-excise the lesion if the pathology report is inconclusive or with a definitive diagnosis that suggests uncertainty in malignant potential. Though these are legitimate diagnoses, I am left with the responsibility of integrating what I see clinically regarding this patient‘s lesion with the pathology report and, as the treating clinician, determine the appropriate management plan for these patients. This can also be a challenging conversation with patients, some of whom more easily accept this conservative approach, yet many don’t want a re-excision based on uncertain information due to body location, lesion size, younger age, etc. It is disappointing to hear that another painful procedure is recommended just because we “don’t really know if it’s cancer” or the patient “might have melanoma.” However, the consequences of misdiagnosing a melanoma as benign could have severe consequences for the patient and this scenario represents a large share of the increased costs associated with incorrect diagnoses in melanoma.

The DiffDx test has spared patients from this intervention when it is not needed, and I have not witnessed recurrence in cases with a benign DiffDx result where we elected to forego re-excision. This is similar to our previous experience with the myPath Melanoma diagnostic test, for which results in a small cohort were published recently showing no evidence of recurrence during long term follow up in patients receiving a benign result who did not receive re-excision (Tschen, Cutis, 2021). A definitive malignant result also gives more diagnostic confidence and makes the conversation easier with the patient that the procedure is truly necessary and is frequently curative (especially in early-stage tumors).

It is important to me that patients have access to this test, and I support the positive coverage article for these tests. Moreover, as the treatment plan for the patient is ultimately my responsibility and can be informed by this test, it is important that dermatologists retain the ability to order this test for appropriate patients.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and WPS:

I am writing this letter to support the approval of a draft LCD for the Castle gene expression profile (GEP) diagnostic tests (MyPath and DiffDx). As a dermatopathologist, effective communication with treating dermatologists is imperative for optimal patient care, and some of the most difficult conversations I have are regarding ambiguous reports in which I have not been able to reach a definitive diagnosis or recommend an appropriate treatment plan. Melanocytic lesions of uncertain malignant potential are challenging histopathologically and a descriptive diagnosis (such as atypical compound melanocytic proliferation) is of great difficulty for the treating physician to convey to the patient. I believe that the draft policy clearly articulates both the unmet clinical need for patients and the literature that supports the ability for GEP tests to better identify these diagnostically challenging lesions.

From a personal standpoint, I have incorporated GEP into my diagnostic workflow for these challenging cases on a routine basis. This has allowed me to render more definitive diagnoses which the treating physician can act upon. Communication between providers is also improved and ultimately leads to better patient outcomes. Based on my experience with GEP testing, I am highly supportive of the proposed LCD providing coverage for these important tests – continued coverage for MyPath and including coverage for DiffDx.

Thank you for your support of this policy.

The following comment was submitted to Palmetto GBA and Noridian:

I have been in high volume dermatopathology practice for over 18 years in good standing in the community.

In my daily practice, I occasionally run into melanocytic lesions difficult to classify, whereby treatment and prognosis, especially in young patients, can vary widely depending on whether the lesion is classified as benign or malignant. I find the DiffDx test useful and I use it as I see fit on difficult cases; histopathology has discordance. I am writing this letter as a long-standing practicing dermatopathologist, with extensive experience in difficult melanocytic lesions. In my high volume practice, I receive many outside consultations with discordant opinions, and I am often the gold standard ‘tie breaker’ based on my level of experience. Occasionally, even within our group, there is not universal consensus as to classification of a lesion. Melanocytic lesions have many different molecular profiles, and understandably because of that, vary from one to the next in their histologic appearance.

I am enthusiastic to write this letter in support of Medicare coverage for diagnostic GEP tests for melanocytic lesions, including the myPath and DiffDx test. On the whole, GEP testing is becoming the new standard of care across the field of oncology and represents an advancement in tools clinicians can use to make better diagnoses and treatment decisions for patients. The DiffDx test offered by Castle is no exception; it has very high sensitivity for capturing patients with malignant lesions while maintaining a very low percentage of samples that receive an intermediate result, providing a clear, actionable result that I can incorporate into my final diagnosis and treatment recommendations for the majority of tested cases. Both MyPath and DiffDx tests give objective results, which set them apart from other ancillary diagnostic tools that could be applied to these lesions (such as FISH and CGH) that require skilled human interpreters and are thus subjective. After 18 years in practice, and seeing tools adopted for similar utilities across various disease states, I recognize the discordance that exists in the interpretation of equivocal melanocytic lesions and I am grateful to see these tests come on to the market to help guide diagnosis of lesions that are difficult in their presentation and not easily adjudicated as malignant melanoma or benign nevi. Alleviation of diagnostic ambiguity will help patients receive the management plan that is best associated with their diagnosis. I anticipate these tests will also supplant the invasive and difficult sentinel node dissections for patients with advanced melanoma as well, making better therapeutic decisions for PD1 and other treatments, as well.

If DiffDx and MyPath are covered tests, there is a higher probability that financial constraints do not hinder the best care for my patients with these melanocytic lesions that are difficult to appropriately classify using histopathology alone.

Thank you for your support of this policy.

The following comment was submitted to Palmetto GBA and WPS:

On behalf of the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP), we thank you for the opportunity to review and comment on the proposed MolDX policy Molecular Assays for the Diagnosis of Cutaneous Melanoma.

The AMP is an international medical and professional association representing approximately 2,500 physicians, doctoral scientists, and medical technologists who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from academic medicine, hospital-based and private clinical laboratories, the government, and the in vitro diagnostics industry.

The CAP is the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs. The CAP serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. We are submitting a joint comment letter because our organizations share the same position regarding this draft LCD.

After reviewing the proposed policy, we ask to consider the following recommendation in the final coverage policy:

The proposed LCD states that molecular assays for diagnosing cutaneous melanoma are to assist dermatopathologists in arriving at the correct diagnosis of melanoma versus non-melanoma lesions when examining skin biopsies. The LCD further states that to receive coverage the test must be ordered by a board-certified or board-eligible dermatopathologist. We are deeply concerned that such limiting criteria set a dangerous precedent which will severely limit access to necessary testing for Medicare patients. Pathologists who are board certified in anatomic pathology routinely diagnose skin nevi and melanomas and are fully qualified to determine when this test is necessary to help arrive at a correct diagnosis. We strongly urge not to limit its criterion for test ordering to dermatopathologists only but rather to expand it to include board certified anatomic pathologists.

The Summary of Evidence section of the proposed LCD references gene expression profile assays myPath^® Melanoma and DecisionDX^® DiffDX™, both proprietary tests. Consistent with our standard practice of not commenting on sole-source or proprietary tests, we will not comment further on the LCD at this time, but should additional tests qualify for coverage under this policy in the future the AMP and CAP will assess this information and may offer additional comments at that time.

Thank you again for the opportunity to review and comment on this proposed policy. As always, AMP and CAP welcome the opportunity to work collaboratively in its efforts to improve the quality of care provided to patients within its jurisdictions.

Thank you for your comment. See Response #1.

The following comment was submitted to Palmetto GBA and CGS:

We are contacting you on behalf of the Dermatology Contractor Advisory Committee (DermCAC), which represents the board-certified dermatologists in your carrier region. We appreciate the opportunity to share the dermatology perspective on the proposed Local Coverage Determination (LCD) MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma and proposed Local Coverage Article (LCA) MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma.

In principle, the DermCAC appreciates and understands the proposed coverage policy explaining the rationale on the indications, limitations, medical necessity and billing and coding instructions when a clinically indicated need has been established for ordering Gene Expression Profile (GEP), following other appropriately indicated dermatopathology testing that yield equivocal/uncertain diagnostic results.

The DermCAC broadly supports the proposed LCD and LCA in that they continue to recognize Gene Expression Profile (GEP) coverage for 23-GEP while adding the 35-GEP to the same coverage policy. As such, we believe that facilitating access to both 23-GEP and 35-GEP translates into appropriate coverage policy that benefit Medicare patients. In addition, we maintain that these tests help dermatologists and dermatopathologists differentiate between melanomas and benign lesions for difficult to diagnose cases.^1,2

Notwithstanding, the DermCAC urges to incorporate the following recommended revisions:

1. Limitations

The proposed draft LCD currently limits the ordering and use of these GEP tests to only board-certified or board-eligible dermatopathologist and fails to account for the legitimate diagnostic needs of board-certified or board-eligible dermatologists who are qualified and often choose to interpret their own histopathology slides. Imposing constraints on dermatologists from ordering indicated GEP testing risks undermining the dermatologist’s professional obligations to their patients with melanoma and comprises the timeliness and quality of care afforded to Medicare patients with melanoma. Therefore, we urge to amend this limited policy scope by recognizing and adding allowances for dermatologists to also order these tests. Excluding board-certified or board-eligible dermatologists from this coverage policy denies patient access to timely and accurate diagnostic testing.

2. Disrupting Clinicopathological Correlation

Updating this proposed coverage policy to reflect clinical reality will allow the ordering dermatologist in effectively treating their patients with melanoma. Much like the patient-physician relationship, the professional relationship that exists between dermatologists and their trusted dermatopathologist is established over time and based on regular consultation that is founded on collaboration, integrity, and reliability. For example, dermatologists rely on both clinical and anatomic pathology laboratory services, based on professional and thoughtful discussions between the ordering physician and the rendering pathologists about microscopic review and description, including differential diagnoses when appropriate. The importance and value of proper clinicopathological correlation leads treating physicians to rely on pathologists with special expertise in anatomic, clinical, and molecular pathology. These relationships and the access to high levels of expertise help physicians provide the highest quality and highest value care possible. For example, clinicopathological correlation in dermatopathology is essential for generating the most accurate histopathologic diagnosis. Thus, the immediate availability of clinical data from the patient chart, including clinical photographs, allows for instant correlation of the clinical presentation with the histology. Careful communication assists in deciding when follow up is appropriate or what, if any, additional treatment is needed. Dermatopathologists often alert the ordering and treating dermatologist to important considerations in differential diagnosis. Over time, the ability to transfer information between dermatologist and pathologist is refined, and clinicopathological correlation improves along with trust and mutual understanding.

3. Relevant Policies Clarifying Dermatology and Dermatopathology

In support of this requested correction, the DermCAC refers to the following longstanding policy adopted by the American Academy of Dermatology Association (AADA), which explains the intrinsic nexus between dermatology and dermatopathology, and the value it provides to patients with melanoma.³

In addition, we refer to long-established, applicable policy excerpted from the Clinical Laboratory Improvement Act of 1988 (CLIA) regulations published in the February 28, 1992 Federal Register [Vol. 57, No. 40, page 7179 (1) (2) (B) (3)], which recognizes the professional qualifications and value of both dermatologists and dermatopathologists:

(2) For tests in dermatopathology, meet one of the following requirements:

(i) (A) Be a doctor of medicine or doctor of osteopathy licensed to practice medicine or osteopathy in the State in which the laboratory is located and—(B) Meet one of the following requirements:

(1) Be certified in anatomic pathology by the American Board of Pathology or the American Osteopathic Board of Pathology or possess qualifications that are equivalent to those required for such certification; or (2) Be certified in dermatopathology by the American Board of Dermatology and the American Board of Pathology or possess qualifications that are equivalent to those required for such certification; or

(5) Be certified in dermatology by the American Board of Dermatology or possess qualifications that are equivalent to those required for such certification; or (ii) An individual qualified under § 493.1449(b) or paragraph (l)(2)(i) of this section may delegate to an individual who is a resident in a training program leading to certification specified in paragraphs (b) or (l)(2)(i)(B) of this section, the responsibility for examination and interpretation of dermatopathology specimens.

4. Additional Modifications Requested

Under the “Coverage Guidance Coverage Indications, Limitations, and/or Medical Necessity” section, the proposed LCD explains that “This Medicare contractor will provide limited coverage for molecular Deoxyribonucleic acid (DNA)/Ribonucleic acid (RNA) assays that aid in the diagnosis or exclusion of melanoma from a biopsy when ALL of the following clinical conditions are met:” and list seven qualifying preconditions. Specifically, the fifth bullet states:

• The patient has not been tested with the same or similar assay for the same clinical indication.

This categorical, bulleted item remains nebulous in that it does not limit this statement to a specific lesion. We are concerned that claims editing software may interpret this as—same clinical indication; same test: no coverage if it has previously been done on a given patient. The DermCAC therefore urges to clarify and correct this confusing ambiguity. Instead, a more appropriate bulleted item should read:

• The patient has not been tested with the same assay for the same clinical lesion.

5. Other Clinical Scenarios Meriting Further Consideration

As currently drafted, this proposed coverage policy raises serious concerns for patients with melanoma. For example, if the melanocytic lesion was tested three (3) years prior and currently appears to have changed, this would not be covered. Though unusual it is still conceivable that a second scenario may involve the lesion being larger in size than the test allows, which would mean that coverage would be disallowed if two areas within the same lesion were tested. A third scenario, which is imaginable, may involve the simultaneously testing of two (2) unusual pigmented macules on the face which would be disallowed due to ICD-10 issues requiring submission of the medical record.

Therefore, we recommend to consider making the above-cited recommended changes to the LCD to ensure patient access to high-quality dermatology and dermatopathology care. We appreciate the opportunity to share our concerns about this proposed LCD.

References were provided for review.

Thank you for your comment.

Please see Response #1. Additionally, we note that this policy does not restrict the ability of a qualified dermatologist or a pathologist to direct a CLIA laboratory.

Finally, in response to your comment we have replaced ‘same clinical indication’ with ‘same clinical lesion’ in the Coverage Indications section of the policy.

The following comment was submitted to CGS and WPS:

The National Comprehensive Cancer Network^® (NCCN^®) appreciates the opportunity to comment on the Proposed Local Coverage Determination (LCD) Molecular Assays for the Diagnosis of Cutaneous Melanoma as it relates to NCCN’s mission of improving and facilitating, quality, effective, equitable, and accessible cancer care. NCCN will focus our comments on areas of alignment between NCCN Guidelines^® and the proposed LCD and ways NCCN content can be used as a resource to inform coverage determinations to keep LCDs evergreen as the science evolves.

NCCN Background

As an alliance of 32 leading academic cancer centers in the United States that treat hundreds of thousands of patients with cancer annually, NCCN^® is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology^® (NCCN Guidelines^®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the United States.

NCCN Guidelines^® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. The NCCN Drugs & Biologics Compendium (NCCN Compendium^®) has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity (PLE) for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

NCCN Guidelines

NCCN develops authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Guidelines are a comprehensive set of 84 guidelines detailing the sequential management decisions and interventions across 218 algorithms that currently apply to 97 percent of cancers affecting patients in the United States. More than 1700 panel members participate in Guideline development. In 2021, there were 13 million downloads of the Guidelines across web-based and mobile applications. NCCN Guidelines are developed by multidisciplinary expert panels from NCCN Member Institutions in an evidence-based process integrated with expert consensus. The NCCN Guidelines are updated at least annually, but quite often are updated more frequently, with 215 total version updates across all guidelines in 2021.

The NCCN Guidelines are considered the standard for clinical care and policy in oncology in the United States. The Guidelines are the most thorough and most frequently updated clinical practice guidelines in any area of medicine, are the most frequently referenced clinical practice guideline in oncology, and are widely available free of charge for non-commercial use. Our Guidelines are also available through a multitude of health information technology vendors, used by payers representing more than 85% of covered lives in the United States, and form the basis for insurance coverage policy and quality evaluation.

NCCN imposes strict policies to shield the guidelines development processes from external influences. The “firewall” surrounding the NCCN Guidelines processes includes: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN’s other business development activities. The guidelines development is supported exclusively by the Member Institutions’ dues and does not accept any form of industry or other external financial support for the guidelines development program.

Guideline Adherence as a Tool to Improve Outcomes, Reduce Costs, and Keep Coverage Evergreen

Numerous independent studies have found adherence to NCCN Guidelines improves care delivery and outcomes for patients with cancer. Improved health outcomes proven through concordance with NCCN Guidelines include: improved rates of survival for colon cancer, ovarian cancer, gastric cancer, nasopharyngeal cancer, and pancreatic cancer; decreased locoregional recurrence of melanoma; and improved pain control.^1,2,3,4,5,6

Guideline adherent care has also been shown to decrease costs to both the payer and the patient. A peer-reviewed, published study by United, eviCore, and NCCN entitled “Transforming Prior Authorization to Decision Support” demonstrated mandatory adherence to NCCN Guidelines and NCCN Compendium^® using a real-time Clinical Decision Support Mechanism by United Healthcare significantly reduced total and episodic costs of care by 20% compared to trend while also reducing denials and increasing access to guideline-concordant care.⁷ A 2019 study "Guideline Discordance and Patient Cost Responsibility in Medicare Beneficiaries With Metastatic Breast Cancer" by Williams, et.al found median cost for metastatic breast cancer patients receiving guideline-discordant treatment was $7,421 versus $5,171 for those receiving guideline-concordant care.⁸ This study found an additional $1,841 in out-of-pocket cost savings for patients receiving guideline concordant care versus patients who received care that did not adhere to guidelines. These cost savings have also been found in studies evaluating the Medicare population. At this year’s ASCO annual conference, CVS Health presented two abstracts looking at total costs of care beginning with the first treatment and for the subsequent 180 days for breast and colon cancer patients in relation to adherence to NCCN Guidelines.^9,10 In both studies, there was a significant reduction in total cost of care with concordance with NCCN Guidelines. In the colon cancer study, this was most prominent and significant in the Medicare population. In the breast cancer study, significant reductions were observed across both commercially insured and Medicare patients, with the greatest reductions again seen in the Medicare population.

NCCN Biomarkers Compendium^®

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.

Nationally Recognized Guidelines as an Evergreening Mechanism for Coverage Determination

Public and commercial payers employ NCCN Guidelines within their coverage mechanisms to ensure evergreening of coverage while also reducing administrative burden. As noted above, adherence to NCCN Guidelines has been proven to improve quality across a variety of outcome measures, reduce costs to the payer and health care system, and reduce costs to the patient. The NCCN Compendium^® has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

Recognizing the value of continuously updated evidence-based guidelines, numerous Medicare Administrative Contractors have cited NCCN Guidelines within their coverage policies as a mechanism to evergreen coverage. NCCN recommends to consider the incorporation of nationally recognized guidelines, and specifically, the NCCN Biomarkers Compendium into the proposed LCD coverage indications to establish clinical utility. This would ensure the LCD stays evergreen while also significantly reducing administrative burden.

NCCN Guideline Recommendations of Relevance to the Proposed LCD

Within the proposed LCD, it proposes to cover molecular Deoxyribonucleic acid (DNA)/Ribonucleic acid (RNA) assays that aid in the diagnosis or exclusion of melanoma from a biopsy when:

• “The test is ordered by a board-certified or board-eligible dermatopathologist
• The specimen is a primary (non-metastatic, non-re-excision specimen) cutaneous melanocytic neoplasm for which the diagnosis is equivocal/uncertain (i.e., clear distinction between benign or malignant cannot be achieved using clinical and/or histopathological features alone) despite the performance of standard-of-care test procedures and relevant ancillary tests (i.e., immunohistochemical stains)
• The specimen includes an area representative of the lesion or portion of the lesion that is suspicious for malignancy
• The patient may be subjected to additional intervention, such as re-excision and/or sentinel lymph node biopsy, as a result of the diagnostic uncertainty
• The patient has not been tested with the same or similar assay for the same clinical indication
• The test is validated for use in the intended-use population and is performed according to its stated intended-use
• The test demonstrates Analytical and Clinical Validity (AV and CV) and Clinical Utility (CU) and undergoes a technical assessment (TA) by MolDX^® to demonstrate compliance of the service with this policy”

NCCN agrees that these tests should be covered in the Cutaneous Melanoma disease setting for histologically equivocal lesions. NCCN would also like to offer the NCCN Biomarkers Compendium as a resource to establish clinical utility within the coverage language as a centralized and comprehensive database of biomarkers offering clinical utility for practice.

NCCN appreciates the reference to NCCN Guidelines within the Analysis of Evidence. As referenced, NCCN Guidelines for Melanoma: Cutaneous state that

"Melanocytic neoplasms of uncertain biologic potential present a unique challenge to pathologists and treating clinicians. Ancillary tests to differentiate benign from malignant melanocytic neoplasms include immunohistochemistry (IHC) and molecular testing via comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), gene expression profiling (GEP), single-nucleotide polymorphism (SNP) array, and next-generation sequencing (NGS). These tests may facilitate a more definitive diagnosis and guide therapy in cases that are diagnostically uncertain or controversial by histopathology. Ancillary tests should be used as adjuncts to clinical and expert dermatopathologic examination and therefore be interpreted within the context of these findings."

NCCN would like to respectfully note that the Proposed LCD cites an outdated version of the guidelines which are frequently updated. The current NCCN Guidelines for Melanoma: Cutaneous are on Version 3 of 2022 and the most up to date version of our guidelines can always be found on our website at NCCN.org.

NCCN appreciates the opportunity to comment on the Proposed Local Coverage Determination Molecular Assays for the Diagnosis of Cutaneous Melanoma. NCCN is happy to serve as a resource and looks forward to working together to ensure Medicare beneficiary access to high-quality cancer care.

References were provided for review.

Thank you for your support of this policy.

Our reference to the relevant NCCN guideline has been updated to reflect the latest version.

The following comment was submitted to WPS:

As a practicing dermatologist, it is extremely difficult when I receive a pathologic diagnosis report that is ambiguous in relation to the malignant potential of a melanocytic, or pigmented lesion (that is, one that is suspicious for melanoma). In most scenarios like this, I take an over-conservative approach and will re-excise the lesion if the pathology report is inconclusive, or states a diagnosis that suggests uncertainty in malignant potential for melanoma. Though these are legitimate pathologic diagnoses, I am left with the responsibility of correlating what I see clinically, regarding the patient‘s lesion with the pathology report. As the treating clinician, I am responsible for determining the appropriate management plan for these patients. Furthermore, this can create a challenging conversation with patients, some of whom may easily accept this conservative approach, yet many don’t want a re-excision based on uncertain information. It is disappointing for a patient to hear that another, potentially painful and costly, procedure is recommended just because we “don’t really know if it’s cancer” or the patient “might have a melanoma.” Also, and even more importantly, the consequences of misdiagnosing a melanoma as benign could have severe consequences for the patient and this scenario often incurs huge costs.

The DiffDx test, has spared patients from a surgical intervention (re-excision) when it is not needed. This is similar to previous experience with the myPath Melanoma diagnostic test, for which results in a small cohort were published recently showing no evidence of recurrence during long term follow up in patients receiving a benign result who did not receive re-excision (Tschen, Cutis, 2021).

A definitive malignant result also gives more diagnostic confidence and makes the conversation easier with the patient that the procedure is truly necessary and is frequently curative (especially in early-stage tumors).

It is important to me that patients have access to this test, and I support the positive coverage article for these tests. Moreover, as the treatment plan for my patients is, ultimately, my responsibility and can be made easier by this test, it is important that I, and all dermatologists, retain the ability to order this test for appropriate patients.

Thank you for your comment. See Response #1.

The following comment was submitted to Noridian:

I am writing in support of the Castle Gene expression profile (GEP) tests to aid in the diagnosis of lesions with ambiguous histopathological findings that are difficult to diagnose without additional ancillary studies. These ancillary diagnostic tools have been helpful in adding confidence to my diagnoses, and ultimately, arrival at the correct diagnosis for the patients whose biopsies I interpret. I occasionally encounter a melanocytic lesion with features that are concerning but I am uncertain as to whether those concerns should constitute a melanoma diagnosis and I remain uncertain about the associated re-excision and frequent follow-up recommendations required for these patients.

Comparable to the myPath Melanoma test (23 genes), the DiffDx Melanoma test (35 genes) has proven to be accurate in distinguishing between benign and malignant lesions. I am comfortable using diagnostic ancillary GEP testing in the best interest of my patients based on the multiple publications demonstrating clinical utility that warrants inclusion as a covered test in addition to the myPath Melanoma test. A benign diagnostic GEP decreases the clinical burden from these equivocal melanocytic lesions, by influencing treatment plans to reduce excision and follow-up visits. A malignant diagnostic GEP result influences me to use more caution with the lesion and even amend or addend my final pathology report to elevate to a definitive melanoma diagnosis. While I am a board-certified dermatopathologist there are certainly situations where a board-certified pathologist could appropriately interpret a challenging melanocytic lesion and identify patients for whom the use of diagnostic ancillary GEP testing would be appropriate. All in all, my experience with diagnostic GEP tests has been a positive one, and I support Medicare coverage of these important clinical tools.

Thank you for your comment. See Response #1.

The following comment was submitted to Noridian:

I strongly support the new draft LCD for Molecular Assays for the Diagnosis of Melanoma. Both myPath Melanoma and DecisionDx DiffDx-Melanoma are diagnostic ancillary tests that are covered under the draft policy and both tests are supported by strong evidence that demonstrates the clinical validity and clinical utility of these tests to provide diagnostic clarity for melanocytic lesions with equivalent histopathology and that cannot be ruled-out as malignant neoplasms. These lesions pose tricky clinical scenarios for pathologists and dermatologists alike and often result in over management of non-malignant lesions; when in doubt, the most common course of action is to re-excise the lesion. In these cases, there is a well-evidenced need for additional objective ancillary diagnostic tools.

Diagnostic GEP tests have been clinically available for 9 years and are routinely used in practice. The robust data and widespread use have led to inclusion in clinical practice recommendations by multiple major guideline committees, including the National Comprehensive Cancer Network (NCCN) and American Academy of Dermatology (AAD) cutaneous melanoma guidelines, as well as the American Society of Dermatopathology Appropriate Use Criteria (ASDP AUC) committee. The NCCN and AAD guidelines recognize the challenge that pathologists face with interpretation of ambiguous melanocytic lesions and notes that ancillary testing can aid in differentiating benign from malignant lesions to inform definitive diagnoses; diagnostic ancillary testing in these guidelines include GEP testing along with other modalities such as FISH and CGH. The ASDP AUC takes a slightly different approach and designated 6 key clinical scenarios as “Majority Usually Appropriate” for GEP testing (designated as qRT-PCR); for example, one such scenario states that GEP is majority usually appropriate when, “Distinction of nevus from primary melanoma in an adult patient when the morphologic findings are ambiguous by light microscopic parameters.” (Fung et al. JCP. 2021). The inclusion of GEP testing alongside other ancillary diagnostic modalities such as FISH and CGH speaks to the strong evidence that these molecular tests have the ability to complement the work that pathologists do when we interpret slides using routine histology. The high level of accuracy from published studies coupled with the objective result of GEP testing enables myPath and DiffDx to be clinically useful tools for ambiguous or equivocal melanocytic neoplasms. As a general rule, pathologists and dermatopathologists do not turn to these guidelines and AUC as a strict prescription that must be filled exactly, but rather as instructive advice to consider along with specific patient clinical factors prior to ordering ancillary studies. The discussion of GEP testing stems from the strong supporting data and the fact that many of my colleagues are also using this GEP approach to inform their reporting of these challenging neoplasms.

I am in an interesting role as both a clinician and a pathologist and so I am very well equipped to recognize the scenarios when GEP testing is appropriate for my patients. I do, however, believe that you do not have to share my exact training background to also recognize these “clinical moments.” I believe that any pathologist, dermatologist or dermatopathologist is trained well enough to designate a lesion as appropriate for testing (following the guidance of the LCD). The training of all members of this particular group of physicians includes significant experience interpreting slides, interpreting pathology reports and planning treatment pathways for patients with melanocytic lesions. To ensure the best patient care and consistency across providers, I strongly support coverage of GEP testing in the diagnosis of melanocytic lesions so that physicians treating patients with these lesions – pathologists, dermatopathologists and dermatologist - can use all order MyPath and DiffDx when medically appropriate.

Thank you for your comment. See Response #1.