Medical Policy: 02.04.72 

Original Effective Date: May 2018 

Reviewed: May 2021 

Revised: May 2020 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Gene expression profiling measures the activity of thousands of genes simultaneously and creates a snapshot of cellular function. Data for gene expression profiles are generated by several molecular technologies including DNA microarrays that measures activity relative to previously identified genes and RNA-Seq that directly sequences and quantifies RNA molecules. Clinical applications of gene expression profiling include disease diagnosis, disease classification, prediction of drug response, and prognosis.

 

Melanoma is a cancer that begins in the melanocytes. Other names for this cancer include malignant melanoma and cutaneous melanoma. Most melanoma cells still make melanin, so melanoma tumors are usually brown or black. But some melanomas do not make melanin and can appear pink, tan or even white. Melanomas can develop anywhere on the skin, but they are more likely to start on the trunk (chest and back) in men and on the legs in women. The neck and face are other common sites.

 

Risk factors for melanoma include skin type, personal history of prior melanoma, multiple clinically atypical moles or dysplastic nevi, a positive family history of melanoma, and rarely, inherited genetic mutations. Genetic counseling could be considered for individuals with a strong family history of invasive melanoma with or without pancreatic cancer. In addition to genetic factors, environmental factors including excess sun exposure and UV-based artificial tanning contribute to the development of melanoma. The interaction between genetic susceptibility and environmental exposure is illustrated in individuals with an inability to tan and fair skin that sunburns easily who have a greater risk of developing melanoma. However, melanoma can occur in any ethnic group and, also in areas of the body without substantial sun exposure.

 

As with nearly all malignancies, the outcome of melanoma depends on the stage at presentation. In the United States, it is estimated that 84% of patients with melanoma initially present with localized disease, 9% with regional disease, and 4% with distant metastatic disease. In general, the prognosis is excellent for patients who present with localized disease and primary tumors 1.0 mm or less in thickness, with 5-year survival achieved in more than 90% of patients. For patients with localized melanomas more than 1.0 mm in thickness, survival rates range from 50% to 90% depending on tumor thickness, ulceration and miotic rate. The likelihood of regional nodal involvement increases with increasing tumor thickness, as well as the presence of ulceration and miotic rate. When regional nodes are involved, survival rates are roughly halved.

 

There is increasing appreciation of the variations in specific genetic alternations among distinct clinical subtypes of melanoma. Currently described clinical subtypes of cutaneous melanoma are: non-chronic sun damage (non-CSD); melanoma on skin without chronic sun-induced damage; CSD: melanomas on skin with chronic sun-induced damage signified by the presence of marked elastosis; and acral; melanomas of the soles, palms, or sub-ungual sites.

 

Different subtypes of melanoma have been found to have very different genetic profiles, some of which have different therapeutic implications. In an analysis of 102 primary melanomas, the non-CSD subtype was found to have the highest proportion of BRAF mutations (56%) compared to CSD, acral and mucosal types (6%, 21% and 3% respectively). On the other hand, incidence of KIT aberrations was 28%, 36%, and 39% in CSD, acral and mucosal subtypes, respectively, but 0% in non-CSD subtypes. NRAS mutations were found in 5% to 20% of the subtypes.

 

Primary care physicians evaluate suspicious pigmented lesions to determine who should be referred to dermatology considering both a patient’s risk factors for melanoma as well as visual examination of the lesion. The visual examination assesses whether the lesion has features suggestive of melanoma. Criteria for features suggestive of melanoma have been developed. One checklist is the ABCDE checklist:

  • Asymmetry
  • Border irregularities
  • Color variegation
  • Diameter ≥ 6 mm
  • Evolution

 

Standard of care for the assessment of clinically suspicious pigmented skin lesions is surgical biopsy and subsequent histopathology. However, histopathology is believed to have inherent limitations. Some lesions that are likely to be true melanomas based on clinical behavior do not meet the complete set of histologic criteria to establish a melanoma diagnosis. There is also considerable interrater variability with visual image and pattern recognition of skin lesions. In an effort to improve patient survival, a number of novel noninvasive techniques have been developed to classify pigmented skin lesions at an earlier stage.

 

Commercially Available Gene Expression Profiling (GEP)

  • DecisionDx Melanoma (Castle Biosciences): DecisionDx- Melanoma is a gene expression profile (GEP) test that was designed to identify the risk of recurrence or metastasis in Stage I, II and III melanoma based on the biological profile of 31 genes (28 prognostic genes and 3 control genes) within a patient’s tumor tissue.

 

The test is used to:

  • Inform patients individual treatment plan; and
  • Whether to perform the SLNB surgical procedure; and
  • Determining the appropriate level of follow-up, imaging and referrals.

 

DecisionDx-Melanoma is performed on formalin-fixed, paraffin embedded (FFPE) primary tumor tissue from either a biopsy or excision.

  • myPath Melanoma (Myriad Genetics, Inc): Per the manufacturers website myPath melanoma test is used as an adjunct to histopathology when the distinction between a benign nevus and a malignant melanoma cannot be made by histopathology alone. The test measures 23 genes for which expression patterns differ between malignant melanoma and benign nevi. These genes are involved in cell differentiation, cell signaling, and immune response signaling. The genes included in myPath Melanoma testing are:
    • PRAMER a single gene involved in cell differentiation
    • S100A7, S100A8, S100A9, S100A12 and P13, a group of genes involved in multiple cell signaling pathways
    • CCL5, CD38, CXCL10, CXCL9, IRF1, LCP2, PTPRC and SELL involved in tumor immune response signaling
    • Nine housekeeping gene that are measured to normalize RNA expression for analysis CLTC, MRFAPI, PPP2CA, PSMA1, RPL13A, RPL8, RPS29, SLC25A3 and TXNLI

 

An algorithm is applied that combines measurements of gene expression, assigns a weight to each gene component and establishes a threshold value. The result is a single numerical score that classifies a melanocytic lesion as “likely benign”, “likely malignant” or “indeterminant.”

  • Pigmented Lesion Assay (PLA) (DermTech): Per the manufacturers website the Pigmented Lesion Assay (PLA) is a non-invasive gene expression tests to identity subtle malignancy changes thereby enhancing early melanoma detection. Using adhesive patches, skin tissue is sampled across an entire lesion. RNA is extracted from the collected skin cells and RT-PCR is used to assess the expression analysis of two genes, PRAME and LINC00518 allows DermTech to distinguish between melanoma and non-melanoma. DermTech’s PLA can aid in the physician’s biopsy decision. The test is intended on pigmented lesion suspicious for melanoma that the physical would like additional information prior to surgical biopsy.
    • PLA Uses Include:
      • Lesion that meet one or more ABCDE criteria
      • Lesion being followed for change
      • Lesions in sensitive areas
      • Lesion on patients with potential risks to surgical biopsy including patients who are anti-coagulated, at risk for infection, and at risk for poor wound healing or elevated abnormal scarring
      • Lesions on patients what are needle averse or biopsy fatigued
    • PLA negative lesions are generally monitored
    • PLA positive lesions are generally surgically biopsied to establish diagnosis

 

Gene Expression Profiling to Guide Initial Biopsy Decisions

Clinical Content and Test Purpose

The purpose of GEP in patients who have suspicious pigmented lesions being considered for biopsy is to inform a decision about whether to biopsy.

 

Patients

The relevant population of interest is patients with suspicious pigmented lesions being considered for referral for biopsy, specifically those lesions meeting one or more ABCDE criteria.

 

Interventions

The test being considered is the DermTech Pigmented Lesion Assay (PLA).

 

Comparators

After a referral from primary care to dermatology settings, dermatologists use visual examination as well as tools such as dermoscopy to make decisions regarding biopsy of suspicious lesions. A meta-analysis of 9 studies (8487 lesions with 375 melanomas) compared dermoscopy with visual examination alone for the diagnosis of melanoma; it reported that, for clinicians with training in dermoscopy, adding dermoscopy to visual examination increased the sensitivity from 71% to 90%. The specificity numerically increased from 80% to 90%, but the difference was not statistically significant.19, Although dermoscopy is noninvasive and may aid in decision making regarding biopsy, it is only used by approximately 50% to 80% of dermatologists in the U. S. due to lack of training, interest, or time required for the examination. 

 

The reference standard for diagnosis of melanoma is histopathology.

 

Outcomes

The beneficial outcomes of a true-positive test result are appropriate biopsy and diagnosis of melanoma. The beneficial outcome of a true-negative test result is potentially avoiding unnecessary biopsy.

 

The harmful outcome of a false-positive result is having an unnecessary biopsy. The harmful outcome of a false-negative result is potential delay in diagnosis and treatment.

 

The timeframe of interest for calculating performance characteristics is time to biopsy result. Patients who forgo biopsy based on test results could miss or delay diagnosis of cancer. Longer follow-up would be necessary to determine the effects on overall survival.

 

Clinically Valid 

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Determining whether a test can guide biopsy decisions is not based only on its sensitivity and specificity, but also on how the accuracy of the existing pathway for making biopsy decisions is changed by the test. Therefore, the appropriate design for evaluating performance characteristics depends on the role of the new test in the pathway for making biopsy decisions. New tests may be used as replacements for existing tests, to triage who proceeds for existing tests or add-on tests after existing tests. For replacement tests, the diagnostic accuracy of both tests should be concurrently compared, preferably in a paired design (ie, patients receive both tests), and all patients receive the reference standard. For a triage test, a paired design is also needed, with the reference standard being performed preferably on all patients but at least for all discordant results. For an add-on test, the included patients can be limited to those who were negative after existing tests with verification of the reference standard in patients who are positive on the new test. 

 

Multiple high-quality studies are needed to establish the clinical validity of a test. The PLA test has one clinical validity study with many methodologic and reporting limitations. Therefore, performance characteristics are not well-characterized. Also, the test has not been compared with dermoscopy, another tool frequently used to make biopsy decisions.

 

Clinically Useful

A test is clinically useful if the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility through a chain of evidence.

 

There is no direct evidence of clinical utility. A chain of evidence for clinical utility cannot be constructed due to lack of robust evidence of clinical validity.

 

Summary of Evidence

The evidence is currently insufficient to support the use of the Pigmented Lesion Assay (PLA) to accurately differentiate melanoma lesions from nonmelanoma lesions. Study limitations include the small study populations, lack of generalizability of study results to more diverse melanoma subtypes, lack of blinding primary readers, as well as early reports of insufficient RNA obtained from study samples. Independent prospective clinical utility studies are currently lacking, and it is unclear if the use of PLA versus conventional diagnostic tools lead to changes in health care decision making and improvements in patient survival. Current practice standards and clinical management guidelines do not include the use of gene expression profiling for suspicious pigmented lesions. Gene expression profiling testing for melanoma is not recommended outside of clinical trials. Additional well-designed randomized controlled trials (RCTs) in larger patient populations with diverse melanoma subtypes are needed to add to the evidence based and corroborate the early study findings.  The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Gene Expression Profiling for Diagnosing Lesions with Indeterminate Histopathology

Clinical Context and Test Purpose 

The purpose of GEP in patients whose melanocytic lesion is indeterminate after histopathology is to aid in the diagnosis of melanoma and decisions regarding treatment and surveillance.

 

Patients

The relevant population of interest is patients whose melanocytic lesion is indeterminate based on clinical and histopathologic features.

 

Interventions

The test being considered is the Myriad myPath Melanoma test.

 

Comparators

The reference standard for diagnosis of melanoma is histopathology. However, in cases of indeterminate histopathology, long-term follow-up is needed to evaluate the clinical outcome, specifically metastasis.

 

Comparative genomic hybridization and FISH are also used to diagnosis indeterminate lesions.

 

Outcomes

The beneficial outcomes of a true-positive test result are a diagnosis of melanoma and corresponding appropriate treatment and surveillance. The beneficial outcome of a true- negative test result is avoiding unnecessary surgery.

 

The harmful outcome of a false-positive result is having an unnecessary surgery and surveillance. The harmful outcome of a false-negative result is a delay in diagnosis and treatment.

 

The National Comprehensive Cancer Network guidelines state that even in the presence of node metastasis, indeterminate neoplasms can demonstrate benign biologic behavior, making it difficult to define a fully malignant lesion and also states that events in the group of indeterminate lesions tend to occur late. Therefore, the guidelines suggest that long-term follow-up is necessary to validate a test for this purpose.

 

Recurrence and metastases can occur many years after treatment of melanoma, at least five years of event-free follow-up is required to confirm negative tests. The event of interest is metastasis.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Multiple high-quality studies are needed to establish the clinical validity of a test. The myPath test has one clinical validity study including long-term follow-up for metastasis as the reference standard. However, it is not clear whether the study population included lesions that were indeterminate following histopathology and the study had other methodologic and reporting limitations. Therefore, performance characteristics are not well-characterized.

 

Clinically Useful

A test is clinically useful if the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility through a chain of evidence.

 

Two decision-impact studies assessed the potential impact of myPath on physicians’ treatment decisions in patients with diagnostically challenging lesions. Given the lack of health outcomes, it is not known whether any treatment changes were clinically appropriate.

 

There is no direct evidence of clinical utility. A chain of evidence for clinical utility cannot be constructed due to lack of robust evidence of clinical validity.

 

Summary of Evidence 

For individuals who have melanocytic lesions with indeterminate histopathologic features who receive gene expression profiling (GEP) with the myPath Melanoma test added to histopathology to aid in diagnosis of melanoma, the evidence includes retrospective and prospective observational studies. No direct evidence of clinical utility was identified. Current practice standards and clinical management guidelines do not include the use of gene expression profiling for melanocytic lesions with indeterminate histopathologic features. Gene expression profiling testing for melanoma is not recommended outside of clinical trials. Additional well-designed randomized controlled trials (RCTs) are needed to compare diagnosis and health outcomes of those evaluated with histopathology alone and those with myPath Melanoma as an adjunct to histopathology. The evidence is insufficient to determine the effects of the technology on net health outcomes.  

 

Gene Expression Profiling to Guide Management Decisions in Melanoma

Clinical Context and Test Purpose 

The purpose of GEP in patients with melanoma is to identify low and high-risk patients classified as stage I or II according to the AJCC criteria. Current guidelines do not recommend adjuvant therapy for AJCC stage I or II patients following surgery. Patients initially staged as I or II who have positive lymph nodes following sentinel lymph node biopsy (SLNB) are then eligible to be treated with adjuvant therapy as stage III patients.

 

Patients 

To select patients for adjuvant therapy and/or enhanced surveillance, the relevant population of interest are patients with AJCC stage I/II cutaneous melanoma.

 

To select patients who can avoid SLNB, the relevant population of interest are patients with AJCC stage I or II cutaneous melanoma who are being considered for SLNB. The manufacturer website says the test is for “eligible patients 55 years of age and older who have tumors less than 2 mm deep (T1-T2”.

 

Interventions 

The test being considered is the Castle Biosciences DecisionDx-Melanoma test.

 

Comparators 

Treatment and surveillance recommendations are based on AJCC staging. SLNB may be used to get more definitive information about the status of the regional nodes compared with a physical examination. The American Society of Clinical Oncology and National Comprehensive Cancer Network have similar but not identical recommendations regarding which patients should undergo SLNB based on thickness and other high-risk features.

 

SLNB has a low rate of complications.

 

Online tools are available to predict prognosis based on the AJCC guidelines.

 

Outcomes

Regarding selecting patients for adjuvant therapy and/or enhanced surveillance:
If the test is used to 'rule-in' AJCC stage I or IIA patients, a negative DecisionDx (class 1) test result would not change outcomes. Per guidelines, the patients would not receive adjuvant therapy or enhanced surveillance, just as without the DecisionDx test. A positive DecisionDx (class 2) test result would indicate that a patient might benefit from adjuvant therapy or enhanced surveillance. Therefore, the potential beneficial outcomes of a true positive result are additional treatment and surveillance and potentially prolonged survival. The potential harmful outcomes of a false-positive result are unnecessary adverse effects and burdens of adjuvant therapy and enhanced surveillance.

 

If the test is used to 'rule-out AJCC stage IIB - III patients, a negative DecisionDx (class 1) test result would indicate that a patient might be able to avoid enhanced surveillance. Therefore, the potential beneficial outcomes of a true negative result are avoiding burdens of surveillance and potential overtreatment. The potential harmful outcomes of a false-negative result are potentially prolonged survival with enhanced surveillance.

 

Regarding selecting patients who can avoid SLNB:

 

For patients meeting guideline-recommended criteria for SLNB, a positive DecisionDx (class 2) test result would not change outcomes. The patients would proceed to SLNB, as they would have without the DecisionDx test, and treatment and imaging decisions would depend on SLNB results. A negative DecisionDx (class 1) test result in patients 55 years of age and older who have tumors less than 2 mm deep (T1-T2) would indicate that a patient could avoid an SLNB. Therefore, the potential beneficial outcomes of a true-negative result are avoidance of an SLNB and related adverse effects and burdens. The potential harmful outcomes of a false-negative result are reduced time to recurrence due to not identifying node-positive patients that would be eligible for beneficial adjuvant treatment and potentially reduced survival.

 

Summary of Evidence

Treatment plans for cutaneous melanoma are based upon individual risk of recurrence. Decisions made post-diagnosis include recommendation for sentinel lymph node biopsy (SNLB), followed by management decisions such as surveillance, frequency of follow-up, and interdisciplinary consultations including possible adjuvant therapy use. These have traditionally been guided by clinicopathologic factors, but discordance exists, as melanoma deaths have occurred in patients diagnosed with disease considered to be early stage by such factors, including a negative SLNB. Gene expression profiling (GEP) testing to include DecisonDx-Melanoma has been proposed to optimize patient care as a predictor of risk of recurrence, distant metastasis and death in stage I-III melanoma and assist in guiding SLNB decisions. While studies have shown some promise in certain clinical situations, current practice standards and clinical management guidelines at this time do not indicate the use of gene expression profiling for the management of cutaneous melanoma. The National Society of Cutaneous Medicine in 2019 published appropriate use criteria for the  integration of diagnostic and prognostic gene expression profile assays for management of cutaneous melanoma. The criteria was developed with "unrestricted educational grants from related companies involved with these technologies". The majority of the panel members were consultants or advisors for Castle BioSciences or Myriad. The criteria were consensus-based using a modified Delphi approach. The 2019 guideline by the American Academy of Dermatology (AAD) regarding care for the management of primary cutaneous melanoma states the following: “There is insufficient evidence to recommend routine molecular profiling assessment for baseline prognostication. Evidence is lacking that molecular classification should be used to alter patient management outside of current guidelines (e.g., NCCN and AAD). The criteria for and the utility of prognostic molecular testing, including GEP, in aiding clinical decision making (e.g., SLNB eligibility, surveillance intensity, and/or therapeutic choice) needs to be evaluated in the context of clinical study or trial.” The National Comprehensive Cancer Network (NCCN) Cutaneous Melanoma Version 2.2021 guideline recommendation states the following regarding molecular prognostic testing: “Commercially available GEP tests are marketed as being able to classify cutaneous melanoma into separate categories based on risk of metastasis. However, it remains unclear whether these tests provide clinically actionable prognostic information when used in addition to or in comparison with known clinicopathologic factors or multivariable nomograms that incorporate patient sex, age, tumor location and thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and SLNB status. Furthermore, the impact of these tests on treatment outcomes or follow-up schedules has not been established.”  Additional well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of gene expression profiling of cutaneous melanoma compared with traditional clinical factors to guide medical management and improve clinical outcomes to include established follow-up schedules. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Practice Guideline and Position Statements

National Comprehensive Cancer Network (NCCN)

Cutaneous Melanoma Version 2.2021
Principles of Molecular Testing:

Emerging Molecular Technologies for Cutaneous Melanoma Diagnosis and Prognostication

Diagnostic Testing for Indeterminate Melanocytic Neoplasms Following Histopathology 

    • Melanocytic neoplasm of uncertain biologic potential present a unique challenge to pathologists and treating clinicians. Ancillary tests to differentiate benign from malignant melanocytic neoplasms include immunohistochemistry (IHC0 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 (NGS0. These tests may facilitate interpretation of 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.

 

Prognostic Testing

      • Commercially available GEP tests are marketed as being able to classify cutaneous melanoma into separate categories based on risk of metastasis. However, it remains unclear whether these tests provide clinically actionable prognostic information when used in addition to or in comparison with known clinicopathologic factors or multivariable nomograms that incorporate patient sex, age, tumor location and thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and SLNB status. Furthermore, the impact of these tests on treatment outcomes or follow-up schedules has not been established.
      • Various (mostly retrospective) studies of prognostic GEP testing suggest its role as an independent predictor of worse outcome, though not superior to Breslow thickness or SNL status. It remains unclear whether this GEP profile is reliably predictive of outcome across the risk spectrum of melanoma. Prospective validation studies (as have been performed in breast cancer) are required to more accurately define the clinical utility of molecular testing prior to widespread implementation of GEP for prognostication of cutaneous melanoma, and in particular to determine its role in guideline surveillance imaging, SLNB, and adjuvant treatment decisions. Existing and emerging GEP platforms and other prognostic techniques should also be compared with optimized contemporary multivariable phenotypic models (i.e., the AJCC 8th edition melanoma risk calculator/prognostic tool in development).

 

Somatic Mutation Testing

      • A number of somatic genetic alterations have been identified in cutaneous melanoma, a few of which are targetable driver mutations that have proven useful to guide treatment decisions and/or clinical trial eligibility.

 

Biopsy: NCCN Recommendations

Patients presenting with suspicious pigmented lesions optimally should undergo an excisional biopsy (elliptical, punch, or saucerization), preferably with 1to 3 mm negative margins. The orientation of the excisional biopsy should always be planned with definitive treatment in mind (e.g., a longitudinal orientation in the extremities parallel to lymphactics). With the increasing use of lymphatic mapping and sentinel node biopsy, biopsies should also be planned so as not to interfere with the procedure. In this regard, wider margins for the initial diagnostic procedure should be avoided.

 

Excisional biopsy may be inappropriate for certain sites (including the face, palmar surface of the hand, sole of the foot, ear, distal digit or sublingual lesion) or for very large lesions. In these instances a full-thickness incisional or punch biopsy of the clinically thickest portion of the lesion is an acceptable option. These procedures should provider accurate primary tumor microstaging, without interfering with definitive local therapy. If the initial biopsy is inadequate to make a diagnosis or accurately microstage the tumor (based on evaluation by a dermatopathologist) for treatment planning, re-biopsy with narrow margin excision should be considered. Shave biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness. However, it is acceptable in a low suspicion setting.

 

Molecular Characterization of the Primary Tumor

Gene expression profiling for melanoma could be an enormously valuable contribution to understanding the biopsy of the disease. However, the difficulty of embracing gene expression profiling as an independent predictor of outcome is illustrated by the inconsistency of results across studies aimed at defining the most predictive gene sets for melanoma. Comparison of the gene signatures identified in these studies show minimal overlap in specific genes thought to be predictive of outcome. The identification and validation of a prognostic gene expression profile is a complicated multi-step and often multi-step process, and there are many ways in which specifics of study design and methodology can impact the end result. The lack of overlap in gene signatures identified as prognostic for melanoma is likely due to substantial differences in study design and methodology. Efforts to develop gene expression profiling prognostic assays for other types of cancer have also resulted in limited for partial overlap in the “gene signature” identified by different studies.

 

American Academy of Dermatology

In 2019, the American Academy of Dermatology updated their 2011 guideline regarding care for the management of primary cutaneous melanoma which states: Recommendations for baseline and surveillance studies and follow-up:

      • Baseline radiologic imaging and laboratory studies are not recommended for asymptomatic patients with newly diagnosed stage 0-II primary CM.
      • Radiologic imaging and laboratory studies for CM at baseline should be performed only to evaluate specific signs or symptoms of synchronous metastasis (regional nodal or distant).
      • The use of LN ultrasound is encouraged at baseline or in surveillance in the setting of an equivocal LN on physical examination, and for surveillance when
        • The patient meets criteria for SLNB but does not undergo the procedure;
        • SLNB is not possible or not technically successful (eg, because of failure of lymphoscintigraphic dye migration and inability to identify a draining SLN); or
        • CLND is not performed in the setting of a positive SLNB; and
        • When radiology expertise in the use of nodal ultrasound surveillance for CM is available.
      • Regular clinical follow-up is recommended as the most important means of detecting CM recurrence. Findings from the history (review of systems) and physical examination should direct the need for further radiologic or laboratory studies to detect local, regional, and distant metastatic disease.
      • Collaboration with medical oncology is recommended for patients with high-risk CM (stage IIB and IIC) and those with a positive SLNB result for discussion of surveillance imaging and clinical comanagement.
      • Surveillance follow-up schedule and consideration of radiographic imaging varies according to the risk of disease recurrence (as determined by stage of disease and other factors) and risk of new primary CM (determined by mole pattern, presence of atypical nevi, and family history). Laboratory studies are not recommended for surveillance of asymptomatic patients with CM.
      • Patient education on self-examination of the skin and LN for the detection of recurrent disease or new primary CM is recommended.
      • There is insufficient evidence to recommend routine molecular profiling assessment for baseline prognostication. Evidence is lacking that molecular classification should be used to alter patient management outside of current guidelines (e.g., NCCN and AAD). The criteria for and the utility of prognostic molecular testing, including GEP, in aiding clinical decision making (e.g., SLNB eligibility, surveillance intensity, and/or therapeutic choice) needs to be evaluated in the context of clinical study or trial.

 

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory developed tests must meet the general regulatory standards of the clinical laboratory Improvement Amendments. The Pigmented Lesion Assay, myPath Melanoma, and DecisionDX-Melanoma are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

 

Prior Approval:

Not applicable.

 

Policy:

See also the following medical policies:

  • 02.04.53 Gene Expression Profiling for Uveal Melanoma
  • 02.04.41 Genetic Testing for Familial Cutaneous Malignant Melanoma

 

Gene expression profiling (GEP) testing in the evaluation of patients with suspicious pigmented lesions, including but not limited to Pigmented Lesion Assay (PLA) is considered investigational. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Gene expression profiling (GEP) testing in the evaluation of patients with melanocytic lesions with indeterminate histopathologic features, including but not limited to myPath Melanoma test is considered investigational. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Gene expression profiling (GEP) testing in the evaluation of patient with cutaneous melanoma as a predictor of risk of recurrence, distant metastasis and death in stage I-III melanoma and assist in guiding SLNB decisions, including but not limited to DecisionDx-Melanoma is considered investigational. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81479 Unlisted molecular pathology procedure
  • 81529 Oncology (cutaneous melanoma), mRNA, gene expression profiling by real-time RT-PCR of 31 genes (28 content and 3 housekeeping), utilizing formalin-fixed paraffin-embeded tissue, algorithm reported a recurrence risk, including likelihood of sentinel lymph node metastasis (DecisionDX Melanoma)
  • 81599 Unlisted multianalyte assay with algorithmic analysis procedure
  • 84999 Unlisted chemistry procedure
  • 0089U Oncology (melanoma), gene expression profiling by RT-PCR, PRAME and LINC00518, superficial collection using adhesive patch(es) (Pigmented Lesion Assay (PLA) DermTech)
  • 0090U Oncology (cutaneous melanoma), mRNA gene expression profiling by RT-PCR of 23 genes (14 content and 9 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a categorical result (ie, benign, indeterminate, malignant) (myPath Melanoma)

 

Selected References:

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. Jan 2018;68(1):7-30. PMID 29313949
  • Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. Sep 2005;41(14):2040-2059. PMID 16125929 
  • Caini S, Gandini S, Sera F, et al. Meta-analysis of risk factors for cutaneous melanoma according to anatomical site and clinico-pathological variant. Eur J Cancer. Nov 2009;45(17):3054-3063. PMID 19545997 
  • Goldstein AM, Chan M, Harland M, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. Feb 2007;44(2):99-106. PMID 16905682 
  • Wendt J, Rauscher S, Burgstaller-Muehlbacher S, et al. Human determinants and the role of melanocortin-1 receptor variants in melanoma risk independent of UV radiation exposure. JAMA Dermatol. Jul 1 2016;152(7):776-782. PMID 27050141 
  • Wiesner T, Obenauf AC, Murali R, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. Aug 28 2011;43(10):1018-1021. PMID 21874003 
  • Chen T, Fallah M, Forsti A, et al. Risk of next melanoma in patients with familial and sporadic melanoma by number of previous melanomas. JAMA Dermatol. Jun 2015;151(6):607-615. PMID 25671687 
  • Jiang AJ, Rambhatla PV, Eide MJ. Socioeconomic and lifestyle factors and melanoma: a systematic review. Br J Dermatol. Apr 2015;172(4):885-915. PMID 25354495 
  • Abbasi NR, Shaw HM, Rigel DS, et al. Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. Jama. Dec 8 2004;292(22):2771-2776. PMID 15585738
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  • Murzaku EC, Hayan S, Rao BK. Methods and rates of dermoscopy usage: a cross-sectional survey of US dermatologists stratified by years in practice. J Am Acad Dermatol. Aug 2014;71(2):393-395. PMID 25037790 
  • Engasser HC, Warshaw EM. Dermatoscopy use by US dermatologists: a cross-sectional survey. J Am Acad Dermatol. Sep 2010;63(3):412-419, 419.e411-412. PMID 20619490 
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  • Myriad. n.d. Understanding the myPath® Melanoma Results;  
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  • Castle Biosciences. Cutaneous Melanoma: DecisionDx-Melanoma Overview. n.d.;
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  • Zager JS, Gastman BR, Messina J, et. al. Performance of a 31-gene expression profile in a previously unreported cohort of 334 cutaneous melanoma patients. J Clin Oncol 2016 34 (15 suppl): p 9581
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  • Ferris LK et. al. Identification of high risk cutaneous melanoma tumors is improved when combining online American Joint Committee on Cancer Individualized Melanoma Patient Outcome Prediction Tool with a 31 gene expression profile based classification. J Am Acad Dermatol 2017
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  • UpToDate. Tumor Node Metastasis (TNM) Staging System and Other Prognostic Factors in Cutaneous Melanoma. Antonio C. Buzaid M.D., Jeffrey E. Gershenwald M.D., FACS Topic last updated February 19, 2019. 
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  • Palmetto GBA  myPath Melanoma assay
  • Palmetto GBA has issued a draft local coverage determination for DecisionDx-Melanoma
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  • Svoboda, R.M., Glazer, A.M., Farberg, A.S. & Rigel, D.S. Factors Affecting Dermatologists' Use of a 31-Gene Expression Profiling Test as an Adjunct for Predicting Metastatic Risk in Cutaneous Melanoma. J Drugs Dermatol 17, 544-547 (2018). PMID: 29742186 
  • Gastman, B.R. et al. Identification of patients at risk of metastasis using a prognostic 31-gene expression profile in subpopulations of melanoma patients with favorable outcomes by standard criteria. J Am Acad Dermatol 80, 149-157 e4 (2019). PMID:30081113
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  • Gastman, B.R. et al. Performance of a 31-gene expression profile test in cutaneous melanomas of the head and neck. Head Neck 41, 871-879 (2019). PMID:30694001
  • Greenhaw, B.N., Zitelli, J.A. & Brodland, D.G. Estimation of Prognosis in Invasive Cutaneous Melanoma: An Independent Study of the Accuracy of a Gene Expression Profile Test. Dermatol Surg 44, 1494-1500 (2018). PMID:29994951
  • Marks, E. et al. Establishing an evidence-based decision point for clinical use of the 31-gene expression profile test in cutaneous melanoma. SKIN J Cutaneous Med 3, 239-249 (2019)
  • Podlipnik, S. et al. Early outcome of a 31-gene expression profile test in 86 AJCC stage IB-II melanoma patients. A prospective multicentre cohort study. J Eur Acad Dermatol Venereol 33, 857-862 (2019). PMID:30702163
  • Castle Biosciences Dossier 2021
  • Kwatra S.G., H.H., Semenov Y.R., Trotter S.C., Holland E., Leachman S. A Dermatologist's Guide to Implementation of Gene Expression Profiling in the Management of Melanoma. J Clin Aesthet Dermatol 2020 13, S3-S14
  • Berman, B. et al. Appropriate Use Criteria for the Integration of Diagnostic and Prognostic Gene Expression Profile Assays into the Management of Cutaneous Malignant Melanoma: An Expert Panel Consensus-Based Modified Delphi Process Assessment. 2019 3, 16 

 

Policy History:

  • May 2021 - Annual Review, Policy Renewed
  • May 2020 - Annual Review, Policy Revised
  • May 2019 - Annual Review, Policy Renewed
  • May 2018 - New Policy created

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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