LCD L39389: MolDX: Molecular Assays for the Diagnosis of Cutaneous Melanoma

The purpose of this test is to assist dermatopathologists to arrive at the correct diagnosis of melanoma versus non-melanoma when examining skin biopsies.

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:

• 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

Tests that demonstrate similar indicated uses and equivalent or superior performance to covered tests may similarly be covered under this policy.

Melanoma is an aggressive cancer with an estimated 106,110 cases and 7,180 deaths in 2021. 1 The lifetime risk of developing melanoma in the United States is approximately 2.6% (1 in 38) for Caucasians, 0.1% (1 in 1,000) for African Americans, and 0.6% (1 in 167) for Latinos . 1 Melanoma is more common in men overall, but before age 50 the rates are higher in women than in men. The average age of people diagnosed with melanoma is 65. Many melanomas are curable if detected early and diagnosed accurately. The five year survival for localized melanoma is 99%, compared with only 27% among patients with distant metastases. 2

Melanoma can be difficult to diagnose, particularly in its earliest stages, yet accurate diagnosis of melanocytic neoplasms is vital to optimal patient outcomes. Histopathologic examination has long been the gold standard for melanoma diagnosis, and while it is adequate for most cases, evidence suggests that approximately 15-20% of all biopsied melanocytic neoplasms are difficult to diagnose by histopathology alone. 3-5 Subspecialty training and experience in dermatopathology is associated with improved diagnostic accuracy and subsequent clinical management of patients with challenging melanocytic lesions. 5-8 However, even experienced dermatopathologists disagree in some cases, and, depending on the type of lesions evaluated, diagnostic discordance may be substantial . 6,7,9,10 In equivocal cases, patients may receive diagnoses that are indeterminate or inaccurate, leading to inappropriate treatment. Unnecessary re-excisions, sentinel lymph node biopsies, and protracted clinical follow-up may result when a diagnostically challenging benign lesion is reported as indeterminate. 11,12 Conversely, a diagnostically challenging melanoma mistakenly classified as a benign nevus may result in undertreatment and subsequent progression to late-stage melanoma. 11,12 Consequently, adjuncts to histopathology have been sought in efforts to improve diagnostic accuracy in equivocal cases.

Gene expression profiles (GEP) can serve as beneficial adjuncts to histopathology in the evaluation of equivocal melanocytic lesions. The myPath® Melanoma assay (Castle Biosciences, Phoenix, AZ) is a 23-gene expression profile (23-GEP) developed to provide an objective, reproducible, and accurate adjunctive method for differentiating malignant melanoma from benign nevi. 13-16 The test is intended for use by dermatopathologists confronting primary cutaneous melanocytic neoplasms for which the diagnosis of malignant melanoma versus benign nevus is equivocal/uncertain (i.e., a clear distinction between benign or malignant cannot be achieved using clinical and/or histopathological features alone). Use of the test in these cases increases definitive diagnoses, and evidence suggests it may reduce unnecessary procedures in benign lesions. 17,18

The myPath® Melanoma test quantifies the expression of 23 genes by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Fourteen of the 23 genes are known to be over-expressed by malignant melanomas relative to benign nevi. The remaining 9 are stably expressed reference genes which allow correction for sample-to-sample variations in RT-PCR efficiency and errors in sample quantification (normalization). The signature genes represent 3 distinct pathways that contribute to melanoma pathogenesis, including aspects of melanocyte differentiation as well as characteristics of the tumor microenvironment such as cell-cell signaling and tumor-induced host immune responses. 13,14 The test uses 5 to 7 standard-thickness (4-5 µm) sections taken from the routinely processed formalin-fixed paraffin-embedded (FFPE) tissue of the existing biopsy specimen, allowing its integration into routine clinical practice and its use even in small, early-stage lesions. The quantified expression of all 23 genes is combined algorithmically and reported as a single numerical score. That number (the myPath® Melanoma ‘score’), is plotted on a scale that depicts the entire range of scores observed in clinical validation studies. 14 Physicians receive a report showing this single numerical score and the corresponding classification: ‘likely malignant’, ‘likely benign’, or ‘indeterminate’.