About 3 million surgical pigmented skin lesion biopsies are performed each year in the USA alone to diagnose fewer than 200 000 new cases of invasive melanoma and melanoma in situ using the current standard of care that includes visual assessment and histopathology. A recently described noninvasive adhesive patch-based gene expression rule-out test [pigmented lesion assay (PLA)] may be helpful in identifying high-risk pigmented skin lesions to aid with surgical biopsy decisions. The main objective of this utility study was to determine the real-world clinical performance of PLA use and assess how the PLA changes physician behavior in an observational cohort analysis of 381 patients assessed with the PLA. All (100%) of 51 PLA(+) test results were clinically managed with surgical biopsy. Of these, 19 (37%) were melanomas, corresponding to a number needed to biopsy of 2.7 and a biopsy ratio of 1.7. All melanomas were histopathologically classified as melanoma in situ or stage 1. Nearly all (99%) of 330 PLA(-) test results were clinically managed with surveillance. None of the three follow-up biopsies performed in the following 3-6 months, were diagnosed as melanoma histopathologically. The estimated sensitivity and specificity of the PLA from these data sets are 95 and 91%, respectively. Overall, 93% of PLA results positive for both LINC00518 and PRAME were diagnosed histopathologically as melanoma. PRAME-only and LINC00518-only lesions were melanomas histopathologically in 50 and 7%, respectively. The PLA alters clinical management of pigmented lesions and shows high clinical performance. The likelihood of positive histopathologic diagnosis of melanoma is higher in PLA results that are positive for both LINC00518 and PRAME.

Background: Management of pigmented lesions currently relies on visual assessment with surgical biopsy and histopathologic examination for those lesions suspicious for melanoma. A non-invasive genomic assay that detects two melanoma-associated biomarkers (PLA, 2-GEP) has recently been validated as an adjunct to visual assessment for distinguishing high-risk pigmented lesions appropriate for biopsy from those that can be safely monitored via clinical surveillance. Objectives: To calculate NPV and PPV of the PLA in real-world use and determine the distribution of PLA-positive lesions among categories in the MPATH-Dx classification scheme for melanocytic neoplasms. Methods: Real-world NPV was determined by following a cohort of 1,233 PLA-negative pigmented lesions for evidence of malignancy for up to 36 months and by re-testing a separate prospective cohort of 302 PLA-negative lesions up to 2 years after initial testing. Real-world PPV was determined by identifying melanoma diagnoses among PLA-positive lesions within a US-based registry of 3,418 PLA-tested cases. Results: Ten early-stage melanomas (4 in situ and 6 pT1a) were identified among 1,233 PLA-negative lesions (0.8%), corresponding to a real-world NPV of 99.2% (CI 95% = 98.5 - 99.6). Of 302 initially PLA-negative lesions subjected to repeat testing an average of 15 months later, 34 were PLA-positive. Biopsy revealed 3 melanomas (all in situ), further confirming an NPV of > 99%. Among 316 PLA-positive cases, 59 were diagnosed as melanoma by histopathology, corresponding to a PPV of 18.7%. Of all PLA-positive lesions, 30.5% had histopathologic diagnoses corresponding to high-risk MPATH-Dx categories (Classes III-V). Conclusions and Relevance: The PLA has an NPV of >99% within the real-world intended use population.  The PLA has a PPV of 18.7% for melanoma and also detects high-risk lesions such as dysplastic nevi with severe / high-grade atypia that are generally targeted for complete excision.

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Impact on clinical practice of a non-invasive gene expression melanoma rule-out test: 12month follow-up of negative test results and utility data from a large US registry study Permalink

Importance: Melanoma is diagnosed in approximately 200,000 people within the US each year and is responsible for more than 6,850 deaths. Currently, clinical suspicion guides biopsy decisions and melanoma is confirmed in approximately 4% of biopsied lesions. A non-invasive two-gene expression test (2-GEP) was shown to enhance the physical exam by evaluating genomic atypia to guide biopsy decisions. This study examines the corresponding histopathology of real-world 2-GEP-positive cases. Methods: Cutaneous lesions suspicious for melanoma (n=3,418) were 2-GEP tested by 90 licensed clinicians in real-world practice. 2-GEP-positive lesions (genomically atypical as indicated by the detection of LINC and/or PRAME) were biopsied in 316 out of 324 (97.5%) cases and 313 pathology reports were available for analysis. Results: Biopsied 2-GEP-positive lesions were separated into diagnostic subgroups based on corresponding pathology reports. The prevalence of melanoma in biopsies of 2-GEP-positive lesions was 18.7%. Gene expression of both LINC and PRAME was present in ever-increasing percentages of melanocytic lesions as pathology reports demonstrated increasing levels of atypia. Notably, 47.5% of the histopathologically-confirmed melanomas demonstrated this double positive genomic signature while 23.7% were single-positive for LINC and 28.8% were single-positive for PRAME.  Discussion: These data show that biopsied 2-GEP-positive lesions are enriched almost five-fold for advanced histopathologic features compared to those biopsied based solely on visual assessment criteria. The close correlation between genomic atypia and atypical pathology should be considered when planning treatment of a 2-GEP-positive lesion.  Consideration of genomic atypia may be a superior approach to guide biopsy decisions and manage pigmented lesions.