Concordance of Preferentially Expressed Antigen in Melanoma by Non-Invasively Collected Polymerase Chain Reaction and Immunohistochemistry on Paraffin Embedded Tissue
Main Article Content
Melanoma, immunostain, IHC, PRAME, dermatopathology, genomics
Pigmented lesion evaluation remains a challenging aspect of dermatology. The DermTech Melanoma Test (DMT) is a non-invasive gene-expression test designed to rule-out melanoma. It consists of the pigmented lesion assay, which detects RNA products of Long Intergenic Non-Coding RNA 00518 (LINC00518) and Preferentially Expressed Antigen in Melanoma (PRAME), and an add-on assay for DNA promoter mutations in telomerase reverse transcriptase (TERT). This registry study examines the concordance of PRAME detection by polymerase chain reaction (PCR) in samples obtained non-invasively prior to biopsy and PRAME detection by immunohistochemistry (IHC) on the same lesions after biopsy.
Between April 2021 and March 2022, multiple geographically diverse sites throughout the US submitted data to a registry to assess real-world use of the DMT. Approximately 8,000 clinically atypical lesions were tested. After receiving the test result, providers followed their clinical judgement for biopsy decision. When lesions expressed genomic markers (LINC, PRAME, and/or TERT) and were biopsied, pathology reports were also submitted to the registry. The presence or absence of PRAME by immunohistochemistry (IHC) was reviewed and compared to the detection of PRAME by PCR from the DMT on the same lesion.
At the 1-year mark of the registry, there were roughly 8,000 unique entries. Of those, 1,021 (12.8%) were positive for one or more of the DMT genomic markers. One thousand three lesions (98.2%) had records available. Pathologists used PRAME IHC for 102 lesions (10.2%). Of those, 40 (39.2%) were positive by IHC, and 62 (60.8%) were negative by IHC. PRAME positivity by PCR correlated with PRAME positivity by IHC in 35 of 40 lesions (87.5%). Conversely, PRAME was detected using PCR in 28 of 62 lesions (45.2%) where it was not detected using IHC.
The higher sensitivity of PCR compared to IHC may explain the higher concordance when PRAME is positive by IHC than when it is negative by IHC. In this data set, when PRAME is positive by IHC it is usually also positive by PCR. When PRAME is negative by IHC, it can still be detected by PCR in a substantial percentage of cases. The increased sensitivity of PCR is likely due to several factors, including its detection of the PRAME mRNA and sampling of the entire lesion. As such, PRAME PCR status may aid pathologists in understanding the risk of melanoma even when IHC is negative. Further research is warranted to understand the clinical implications of PRAME PCR versus IHC positivity.
2. Jackson SR, Jansen B, Yao Z, Ferris LK. Risk Stratification of Severely Dysplastic Nevi by Non-Invasively Obtained Gene Expression and Mutation Analyses. SKIN The Journal of Cutaneous Medicine. 2020;4(2):105-110.
3. Brouha B, Ferris LK, Skelsey, MK, et al. Genomic Atypia to Enrich Melanoma Positivity in Biopsied Lesions: Gene Expression and Pathology Findings From a Large U.S. Registry Study. SKIN. 2021;5(1),13–18.