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Background: Melanoma is a type of cancer with robust response to immunotherapy. Programmed death ligand 1 (PD-L1) testing is not required to treat patients, but most studies have demonstrated correlations between PD-L1 expression and treatment response using various assays and scoring methods. This multicenter study aimed to harmonize PD-L1 immunohistochemistry (IHC) and scoring in melanoma. To provide a reference for PD-L1 expression independent of the IHC protocol, PD-L1 mRNA expression was determined via RNAscope, then compared to IHC.Methods: Standardized PD-L1 assays (22C3, 28–8, SP142, and SP263) and laboratory-developed tests (clone QR1 and 22C3) were evaluated on three IHC platforms using a training set of 7 cases. mRNA expression was determined via RNAscope (CD274/PD-L1 probe) and analyzed by image analysis. PD-L1 IHC findings were scored by seven blinded pathologists using the tumor proportion score (TPS), combined positive score (CPS), and MELscore. After the study, a standardized method was proposed; this was validated by three blinded pathologists on a set of 40 metastatic melanomas that were stained using three protocols.Results: Concordances among various antibody/platforms were high across antibodies (e.g., intraclass correlation coefficient [ICC] > 0.80 for CPS), except for SP142. Two levels of immunostaining intensities were observed: high (QR1 and SP263) and low (28–8, 22C3, and SP142). Reproducibilities across pathologists were higher for QR1 and SP263 (ICC ≥ 0.87 and ≥ 0.85 for TPS and CPS, respectively). QR1, SP263, and 28-8 showed the highest concordance with mRNA expression (ICC ≥ 0.81 for CPS). Accordingly, we proposed a standardized method for PD-L1 immunodetection and scoring, then tested it on 40 metastatic melanomas. This method included analysis of specimen quality (e.g., host-tumor interface and pigmentation). Concordances among antibodies were excellent for all criteria, and concordances among pathologists were better for the MELscore than for other scores.Conclusion: Harmonization of PD-L1 staining and scoring in melanomas with good concordance is achievable using the PD-L1 IHC protocols applied to other cancers; this reproducible approach can simplify daily practice. Our proposal for a PD-L1 standardized methodology has higher reproducibility across pathologists for clinical and research use. |
