Subtype performance of the ancillary diagnostic 23- and 35-gene expression profile (GEP) tests for difficult-to-diagnose melanocytic lesions

Abstract

Background: Histopathological examination is adequate for most melanocytic neoplasms; however, there is a subset of lesions that are difficult to diagnose. The 23- and 35-gene expression profile (GEP) tests deliver results of suggestive of benign neoplasm, suggestive of malignant neoplasm, or intermediate (cannot exclude malignancy). They are intended to provide clinicians with objective results to be interpreted in the context of clinical, laboratory, and histopathological features to achieve a definitive diagnosis. Both GEPs are stand-alone tests that are independently validated and clinically available. Greater than 99% benign or malignant reporting is achieved clinically when the 23-GEP test is processed first, and if an intermediate result or test failure occurs, the 35-GEP is utilized. Methods: The performance of the 23- and 35-GEP tests using this methodology was tested on unequivocal cases from a variety of subtypes (101 benign, 249 malignant). Lesions were included if 2/3 dermatopathologist diagnoses were concordant. Subtype designation was determined by the dermatopathologist that submitted the lesion for the study. Results: The overall accuracy metrics in this cohort were 96.0% sensitivity and 87.8% specificity. The results demonstrated 100% sensitivity in several melanoma subtypes including acral lentiginous (n=15), desmoplastic (n=20), melanoma in situ (n=16), and nevoid (n=16). Other melanoma subtypes showed sensitivity metrics of: lentigo maligna, 96.7% (n=31); nodular, 95.1% (n=81); superficial spreading, 97.7% (n=42); and spitzoid, 85.0% (n=20). Subtypes of benign nevi showed a specificity of: blue, 96.7% (n=30); compound, 85.7% (n=42); junctional, 77.8% (n=18); and Spitz, 100% (n=7). Conclusions: Overall, we demonstrate that use of the 23- and 35-GEP diagnostic test workflow results in high accuracy across many subtypes of benign and malignant melanocytic neoplasms. Financial Disclosures: JAP has served as a consultant for Castle Biosciences, Inc. SIE is a consultant and shareholder of Castle Biosciences, Inc. BHR, JJS, JHR, JKW, SJK, and MSG are employee shareholders of Castle Biosciences, Inc. KM has served as a consultant and investigator for studies supported by Castle Biosciences, Inc. This study was supported by Castle Biosciences, Inc.