Development and Validation of a Diagnostic 35-Gene Expression Profile Test for Ambiguous or Difficult-to-Diagnose Suspicious Pigmented Skin Lesions

Main Article Content

Sarah Estrada
Jeffrey Shackelton
Nathan Cleaver
Natalie Depcik-Smith
Clay Cockerell
Stephen Lencioni
Howard Martin
Jeffrey Wilkinson
Lauren Meldi Sholl
Michael Berg
Brooke Russell
Olga Zolochevska
Kyle Covington
Aaron Farberg
Matthew Goldberg
Pedram Gerami
Gregory Hosler

Keywords

35-GEP, diagnostic test, validation, melanoma, benign nevi

Abstract

Purpose: A clinical hurdle for dermatopathology is the accurate diagnosis of melanocytic neoplasms. While histopathologic assessment is frequently sufficient, high rates of diagnostic discordance are reported. The development and validation of a 35-gene expression profile (35-GEP) test that accurately differentiates benign and malignant pigmented lesions is described.


Methods: Lesion samples were reviewed by at least three independent dermatopathologists and included in the study if 2/3 or 3/3 diagnoses were concordant. Diagnostic utility of 76 genes was assessed with quantitative RT-PCR; neural network modeling and cross-validation were utilized for diagnostic gene selection using 200 benign nevi and 216 melanomas for training. To reflect the complex biology of melanocytic neoplasia, the 35-GEP test was developed to include an intermediate-risk zone.


Results: Validation of the 35-GEP was performed in an independent set of 273 benign and 230 malignant lesions. The test demonstrated 99.1% sensitivity, 94.3% specificity, 93.6% positive predictive value and 99.2% negative predictive value. 96.4% of cases received a differential result and 3.6% had intermediate-risk.


Conclusions: The 35-GEP test was developed to refine diagnoses of melanocytic neoplasms by providing clinicians with an objective tool. A test with these accuracy metrics could alleviate uncertainty in difficult-to-diagnose lesions leading to decreased unnecessary procedures while appropriately identifying at-risk patients.

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