Abstract

Introduction: Poorly differentiated histology has been identified as an independent predictor of outcomes for cSCC and is also included as a high-risk factor for the Brigham and Women's Hospital (BWH) staging system. However, determining differentiation status is subjective and multiple studies have shown minimal concordance among pathologists/dermatopathologists. In a cohort of high-risk cSCCs, inclusive of all differentiation grades, the 40-GEP (an objective prognostic biomarker test) has been independently validated and stratifies tumors into three biological risk groups based on low (Class 1), moderate (Class 2A), or high (Class 2B) risk for regional or distant metastasis.

Objective: The study aimed to investigate the 40-GEP’s ability to stratify risk among a potentially histologically ambiguous cohort.

Methods: Within a cohort of comprehensively staged, primary cSCCs having one or more risk factors (n=954; n=420-published, n=534-unpublished data), a subgroup of cases in which the BWH T-stage would have been altered had the tumor's differentiation status been upgraded from "moderate" to "poor" or downgraded from "poor" to "moderate” was identified as the ‘differentiation uncertainty cohort’ (n=391; n=171-previously presented, n=220-unpublished data).

Results: The ‘differentiation uncertainty cohort’  contained 278 (58%) and 113 (23%) patients up- and down-staged, respectively. Kaplan-Meier analysis demonstrated an overall 3-year metastasis-free survival of 82.4%. Notably, the 40-GEP was able to stratify metastatic risk significantly (Class 1=88.3%, Class 2A=78.9%, Class 2B=72.4%; p=0.02).

Conclusion: In this expanded cohort, the 40-GEP provides objective information in situations where the distinction between poorly and moderately differentiated grading impact staging and, therefore, could enhance current risk-aligned patient management decisions.