Prognostic Value of an Integrated Human Papillomavirus and Immunoscore Model to Predict Survival in Vulva Squamous Cell Carcinoma.

Abstract

Although the prognostic value of immune-related biomarkers is well characterized in many solid tumors, their significance in vulva squamous cell carcinoma (VSCC) remains unclear. In this study, we report a comprehensive analysis of programmed death ligand protein 1 (PD-L1) and immune cell infiltration in VSCC and establish immunoscore models for classification of the disease. Tissue microarrays, immunohistochemistry, and digital quantification were used to investigate the number of CD4+, CD8+, CD68+, CD14+, FoxP3+, and PD-L1+ cells in epithelial and stromal compartments of VSCC (n = 117). Immunoscores were developed using these parameters and applying the least absolute shrinkage and selection operator to identify predictors of survival. Immunoscores were then integrated with human papillomavirus (HPV) status, as determined using messenger RNA in situ hybridization, to construct internally validated nomograms. The prognostic models were subsequently applied in whole tissue sections (n = 25) to investigate agreement. Advanced VSCC (International Federation of Gynecology and Obstetrics stage III/IV) was characterized by high densities of CD68+ macrophages and PD-L1+ cells (Spearman correlation, ρ = 0.80) in the epithelium. PD-L1 status independently predicted poor progression-free survival (PFS) (hazard ratio = 1.828; 95% CI, 1.039-3.215; P = .036). Immunoscore^PFS and immunoscore^DSS were developed and found to be independent prognosticators of PFS (P = .003) and disease-specific survival (DSS) (P = .007), respectively. Integrating immunoscores with HPV status (IS-HPV index) improved model performance. The concordance index of IS-HPV index^PFS was 0.750 for prediction of PFS compared with 0.666 for HPV status and 0.667 for immunoscore^PFS. The concordance index of IS-HPV index^DSS was 0.752 for predicting DSS compared with 0.631 for HPV status and 0.715 for immunoscore^DSS. Strong agreement (phi coefficient [ϕ] = 0.76-0.8) was observed when the IS-HPV index models developed using tissue microarrays were applied to whole tissue sections. In summary, an index based on HPV status and an immunoscore built on PD-L1 expression and immune cell infiltrates could potentially serve as prognostic tools to refine risk stratification in VSCC. Further validation is warranted to demonstrate clinical use.