Digital Slide Assessment for Programmed Death-Ligand 1 Combined Positive Score in Head and Neck Squamous Carcinoma: Focus on Validation and Vision

Head and neck squamous cell carcinoma (HNSCC) represents a leading cause of mortality in some countries. The 5-years overall survival has improved modestly over the past 3 decades and is still only at 50–65% despite combined surgical resection and radiotherapy and/or chemotherapy (Johnson et al., 2020). In recent years, new immunotherapy drugs inhibiting the interaction between programmed death 1 (PD-1) expressed on T-helper lymphocytes and its ligand programmed death-ligand-1 (PD-L1) expressed on cancer cells have been utilized as an effective treatment for different types of advanced cancers including HNSCC. The binding of PD1 to its ligand PD-L1 normally reduces the proliferation and activity of cytotoxic CD8 T lymphocytes against presented antigens, thus inducing self-tolerance. The introduction of immunotherapy drugs targeting the PD1/PD-L1 axis represented a turning point in the therapy of HNSCC. PD-L1 status is assessed by immunohistochemistry (IHC) using the combined positive score (CPS). This integrated scoring system considers the expression of the PD-L1 immune checkpoint biomarker on the cell membrane of both tumor and tumor-associated inflammatory cells. The CPS assessment is often performed on small biopsy material, as candidate patients present with advanced cancer are often unfit for large surgery as are those with recurrence after adjuvant therapy. PD-L1 expression is associated with an increased objective response rate to therapy, with better responses observed when the CPS ≥ 20, as was recently shown in clinical trials investigating the efficacy of this first-line immune checkpoint inhibitor in recurrent and/or metastatic HNSCC (Burtness et al., 2019). This finding is crucial for clinicians in order for them to prescribe the best course of treatment for cancer patients. Consequently, it is to be expected that pathologists are increasingly requested to assess companion PD-L1 CPS on HNSCC specimens in order to meet the rising demand of selecting suitable patients for immunotherapy. Reliable immunohistochemical assessment of PD-L1 requires not only expertize in head and neck pathology, but also validated IHC assays and tailored training for accurate, standardized and reproducible PD-L1 scoring among pathologists (Pagni et al., 2020). Efficiency and high diagnostic quality are extremely important for PD-L1 scoring. Training of pathologists is key to achieving this goal. The CPS is more complex than the Tumor Proportion Score (TPS), as it requires specific and separate counting of tumor and immune cells that are positive for PD-L1. TPS evaluates PD-L1 expression by the ratio of stained tumor cells to the total number of viable tumor cells. As depicted in Figure 1, CPS assessment requires additional steps: first of all, the total number of viable tumor cells are counted to and represent the denominator of the formula. Edited by: Fabricio Alves Barbosa da Silva, Oswaldo Cruz Foundation (Fiocruz), Brazil