PD-L1 immunohistochemistry is increasingly employed as a predictive biomarker to select patients for treatment with checkpoint inhibitors in a number of different tumor types. PD-L1 IHC was first adopted as the standard of care to select patients with metastatic non small cell lung carcinoma whose tumors lack an actionable mutation for single agent treatment with a checkpoint inhibitor [6]. In this context, the current cutpoints in the first line setting have been tumor proportion scores (TPS) of 1% and 50%. TPS scoring differs from the CPS scoring system used in head and neck squamous cell carcinoma and other tumor types in that only tumor cell staining is counted while immune cell staining is ignored.

The bulk of the prior work comparing the suitability of various specimen types for PD-L1 IHC has focused on TPS scoring and non small cell lung carcinoma. Most studies have demonstrated a moderate degree of concordance between cell blocks and small biopsies on the one hand and resected specimens on the other with levels of concordance between the two ranging from 67–95% around the clinically relevant cutpoints [7–12]. In most discrepant cases, the TPS scores derived from the cell block or small biopsy were lower than those obtained from the larger specimens. The lack of correlation in discrepant cases has largely been attributed to intratumoral heterogeneity in expression of PD-L1 by the tumor cells. In our series of resected head and neck squamous cell carcinoma cases, we similarly observed a significant degree of intratumoral heterogeneity in regards to tumor cell staining with positive cells tending to be located at the periphery of the tumor adjacent to the peritumoral stroma.

Immune cell staining for PD-L1, which is incorporated into the CPS score, has been noted to be similarly heterogeneous. We observed that in resected specimens of head and neck squamous cell carcinoma, immune cell staining tended to be primarily localized to the peritumoral stroma with few tumor infiltrating lymphocytes in most cases. This pattern of cuffing of tumor by a PD-L1 positive immune cell infiltrate has been noted to be particularly characteristic of HPV driven oropharyngeal carcinoma [13]. One possible explanation for the underscoring of aspirate cell blocks and core biopsies relative to resected specimens and excisional biopsies is a failure to sample the peritumoral stroma in small biopsies. In four of our discrepant cases around the 1% cutpoint, we noted that while tumor cell staining was similarly negative in both paired specimens, the degree of immune cell staining was considerably less in the core biopsy or aspirate cell block relative to the excisional biopsy or resection.

To our knowledge, ours is the first study to address the issue of CPS scoring in core biopsies and aspirate cell blocks in patients with head and neck squamous cell carcinoma obtained in a clinical context. This issue is of significant relevance as many patients with head and neck cancer and in particular HPV driven oropharyngeal carcinoma will initially come to clinical attention due to an enlarged cervical lymph node which will then be biopsied by these modalities.

As a checkpoint inhibitor, pembrolizumab, has now been approved by the FDA as first line therapy in this disease, accurate assessment of the CPS in patients with head and neck cancer is of paramount importance in determining initial therapy. Based on the results of the KEYNOTE 048 trial, patients who present with metastatic or unresectable disease are eligible for single agent therapy with pembrolizumab if their tumor demonstrates a CPS ≥ 1%. As was demonstrated in this trial, the clinical benefit was most pronounced in the patient population with a CPS > 20% and thus accurately assessing the CPS around both cutpoints is of value in triaging patients appropriately.

In the emerging therapeutic paradigm, patients with metastatic or recurrent disease with CPS > 20% would likely receive single agent pembrolizumab while patients with CPS = 1–20% would be eligible for either single agent pembrolizumab or a regimen combining platinum based chemotherapy and pembrolizumab. Patients with CPS