Spatial Intratumoral Heterogeneity Expression of PD-L1 Antigen in Head and Neck Squamous Cell Carcinoma

Nir Hirshoren*, Issa Al-Kharouf, Jeffrey M. Weinberger, Ron Eliashar, Aron Popovtzer, Ariela Knaanie, Yakov Fellig, Tzahi Neuman, Karen Meir, Alexander Maly, Gilad W. Vainer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Introduction: Immune-checkpoint inhibitors have demonstrated a significant survival benefit in metastatic and non-resectable head and neck squamous cell carcinoma (HNSCC). Patients with a combined positivity score (CPS) of 20 and higher benefit the most from therapy. Inaccurate definition of the CPS category might lead to the incorrect stratification of patients to immunotherapy. This study's main aim was to investigate programmed death-ligand 1 (PD-L1) antigen expression in HNSCC in diverse clinical situations and histological settings. Materials and Methods: This is a prospective cohort study conducted in a tertiary referral medical center. Tissues were investigated for PD-L1 expression using the FDA-approved 22C3 immunohistochemistry assay (Dako). We analyzed potential associations between the CPS category and meaningful demographic, clinical, and outcome metrics. Furthermore, we investigated morphologically separate sites for CPS scores in whole surgical tissue specimens and matched preoperative biopsies. Results: We analyzed 36 patients, of whom 26 had oral cavity SCC and 10 had laryngeal SCC. The overall, disease-specific, and progression-free survival of the HNSCC group of patients were not associated with the CPS category (p = 0.45, p = 0.31, and p = 0.88, respectively). There was a significant (18%, 95% CI 0.65-0.9) inconsistency between the CPS category determined in biopsies versus whole carcinoma analyses. We also found an uneven distribution of whole-tumor CPS attributed to spatial carcinoma invasiveness, tumor differentiation, and inflammatory cell infiltration heterogeneity. Discussion and Conclusions: Our data suggest that careful selection of tumor area for CPS analysis is important. PD-L1 antigen expression, clinically represented by CPS, may be up- or down-categorized in different clinical and pathological circumstances. The high whole-tissue CPS category scatter may clinically result in potential treatment modifications. We argue that CPS analysis requires not only adequacy (at least 100 viable tumor cells), but also correct representation of the tumor microenvironment.

Original languageAmerican English
Pages (from-to)464-470
Number of pages7
Issue number7
StatePublished - 1 Jun 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) Published by S. Karger AG, Basel.


  • Head and neck neoplasm
  • Programmed cell death ligand 1
  • Survival analysis
  • Tissue array analysis


Dive into the research topics of 'Spatial Intratumoral Heterogeneity Expression of PD-L1 Antigen in Head and Neck Squamous Cell Carcinoma'. Together they form a unique fingerprint.

Cite this