Concordance, Correlation, and Clinical Impact of Standardized PD-L1 and TIL Scoring in SCCHN

Abstract

Background: The clinical significance of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression has been thoroughly researched in squamous cell carcinoma of the head and neck (SCCHN). To address the impact of intra- and intertumoral heterogeneity in these biomarkers, we explored the concordance of PD-L1 combined positive score (CPS) and stromal TILs in different paired tissue sample types, while evaluating their internal relationship and prognostic impact. Methods: A total of 165 tissue blocks from 80 SCCHN patients were reviewed for TILs and PD-L1 CPS. Concordance between paired tissue samples was evaluated, and their association with several clinicopathological variables, overall survival (OS), and disease-free survival (DFS) was determined. Results: Biopsies and paired resection material were severely discordant in 39% and 34% of samples for CPS and TIL count, respectively, of which CPS was underscored in 27% of biopsies. In paired primary tumor–metastatic lesions, the disagreement was lower for CPS (19%) but not for TIL count (44%). PD-L1 CPS was correlated with prolonged OS when calculated from tissue acquirement, while extended OS and DFS were observed for high TIL density. Conclusion: Intertumoral and, especially, intratumoral heterogeneity were confounding factors when determining PD-L1 CPS and TIL count on paired tissue samples, indicating the increasing necessity of assessing both biomarkers on representative tissue material. Although TILs hold valuable prognostic information in SCCHN, the robustness of PD-L1 as a biomarker in SCCHN remains ambiguous.

Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

“…The selection of a proper tissue section (or sections), followed by the selection of ‘appropriate-for-scoring’ tumor areas at low magnification, followed by determination of the type of inflammatory infiltrates (mononuclear vs. granulocytic) at higher magnification is an accepted first step. Necrotic areas and areas with superficial ulceration, often infiltrated by granulocytes, are excluded from the analysis and so is pre-existing lymphoid tissue [ 24 , 25 ]. However, tertiary lymphoid structures have a distinct prognostic value and should be separately assessed.…”

Standardized Digital Image Analysis of PD-L1 Expression in Head and Neck Squamous Cell Carcinoma Reveals Intra- and Inter-Sample Heterogeneity with Therapeutic Implications

“…Previously reported concordance rates when comparing data from a single sample to repeated biopsy analyses from the same primary tumor ranged from 52% to 97.1% for CPS and 36% to 70% for TPS [ 14 , 24 , 29 , 31 , 32 , 33 ]. When assessing concordance rates based on therapy-relevant categories, discrepancy rates were notably lower but nevertheless substantial at up to 34% for CPS [ 31 ]. The discordance rates between categories have been shown to further increase, based on the number of samples analyzed within the tumor, reaching 64% in large-scale analyses [ 14 ].…”

“…The discordance rates between categories have been shown to further increase, based on the number of samples analyzed within the tumor, reaching 64% in large-scale analyses [ 14 ]. Of note, the discrepancies more likely affect CPS than TPS, which is most likely due to a potential underrepresentation of the stroma in biopsies, as mentioned above [ 24 , 30 , 31 ].…”

“…Although not significant, in some cases pairwise comparisons between primary tumor and lymph node showed a substantially lower PD-L1 expression in the lymph node [ 28 , 32 , 36 , 37 , 38 , 39 ]. This may explain some of the differences in response between the primary tumor and lymph node observed in neoadjuvant immunotherapy seen in clinical trials [ 11 , 31 , 38 , 39 , 40 ].…”

“…In particular, the previously described deviations of 62% to 77% show clear biological differences, so that in the presence of non-resectable distant metastases, histological confirmation of this tissue appears to be useful for the treatment decision. Variation may be due to a small sample size, selection bias, or the antibody used [ 31 , 42 ].…”