Clinicopathologic and Prognostic Significance of Programmed Cell Death Ligand 1 Expression in Patients with Non-Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis

Abstract

The results confirm the prognostic significance of PD-L1 expression in thyroid cancer patients. PD-L1 expression has the potential to be implemented as a prognostic biomarker used to guide clinicians in identifying patients with more aggressive cancers, and for the selection of individuals that would derive durable clinical benefit from anti-PD-1/PD-L1 immunotherapy. Prospective clinical trials will be useful to support these findings.

Do we need PD‐L1 as a biomarker for thyroid cytologic and histologic specimens?

“…First, there are many technical and criteria/interpretational issues with PD‐L1 immunochemistry that are outside the scope of this editorial but are nicely reviewed by Kim and Chung . Studies evaluating the expression of PD‐L1 by immunohistochemistry in thyroid cancer and other organs have used different tissue preparations/fixations, processing procedures, detection antibodies, evaluated cells (tumor cells with or without immune cells), cutoff values, and control tissues (when available) . Also, interpretations of results (ie, membranous and/or cytoplasmic staining of tumor cells) varies in different reports.…”

“…Although a strong staining may be informative and potentially relevant, a negative staining should be taken with caution, especially on cytology. Therefore, although immunocytochemistry for thyroid FNAs (eg, HBME‐1, galectin‐3, BRAF V600E) is used by some laboratories, it is not widely accepted by most laboratories, and PD‐L1 immunocytochemistry is even more questionable given the finding that its expression is often focal and heterogeneous . Also, an important pitfall (false‐positive) for PD‐L1 as a marker of neoplasia/malignancy for thyroid includes autoimmune thyroid diseases (AITDs) such as Graves and Hashimoto, in which reactive thyroid follicular cells (TFCs) are well recognized as mimics of PTC that may result in a false‐positive diagnosis.…”

“…In an era of personalized medicine, this is likely to be much more informative and relevant for prognostic/therapeutic purposes than a single marker like PD‐L1 with so many flaws. Because of the multifactorial, variable, and complex nature of cancer‐immune interactions, combinations of biomarker assays, by definition, will be required . This was also the case for molecular markers, in which a comprehensive panel of gene alterations (ie, ThyroSeqV3) is now much more informative and relevant than a single‐gene alteration such as BRAF V600E or RAS .…”

“…5 Studies evaluating the expression of PD-L1 by immunohistochemistry in thyroid cancer and other organs have used different tissue preparations/ fixations, processing procedures, detection antibodies, evaluated cells (tumor cells with or without immune cells), cutoff values, and control tissues (when available). 4,5,17 Also, interpretations of results (ie, membranous and/or cytoplasmic staining of tumor cells) varies in different reports. In addition to these inherent preanalytical, analytical, and postanalytical issues, PD-L1 is a protein that is expressed with biologic continuity, akin to a microRNA, and often shows significant intratumoral heterogeneity (both spatial and temporal), 5,14,15 unlike a genetic alteration such as a BRAF V600E mutation, which is a binary system, [9][10][11] or p16 immunohistochemistry for human papillomavirus-related squamous cell carcinoma ("block positivity").…”

“…Therefore, although immunocytochemistry for thyroid FNAs (eg, HBME-1, galectin-3, BRAF V600E) is used by some laboratories, it is not widely accepted by most laboratories, and PD-L1 immunocytochemistry is even more questionable given the finding that its expression is often focal and heterogeneous. 15,17 Also, an important pitfall (false-positive) for PD-L1 as a marker of neoplasia/malignancy for thyroid includes autoimmune thyroid diseases (AITDs) such as Graves and Hashimoto, in which reactive thyroid follicular cells (TFCs) are well recognized as mimics of PTC that may result in a false-positive diagnosis. It has been shown that PD-L1 is consistently expressed by TFCs in AITD glands and that this adaptive response ("don't kill me signal") may restrain the autoimmune response and explain the chronicity of AITDs.…”