Cytology for PD-L1 testing: A systematic review

Abstract

Evaluation of tumoral programmed cell death ligand-1 (PD-L1) expression is standard practice for patients with advanced non-small-cell lung cancer (NSCLC) who may be candidates for treatment targeting the programmed cell death-1 (PD-1)/PD-L1 pathway. Currently, all of the commercially available immunohistochemistry assays have been validated for use with histology specimens although, in routine clinical practice, approximately 30-40 % of patients with advanced NSCLC have only cytology specimens available for diagnosis, staging, and biomarker analysis. This systematic review evaluated the success rate, concordance, and clinical utility of using cytology specimens to assess tumor PD-L1 expression levels compared with histology specimens from patients with advanced NSCLC. EMBASE and PubMed database searches identified 142 unique, relevant publications, of which 15 met the inclusion criteria for at least one analysis. In 709 specimens, across seven publications, the proportion of cytology specimens evaluable for PD-L1 testing was 92.0 %. Among nine studies eligible for concordance analysis between cytology and histology specimens at a PD-L1 tumor cell expression cutoff of ≥50 %, overall percentage agreement was 89.7 % (n = 428), 72.0 % for positive percentage agreement (n = 218), and 95.0 % for negative percentage agreement (n = 258); results using a tumor PD-L1 expression cutoff of ≥1 % were similar. Our analyses suggest that using cytology specimens to assess PD-L1 expression is feasible, with good levels of concordance between cytology and histology specimens using PD-L1 tumor cell expression cutoffs of ≥1 % and ≥50 %. In conclusion, there is no convincing evidence that cytology specimens are inadequate or inferior to histology specimens for assessing PD-L1 expression in patients with NSCLC.

Reply to Scoring of PD‐L1 positivity: Are we analyzing enough cells?

“…This consensus was made in full acceptance of the fact that more cells than this would clearly provide greater accuracy, but raising the threshold would exclude an unacceptable number of specimens from assessment and ultimately deprive patients of the potential benefit of therapy with immunomodulating drugs. As described in our article 2 and confirmed in a recent comprehensive review, 3 at this threshold, the failure rates for both histology and cytology specimens are of the order of 10%.…”

PD‐L1 expression in NSCLC: Role of cell blocks and concordance between samples

“…Immunocytochemistry for PD‐L1 on cytological smears has provided excellent results, but it is more challenging. Cytological smears are usually prepared with alcohol‐based fixative, display more dispersed cells and are more difficult to evaluate in a membrane staining such as PD‐L1 6 . Cell blocks, instead, are processed in formalin‐based fixatives, are more easily interpreted, and immunohistochemical analyses on them are more similar to their histopathological counterparts 15 …”

“…Immunocytochemical analysis of PD‐L1 in cytological smears have provided reliable results, especially in cases of high (≥50%) PD‐L1 expression 5 . In cell blocks, only a few studies have been conducted so far, with encouraging results 6 . Furthermore, PD‐L1 expression has shown considerable variation in different specimens of the same patient, 7 and in different areas of the same specimen, 8 highlighting its spatial and temporal heterogeneity in tissue samples.…”

A noninterventional, multinational study to assess PD‐L1 expression in cytological and histological lung cancer specimens

“…Patients with only cytological material have always been excluded from pivotal clinical studies in NSCLC. 11 To date, small cell lung cancer (SCLC) does not require additional testing because of the absence of approved targeted therapies.…”