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J Thorac Oncol. 2019 Jan;14(1):45-53. doi: 10.1016/j.jtho.2018.09.025. Epub 2018 Oct 6.

Critical Appraisal of Programmed Death Ligand 1 Reflex Diagnostic Testing: Current Standards and Future Opportunities.

Author information

1
Molecular Pathology Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Ireland, United Kingdom.
2
Molecular Pathology Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Ireland, United Kingdom; Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, Ireland, United Kingdom; Northern Ireland Biobank, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Ireland, United Kingdom.
3
Molecular Pathology Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Ireland, United Kingdom; Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, Ireland, United Kingdom.
4
Molecular Pathology Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Ireland, United Kingdom; Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, Ireland, United Kingdom. Electronic address: m.salto-tellez@qub.ac.uk.

Abstract

INTRODUCTION:

Patient suitability to anti-programmed death ligand 1 (PD-L1) immune checkpoint inhibition is key to the treatment of NSCLC. We present, applied to PD-L1 testing: a comprehensive cross-validation of two immunohistochemistry (IHC) clones; our descriptive experience in diagnostic reflex testing; the concordance of IHC to in situ RNA (RNA-ISH); and application of digital pathology.

METHODS:

Eight hundred thirteen NSCLC tumor samples collected from 564 diagnostic samples were analyzed prospectively, and 249 diagnostic samples analyzed retrospectively in tissue microarray format. Validated methods for IHC and RNA-ISH were tested in tissue microarrays and full sections and the QuPath system were used for digital pathology analysis.

RESULTS:

Antibody concordance of clones SP263 and 22C3 validation was 97% to 98% in squamous cell carcinoma and adenocarcinomas, respectively. Clinical NSCLC cases were reported as PD-L1-negative (48%), 1% to 49% (23%), and more than 50% (29%), with differences associated to tissue-type and EGFR status. Comparison of IHC and RNA-ISH was highly concordant in both subgroups. Comparison of digital assessment versus manual assessment was highly concordant. Discrepancies were mostly around the 1% clinical threshold. Challenging IHC interpretation included 1) calculating the total tumor cell denominator and the nature of PD-L1 expressing cell aggregates in cytology samples; 2) peritumoral expression of positive immune cells; 3) calculation of positive tumor percentages around clinical thresholds; and 4) relevance of the 100 malignant cell rule.

CONCLUSIONS:

Sample type and EGFR status dictate differences in the expected percentage of PD-L1 expression. Analysis of PD-L1 is challenging, and interpretative guidelines are discussed. PD-L1 evaluations by RNA-ISH and digital pathology appear reliable, particularly in adenocarcinomas.

KEYWORDS:

Clinical workflow; Image analysis; Programmed death ligand 1; RNAscope; Validation

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