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Penault-Llorca F, Kerr KM, Garrido P, Thunnissen E, Dequeker E, Normanno N, Patton SJ, Fairley J, Kapp J, de Ridder D, Ryška A, Moch H. Expert opinion on NSCLC small specimen biomarker testing - Part 2: Analysis, reporting, and quality assessment. Virchows Arch 2022; 481:351-366. [PMID: 35857103 PMCID: PMC9297263 DOI: 10.1007/s00428-022-03344-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 05/16/2022] [Accepted: 05/18/2022] [Indexed: 10/31/2022]
Abstract
The diagnostic work-up for non-small cell lung cancer (NSCLC) requires biomarker testing to guide therapy choices. This article is the second of a two-part series. In Part 1, we summarised evidence-based recommendations for obtaining and processing small specimen samples (i.e. pre-analytical steps) from patients with advanced NSCLC. Here, in Part 2, we summarise evidence-based recommendations relating to analytical steps of biomarker testing (and associated reporting and quality assessment) of small specimen samples in NSCLC. As the number of biomarkers for actionable (genetic) targets and approved targeted therapies continues to increase, simultaneous testing of multiple actionable oncogenic drivers using next-generation sequencing (NGS) becomes imperative, as set forth in European Society for Medical Oncology guidelines. This is particularly relevant in advanced NSCLC, where tissue specimens are typically limited and NGS may help avoid tissue exhaustion compared with sequential biomarker testing. Despite guideline recommendations, significant discrepancies in access to NGS persist across Europe, primarily due to reimbursement constraints. The use of increasingly complex testing methods also has implications for the reporting of results. Molecular testing reports should include clinical interpretation with additional commentary on sample adequacy as appropriate. Molecular tumour boards are recommended to facilitate the interpretation of complex genetic information arising from NGS, and to collaboratively determine the optimal treatment for patients with NSCLC. Finally, whichever testing modality is employed, it is essential that adequate internal and external validation and quality control measures are implemented.
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Affiliation(s)
| | - Keith M Kerr
- Department of Pathology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, UK
| | - Pilar Garrido
- Medical Oncology Department, Hospital Universitario Ramón Y Cajal, University of Alcalá, Madrid, Spain
| | - Erik Thunnissen
- Amsterdam University Medical Center, VU Medical Center, Amsterdam, the Netherlands
| | - Elisabeth Dequeker
- Department of Public Health, Biomedical Quality Assurance Research Unit, Campus Gasthuisberg, University Leuven, Leuven, Belgium
| | - Nicola Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori "Fondazione Giovanni Pascale" IRCCS, Naples, Italy
| | | | | | | | | | - Aleš Ryška
- Department of Pathology, Charles University Medical Faculty Hospital, Hradec Králové, Czech Republic
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
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Koomen BM, Voorham QJM, Epskamp-Kuijpers CCHJ, van Dooijeweert C, van Lindert ASR, Deckers IAG, Willems SM. Considerable interlaboratory variation in PD-L1 positivity in a nationwide cohort of non-small cell lung cancer patients. Lung Cancer 2021; 159:117-126. [PMID: 34332333 DOI: 10.1016/j.lungcan.2021.07.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/14/2021] [Accepted: 07/16/2021] [Indexed: 11/24/2022]
Abstract
OBJECTIVES Immunohistochemical expression of programmed death-ligand 1 (PD-L1) is used as a predictive biomarker for prescription of immunotherapy to non-small cell lung cancer (NSCLC) patients. Accurate assessment of PD-L1 expression is therefore crucial. In this study, the extent of interlaboratory variation in PD-L1 positivity in the Netherlands was assessed, using real-world clinical pathology data. MATERIALS AND METHODS Data on all NSCLC patients in the Netherlands with a mention of PD-L1 testing in their pathology report from July 2017 to December 2018 were extracted from PALGA, the nationwide network and registry of histo- and cytopathology in the Netherlands. PD-L1 positivity rates were determined for each laboratory that performed PD-L1 testing, with separate analyses for histological and cytological material. Two cutoffs (1% and 50%) were used to determine PD-L1 positivity. Differences between laboratories were assessed using funnel plots with 95% confidence limits around the overall mean. RESULTS 6,354 patients from 30 laboratories were included in the analysis of histology data. At the 1% cutoff, maximum interlaboratory variation was 39.1% (32.7%-71.8%) and ten laboratories (33.3%) differed significantly from the mean. Using the 50% cutoff, four laboratories (13.3%) differed significantly from the mean and maximum variation was 23.1% (17.2%-40.3%). In the analysis of cytology data, 1,868 patients from 23 laboratories were included. Eight laboratories (34.8%) differed significantly from the mean in the analyses of both cutoffs. Maximum variation was 41.2% (32.2%-73.4%) and 29.2% (14.7%-43.9%) using the 1% and 50% cutoffs, respectively. CONCLUSION Considerable interlaboratory variation in PD-L1 positivity was observed. Variation was largest using the 1% cutoff. At the 50% cutoff, analysis of cytology data demonstrated a higher degree of variation than the analysis of histology data.
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Affiliation(s)
- Bregje M Koomen
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands.
| | | | - Chantal C H J Epskamp-Kuijpers
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands; PALGA Foundation, De Bouw 123, 3991 SZ, Houten, the Netherlands
| | - Carmen van Dooijeweert
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
| | - Anne S R van Lindert
- Department of Pulmonology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
| | | | - Stefan M Willems
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
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Shidham VB, Layfield LJ. Cell-blocks and immunohistochemistry. Cytojournal 2021; 18:2. [PMID: 33598043 PMCID: PMC7881511 DOI: 10.25259/cytojournal_83_2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 12/26/2020] [Indexed: 12/25/2022] Open
Abstract
The interpretation of results on immunostained cell-block sections has to be compared with the cumulative published data derived predominantly from formalin-fixed paraffin-embedded (FFPE) tissue sections. Because of this, it is important to recognize that the fixation and processing protocol should not be different from the routinely processed FFPE surgical pathology tissue. Exposure to non-formalin fixatives or reagents may interfere with the diagnostic immunoreactivity pattern. The immunoprofile observed on such cell-blocks, which are not processed in a manner similar to the surgical pathology specimens, may not be representative resulting in aberrant results. The field of immunohistochemistry (IHC) is advancing continuously with the standardization of many immunomarkers. A variety of technical advances such as multiplex IHC with refined methodologies and automation is increasing its role in clinical applications. The recent addition of rabbit monoclonal antibodies has further improved sensitivity. As compared to the mouse monoclonal antibodies, the rabbit monoclonal antibodies have 10 to 100 fold higher antigen affinity. Most of the scenarios involve the evaluation of coordinate immunostaining patterns in cell-blocks with relatively scant diagnostic material without proper orientation which is usually retained in most of the surgical pathology specimens. These challenges are addressed if cell-blocks are prepared with some dedicated methodologies such as NextGen CelBloking™ (NGCB) kits. Cell-blocks prepared by NGCB kits also facilitate the easy application of the SCIP (subtractive coordinate immunoreactivity pattern) approach for proper evaluation of coordinate immunoreactivity. Various cell-block and IHC-related issues are discussed in detail.
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Affiliation(s)
- Vinod B. Shidham
- Department of Pathology, Wayne State University School of Medicine, Karmanos Cancer Center and Detroit Medical Center, Detroit, Michigan, USA
| | - Lester J. Layfield
- Department of Pathology and Anatomical Sciences, University of Missouri, One Hospital Drive, Columbia, Missouri, United States
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Paver EC, Cooper WA, Colebatch AJ, Ferguson PM, Hill SK, Lum T, Shin JS, O'Toole S, Anderson L, Scolyer RA, Gupta R. Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation. Pathology 2020; 53:141-156. [PMID: 33388161 DOI: 10.1016/j.pathol.2020.10.007] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 10/05/2020] [Accepted: 10/08/2020] [Indexed: 12/20/2022]
Abstract
Immunotherapy with checkpoint inhibitors is well established as an effective treatment for non-small cell lung cancer and melanoma. The list of approved indications for treatment with PD-1/PD-L1 checkpoint inhibitors is growing rapidly as clinical trials continue to show their efficacy in patients with a wide range of solid tumours. Clinical trials have used a variety of PD-L1 immunohistochemical assays to evaluate PD-L1 expression on tumour cells, immune cells or both as a potential biomarker to predict response to immunotherapy. Requests to pathologists for PD-L1 testing to guide choice of therapy are rapidly becoming commonplace. Thus, pathologists need to be aware of the different PD-L1 assays, methods of evaluation in different tumour types and the impact of the results on therapeutic decisions. This review discusses the key practical issues relating to the implementation of PD-L1 testing for solid tumours in a pathology laboratory, including evidence for PD-L1 testing, different assay types, the potential interchangeability of PD-L1 antibody clones and staining platforms, scoring criteria for PD-L1, validation, quality assurance, and pitfalls in PD-L1 assessment. This review also explores PD-L1 IHC in solid tumours including non-small cell lung carcinoma, head and neck carcinoma, triple negative breast carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal carcinoma, colorectal carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The review aims to provide pathologists with a practical guide to the implementation and interpretation of PD-L1 testing by immunohistochemistry.
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Affiliation(s)
- Elizabeth C Paver
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia
| | - Wendy A Cooper
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Western Sydney University, Campbelltown, NSW, Australia
| | - Andrew J Colebatch
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Peter M Ferguson
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Sean K Hill
- Gold Coast University Hospital, Southport, Qld, Australia
| | - Trina Lum
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia
| | - Joo-Shik Shin
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
| | - Sandra O'Toole
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
| | - Lyndal Anderson
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Western Sydney University, Campbelltown, NSW, Australia
| | - Richard A Scolyer
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Ruta Gupta
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia.
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5
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Affiliation(s)
- Erik Thunnissen
- Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
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Torlakovic EE. How to Validate Predictive Immunohistochemistry Testing in Pathology? Arch Pathol Lab Med 2020; 143:907. [PMID: 31339752 DOI: 10.5858/arpa.2019-0056-le] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Emina Emilia Torlakovic
- Department of Pathology and Laboratory Medicine, Saskatchewan Health Authority and University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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7
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Gkiouras K, Grammatikopoulou MG, Theodoridis X, Pagkalidou E, Chatzikyriakou E, Apostolidou AG, Rigopoulou EI, Sakkas LI, Bogdanos DP. Diagnostic and clinical significance of antigen-specific pancreatic antibodies in inflammatory bowel diseases: A meta-analysis. World J Gastroenterol 2020; 26:246-265. [PMID: 31988587 PMCID: PMC6962435 DOI: 10.3748/wjg.v26.i2.246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/19/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-invasive criteria are needed for Crohn's disease (CD) diagnosis, with several biomarkers being tested. Results of individual diagnostic test accuracy studies assessing the diagnostic value of pancreatic autoantibodies-to-glycoprotein-2 (anti-GP2) tests for the diagnosis of CD appear promising. AIM To systematically review and meta-analyze evidence on the diagnostic accuracy of anti-GP2 tests in patients with suspected/confirmed CD. METHODS An electronic search was conducted on PubMed, Cochrane-CENTRAL and grey literature (CRD42019125947). The structured research question in PICPTR format was "Population" including patients with symptoms akin to CD, the "Index test" being anti-GP2 testing, the "Comparator" involved standard CD diagnosis, the "Purpose of test" being diagnostic, "Target disorder" was CD, and the "Reference standard" included standard clinical, radiological, endoscopical, and histological CD diagnostic criteria. Quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool and hierarchical models were employed to synthesize the data. RESULTS Out of 722 studies retrieved, 15 were meta-analyzed. Thirteen studies had industry-related conflicts-of-interest, and most included healthy donors as controls (spectrum bias). For the combination of IgA and/or IgG anti-GP2 test, the summary sensitivity was 20% (95% confidence interval: 10%-29%) at a median specificity of 97%. If the test was applied in 10000 suspected patients, 9669 would be true negatives and in 26, the diagnosis would be missed. In this hypothetical cohort, the anti-GP2 would fail to produce a diagnosis for 81.3% of the positive cases. Low summary points of sensitivity and high specificity were estimated for the IgG or IgA anti-GP2 test. Analogous results were observed when the analyses were restricted using specific cut-offs, or when ulcerative colitis patients were used as comparators. CONCLUSION Anti-GP2 tests demonstrate low sensitivity and high specificity. These results indicate that caution is required before relying on its diagnostic value. Additionally, the need for improving the methodology of diagnostic test accuracy studies is evident.
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Affiliation(s)
- Konstantinos Gkiouras
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Maria G Grammatikopoulou
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Sindos Campus, Thessaloniki GR57400, Greece
| | - Xenophon Theodoridis
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Eirini Pagkalidou
- Laboratory of Hygiene, Social and Preventive Medicine and Medical Statistics, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Evangelia Chatzikyriakou
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
- Laboratory of Clinical Neurophysiology, AHEPA University Hospital, Faculty of Medicine, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Anna G Apostolidou
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Sindos Campus, Thessaloniki GR57400, Greece
| | - Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Biopolis, Larissa GR41110, Greece
| | - Lazaros I Sakkas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
| | - Dimitrios Petrou Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Division of Transplantation, Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London Medical School, London GR41110, United Kingdom
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8
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Lantuejoul S, Sound-Tsao M, Cooper WA, Girard N, Hirsch FR, Roden AC, Lopez-Rios F, Jain D, Chou TY, Motoi N, Kerr KM, Yatabe Y, Brambilla E, Longshore J, Papotti M, Sholl LM, Thunnissen E, Rekhtman N, Borczuk A, Bubendorf L, Minami Y, Beasley MB, Botling J, Chen G, Chung JH, Dacic S, Hwang D, Lin D, Moreira A, Nicholson AG, Noguchi M, Pelosi G, Poleri C, Travis W, Yoshida A, Daigneault JB, Wistuba II, Mino-Kenudson M. PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee. J Thorac Oncol 2019; 15:499-519. [PMID: 31870882 DOI: 10.1016/j.jtho.2019.12.107] [Citation(s) in RCA: 217] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/29/2019] [Accepted: 12/12/2019] [Indexed: 12/20/2022]
Abstract
The recent development of immune checkpoint inhibitors (ICIs) has led to promising advances in the treatment of patients with NSCLC and SCLC with advanced or metastatic disease. Most ICIs target programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) axis with the aim of restoring antitumor immunity. Multiple clinical trials for ICIs have evaluated a predictive value of PD-L1 protein expression in tumor cells and tumor-infiltrating immune cells (ICs) by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms, and many laboratories have set up in-house or laboratory-developed tests that are more affordable than the generally expensive clinical trial-validated assays. Although PD-L1 IHC test is now deployed in most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging owing to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. Because many articles have been published since the issue of the IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer, this review by the IASLC Pathology Committee provides updates on the indications of ICIs for lung cancer in 2019 and discusses important considerations on preanalytical, analytical, and postanalytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance, and training.
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Affiliation(s)
- Sylvie Lantuejoul
- Centre Léon Bérard Unicancer, Lyon, France; Université Grenoble Alpes, Grenoble, France
| | - Ming Sound-Tsao
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | | | - Nicolas Girard
- Institut Curie, Paris, and Université Claude Bernard, Lyon, France
| | - Fred R Hirsch
- Center for Thoracic Oncology, The Tisch Cancer Institute, New York, New York; Ichan School of Medicine, Mount Sinai Health System, New York, New York
| | | | | | - Deepali Jain
- All India Institute of Medical Sciences, New Delhi, India
| | | | | | - Keith M Kerr
- Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom
| | | | | | | | | | - Lynette M Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; Department of Pathology, Harvard Medical School, Boston, Massachusetts
| | - Erik Thunnissen
- Department of Pathology, VU University Medical Center, Amsterdam, Netherlands
| | | | | | - Lukas Bubendorf
- Institute of Pathology, University of Basel, Basel, Switzerland
| | - Yuko Minami
- Ibarakihigashi National Hospital, Tokai, Japan
| | - Mary Beth Beasley
- Ichan School of Medicine, Mount Sinai Health System, New York, New York
| | | | - Gang Chen
- Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jin-Haeng Chung
- Seoul National University Bundang Hospital, Seoul, South Korea
| | - Sanja Dacic
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - David Hwang
- Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Dongmei Lin
- Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Andre Moreira
- New York University School of Medicine, New York, New York
| | - Andrew G Nicholson
- Royal Brompton and Harefield NHS Foundation Trust, London, and National Heart and Lung Institute, Imperial College, United Kingdom
| | | | | | - Claudia Poleri
- Office of Pathology Consultants, Buenos Aires, Argentina
| | - William Travis
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | | | | | - Mari Mino-Kenudson
- Department of Pathology, Harvard Medical School, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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Dodson A, Parry S, Lissenberg-Witte B, Haragan A, Allen D, O'Grady A, McClean E, Hughes J, Miller K, Thunnissen E. External quality assessment demonstrates that PD-L1 22C3 and SP263 assays are systematically different. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2019; 6:138-145. [PMID: 31849189 PMCID: PMC7164369 DOI: 10.1002/cjp2.153] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/18/2019] [Accepted: 11/24/2019] [Indexed: 12/20/2022]
Abstract
PD‐L1 inhibitors are part of first line treatment options for patients with advanced non‐small cell lung cancer. PD‐L1 immunohistochemistry (IHC) assays act as either a companion or a complementary diagnostic. The purpose of this study is to describe the experience of external quality assurance (EQA) provider UK NEQAS ICC and ISH with the comparison of different PD‐L1 assays used in daily practice. Three EQA rounds (pilot, run A and run B) were carried out using formalin fixed paraffin embedded samples with sample sets covering a range of epitope concentrations, including ‘critical samples’ near to clinical threshold cut‐offs. An expert panel (n = 4) evaluated all returned slides simultaneously and independently on a multi‐header microscope together with the participants own in‐house control material. The tonsil sample was evaluated as ‘acceptable’ or ‘unacceptable’, and for the other samples the percentage of PD‐L1 stained tumour cells were estimated in predetermined categories (<1%, 1 to <5%, 5 to <10%, 10 to <25%, 25 to <50%, 50 to <80%, 80 to 100%). In the pilot and the two subsequent runs the number of participating laboratories was 43, 69 and 76, respectively. The pass rate for the pilot run was 67%; this increased to 81% at run A and 82% at run B. For two ‘critical samples’, in runs A and B, 22C3 IHC had significantly higher PD‐L1 expression than SP263 IHC (p < 0.001), whilst the PD‐L1 scores for the other six samples were similar for all assays. In run A the laboratory developed tests (LDTs) using 22C3 scored lower than the commercial 22C3 tests (p = 0.01). After the initial testing, improvement in performance of PD‐L1 IHC is shown for approved and LDT PD‐L1 assays. Equivalency of approved PD‐L1 22C3 and SP263 assays cannot be assumed as the scores cross the clinically relevant thresholds of 1% and 50% PD‐L1 expression.
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Affiliation(s)
- Andrew Dodson
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation, London, UK
| | - Suzanne Parry
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation, London, UK
| | - Birgit Lissenberg-Witte
- Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Alex Haragan
- Department of Pathology, Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK
| | | | - Anthony O'Grady
- Department of Pathology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Emma McClean
- Oncology, Haematology and Cellular Pathology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Jamie Hughes
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation, London, UK
| | - Keith Miller
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation, London, UK
| | - Erik Thunnissen
- Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Butter R, 't Hart NA, Hooijer GKJ, Monkhorst K, Speel EJ, Theunissen P, Thunnissen E, Von der Thüsen JH, Timens W, van de Vijver MJ. Multicentre study on the consistency of PD-L1 immunohistochemistry as predictive test for immunotherapy in non-small cell lung cancer. J Clin Pathol 2019; 73:423-430. [PMID: 31822512 DOI: 10.1136/jclinpath-2019-205993] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/23/2019] [Accepted: 11/16/2019] [Indexed: 12/16/2022]
Abstract
AIMS Investigate the impact of interlaboratory- and interobserver variability of immunohistochemistry on the assessment of programmed death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). METHODS Two tissue microarrays (TMAs) were constructed from 50 (TMA-A) and 51 (TMA-B) resected NSCLC cases, and distributed among eight centres. Immunostaining for PD-L1 was performed using Agilent's 22C3 pharmDx Assay (pharmDx) and/or a 22C3 laboratory developed test (LDT). The interlaboratory variability of staining- and interobserver variability of scoring for PD-L1 were assessed in selected critical samples (samples at the cut-off of positivity) and non-critical samples. Also, PD-L1 epitope deterioration in time in stored unstained slides was analysed. Krippendorff's alpha values (0=maximal, 1=no variability) were calculated as measure for variability. RESULTS For interlaboratory variability of immunostaining, the percentage of PD-L1 positive cases among centres ranged 40%-51% (1% cut-off) and 23%-30% (50% cut-off). Alpha values at 1% cut-off were 0.88 (pharmDx) and 0.87 (LDT) and at 50% cut-off 0.82 (pharmDx) and 0.95 (LDT). Interobserver variability of scoring resulted in PD-L1 positive cases ranging 29%-55% (1% cut-off) and 14%-30% (50% cut-off) among pathologists. Alpha values were at 1% cut-off 0.83 (TMA-A) and 0.66 (TMA-B), and at 50% cut-off 0.77 (TMA-A) and 0.78 (TMA-B). Interlaboratory variability of staining was higher (p<0.001) in critical samples than in non-critical samples at 50% cut-off. Furthermore, PD-L1 epitope deterioration in unstained slides was observed after 12 weeks. CONCLUSIONS The results provide insight in factors contributing to variability of immunohistochemical assessment of PD-L1, and contribute to more reliable predictive testing for PD-L1.
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Affiliation(s)
- Rogier Butter
- Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Nils A 't Hart
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerrit K J Hooijer
- Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Kim Monkhorst
- Department of Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Ernst-Jan Speel
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Paul Theunissen
- Department of Pathology, Zuyderland Medical Center, Heerlen, The Netherlands
| | - Erik Thunnissen
- Department of Pathology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jan H Von der Thüsen
- Department of Pathology, Erasmus University Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Wim Timens
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marc J van de Vijver
- Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.,Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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11
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Troxell ML, Fulton RS, Swanson PE, Bellizzi AM, Fitzgibbons PL, Ambaye AB, Haas TS, Goldsmith JD, Loykasek PA, Miller DV, O'Malley D, Qiu J, Salama ME, Schaberg KB, Schwartz RA, Shia J, Summers TA, Wu Y. Predictive Markers Require Thorough Analytic Validation. Arch Pathol Lab Med 2019; 143:907-909. [PMID: 31339757 DOI: 10.5858/arpa.2019-0112-le] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Megan L Troxell
- 1 Department of Pathology, Stanford University Medical Center, Stanford, California
| | | | - Paul E Swanson
- 3 Department of Pathology, University of Washington, Seattle
| | | | | | - Abiy B Ambaye
- 6 Department of Pathology, University of Vermont, Burlington
| | - Thomas S Haas
- 7 Department of Pathology, St Francis Hospital, Milwaukee, Wisconsin
| | - Jeffrey D Goldsmith
- 8 Department of Pathology, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts
| | | | - Dylan V Miller
- 10 Intermountain Central Laboratory, University of Utah, Salt Lake City
| | | | - Jingxin Qiu
- 12 Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | | | - Kurt B Schaberg
- 14 Department of Pathology, University of Kentucky, Lexington
| | - Robert A Schwartz
- 15 Department of Pathology, Waterbury Hospital, Waterbury, Connecticut
| | - Jinru Shia
- 16 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Thomas A Summers
- 17 Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
| | - Yaping Wu
- 18 Oregon Regional Pathology Services, Providence Health & Services, Portland
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