e-Learning for Instruction and to Improve Reproducibility of Scoring Tumor-Stroma Ratio in Colon Carcinoma: Performance and Reproducibility Assessment in the UNITED Study.

BACKGROUND: The amount of stroma in the primary tumor is an important prognostic parameter. The tumor-stroma ratio (TSR) was previously validated by international research groups as a robust parameter with good interobserver agreement. OBJECTIVE: The Uniform Noting for International Application of the Tumor-Stroma Ratio as an Easy Diagnostic Tool (UNITED) study was developed to bring the TSR to clinical implementation. As part of the study, an e-Learning module was constructed to confirm the reproducibility of scoring the TSR after proper instruction. METHODS: The e-Learning module consists of an autoinstruction for TSR determination (instruction video or written protocol) and three sets of 40 cases (training, test, and repetition sets). Scoring the TSR is performed on hematoxylin and eosin-stained sections and takes only 1-2 minutes. Cases are considered stroma-low if the amount of stroma is ≤50%, whereas a stroma-high case is defined as >50% stroma. Inter- and intraobserver agreements were determined based on the Cohen κ score after each set to evaluate the reproducibility. RESULTS: Pathologists and pathology residents (N=63) with special interest in colorectal cancer participated in the e-Learning. Forty-nine participants started the e-Learning and 31 (63%) finished the whole cycle (3 sets). A significant improvement was observed from the training set to the test set; the median κ score improved from 0.72 to 0.77 (P=.002). CONCLUSIONS: e-Learning is an effective method to instruct pathologists and pathology residents for scoring the TSR. The reliability of scoring improved from the training to the test set and did not fall back with the repetition set, confirming the reproducibility of the TSR scoring method. TRIAL REGISTRATION: The Netherlands Trial Registry NTR7270; https://www.trialregister.nl/trial/7072. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/13464.

Incidents in Molecular Pathology: Frequency and Causes During Routine Testing.

CONTEXT.­: Errors in laboratory medicine could compromise patient safety. Good laboratory practice includes identifying and managing nonconformities in the total test process. Varying error percentages have been described in other fields but are lacking for molecular oncology. OBJECTIVES.­: To gain insight into incident causes and frequency in the total test process from 8 European institutes routinely performing biomarker tests in non-small cell lung cancer and colorectal cancer. DESIGN.­: All incidents documented in 2018 were collected from all hospital services for pre-preanalytical entries before the biomarker test, as well as specific incidents for biomarker tests. RESULTS.­: There were 5185 incidents collected, of which 4363 (84.1%) occurred in the pre-preanalytical phase (all hospital services), 2796 of 4363 (64.1%) related to missing or incorrect request form information. From the other 822 specific incidents, 166 (20.2%) were recorded in the preanalytical phase, 275 (33.5%) in the analytical phase, and 194 (23.6%) in the postanalytical phase, mainly due to incorrect report content. Only 47 of 822 (5.7%) incidents were recorded in the post-postanalytical phase, and 123 (15.0%) in the complete total test process. For 17 of 822 (2.1%) incidents the time point was unknown. Pre-preanalytical incidents were resolved sooner than incidents on the complete process (mean 6 versus 60 days). For 1215 of 5168 (23.5%) incidents with known causes a specific action was undertaken besides documenting them, not limited to accredited institutes. CONCLUSIONS.­: There was a large variety in the number and extent of documented incidents. Correct and complete information on the request forms and final reports are highly error prone and require additional focus.

PD-L1 immunohistochemistry in non-small-cell lung cancer: unraveling differences in staining concordance and interpretation.

Programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) is accepted as a predictive biomarker for the selection of immune checkpoint inhibitors. We evaluated the staining quality and estimation of the tumor proportion score (TPS) in non-small-cell lung cancer during two external quality assessment (EQA) schemes by the European Society of Pathology. Participants received two tissue micro-arrays with three (2017) and four (2018) cases for PD-L1 IHC and a positive tonsil control, for staining by their routine protocol. After the participants returned stained slides to the EQA coordination center, three pathologists assessed each slide and awarded an expert staining score from 1 to 5 points based on the staining concordance. Expert scores significantly (p < 0.01) improved between EQA schemes from 3.8 (n = 67) to 4.3 (n = 74) on 5 points. Participants used 32 different protocols: the majority applied the 22C3 (56.7%) (Dako), SP263 (19.1%) (Ventana), and E1L3N (Cell Signaling) (7.1%) clones. Staining artifacts consisted mainly of very weak or weak antigen demonstration (63.0%) or excessive background staining (19.8%). Participants using CE-IVD kits reached a higher score compared with those using laboratory-developed tests (LDTs) (p < 0.05), mainly attributed to a better concordance of SP263. The TPS was under- and over-estimated in 20/423 (4.7%) and 24/423 (5.7%) cases, respectively, correlating to a lower expert score. Additional research is needed on the concordance of less common protocols, and on reasons for lower LDT concordance. Laboratories should carefully validate all test methods and regularly verify their performance. EQA participation should focus on both staining concordance and interpretation of PD-L1 IHC.

Managing Deviating EQA Results: A Survey to Assess the Corrective and Preventive Actions of Medical Laboratories Testing for Oncological Biomarkers.

Laboratories testing predictive biomarkers in lung and colorectal cancer are advised to participate in external quality assessment (EQA) schemes. This study aimed to investigate which corrective actions were taken by laboratories if predetermined performance criteria were not met, to ultimately improve current test practices. EQA participants from the European Society of Pathology between 2014 and 2018 for lung and colorectal cancer were contacted, if they had at least one analysis error or test failure in the provided cases, to complete a survey. For 72.4% of 514 deviating EQA results, an appropriate action was performed, most often including staff training (15.2%) and protocol revisions (14.6%). Main assigned persons were the molecular biologist (40.0%) and pathologist (46.5%). A change in test method or the use of complex techniques, such as next-generation sequencing, required more training and the involvement of dedicated personnel to reduce future test failures. The majority of participants adhered to ISO 15189 and implemented suitable actions by designated staff, not limited to accredited laboratories. However, for 27.6% of cases (by 20 laboratories) no corrective action was taken, especially for pre-analytic problems and complex techniques. The surveys were feasible to request information on results follow-up and further recommendations were provided.