Quality in Central Pathology Assessment in Pulmonary Carcinoid and Large Cell Neuroendocrine Carcinoma: A Systematic...

Accurate pathology classification of lung neuroendocrine neoplasms (LNENs) can be challenging, particularly in small biopsies, resulting in substantial interobserver variability. To overcome this issue, central pathology review is frequently used in clinical and translational studies to improve diagnostic accuracy, but its methodology and impact remain poorly characterized. This systematic review was conducted in accordance with the PRISMA 2020 guidelines and prospectively registered in PROSPERO (CRD42022354131). A comprehensive literature search of Embase, MEDLINE, Web of Science, Cochrane Central, and Google Scholar was performed (August 2022; updated January 2025). Eligible studies included original research involving ≥20 patients with pulmonary carcinoid and/or large cell neuroendocrine carcinoma that applied central pathology review. Two reviewers independently screened studies and extracted data on study characteristics, central pathology review methodology, and diagnostic concordance. Due to anticipated heterogeneity, results were synthesized descriptively without meta-analysis. A total of 8892 records was identified, of which 359 studies met the inclusion criteria. A central pathology review was described in 106 studies (29.5%). Methodology varied widely, including the number of pathologists (median 2 pathologists, ranging from 1 to 19), or not reported (12.3%)), definition of the consensus, and procedures to resolve disagreement. Diagnostic concordance measures were reported in only 21 studies (19.8%): unanimous diagnoses had a median of 59.3% (range 11.8-100%), while consensus rates had a median of 63.8% (range 22.3-100%), and disagreement rates had a median of 17.3% (range 6.3-36.7%. Interobserver variability, most often assessed using Cohen's kappa, ranged from 0.21 to 0.98. Overall, both implementation and reporting of central pathology review showed substantial heterogeneity. Central pathology review is applied in fewer than one-third of studies on LNENs and is characterized by marked heterogeneity in methodology, reporting, and assessment of diagnostic agreement. The frequent absence of standardized consensus criteria and concordance measures limits comparability and interpretability across studies. Greater transparency and standardization of central pathology review procedures, such as the structured reporting form proposed in this study, are needed to improve diagnostic reliability and reproducibility in pathology-driven translational and clinical research.