WHOverlap Multicentre Study: Dissecting the Insufficient/Inadequate/Non-Diagnostic Category and Its Overlap with the Benign Category in the WHO Reporting System for Lung Cytopathology

Abstract – Introduction: Distinguishing between nondiagnostic (ND) and benign (B) categories in lung cytopathology remains clinically challenging, especially given the significant overlap and the high risk of malignancy (ROM) often reported for ND cases. The 2022 WHO Reporting System for Lung Cytopathology addresses these issues but acknowledges that ND may carry up to a 60% ROM. We conducted a large, multicenter study to clarify the ND-B boundary and evaluate how radiologic findings influence ROM. Methods: From 12 institutions, 363 consecutive lung cytopathology cases categorized as insufficient/inadequate/ND (I/I/ND) or B with histopathological follow-up were analysed. The locally categorized cytopathological cases were subclassified centrally into: ND with insufficient cellularity (IS-C), artefactual/sample preparation error (IS-P), non-representative (NR1: no suspicious lesion; NR2: suspicious lesion); and B (B1: benign cells, no suspicious lesion; B2: benign cells, suspicious lesion). ROM was defined as the percentage of histologically confirmed malignancies in each group. Results: Overall, 60.6% (220/363) of cases were confirmed as malignant on histopathological evaluation. Within the ND category (n = 149), 70.5% (105/149) were malignant, exceeding the malignancy risk range estimated by the WHO system (40–60%). In comparison, the ROM for cases classified as B (n = 214) was 53.7% (115/214), which is consistent with the WHO system reference range. Notably, when ND or B cytopathology coincided with suspicious imaging findings (NR2 [n = 57] or B2 [n = 124]), the ROM exceeded 75% (134/181). These results indicate that subclassification based on imaging findings provides a more refined estimation of malignancy risk. Cases with B cytopathology may still carry a high likelihood of malignancy when imaging features are suspicious, reinforcing the importance of integrated diagnostic evaluation. Conclusions: These findings demonstrate that imaging correlation is critical for accurate risk assessment in the overlap between the ND and B cytopathology categories. Subclassification of ND and B cases based on imaging features and consistent reporting of ROM can help identify patients who may benefit from repeat sampling or further diagnostic evaluation. This approach has the potential to enhance diagnostic accuracy and improve clinical decision-making.