The Atypical and Suspicious for Malignancy Categories of the WHO Reporting System for Lymph Node, Spleen, and Thymus Cytopathology: Review of their Diagnostic Utility, Limitations, and Clinical Impact

ABSTRACT Background Fine‐needle aspiration biopsy (FNAB) is the preferred first‐line diagnostic tool for evaluating lymphadenopathy due to its minimally invasive nature and cost‐effectiveness. However, cytopathological interpretation of lymph node FNAB remains challenging because of the wide morphological spectrum of lymphoid lesions. The World Health Organization (WHO) Reporting System for Lymph Nodes, Spleen, and Thymus Cytopathology (WHO System) incorporates the “Atypical” and “Suspicious for malignancy” (“SFM”) categories to manage diagnostic uncertainty, yet their reproducibility and clinical implications remain undetermined. Methods This review with illustrative case‐based applications of the WHO System discusses the use, diagnostic performance, and limitations of the “Atypical” and “SFM” categories. Comparative analysis of published data, including interobserver concordance and risk of malignancy (ROM) studies, has been performed, with reference to the Sydney System and the multicenter DELYCYOUS study. Results Cases categorized as “Atypical” demonstrate highly variable ROM (28.6%–76.9%, mean ≈65%), reflecting heterogeneity in application and ancillary test integration, whereas the “SFM” category consistently exhibits high ROM (82%–100%, mean ≈95%). Interobserver agreement remains poor ( κ = 0.075 for “Atypical”; κ = 0.104 for “Suspicious for malignancy”), highlighting interpretive subjectivity. Diagnostic pitfalls include artifactual monomorphism mimicking high‐grade lymphoma and underdiagnosis of paucicellular Hodgkin lymphoma or T‐cell proliferations. Ancillary tests, while essential, may also yield misleading results—such as monoclonal B‐cell populations in reactive conditions—potentially leading to overinterpretation. Conclusions The “Atypical” and “SFM” categories are indispensable for diagnostic stratification and clinical management but suffer from limited reproducibility and intrinsic ambiguity. Their optimal application requires standardized diagnostic criteria of specific lesions, which are provided in the WHO System, institutional consistency, and integrated use of cytomorphological, immunophenotypical, and molecular data to minimize diagnostic uncertainty and improve patient outcomes.