Practical Imaging Approach to Determining the Cause of Nonneoplastic Lymphadenopathy.

In the daily clinical practice of radiologists, unexpected lymphadenopathy is frequently encountered, the majority of which is nonneoplastic. The causes of nonneoplastic lymphadenopathy are variable, and nonspecific histologic findings may challenge the accurate diagnosis. Therefore, inferring or identifying the cause based on imaging findings carries substantial clinical relevance. The causes of nonneoplastic lymphadenopathy can be broadly categorized as follows: (a) infections that lead to lymphadenitis; (b) systemic disorders such as sarcoidosis, Kawasaki disease, rheumatoid arthritis, systemic lupus erythematosus, immunoglobulin G4-related disease, Castleman disease, dermatopathic lymphadenopathy, and histiocytosis; (c) iatrogenic causes including drug-induced lymphadenopathy and COVID-19 vaccine-related lymphadenopathy; and (d) miscellaneous causes including congestion from heart failure, foreign body lymphadenopathy from substances such as silicone, epithelial inclusions in lymph nodes, and tumor-associated reactive lymphadenopathy. The distribution of lymphadenopathy, imaging characteristics of the enlarged lymph nodes themselves (eg, necrosis, cystic changes, hypervascularity, or calcification), and additional imaging findings in other organs can help narrow down the differential diagnosis and potentially identify the most likely cause. Even when the underlying cause of lymphadenopathy does not require treatment, establishing the likely cause and correctly excluding malignancy can prevent unnecessary tests and excessive interventions, such as biopsies. Thus, radiologists can play a crucial role in directing the management of such patients and must be familiar with the various conditions that result in nonneoplastic lymphadenopathy, their imaging findings, and their clinical manifestations. The authors provide an overview of these conditions and their imaging appearances and discuss approaches for identifying the cause of nonneoplastic lymphadenopathy based on imaging findings as well as clinical information. ©RSNA, 2025 Supplemental material is available for this article.