Erdheim-Chester Disease: A Diagnostic Challenge

Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis characterized by excessive production and accumulation of histiocytes within various tissues. The discovery of activating mutations within the Mitogen-Activated Protein Kinase (MAPK) pathway has established its neoplastic nature and enabled the use of targeted therapeutic approaches. Despite these advances, ECD remains a diagnostic challenge, often due to its nonspecific symptoms, multisystemic involvement, and consequent delay in diagnosis. We report three cases of ECD illustrating its diverse clinical presentations and diagnostic complexity. The first case involved an elderly woman with retroperitoneal and pericardial involvement, who developed urinary sepsis and died shortly after diagnosis. The second case was a man in his seventies with cardiovascular and renal involvement who did not respond to corticosteroids or peginterferon alfa-2a and died within a year. The third case, also a man in his seventies, presented with similar multisystemic involvement but achieved clinical and radiological improvement following targeted v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibition. These cases highlight the heterogeneous course of ECD and the critical importance of early recognition and tailored therapy. Reporting additional cases contributes to a deeper understanding of its variable features, diagnostic pitfalls, and treatment outcomes.