Supplementary Material for: Extensive Bone marrow involvement by BRAFV660E mutated biphenotypic Erdheim Chester Neoplasm/Rosi Dorfman disease (mixed histiocytic neoplasm) (ECD/RDD) with atypical histological features and fulminant hemophagocytosis

Background Erdheim-Chester disease (ECD) is a recently recognized clonal hematopoietic neoplasm characterized by activating alterations in the MAPK pathway. It involves multiorgan accumulation of abnormal histiocytes, leading to nonspecific clinical manifestations due to inflammation and fibrosis caused by histiocytic infiltration. Case Presentation We present a 45-year-old male with nonspecific clinical symptoms and progressive skin and abdominal lesions. Multiple tissue biopsies revealed fibrohistiocytic infiltration but provided an inconclusive diagnosis. Imaging studies showed extensive fibrosis in the perinephric regions on CT and sclerotic foci in long and pelvic bones on PET/CT. Bone marrow biopsy revealed abnormal histiocytes with multinucleated giant forms, prominent emperipolesis, active hemophagocytosis, and condensed hemosiderin deposition. Immunohistochemistry showed positive histiocytes for CD68, CD163, and partially for S-100. Molecular analysis confirmed the BRAFV660E mutation, establishing a diagnosis of ECD with atypical histologic features and findings overlapping with Rosai-Dorfaman (mixed histiocytosis). The diagnosis was challenging due to extensive fibrosis, the lack of typical histopathologic features of ECD, in addition to concurrent involvement by Rosai-Dorfman cells (mixed histiocytosis), activated macrophages, and dense hemosiderin deposition—a morphologic characteristic not previously described in ECD. Unfortunately, the diagnosis was delayed by six years, which tragically led to a fatal outcome. Conclusion The case highlights the need to recognize that ECD diagnosis requires integrating histopathology with clinical and radiographic findings. It emphasizes the importance of awareness of mixed histiocytosis features and the role of detecting BRAF mutations, even though immunohistochemistry, in suspected histiocytic neoplasms. Extensive bone marrow involvement by Erdheim-Chester disease (ECD) is rarely described. To our knowledge, there are no prior reports of bi-phenotypic (concurrent) ECD/RDD mixed histiocytosis affecting the bone marrow.