Non-neoplastic histiocytic proliferations in bone marrow: a case series of uncommon morphologic findings

Non-neoplastic histiocytic proliferations in the bone marrow represent a heterogeneous group of reactive processes that can pose significant diagnostic challenges for pathologists. These proliferations are typically driven by underlying conditions such as infections (e.g., mycobacterial, fungal, or viral), inflammatory or autoimmune disorders, lysosomal storage disorders such as Gaucher disease, hemophagocytic syndromes, drug effects, and malignancy-associated cytokine activation. Morphologically, they may manifest as increased histiocytes with or without hemophagocytosis, granuloma formation, or accumulation of pigmented macrophages (e.g., sea-blue histiocytes), often in the context of altered marrow cellularity. One of the key diagnostic pitfalls lies in distinguishing reactive histiocytic proliferations from neoplastic entities, including histiocytic sarcoma or marrow involvement by hematologic malignancies with histiocytic differentiation. Features such as cytologic atypia, destructive growth patterns, and immunophenotypic aberrancies must be carefully assessed, but even these can overlap in reactive conditions, particularly in the setting of intense immune activation. Ancillary studies, including immunohistochemistry and molecular testing, are often necessary and must be interpreted in the appropriate clinical and morphologic context. For practicing pathologists, awareness of these reactive patterns is essential to avoid overdiagnosis and inappropriate clinical management. A systematic approach that integrates morphology, clinical history, laboratory findings, and ancillary studies is critical. Multidisciplinary communication is often necessary, particularly in complex cases where histiocytic proliferation is a secondary manifestation of systemic disease. In this article we have described the morphologic findings of non-neoplastic histiocytic proliferations in the bone marrow in an attempt to guide in the appropriate diagnosis of these entities in the appropriate clinical context.