Overview of the origin and development of various cell types within the mononuclear phagocyte system, as well as those of stroma-derived/mesenchymal origin in lymphoid tissues, alongside their neoplastic counterparts. Abbreviations: BM, bone marrow; CMPs, common myeloid progenitors; CLPs, common lymphoid progenitors; GMPs, granulocyte–macrophage progenitors; cMoPs, common monocyte progenitors; CDPs, common dendritic cell progenitors; cDC, conventional dendritic cells; pDCs, plasmacytoid dendritic cells; moDC, monocyte-derived dendritic cell; JXG, juvenile xanthogranuloma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; ALK + H, ALK-positive histiocytosis; HS, histiocytic sarcoma; LCH, Langerhans cell histiocytosis; LCS, Langerhans cell sarcoma; IDDS, interdigitating dendritic cell sarcoma; IDDT, indeterminate dendritic cell tumor; MPDCP, mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm; BPDCN, blastic plasmacytoid dendritic cell neoplasm; SLO, secondary lymphoid organ; TLT, tertiary lymphoid tissue; FDC, follicular dendritic cell; FRC, fibroblastic reticular cell; FDCS, follicular dendritic cell sarcoma; EBV, Epstein Barr virus; FRCT, fibroblastic reticular cell tumor|@|~(^,^)~|@|Tumor cells of LCH are round-to-oval histiocytes, with characteristic nuclear grooves and convolution, and prominent eosinophil infiltrates noted within the tumor microenvironment (A and B). In another LCH, tumor cells showing nuclear grooves are admixed with multinucleated giant cells of the osteoclast type, foamy histiocytes, and numerous small lymphocytes (C and D). In LCS, high-grade cytologic pleomorphism and confluent tumor necrosis are observed (E and F). In IDDS, the tumor cells appear as spindle to epithelioid cells, with a fascicular growth pattern, interspersed with small lymphocytes (G and H). LCH, Langerhans cell histiocytosis; LCS, Langerhans cell sarcoma; IDDS, interdigitating dendritic cell sarcoma|@|~(^,^)~|@|JXG (A and B), noted as a well-circumscribed lesion (inset, B), consists of foamy histiocytes and Touton giant cells, mixed with lymphocytes. In ECD (C and D), a collection of foamy histiocytes intermingled with lymphocytes is observed. In RDD (E and F), prominent foamy histiocytes exhibiting emperipolesis are identified, accompanied by extensive plasma cell infiltration. At low magnification, the histiocytic clusters and lymphoplasmacytic tumor microenvironment create a contrasting light and dark pattern (inset, F). In ALK-positive histiocytosis (G and H), oval to spindle cells exhibit growth in fascicular and storiform patterns, interspersed with lymphocytes. Lastly, in HS (I-L), large pleomorphic tumor cells show high-grade cytologic atypia with increased mitosis and confluent tumor necrosis, displaying a storiform or whirling pattern that displaces the normal architecture of the lymph node. Abbreviations: JXG, juvenile xanthogranuloma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; HS, histiocytic sarcoma|@|~(^,^)~|@|In BPDCN (A and B), immature blastic tumor cells infiltrate the dermis and subcutis, while sparing the epidermis. In FDCS (C and D), spindled and ovoid tumor cells, occasionally showing binucleation, grow in a fascicular pattern, interspersed with small lymphocytes. In EBV + FDSC, spindle-to-oval cells, resembling follicular dendritic cells, are either dispersed or form loose whorled fascicles, admixed with a rich and prominent lymphoplasmacytic infiltrate (E and F). Abbreviations: BPDCN, blastic plasmacytoid dendritic cell neoplasm; FDCS, follicular dendritic cell sarcoma; EBV, Epstein–Barr virus; EBV + FDCS, EBV-positive inflammatory follicular dendritic cell sarcoma|@|~(^,^)~|@|Representative images of immunohistochemical expression in each subtype. Abbreviations: LCH, Langerhans cell histiocytosis; LCS, Langerhans cell sarcoma; IDDS, interdigitating dendritic cell sarcoma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; ALK + H, ALK-positive histiocytosis; HS, histiocytic sarcoma; BPDCN, blastic plasmacytoid dendritic cell neoplasm; FDCS, follicular dendritic cell sarcoma; EBV, Epstein Barr virus; EBV + FDCS, EBV-positive inflammatory follicular dendritic cell sarcoma|@|~(^,^)~|@|Brief pathways affecting the pathogenesis of histiocytic and dendritic cell neoplasms. The MAPK pathway plays a pivotal role. Mutations in this pathway, especially the BRAF V600E mutation, are thought to originate from hematopoietic progenitors in the bone marrow, particularly in the pathogenesis of LCH and ECD. Additionally, gene mutations may occur in elements upstream of BRAF, such as RAS, or downstream, such as MAP2K1 (MEK1). Moreover, ALK gene translocation and CSF1R mutation, which affect the transmembrane RTK, can also be present in certain subtypes and are related to both MAPK and PI3K/AKT/mTOR pathways. The proliferation and accumulation of neoplastic histiocytes in tissues can lead to clinical symptoms such as inflammatory reactions, fibrosis, and tissue destruction. Abbreviations: RTK, receptor tyrosine kinase; BM, bone marrow; MAPK, mitogen-activated protein kinase; LCH, Langerhans cell histiocytosis; ECD, Erdheim-Chester disease|@|~(^,^)~|@|Overall diagnostic process flow for the classification of histiocytic and dendritic cell neoplasms incorporates clinical presentations, morphology, immunohistochemistry, and molecular markers. Abbreviations: LC, Langerhans cell; XG, xanthogranuloma; IDDT, indeterminate dendritic cell tumor; LCH, Langerhans cell histiocytosis; JXG, juvenile xanthogranuloma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; IgG4-RD, IgG4-related disease; ALK + H, ALK-positive histiocytosis; IDDS, interdigitating dendritic cell sarcoma; HS, histiocytic sarcoma; LCS, Langerhans cell sarcoma; FDCS, follicular dendritic cell sarcoma; EBV, Epstein Barr virus; EBV + FDCS, EBV-positive inflammatory follicular dendritic cell sarcoma; FRCT, fibroblastic reticular cell tumor; BPDCN, blastic plasmacytoid dendritic cell neoplasm; HLM, hematolymphoid malignancies

© Blood Research