AbstractFibroma of tendon sheath (FTS) and tendosynovial giant cell tumor show similarities in site of incidence, benign clinical features, and biologic behavior. Whether FTS and GCT are related histogenetically and biologically has recently been studied immunohistochemically. Factor XIIIa+ dendrophages are dendritic stromal histiocytes that differentiate early in embryogenesis from primitive mesenchyme and persist in fetoplacental and adult collagenous connective tissues. FXIIIa is a fibroblast growth factor that also catalyses cross-linking of matrix protein monomers. CD34, the human progenitor antigen, is a transmembrane glycoprotein involved in signal transduction. CD34 is expressed on widely distributed fibroblast-like progenitor cells as well as endothelium in both the embryo and the adult. To explore whether FXIIIa+ dendrophages and CD34+ mesenchymal cells participate in the morphogenesis of FTS and GCT, we studied 5 FTS and 9 GCT with antibodies to factor XIIIa (FXIIIa), CD34, HHF35 actin, vimentin, and S-100. Six samples of embryonic and fetal mesenchyme were also studied. 5/5 FTS contained numerous FXIIIa+ dendritic cells that were deployed in myxohyaline stroma that also contained numerous CD34+ capillaries and foci of CD34+/actin+myofibroblasts in 4/5 FTS. GCT were cellular, relatively avascular and had minimal stroma. All 9 GCT were variably FXIIIa+. Spindled and histiocytoid mononuclear cells and pseudoadenoid space lining cells in GCT showed negative to often strong FXIIIa reactivity in a random pattern throughout the tumors. Strong reactivity was distributed haphazardly in geographic zones. Actin and CD34 were negative in GCT except for a few vessels. FXIIIa+ cells were numerous also in embryonic dermis, tendosynovial anlagen, mineralizing cartilage anlagen of bones, and the stsoma of chorionic villi suggesting that FXIIIa+ cells are active in stromal morphogenesis and matrix remodeling.We conclude that pleiotropic tendosynovial FXIIIa+ dendrophages participate in the morphogenesis of both FTS and GCT. FTS is a rapidly evolving process that is initially cellular and angioformative and later undergoes myofibroblastic sclerosis. It is rich in strongly staining FXIIIa+ dendrophages at all stages of development. FXIIIa+ dendrophage modulation of phenotypic changes in neighboring tendosynovial CD34+ dendritic progenitor cells may control the circumscribed growth of FTS. GCT appears to also arise from proliferating tendosynovial FXIIIa+ dendrophages that instead undergo macrophage-like cytodifferentiation with little induction of other stromal cells. Thus, FTS and GCT appear to be divergent tissue responses to stress or trauma in tendosynovial tissues, both of which involve FXIIIa+ fibrohistiocytic mesenchymal cells. (The J Histotechnol19:45, 1996)