This article presents a structured review of contemporary data on giant multinucleated cells (GMCs) as a significant morphological phenomenon in human pathology. Their pathogenetic and diagnostic relevance is highlighted in the context of chronic inflammation, granulomatous reactions, neoplastic conditions, and virus-associated processes. The relevance of this review is underscored by the fact that, despite substantial advances in immunohistochemical and molecular genetic techniques, histomorphological analysis remains the cornerstone of primary diagnostic evaluation, particularly in chronic inflammatory and granulomatous lesions. The identification of GMCs in biopsy specimens is frequently associated with persistence of a pathogenic stimulus, prolonged immune activation, and reactive tissue remodeling. However, their morphological similarity across diverse pathological conditions poses a risk of diagnostic misinterpretation. The aim of this study was to systematize the literature regarding the morphogenesis, morphological variants, and principles of diagnostic interpretation of GMCs. Publications indexed in PubMed, Scopus, Web of Science, and Google Scholar were analyzed with emphasis on morphological, pathogenetic, and clinicopathological aspects. Two principal mechanisms of GMC formation are summarized. The syncytial mechanism involves active fusion of cells of the macrophage lineage under conditions of chronic immune stimulation and is accompanied by cytoskeletal reorganization, altered expression of adhesion molecules, and cytokine-mediated regulation. The polykarionic mechanism is associated with impaired cytokinesis and repeated nuclear division without cell separation, a process more commonly observed in neoplastic, virus-induced, or severe degenerative conditions. Distinguishing between these pathways is emphasized as diagnostically critical. The main morphological variants of GMCs are described, including Langhans-type giant cells characterized by peripheral nuclear arrangement, foreign body giant cells with haphazard nuclear distribution, and Touton giant cells exhibiting lipid-rich cytoplasmic vacuolization. Their typical associations with granulomatous inflammation, foreign body reactions, and lipid metabolism disturbances are outlined. Particular attention is paid to morphological pitfalls, especially the differentiation of reactive macrophage-derived GMCs from multinucleated tumor cells, viral syncytia, and physiological multinucleated cells such as osteoclasts. It is stressed that the presence of GMCs does not constitute an independent diagnostic criterion and requires comprehensive evaluation incorporating lesion architecture, inflammatory cell composition, nuclear atypia, and proliferative activity. In diagnostically challenging cases, the application of immunohistochemical markers of macrophage lineage and proliferation indices is considered appropriate. The proposed systematic morphological approach to the interpretation of GMCs contributes to improved accuracy of pathological diagnosis, optimization of differential diagnostic assessment, and reduction of interpretative errors in clinical practice.
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