Molecular pathological insights into tumorigenesis and progression of giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a primary bone tumor that typically exhibits benign histological appearance and clinical behavior in most cases, with local aggressiveness and rare metastasis. It predominantly affects individuals in the young adult age group. It is characterized by the presence of multinucleated osteoclastic giant cells and a stromal population of neoplastic cells. A key hallmark for GCTB pathogenesis is the G34W genetic mutation in the histone H3.3 gene, which is restricted to the population of cancerous stromal cells and is absent in osteoclasts and their progenitor cells. This review presents a comprehensive overview of the pathology of GCTB, including its histopathological characteristics, cytological features, histopathological variants, and their clinical relevance. We also discuss recent insights into genetic alterations in relation to the molecular pathways implicated in GCTB. A summary of the current understanding of GCTB pathology will update the knowledge base to guide the diagnosis and management of this unique bone tumor.