Giant cell tumor of bone: An update, including spectrum of pathological features, pathogenesis, molecular profile and the differential diagnoses

Giant cell tumor of bone (GCTB) is an enigmatic tumor. Despite its benign histological appearance and clinical behavior in most cases, it is associated with recurrences, uncommonly metastasis, and rarely with a malignant transformation. During the last few years, there has been a significant evolution in the diagnosis and management of GCTB, including discoveries related to the underlying pathogenesis (RANK/RANK/OPG pathway), with treatment-related implications in the form of denosumab (approved inhibitor for targeting RANKL), leading to improved surgical resections, especially in cases of recurrent, large and borderline resectable tumors. Lately, a specific Histone mutation, namely H3.3G34W underlying almost all GCTBs has been discovered, further leading to the identification of a highly sensitive and specific immunohistochemical antibody marker, H3.3G34W, which is very useful for an exact diagnosis of a GCTB, including its differentiation from its various mimics, which has significant implications. This review describes clinicopathological features of a GCTB, including its variable features, recent concepts, underlying pathogenesis, post-denosumab related changes and various entities that constitute its differential diagnosis, including their molecular signatures, with treatment-related implications.