An Update on Selected Giant Cell-Rich Tumors of Soft Tissue

Giant cell-rich tumors of soft tissue present a significant diagnostic challenge due to pronounced morphological overlap, particularly in limited tissue samples. This review provides a streamlined update on the clinicopathological and molecular features of nine distinct entities: nodular fasciitis, juvenile xanthogranuloma, phosphaturic mesenchymal tumor, tenosynovial giant cell tumor, giant cell fibroblastoma, giant cell-rich solitary fibrous tumor, giant cell tumor of soft tissue, keratin-positive giant cell-rich tumor, and undifferentiated pleomorphic sarcoma. While these neoplasms are unified by a prominence of multinucleated giant cells, recent genomic insights have identified signature, diagnostically defining molecular drivers. We highlight characteristic gene fusions, including USP6, NTRK1, FN1, CSF1, COL1A1-PDGFB, NAB2-STAT6, and HMGA2-NCOR2, as well as entities characterized by non-recurrent or highly complex genomic alterations. Synthesizing these data, this review underscores the critical role of advanced molecular testing in resolving diagnostic ambiguities, refining tumor classification, and guiding targeted therapeutic strategies.