Malignant Giant Cell Tumor of Bone

Giant cell tumors of bone are locally aggressive, frequently harbor H3F3A p.G34W mutations, and rarely undergo malignant transformation. The pathogenesis of malignant transformation remains incompletely characterized. Herein, we present 28 malignant giant cell tumors of bone from 14 males and 14 females, aged 16 to 65 (median 39) years. Primary sites included long bones (n=20), pelvis (n=3), vertebrae (n=2), and rarely rib, phalanx, and cuneiform (n=1 each). Sixteen (62%) of 26 tumors with available history represented malignant transformation or recurrence of conventional giant cell tumors of bone, at intervals of 1.3 to 35 (median 7.3) years before malignant transformation. Eight of 15 patients with available treatment history received denosumab before a diagnosis of malignancy. Ten (38%) of 26 tumors with available history likely arose de novo, including 7 with conventional areas and 3 H3F3A -mutant sarcomas lacking conventional giant cell tumor of bone. Of 28 malignant giant cell tumors of bone, 18 (64%) and 10 (36%) harbored osteoblastic and chondroblastic elements, respectively. Among 23 tumors with available genetic testing or surrogate immunohistochemistry, 17 (74%) were p.G34W-mutant, whereas other tumors carried H3F3A p.G34L (n=2), p.G34V (n=2), and p.G34R (n=1) alterations; 1 tumor harbored H3F3B p.K116E and p.R117S in cis. Seven (70%) of 10 malignant giant cell tumors of bone showed complex copy number alterations by single nucleotide polymorphism (SNP) array, DNA next-generation sequencing (NGS), and/or karyotype analysis. In contrast, complex chromosomal alterations were lacking in 32 conventional giant cell tumors of bone tested (24 by karyotype, 7 by SNP array, 1 by DNA NGS), 3 atypical giant cell tumors of bone with isolated marked nuclear atypia (2 by karyotype, 1 by SNP array) and 3 metastasizing conventional giant cell tumors of bone (2 by DNA NGS, 1 by karyotype). Clinical follow-up was available for 20 patients (71%), and one additional patient had metastases at presentation. Overall, 14 of 21 patients (67%) developed metastases, and 10 of 20 patients with follow-up (50%) died of disease at 2 months to 9.6 years (median 7 mo). Most patients were treated with chemotherapy; 1 patient (PD-L1 TPS >95%) was treated with pembrolizumab, with complete clinical response of metastatic disease at 2.5 years. In conclusion, malignant giant cell tumors of bone typically arise from long bones, harbor osteosarcomatous and/or chondrosarcomatous differentiation, and show significant risk for distant metastasis and demise. Our data suggest that copy number analysis may be useful in distinguishing malignant giant cell tumors of bone from their conventional, atypical, and metastasizing conventional counterparts.