Malignant and metastatic giant cell tumors of bone; clinical course of primary or secondary malignant and pulmonary metastatic variants.

Aims: Giant cell tumor of bone (GCTB) is a rare, locally aggressive, intermediate-grade neoplasm. While typically benign, GCTB can exhibit atypical behavior, including indolent pulmonary metastases and malignant transformation. This study characterizes malignant and metastatic GCTB, distinguishing primary malignant GCTB (PM-GCTB), secondary malignant GCTB (SM-GCTB), and secondary osteosarcoma, and evaluates their outcomes. Methods: A retrospectively review of 520 patients with suspected GCTB treated between 1985-2021 was performed, with malignant cases followed through 2025. Diagnosis was confirmed histologically and, where available, by H3F3A/H3F3B mutation testing. PM-GCTB was defined as a de novo high-grade sarcoma. SM-GCTB and secondary osteosarcoma were defined as malignant transformations of previously benign, histologically proven GCTB. Benign pulmonary metastases were analyzed separately. Outcomes were descriptively assessed. Results: Twelve patients (2.4 %) had malignant GCTB: five PM-GCTB (1.0 %), five SM-GCTB (1.0 %), and two secondary osteosarcoma (0.4 %). Three patients (0.6 %) developed histologically benign pulmonary metastases with indolent behavior. Three SM-GCTB patients transformed within one year despite benign baseline pathology, indicating true rapid malignant progression rather than diagnostic error. Median latency to malignant transformation was 7.5 years for SM-GCTB and up to 35 years for secondary osteosarcoma. SM-GCTB showed the highest disease-specific mortality (80 %), compared to PM-GCTB (20 %) and secondary osteosarcoma (0 %). None malignant transformations occurred following denosumab or radiotherapy. Conclusion: Three aggressive GCTB variants were identified: benign pulmonary metastatic GCTB, PM-GCTB, and secondary malignant transformation. SM-GCTB and osteosarcoma arise from benign GCTB but differ in morphology and prognosis. Because malignant transformation is exceptionally rare and symptomatic, a patient-centered, symptom-driven follow-up strategy is preferred over routine lifelong radiologic surveillance.