Malignancy in giant cell tumor of bone: analysis of an open-label phase 2 study of denosumab

Abstract

Background: Giant cell tumor of bone (GCTB) is a rare osteoclastogenic stromal tumor. GCTB can rarely undergo malignant transformation. This post hoc analysis evaluated and classified malignancies in patients with GCTB who received denosumab.

Methods: This analysis was conducted on patients with pathologically confirmed GCTB and measurable active disease treated with denosumab 120 mg subcutaneously once every 4 weeks, with loading doses on study days 8 and 15, as part of a phase 2, open-label, multicenter study. We identified potential cases of malignancy related to GCTB through an independent multidisciplinary review or medical history, associated imaging or histopathologic reports, and disease course. The findings were summarized and no statistical analysis was performed.

Results: Twenty of five hundred twenty-six patients (3.8%) who received at least one dose of denosumab were misdiagnosed with GCTB that was later discovered to be malignancies: five primary malignant GCTB, five secondary malignant GCTB, four sarcomatous transformations, and six patients with other malignancies (giant cell-rich osteosarcoma, undifferentiated pleomorphic sarcoma, spindle cell sarcoma, osteogenic sarcoma, phosphaturic mesenchymal tumor of mixed connective tissue type, and fibrosarcoma/malignant fibrous histiocytoma). Many malignancies were present before denosumab was initiated (8 definitive cases, 7 likely cases), excluding potential involvement of denosumab in these cases. Signs associated with potential misdiagnoses of GCTB included poor mineralization with denosumab treatment, rapid relapse in pain, or a failure of the typical dramatic improvement in pain normally observed with denosumab.

Conclusions: Although rare, GCTB can undergo malignant transformation, and rates in this study were consistent with previous reports. Signs of poor mineralization or lack of response to denosumab treatment may warrant close monitoring.

Trial registration: clinicaltrials.gov , ( NCT00680992 ). Registered May 20, 2008.

Keywords: Bone neoplasms; Denosumab; Giant cell tumor of bone; RANK ligand.

Conflict of interest statement

Dr. Palmerini has served on advisory boards for Amgen, Daiichi Sankyo, Lilly, EUSA Pharma, and Deciphera; has received other research support from Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, and PharmaMar; and has received travel support from Lilly, PharmaMar, and Takeda.

Dr. Seeger reports nothing to disclose.

Drs. Gambarotti, Righi, and Picci received institutional funding from Amgen for clinical and pathological input and revision of the cases reported in this study.

Dr. Reichardt has received personal fees from Novartis, Pfizer, Bayer, PharmaMar, Clinigen, Lilly, Deciphera, Merck, Roche, and Amgen Inc.

Dr. Bukata has served as a consultant for Amgen and Radius, speakers’s bureau for Radius, and board service for the Orthopaedic Research Society and the US National Osteoporosis Foundation.

Dr. Blay has received research grants and honoraria from Novartis and Amgen Inc.

Drs. Dai and Jandial are employed by and own stock in Amgen Inc.

Figures

Fig. 1

Profile of the randomized controlled trial. Patients were divided into three cohorts: patients with surgically unsalvageable tumors (Cohort I), patients with surgically salvageable tumors (Cohort II), and patients rolled over from a previous study (Cohort III)

Fig. 2

Summary of clinical courses of patients who developed malignancies during the primary study. Each bar represents one patient (patient number, age range in years); the length of the bar shows the length of time from benign diagnosis to malignant diagnosis. Patient numbers and age ranges (in brackets), instead of age at treatment, are identifiers for the purposes of this publication only and do not link to patients.  GCTB giant cell tumor of bone, XRT, radiation therapy

Fig. 3

Misdiagnosis of GCTB. a Typical response of GCTB to denosumab leads to bone formation and calcification (top two images are axial CT soft tissue window and bottom two images are anteroposterior radiographs). b In misdiagnosed PMGCTB, poor calcification in response to denosumab is shown (top two images are axial T1-weighted MRI, axial CT bone windows and bottom two are axial CT soft tissue windows)

Fig. 4

Histologic features of malignancy in GCTB. a Primary malignant GCTB, pre-denosumab: proliferation of ovoid to spindle bland-appearing cells, with scattered reactive multinucleated osteoclast-like giant cells (top right of image), consistent with GCTB, juxtaposed to a proliferation of atypical spindle and pleomorphic cells, growing in fascicles, consistent with undifferentiated pleomorphic sarcoma (red circle). b Secondary malignant GCTB, pre-denosumab, (recurrence in 2008): histological features consistent with GCTB (bottom right of image), juxtaposed to a proliferation of atypical spindle cells, infiltrating in between the host bony trabeculae, consistent with high-grade undifferentiated spindle cell sarcoma (red circle)