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

Emanuela Palmerini,Alberto Righi,Marco Gambarotti,Peter Reichardt,Jean-Yves Blay,Piero Picci,Susan Bukata,Danielle Jandial,Tian Dai,Leanne L Seeger

doi:10.1186/s12885-020-07739-8

Abstract

BackgroundGiant 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.MethodsThis 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.ResultsTwenty 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.ConclusionsAlthough 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 registrationclinicaltrials.gov, (NCT00680992). Registered May 20, 2008.

Highlights

Giant cell tumor of bone (GCTB) is a rare osteoclastogenic stromal tumor
Primary malignant giant cell tumor of bone (PMGCTB) is observed at initial GCTB diagnosis as an area of highly pleomorphic mononuclear cells coexistent and adjacent to an area of otherwise conventional benign GCTB area within the same lesion; sampling error in biopsies can be associated with missed diagnosis of PMGCTB [6]
The overall incidence of an adverse event of new malignancy in GCTB was 3.8% (20/526): five (1.0%) had PMGCTB, five (1.0%) had Secondary malignant giant cell tumor of bone (SMGCTB), four (0.8%) had sarcomatous transformation, and six (1.0%) had a misdiagnosis of benign GCTB

Summary

Introduction

This post hoc analysis evaluated and classified malignancies in patients with GCTB who received denosumab. GCTB can undergo malignant transformation to high-grade sarcoma, such as osteosarcoma or undifferentiated sarcoma [4]. Differential diagnoses of PMGCTB include giant cell-rich osteosarcoma, benign GCTB, aneurysmal bone cysts, chondroclastomas, and brown tumor of bone [7]. SMGCTB occurs at the site of a previously treated benign GCTB lesion and the pre-existing GCTB may be evident. SMGCTB may occur after exclusive surgical treatment in the absence of prior radiotherapy [9]. Such cases are described as sarcomatous transformation of a previously documented benign GCTB. Misdiagnosis of GCTB, instead of PMGCTB or SMGCTB, can lead to improper treatment of an aggressive disease with typically poor prognosis [7]

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