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Denosumab-treated Giant Cell Tumor of Bone Exhibits Morphologic Overlap With Malignant Giant Cell Tumor of Bone

Wojcik, John MD, PhD*; Rosenberg, Andrew E. MD; Bredella, Miriam A. MD; Choy, Edwin MD, PhD§; Hornicek, Francis J. MD, PhD; Nielsen, G. Petur MD; Deshpande, Vikram MD

The American Journal of Surgical Pathology: January 2016 - Volume 40 - Issue 1 - p 72–80
doi: 10.1097/PAS.0000000000000506
Original Articles

Giant cell tumor (GCT) of bone is a locally aggressive benign neoplasm characterized by an abundance of osteoclastic giant cells that are induced by the neoplastic mononuclear cells; the latter express high levels of receptor activator of nuclear factor κ-B ligand (RANKL). Denosumab, a RANKL inhibitor, which is clinically used to treat GCT, leads to a marked alteration in the histologic appearance of the tumor with giant cell depletion and new bone deposition, leading to substantial histologic overlap with other primary tumors of bone. Most significantly, denosumab-treated GCT (tGCT) with abundant bone deposition may mimic de novo osteosarcoma, or GCT that has undergone malignant transformation. To histologically characterize tGCT, we identified 9 cases of GCT biopsied or resected after denosumab treatment. tGCT cases included 16 specimens from 9 patients including 6 female and 3 male individuals aged 16 to 47 (median 32) years. Duration of treatment varied from 2 to 55 months. We compared these tumors with malignant neoplasms arising in GCTs (n=9). The histology of tGCT was variable but appeared to relate to the length of therapy. All tGCTs showed marked giant cell depletion. Early lesions were highly cellular, and the combination of cellularity, atypia, and haphazard bone deposition caused the lesion to resemble high-grade osteosarcoma. Unlike de novo high-grade osteosarcoma or malignancies arising in GCT, however, tGCT showed less severe atypia, reduced mitotic activity, and lack of infiltrative growth pattern. Tumor in patients on prolonged therapy showed decreased cellularity and abundant new bone, deposited as broad, rounded cords or long, curvilinear arrays. The latter morphology was reminiscent of low-grade central osteosarcoma, but, unlike low-grade central osteosarcoma, tGCT was negative for MDM2 and again lacked an infiltrative growth pattern. Overall, tGCT may have a wide range of morphologic appearances. Because the treated tumors bear little resemblance to their pretreatment counterparts, careful attention to the history of denosumab administration is crucial to avoid a misdiagnosis with an important impact on therapy. Unlike malignant GCTs, tGCTs lack significant nuclear atypia, mitotic activity, and infiltration of preexisting bone, but instead show a unique pattern of intralesional bone deposition.

*Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA

Department of Pathology, Miller School of Medicine, Jackson Memorial Hospital, University of Miami, Miami, FL

Department of Radiology

§Department of Medicine, Division of Oncology

Department of Orthopaedics

Department of Pathology, Massachusetts General Hospital, Boston, MA

P.N. and V.D. are co-final authors.

Conflicts of Interest and Source of Funding: Dr. Choy reports receiving consultation fees from Amgen, and his institution received research funding to support clinical trial activities. The other authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Vikram Deshpande, MD, Department of Pathology, Massachusetts General Hospital, Warren 2/55 Fruit Street, Boston, MA 02114 (e-mail:

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