Spectrum of histological features of Denosumab treated Giant Cell Tumor of Bone; potential pitfalls and diagnostic challenges for pathologists

Objectives: Denosumab is Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL) inhibitor which is being used in the treatment of locally advanced, recurrent and metastatic Giant Cell Tumor of Bone (GCTB). It causes reduction in monocyte recruitment and Osteoclast-Like Giant Cell (OLGC) formation which limits bone destruction. After Denosumab treatment, GCTB exhibit diverse morphological features which can pose diagnostic challenge. Our aim was to study the spectrum of histologic features seen in Denosumab treated GCTB which could be helpful in establishing correct diagnosis. Methods: We retrieved and reviewed H&E stained microscopic glass slides of 38 GCTB cases who received Denosumab as neoadjuvant treatment. These cases were treated at different institutes and diagnosed at our institute between January 2017 and October 2019. Morphologic features such as presence of residual OLGC, appearances of mononuclear stromal and bony components were assessed along with other non-specific features. Results: Patients' median age was 29 years. Male to female ratio was 1.53:1. Femur was the most commonly involved bone. Microscopically, peripheral shell of reactive bone was observed in all cases. In 20 (52.6%) cases, there was complete elimination of OLGC. Mononuclear stromal cells were predominantly bland spindle shaped and arranged in fascicular and storiform patterns. Focal atypia was noted in 3 cases. Bony component manifested as trabeculae of woven bone with osteoblastic rimming and immature trabeculae of unmineralized osteoid with haphazardly present osteoblasts. Spectrum of stromal changes included cystic spaces, foamy macrophages, inflammatory infiltrate, hemangiopericytoma-like (HPC-like) vessels, hyalinization, edematous areas and hemosiderin pigment. The tumors showed areas which resembled other bony and soft tissue lesions such non-ossifying fibroma, fibrous dysplasia, osteoblastoma, sclerosing epithelioid fibrosarcoma and osteosarcoma. Conclusion: Denosumab treatment induces a variety of changes in GCTB. Clinical history and knowledge of these features are necessary for excluding differential diagnoses and avoiding misdiagnosis.