Original ArticlesChondroblastoma Expresses RANKL by RNA In Situ Hybridization and May Respond to Denosumab TherapySuster, David I. MD*; Kurzawa, Pawel MD, PhD†,‡; Neyaz, Azfar MD*; Jarzembowski, Jason A. MD, PhD§; Lozano-Calderon, Santiago MD∥; Raskin, Kevin MD∥; Schwab, Joseph MD∥; Choy, Edwin MD, PhD¶; Chebib, Ivan MD*; Deshpande, Vikram MD*Author Information Departments of *Pathology ∥Orthopaedics ¶Department of Medicine, Division of Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA †Department of Clinical Pathology, Poznań University of Medical Sciences ‡Pathology Department, University Hospital of Lord’s Transfiguration, Partner of Karol Marcinkowski University of Medical Sciences, Poznań, Poland §Department of Pathology, Children’s Hospital of Wisconsin, Milwaukee, WI D.I.S. and P.K. contributed equally. Conflicts of Interest and Source of Funding: Partially funded by a sponsored research agreement between the authors’ institution and Affymetrix (Santa Clara, CA) and Biotechne. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: David I. Suster, MD, Department of Pathology, Massachusetts General Hospital, Warren 2, 55 Fruit Street, Boston, MA 02214 (e-mail: [email protected]). The American Journal of Surgical Pathology: December 2020 - Volume 44 - Issue 12 - p 1581-1590 doi: 10.1097/PAS.0000000000001568 Buy SDC Metrics Abstract Lesions of bone featuring osteoclast-like giant cells comprise a diverse group of entities, including giant cell tumor (GCT) of bone, chondroblastoma, and aneurysmal bone cyst, among others. The receptor activator of nuclear factor-κB ligand (RANKL) has been implicated in the pathogenesis of GCT of bone and may play a role in the pathogenesis of other giant cell–rich lesions as well. In addition, RANKL inhibitors (denosumab) have also been shown to have some efficacy in treating some giant cell–rich lesions. Herein, we examine RANKL expression by RNA in situ hybridization in a total of 84 osseous lesions with a focus on chondroblastoma, GCT, fibrous dysplasia, and aneurysmal bone cyst. The lesions were tested for RANKL expression using a chromogenic RNA in situ hybridization assay. RANKL expression was identified in 24/25 (96%) GCT, 24/26 (92%) chondroblastomas, 6/7 (86%) aneurysmal bone cysts, and 3/16 (19%) patients with fibrous dysplasia. RANKL expression was statistically lower in chondroblastoma and aneurysmal bone cyst compared with GCT. RANKL reactivity in fibrous dysplasia was exclusively seen in the 3 cases with osteoclast-type giant cells. Our results indicate a high proportion of chondroblastomas, GCTs, and aneurysmal bone cysts express RANKL while reactivity in fibrous dysplasia is dependent on the presence of osteoclast-type giant cells. On the basis of the success of denosumab therapy for GCTs, our results indicate that it may be a potential therapeutic option in other primary osseous tumors. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.