Malignant chondroblastoma is a recently described variant of chondroblastoma showing a distinct age/site distribution and morphology along with the typical H3-3B p.K36M mutation. We sought to further compare conventional and malignant chondroblastoma. Malignant chondroblastomas were collected. H3-3 K36M immunohistochemistry, as well as DNA methylation and copy number profiling, were performed and compared with conventional chondroblastoma. Forty-one samples from 26 patients were identified (20 males, 6 females; age: 19-62 years; median: 39 years). Anatomical sites included rib (7), pelvis (4), acromion (4), scapula (4), spine (2), long bone (3), calcaneus (1), and talus (1). Imaging showed an expansile mass with variable cortical erosion and/or breakthrough. Most patients (n = 17) showed sheets of atypical ovoid cells deposited in a myxoid stroma. Osteoclast-like giant cells/matrix formation was scarce. Six patients had tumors with features of conventional chondroblastoma but significant cytologic atypia. Three tumors demonstrated a morphology indistinguishable from conventional chondroblastoma except for extensive permeation, and one of these cases showed a transition to high-grade sarcoma. The final case was composed only of high-grade pleomorphic sarcoma that harbored an H3F3A p.K36M mutation. When an adjacent host bone was present, permeative growth through the cortex and native trabeculae was noted. All samples tested positive for the H3-3 K36M-specific antibody (26 of 26). Methylome profiling of 28 specimens from 24 patients revealed that 26 of these specimens formed a distinct cluster on a uniform manifold approximation and projection dimension reduction plot separate from conventional chondroblastoma and high-grade osteosarcoma. Of 26 methylomes from which interpretable copy number profiles can be derived, 12 had no variations, whereas 14 had copy number changes. Of 22 patients, 11 experienced local recurrence, 8 patients developed metastasis, and 3 patients died of disease. Malignant chondroblastoma is a rare, clinically and epigentically distinct variant of chondroblastoma with a predilection for the flat bones of skeletally mature individuals and high rates of local recurrence and distant metastases. A subset transforms into high-grade pleomorphic sarcoma, either de novo or in subsequent recurrences. Malignant chondroblastoma with high-grade features and/or copy number variations appears to have a higher propensity for adverse events, including death from disease.

Bioptical Laboratory Ltd Pilsen Czech Republic; Department of Pathology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Bone Tumor Reference Center at the Institute for Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Bone Tumor Reference Center at the Institute for Medical Genetics and Pathology University Hospital Basel Basel Switzerland; Basel Research Centre for Child Health Basel Switzerland

Department of Anatomic Pathology Cleveland Clinic Cleveland Ohio

Department of Anatomic Pathology University of Pittsburgh Pittsburgh Pennsylvania

Department of Musculoskeletal Pathology The Royal Orthopaedic Hospital Birmingham United Kingdom and University Hospitals of Birmingham and Royal Orthopaedic Hospital

Department of Pathology and Immunology Division of Anatomic Pathology Washington University School of Medicine St Louis Missouri

Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis Indiana

Department of Pathology Brigham and Women's Hospital Boston Massachusetts

Department of Pathology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts

Department of Pathology Stanford University School of Medicine Stanford California

Department of Pathology The Johns Hopkins Medical Institutions Baltimore Maryland

Division of Anatomical Pathology Department of Pathology and Laboratory Medicine The Ottawa Hospital University of Ottawa Ottawa Ontario Canada

Musculoskeletal Radiology Cleveland Clinic Cleveland Ohio

Section of Histopathology Department of Pathology and Laboratory Medicine Aga Khan University Hospital Karachi Pakistan

Technical University of Munich TUM School of Medicine and Health Institute of General and Surgical Pathology Munich Germany

Thoracic Surgery Cleveland Clinic Cleveland Ohio

University of California San Francisco School of Medicine San Francisco California

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