Malignant Chondroblastoma: An Epigenetically Distinct Subtype of Chondroblastoma with a Predilection for the Skeletally Mature.

Abstract

Background: 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.

Design: Malignant chondroblastomas were collected. H3-3 K36M immunohistochemistry, as well as DNA methylation and copy number profiling, were performed and compared to conventional chondroblastoma.

Results: 41 samples from 26 patients were identified (20 males, six females; age 19 to 62 years; median 39 years). Anatomic 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 were scarce. 6 patients had tumors with features of conventional chondroblastoma but significant cytologic atypia. 3 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 which harbored an H3F3A p.K36M mutation. When 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 UMAP 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, while 14 had copy number changes. Of 22 patients, 11 experienced local recurrence, 8 patients developed metastasis, and 3 patients died of disease.

Conclusion: 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 transform into high-grade pleomorphic sarcoma, either de novo or in subsequent recurrences. Malignant chondroblastoma with high grade features and/or copy number variations appear to have a higher propensity for adverse events, including death from disease.