Clear Cell Chondrosarcoma With Somatic VHL Inactivation: A Case Report With Integrated Genomic and Transcriptomic...

Clear cell chondrosarcoma (CCC) is a rare, low-grade malignant bone tumor and a specific subtype of chondrosarcoma. In contrast to conventional central chondrosarcoma, which often exhibits recurrent IDH1/2 mutations, CCC is IDH-wildtype, and its genomic profile remains uncharacterized. Sporadic cases have been described in association with von Hippel-Lindau (VHL) disease, but somatic VHL alterations have not been demonstrated in this tumor.

A 35-year-old man presented with local recurrence of a distal femoral tumor 5 years after curettage and allograft reconstruction for a tumor that was initially diagnosed as clear cell chondrosarcoma. The recurrent tumor was resected and analyzed using a comprehensive DNA/RNA next-generation sequencing assay with matched germline testing to distinguish somatic from germline alterations.

The recurrent tumor measured 5.0 cm and showed classic CCC morphology with focal areas of conventional chondrosarcoma-like differentiation. No IDH1/2 mutations were identified. Two pathogenic loss-of-function variants were detected: COL2A1 c.1262_1266+2delinsTCC (variant allele frequency [VAF], 34%) and VHL c.341-2A>C (VAF, 45%). The tumor had a low tumor mutational burden, low loss of heterozygosity, and a complex karyotype with monosomy of chromosome 3. Gene expression profiling revealed decreased VHL mRNA expression. Germline testing showed no germline VHL alteration, confirming somatic VHL inactivation.

To our knowledge, this report is the first to describe a molecularly profiled CCC with somatic VHL inactivation. These results expand the evolving genomic spectrum of CCC beyond its previously known IDH-wildtype status and suggest that VHL pathway dysregulation may contribute to tumorigenesis in a subset of cases.