Malignant transformation of fibrous dysplasia in long bones: a clinicopathological and molecular study of 19 cases.

AIMS: Malignant transformation of fibrous dysplasia (FD) in long bones is very rare. This study aimed to explore its clinicopathological and molecular characteristics to reveal the diagnostic features and pathogenesis.

METHODS: We conducted a clinicopathological analysis of 19 FD-associated sarcomas. Sanger and next-generation sequencing were used to detect molecular alterations, and clinical, radiological and histopathological features were reviewed in detail.

RESULTS: The cohort consisted of 10 female and nine male patients (mean age, 48.4 years). Eleven patients had a previous diagnosis of FD, and eight patients presented de novo with acute symptoms like pain, swelling or dysfunction. Radiologically, in the monostotic cases (n=13), osteolytic lesions were observed with ill-defined margins, cortical destruction and soft tissue masses. Polyostotic cases (n=6) had both malignant masses and classic FD features of other skeletal sites. Histopathologically, osteosarcoma was the most common (57.9%), followed by undifferentiated pleomorphic sarcoma (26.3%), grade 2 spindle cell sarcoma (not otherwise specified, 5.3%) and low-grade central osteosarcoma (10.5%). Molecular analysis revealed identical GNAS mutations in paired FD and malignant components. Next-generation sequencing identified universal CDKN2A/B alterations (100%), along with concurrent TP53 (28.6%), TERT (28.6%) and KDM6A (28.6%) mutations, indicating a potential collaborative role in the FD malignant transformation process.

CONCLUSIONS: Our analysis revealed unique clinicopathological characteristics and genetic markers in FD-associated sarcomas, deepening our knowledge of the mechanisms behind malignant transformation in FD and offering diagnostic tools for enhanced pathological assessment.