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.