Proffered Papers— Diagnostic Imaging/Pathology

UPREGULATION OF PTHrP AND BCL-2 EXPRESSION CHARACTERIZES EARLY MALIGNANT TRANSFORMATION OF OSTEOCHONDROMA TOWARDS PERIPHERAL CHONDROSARCOMA AND IS A LATE EVENT IN CENTRAL CHONDROSARCOMA

Bovee JVMG, Van den Broek LJCM, Cleton-Jansen AM, Hogendoorn PCW. (Department of Pathology, leiden University Medical Center, Leiden, The Netherlands)

Chondrosarcomas are malignant cartilage-forming tumors arising centrally in bone (central chondrosarcoma), or within the cartilaginous cap of osteochondroma (peripheral chondrosarcoma). For hereditary multiple osteochondromas, two responsible genes, EXT1 and EXT2, have been cloned. Their recently elucidated role in heparan sulfate biosynthesis and Hedgehog (Hh) diffusion leads to the hypothesis that EXT inactivation affects fibroblast growth factor (FGF) and Indian Hedgehog (IHh)/PTHrP signaling, two important pathways in chondrocyte proliferation and differentiation. We investigated the immunohistochemical expression of molecules involved in IHh/PTHrP (PTHrP, PTHrP-receptor, Bcl-2) and FGF (FGF2, FGFR1, FGFR3 and p21) signaling in osteochondromas (n=24), peripheral (n=29) and central (n=20) chondrosarcomas. IHh/PTHrP and FGF signaling molecules are mostly absent in osteochondromas. Although no somatic EXT mutations were found in sporadic osteochondromas, the putative EXT downstream targets are affected similarly in sporadic and hereditary tumors. In chondrosarcomas, re-expression of FGF2, FGFR1, PTHrP, Bcl-2 and p21 is found. Expression levels increase with increasing histological grade. Upregulation of PTHrP and Bcl-2 characterizes malignant transformation of osteochondroma since PTHrP and Bcl-2 expression is significantly higher in borderline and grade I peripheral chondrosarcomas as compared to osteochondromas. In contrast, upregulation of PTHrP and Bcl-2 seems to be a late event in central cartilaginous tumorigenesis since expression is mainly restricted to high grade central tumors.