Bone Tumors and Cartilage Formation

Classification of Bone Tumors

• Mesenchymal tumors
• Biologic behavior: benign, intermediate (locally aggressive, rarely metastasizing), malignant
• Hallmarks of cancer: clonal expansion, multistep progression model

Cartilage Tumors

• Most benign tumors are cartilage tumors
• Benign cartilage tumors:
  • Osteochondroma: bone surface, cartilage cap, stalk continuous with underlying bone
  • Enchondroma: in marrow of bone, often in hands and feet
• Malignant cartilage tumors:
  • Peripheral chondrosarcoma (~15%): bone surface, secondary to osteochondroma
  • Central chondrosarcoma (75%): in marrow, primary or secondary to enchondroma

Osteochondroma

• Almost always arises in long bone, adjacent to growth plates
• Located at bone surface, formation of cartilage cap
• Marrow cavity continuous with that of underlying bone
• 86% solitary (sporadic), 14% multiple osteochondromas (MO)
• Peak age in young patients due to open growth plate
• Adults have a closed growth plate, so they don't develop new osteochondromas

Multiple Osteochondromas (MO)

• Hereditary disorder
• Autosomal dominant
• Can lead to deformation of bones
• Mutations in EXT1 (8q24) or EXT2 (11p)
• 1-5% secondary peripheral chondrosarcoma

Normal EXT Function

• EXT genes responsible for sugar chain attachment to heparan sulphate proteoglycans (HSPG)
• HSPG involved in signaling of FGF, VEGF, Hedgehog, Wnt, and TGFb/BMP
• These pathways are important for normal growth plate

Endochondral Ossification

• Occurs in osteochondroma
• IHH coordinates skeletal morphogenesis
• IHH induces bone collar formation

Osteochondroma Formation

• First mutation in EXT occurs
• Second hit in EXT occurs
• Heparan sulphate proteoglycans is no longer formed, affecting Hedgehog signaling
• Bony collar is not properly formed, resulting in a hole
• Mutant cells grow out, forming an osteochondroma with some normal cells

Progression towards Secondary Peripheral Chondrosarcoma

• Osteochondroma forms a niche for normal cells to acquire other mutations leading to malignancy
• Often, another mutation inactivates cell cycle genes (e.g. INK4 or Trp53)

Central Cartilaginous Tumors

• Enchondromatosis: Ollier disease
  • Unilateral predominance
  • Non-hereditary
  • Rare (1:100,000)
  • Risk of malignant transformation 40%

IDH1 or IDH2 Mutations

• Often found in Ollier, secondary CS, and primary central CS
• IDH mutants converge a-KG to D2HG
• D2HG affects DNA methylation and histone modifications
• Inhibition of mutant IDH does not lead to less cell viability and migration