Bone Tumors and Cartilage Formation

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Questions and Answers

What is the primary mechanism involved in the formation of cartilage tumors?

Multistep progression

Mesenchymal tumor formation

Abnormal bone development

Clonal expansion (correct)

What is the most common type of benign cartilage tumor?

Osteochondroma (correct)

Chondrosarcoma

Enchondroma

Central chondrosarcoma

What is the characteristic feature of an osteochondroma?

Location at the bone surface with a continuous stalk with the underlying bone (correct)

Clonal expansion of cartilage cells

Formation of cartilage cap in the marrow of bone

Multistep progression model

What is the approximate percentage of solitary osteochondromas?

86% Signup and view all the answers

What is the term for the process by which a benign tumor becomes malignant?

Malignant transformation Signup and view all the answers

What is the term for the biologic behavior of a tumor that grows rapidly but rarely metastasizes?

Locally aggressive Signup and view all the answers

What is the main reason why adults do not develop new osteochondromas?

Because they have a closed growth plate Signup and view all the answers

What is the function of EXT genes in normal growth plate development?

They are involved in the signaling of FGF and VEGF Signup and view all the answers

What is the result of inactivated Hedgehog in mice?

Smaller mice with little bone formation Signup and view all the answers

What is the role of EXT1 in osteochondroma formation?

It acts as a tumor suppressor gene Signup and view all the answers

What is the characteristic of Enchondromatosis (Ollier disease)?

It is a unilateral disorder with a high risk of malignant transformation Signup and view all the answers

What is the effect of IDH mutations in central cartilage tumors?

They lead to the conversion of a-KG to D2HG Signup and view all the answers

What is the characteristic of Multiple Osteochondromas (MO)?

It is an autosomal dominant disorder Signup and view all the answers

What is the role of IHH in skeletal morphogenesis?

It coordinates skeletal morphogenesis Signup and view all the answers

What is the characteristic of osteochondromas?

They are not entirely clonal Signup and view all the answers

What is the result of the progression of osteochondromas towards secondary peripheral chondrosarcoma?

The formation of a malignant tumor without EXT mutations Signup and view all the answers

Study Notes

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

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Description

Test your understanding of bone tumors, mechanisms of cartilage tumor formation, and their relation to normal bone development. Includes terminology on biologic behavior and hallmarks of cancer.