Bone Forming Tumors: Osteosarcoma

Bone Forming Tumors

• Osteoma, osteoid osteoma, osteoblastoma, and osteosarcoma are types of bone forming tumors
• Osteosarcoma is a high-grade conventional tumor

Osteosarcoma

• Most commonly occurs around the knee, at the end of long bones
• Characterized by osteoids (non-mineralized bone matrix)
• Typically presents as a painful mass in the bone, especially at night due to low cortisol levels
• Most common in long bones of the extremities, especially distal femur and proximal tibia
• Conventional high-grade is the most common and aggressive type
• Diagnosis is typically made with an X-ray, which may show both lytic and sclerotic patterns

Codman Triangle

• Periost is lifted by the tumor in the bone

Histology

• Severe anaplasia and pleomorphism (different formed nuclei)
• Eosinophilic cytoplasm (more pink)
• Identification of neoplastic disorganized woven bone with a lace-like pattern
• Unmineralized matrix > osteoid
• Subclassification according to matrix (some make cartilage, some bone, and some fibroblastic tissue)
• No specific immune histochemical staining (SATB2) -> marker for bone differentiation

Classification

• Conventional osteosarcoma: 80%
• Telangiectatic osteosarcoma: ~4% -> a lot of blood vessels and blood
• Small cell osteosarcoma: 1.5% -> less aggressive form, less metastasis
• Several other rare osteosarcoma subtypes

Clinical

• Most prevalent malignant primary bone tumor
• Occurs mainly in adolescents/young adults
• Bimodal age distribution (young adults, but also older people due to radiation or Paget's disease)

Survival

• Chemotherapy resistance: poor survival in 40% of patients
• Metastases, especially to the lungs, are the cause of poor survival

Treatment

• Surgery, amputation or limb salvage
• Neo-adjuvant chemotherapy (before surgery, less heavy surgery)
  • Doxorubicin
  • Cisplatin
  • Methotrexate
• Surgery > resection is studied response to chemotherapy
  • >90% necrosis: considered as good response
  • Associated with good prognosis
• Post-surgery chemotherapy

Issues in Osteosarcoma Studies

• Relatively rare
• Preoperative chemotherapy destroys tissue for research
• No specific hereditary syndrome for OS
• No benign precursor
• Gross genetic instability, chromothripsis & kataegis (a lot of breaks in the chromosomes)

Immunotherapy

• Ongoing research
• High genetic instability > neoantigens
• High T-cell infiltrate
• Need HLA expression
• Expression of T-cell blocking proteins
• Blocking checkpoints: avoiding immune destruction, genome instability & mutations

Pathways

• Research: two genes inactivated -> RB and P53

Hereditary Disorders

• Li-Fraumeni syndrome: P53 gene
• Related to osteosarcoma

Li-Fraumeni Syndrome

• Autosomal dominant with high penetrance (93% before age 50)
• TP53 gene is mostly mutated, sometimes CHK2
• Sarcoma is the index diagnosis
  • 25% of LFS tumors are sarcoma
  • Of these, 40% are osteosarcoma
• Of note: TP53 mutations also occur in dog osteosarcoma

P53 and Cell Cycle

• P53 detects molecular changes and stops the cell cycle
• Loss of P53 leads to genetic instability

Knudson's Two-Hit Hypothesis

• For tumor progressor gene inactivation

Retinoblastoma

• Malignant tumor of the retina (primary)
• Birth/childhood
• Unilateral/bilateral
• Sporadic/hereditary
• Second tumor: 60% sarcoma, mainly osteosarcoma

Rb Mutation Spectrum

• RB1 is a huge gene
• Mutations occur on all parts of RB1

Rb and Cell Cycle

• Rb is also involved in the cell cycle

Rb and Osteosarcoma

• 70% of primary osteosarcomas

Rb1/TP53 Mouse Model

• Conditional knockout for Rb1 and Tp53 > only osteoblastic precursor cells have Rb1 and Tp53 loss (Osx-Cre)
• These mice get osteosarcoma
• These osteosarcomas are mostly metastatic
• Apparently, there is synergy between Rb and Tp53, needs to occur both

Paget's Disease of Bone

• Increased bone resorption
• Increased bone formation
• Pain, fractures, deformities
• Bone tissue of poor quality
• Secondary tumors
• Primary abnormality resides in osteoclasts (osteoclasts are too active)

Osteosarcoma in Paget's Disease

• Increased risk to get osteosarcoma (0.15-1%)
• Age of onset is late
• Characterized by giant multinucleated osteoclasts