Malignant bone tumours

1. METASTATIC BONE TUMOURS

• Most common cause of bone malignancy is metastasis from a primary tumour elsewhere in the body
• Most common primary sites – breast, prostate, lung, kidney, bowel and thyroid
• Sites most affected – vertebrae, ribs, pelvis, humerus, femur

Normal bone metabolism

• Three components of osteoclast metabolism are OPG, RANKL and RANK
  • RANKL activates RANK – expands the pool of osteoclasts, leading to increased bone resorption
  • OPG neutralises RANK – diminishes the pool of osteoclasts, leading to decreased bone resorption
• RANKL and OPG are regulated by various cytokines, hormones and drugs
  • M-CSF, IL-1, TNF-α, IL-6

Pathophysiology

Osteolytic lesions

• Skeletal malignancies disrupt the OPG-RANKL-RANK signal transduction pathway
  • Promote enhanced osteoclast formation and therefore accelerate bone resorption
• When breast cancer cells migrate to bone there is an overproduction of PTHrP (parathyroid hormone-related peptide) – activates osteoblasts to produce RANKL and downregulate OPG
  • Leads to production of osteoclasts – causing osteolysis
  • This causes increases levels of bone-derived growth factors (TGF-β, IGF-1) and extracellular calcium
  • Creates a vicious cycle where interactions between tumour cells and osteoclasts leads to increased osteoclastogenesis and also aggressive growth and behaviour of tumour cells

Osteoblastic lesions

• More common in prostate and small cell lung cancer
• Prostate-specific antigen (PSA) can cleave PTHrP – allows the osteoblastic reaction to predominate by decreasing bone reabsorption
• Associated with secretion of endothelin-1

Clinical features

• Pain – usually worse at night
• Pathologic fracture – in absence of trauma
• Systemic symptoms – weight loss, anorexia, fever
• Symptoms of hypercalcemia – nausea, vomiting, constipation, confusion

Diagnosis

• Tc⁹⁹ bone scan – shows ‘hot’ areas at sites of metastases
• X-ray
• CT/MRI
• Bloods
  • High serum ALP
  • Hypercalcemia
  • High PSA in prostatic metastases

Treatment

• Identify the primary site if unknown
• Analgesia
• Prevention of pathologic fracture
• Radiotherapy
• Chemotherapy

2. PRIMARY BONE TUMOURS

Mutliple Myeloma

• Monoclonal proliferation of plasma cells which produces abnormal paraproteins (Ig light chain)

Epidemiology

• Most common primary bone malignancy
• More common in males
• Median age of patients is 60 years

Pathophysiology

• Malignant plasma cells cause stimulation of osteoclast activity
• Plasma cells bind bone marrow stromal cells – stimulate production of RANKL and other pro-osteoclastic mediators (M-CSF, IL-6, TNF)
• OPG synthesis is suppressed, resulting in further osteoclast activation

Clinical features

• Localised bone pain – spine or rib pain most common
• Pathologic fracture
• Fatigue

Diagnosis

• Diagnostic criteria – monoclonal plasma cells ≥10% on bone marrow biopsy and ≥1 of CRAB
  • Hypercalcemia
  • Renal insufficiency
  • Anemia
  • Bone lesions
• Urine – Bence-Jones proteinuria
•  X-ray – multiple ‘punched-out’ lytic lesions
• MRI
• PET scan – most sensitive

Treatment

• Radiation
• Chemo – melphalan, prednisone, thalidomide
• Surgical stabilisation – for impending fracture

Osteosarcoma

• Malignant tumour of the mesenchymal cells, characterised by formation of osteoid or bone by the tumour cells

Epidemiology

• Primary osteosarcoma is most common in younger patients – 10-20 years old
  • Slight male preponderance
  • Most common sites – distal femur, tibia, humerus
• Secondary osteosarcoma is more common in the elderly

Etiology

• No known etiology for primary osteosarcoma
• Secondary osteosarcoma
  • Paget’s disease of the bone , history of radiotherapy/chemotherapy, bone infarcts, chronic osteomyelitis
  • Inherited conditions – familial retinoblastoma syndrome, Li-Fraumeni syndrome

Classification

• Primary osteosarcoma
  • Conventional-intramedullary – osteoblastic, chondroblastic, fibroblastic
  • Small cell
  • Telangiectatic
  • Surface osteosarcomas – parosteal, periosteal, high grade surface
• Secondary osteosarcomas

Pathophysiology

• Rapid bone growth (i.e. in adolescent growth spurt) is associated with increased risk of osteosarcoma
• Mutations in p53 and Rb genes are implicated

Clinical features

• Localised pain – worsens over weeks
  • Deep and dull in characteristic
• Swelling
• Limited range of motion
• Limp
• Overlying skin ulceration – uncommon

Diagnosis

• X-ray – neoplasm usually located in metaphysis of long bone
  • Poorly circumscribed lesion with mixed radio-dense and radiolucent areas
  • Codman triangle – a triangular area of new subperiosteal bone that is created when a tumour raises the periosteum away from the bone
  • Sunburst appearance
• CT/MRI
• Tc⁹⁹ bone scan
• Bone biopsy
• Bloods – raised ALP and LDH

Treatment

• Chemotherapy – methotrexate, doxorubicin, cisplatin, cyclophosphamide
• Radiotherapy
• Surgery – limb salvage resection, amputation

Chondrosarcoma

• Malignant primary bone tumour composed of chondrocytes – variable degrees of malignancy

Epidemiology

• Older patients, slight male preponderance
• Most common sites – pelvis, femur, scapula

Etiology/classification

• Primary chondrosarcoma – unknown etiology
  • Dedifferentiated chondrosarcoma
  • Clear cell chondrosarcoma
  • Mesenchymal chondrosarcoma
• Secondary chondrosarcoma – arises from benign cartilage lesions
  • E.g. osteochondroma, Enchondroma , Ollier’s disease , Maffucci’s syndrome

Clinical features

• Pain
• Slow growing mass
• Symptoms of bowel/bladder obstruction due to mass effect
• Pathologic fracture

Diagnosis

• X-ray – lytic or blastic lesion with reactive thickening of cortex
  • Intralesional calcifications
  • Moth-eaten appearance – in high grade tumours
• CT – endosteal scalloping; calcifications
• MRI
• Tc⁹⁹ bone scan

Treatment

• Chemotherapy
• Intra-lesional curettage – for low grade lesions
• Wide surgical excision