Malignant bone tumors

Malignant bone tumors can be classified as primary (arising from abnormal bone or cartilage cells) or secondary (bone metastases of other tumors). The most common primary bone tumors are osteosarcomas, Ewing sarcomas, and chondrosarcomas. These tumors differ with regard to primary localization, radiographic characteristics, and the patient age at which they usually develop. Progressive, localized pain that worsens at night or with physical activity is common and usually accompanied by swelling. In Ewing sarcoma and osteosarcoma, symptoms often first manifest after an injury. Diagnosis is confirmed by imaging and biopsy. Depending on the type and stage of the tumor, chemotherapy, radiation therapy, and/or definitive surgical resection may be required. Bone tumors may also occur secondary to metastases of other primary cancers. The metastases are commonly detected in the spine and pelvis and usually arise from the lung, breast, and prostate cancer. Treatment focuses on the underlying malignancy and additional management of pain and prevention of fractures related to the metastases.

• Description: : highly malignant bone tumor arising from neuroectodermal cells; ; associated with various chromosomal translocations of the EWSR1 gene (chromosome 22)
• Epidemiology
  • Incidence: peak at 10–15 years
  • Sex: ♂ > ♀
  • Ethnicity: primarily affects whites
• Clinical features
  • Frequently first manifests with localized pain (progressive, worsens at night), hyperthermia, and swelling after trauma to the bone (tissue mass that is tender to palpation and accompanied by erythema)
  • B symptoms are common
• Localization
  • Primary tumor: often diaphyses of long bones (particularly femur, tibia, fibula, and humerus) and bones of the pelvis
  • Metastasis: lungs, skeletal system, bone marrow
• Diagnostics
  • Conventional x-ray: lytic bone lesions, onion skin appearance of the periosteum
  • Laboratory findings: ↑ ESR, ↑ LDH, leukocytosis
  • Biopsy
    • Anaplastic small-blue-round-cell malignancy
    • Cells contain glycogen accumulations and are usually CD99-positive
    • Chromosomal translocation t(11;22)(q24;q12);
• Treatment
  • Surgery; (definitive resection) plus neoadjuvant and adjuvant polychemotherapy
  • Additionally: neoadjuvant and/or adjuvant radiation therapy
• Prognosis
  • Extremely aggressive, early metastasis
  • Five-year survival rate of ∼ 70%

References:^{[1][2][3][4][5][6]}

• Description: : malignant, osteoid and bone-forming tumor arising from mesenchymal stem cells (osteoblasts) located in the periosteum
• Etiology
  • Primary osteosarcoma: unknown
  • Secondary osteosarcoma: Paget's disease of bone, radiation injury, bone infarction
• Epidemiology
  • Incidence: bimodal distribution
    • Primary osteosarcoma: puberty/adolescence
    • Secondary osteosarcoma: advanced age
  • Sex: ♂ > ♀
  • Most common primary bone malignancy .
  • Increased incidence in patients with retinoblastoma and Li-Fraumeni syndrome
• Clinical findings
  • Frequently first manifests with pain (progressive, worsens at night and with activity); ; swelling after trauma to the bone (tissue mass that is tender to palpation; and accompanied by erythema)
  • Limping; and decreased range of motion
  • B symptoms
• Localization
  • Primary tumor: metaphyses of long bones (particularly distal femur and proximal tibia)
  • Metastases: lungs , skeletal system, regional lymph nodes
• Diagnostics
  • Imaging
    • Conventional x-ray
      • Signs of osteolysis adjacent to osteosclerosis (moth eaten appearance)
      • Sunburst appearance of lytic bone lesions and/or codman triangles
    • MRI: assesses involvement of soft tissue, evaluation in cases of unclear radiographic findings
  • Biopsy
    • Osteosarcomas always feature woven bone matrix → distinction from chondrosarcomas and fibrosarcomas
    • Most common type: conventional osteosarcomas (∼ 90%)
  • Laboratory: ↑ alkaline phosphatase, ↑ LDH, ↑ ESR
• Treatment
  • Surgery (definitive resection); with neoadjuvant and adjuvant polychemotherapy (e.g., combination of methotrexate, doxorubicin, cisplatin, and ifosfamide)
  • Histological examination of the resected bone to evaluate the effect of neoadjuvant chemotherapy (major prognostic factor)
• Prognosis: five-year survival rate of ∼ 70%

Osteosarcomas are usually resistant to radiation therapy!

References:^{[7][3][6][8][9][10]}

• Description: malignant tumor arising from mesenchymal cells that produce cartilage
• Etiology
  • Primary chondrosarcoma: unknown
  • Secondary chondrosarcoma: e.g., osteochondroma, Paget's disease of bone, radiation
• Epidemiology
  • Age: usually > 50 years
  • Sex: ♂ > ♀
• Clinical findings
  • Deep, dull pain (worsens at night, insidious progression over months to years)
  • Local swelling
  • Pathological fractures
  • Neurovascular disturbances and/or limited range of motion
• Localization: mainly pelvis, ribs, proximal femur, and proximal humerus
• Diagnostics
  • Conventional x-ray or CT
    • Osteolysis with moth-eaten appearance
    • Calcifications (rings and arcs calcification, popcorn calcification)
    • Endosteal scalloping and cortical breach with infiltration of soft tissue
  • MRI: rim-like contrast enhancement
  • Biopsy
    • Lobulated appearance (hyaline cartilage nodules with peripheral calcification )
    • Grading
      • Grade I : metastases are rare
      • Grade II : metastases in 10–15%
      • Grade III : metastases in > 50%
• Treatment
  • Surgery (definitive resection)
  • Chemotherapy and radiation therapy, possibly as adjuvant therapy or as palliative treatment
• Prognosis
  • Five-year survival rate of ∼ 50–60%
  • Late recurrences are possible → regular follow-ups for 10 years

References:^[11][12][13]

Imaging

General approach

• Detection and evaluation of possible primary bone tumors
  • Plain radiography (initial test of choice): fast and efficient overview, detection of bone lesions and indication of probable histological type (malignant or benign)
  • CT: beneficial in areas with complex bony structures; may be required to evaluate bone stability
  • MRI: assesses the extent of soft tissue and bone marrow involvement
  • Scintigraphy: measures metabolic activity of bone lesions
• Detection of metastases (See secondary malignancies of the bone below.)

Radiographic signs of malignant bone tumors

• Margins of the lesion: the more poorly defined the margins of the lesion are the more rapid the tumor growth
  • Type I: geographic
  • Type II: moth-eaten appearance
  • Type III: permeative
• Periosteal reactions
  • Continuous periosteal reactions
    • Solid periosteal reaction: increased formation of new bone, with or without cortical destruction; indicates slow tumor growth
    • Lamellated periosteal reaction: may occur as single or multiple (onion skin appearance) layers; indicates rapid tumor growth
    • Spiculated periosteal reaction: spicules (new bone formations) that grow along Sharpey's fibres ; indicates more aggressive tumor growth compared to the solid and lamellated types.
      • Hair-on-end appearance: spicules that extend perpendicular to the bone surface
      • Sunburst appearance: divergent spicules that resemble a sunburst
  • Interrupted periosteal reactions
    • Codman triangle: develops as a result of the destruction of singular or multiple periosteal lamellae

Biopsy

• Indications: confirmation of radiologic diagnosis ; guidance of therapeutic procedures
• Techniques: open biopsy, needle biopsy (e.g., fine needle aspiration)

Laboratory tests

• White blood count
• ESR
• Alkaline phosphatase
• LDH

References:^{[16][17][18][19]}

	Age group	Main localization	Radiographic characteristics	Treatment	Five-year survival rate
Ewing sarcoma	Children/adolescents	Diaphysis of long bones	Onion skin appearance	Surgery Polychemotherapy Radiation	∼ 70%
Osteosarcoma	Adolescents/young adults	Metaphysis of long bones	Sunburst appearance Codman triangles Moth-eaten appearance	Surgery Polychemotherapy	∼ 70%
Chondrosarcoma	Adults	Pelvis, ribs, proximal femur and proximal humerus	Moth-eaten appearance Endosteal scalloping Intralesional calcifications	Surgery	∼ 50-60%

Differential diagnosis of bone pain in children

• Benign bone conditions
  • Osteomyelitis
  • Langerhans cell histiocytosis
  • Aneurysmal bone cysts
  • Giant cell tumor of the bone
• Growing pains
  • Epidemiology: : affects up to 35% of all children; most commonly seen at 3–12 years of age
  • Etiology: unknown
  • Clinical features
    • Episodic, bilateral pain that affects predominantly the lower extremities (shins, calves, thighs, popliteal fossa)
    • Pain typically occurs late in the day or during the night → children awaken from sleep
    • May be mild to severe and lasts for a few minutes to several hours; usually resolves by morning
    • Pain is not present during the day or activities
  • Diagnosis: clinical; imaging shows no abnormalities and is not indicated
  • Treatment: reassurance; acetaminophen/NSAIDs and massages during acute pain episodes may alleviate symptoms
  • Prognosis: : good; most cases resolve spontaneously by late childhood

References:^[8][13][20]

Description

• Definition: secondary bone tumors due to metastasis (predominantly hematogenous) of primary malignancies of other organs
• Etiology
  • Primary malignancies: most commonly lung, breast, and prostate cancer (together comprising 80% of cases) )
• Epidemiology
  • Bone metastases comprise 70% of all malignant bone tumors
  • Bones are the third most common site of metastases, after the lung and the liver.
• Localization: most commonly spine (∼ 40%) and pelvis (∼ 20%)
• Classification: based on radiological findings
  • Osteoblastic metastasis; : new bone formation by osteoblasts outweighs osteolytic processes → increase in radiographic density; (e.g., prostate cancer, small cell lung cancer)
  • Osteolytic metastasis; : osteolytic processes outweigh new bone formation → decrease in radiographic density; (e.g., thyroid cancer, kidney cancer, melanoma, non-small cell lung cancer, multiple myeloma)
  • Mixed metastasis (e.g., breast cancer, gastrointestinal cancer)

Clinical findings

• Often no or few symptoms (incidental finding during routine staging of the primary tumor)
• Local pain and swelling
• Pathologic fractures
• Spinal cord compression and/or radicular symptoms

Diagnostics

Approach

• Imaging is generally only performed in patients with primary malignancies who have clinical signs or laboratory findings (e.g., elevated alkaline phosphatase, hypercalcemia) indicating metastatic bone disease
• Biopsy is performed to confirm the diagnosis when imaging is insufficient or the patient has no known history of cancer

Laboratory

• Elevated serum calcium

Radiographic imaging

• Choice of imaging studies depends on
  1. The location of the suspected lesion and the clinical presentation
  2. The most likely underlying primary tumor
• For suspected spinal lesions:
  • Contrast-enhanced MRI (first-line modality; ); used to detect tumor extension and possible spinal cord compression
  • CT may be performed to assess vertebral bone integrity
• For suspected extremity lesions:
  • Conventional X-ray (initial test) However, lesions are only visible if extensive density loss occurs and periosteal reactions are often scarce to nonexistent.
  • Followed by CT or MRI if pathological fracture is identified or suspected for operative planning
• Whole-body skeletal imaging: indicated if a metastatic lesion is identified to detect additional, asymptomatic sites of metastasis
  • Bone scintigraphy (bone scan): most commonly used test to detect metastases within the entire skeleton and indicate biological activity of lesions (osteoblastic, osteolytic)
  • PET scan: useful to detect metastases and for staging, particularly for bone metastases from breast and lung cancer
  • X-ray skeletal survey: primarily used for purely lytic metastatic bone disease (particularly multiple myeloma)
  • Whole body MRI or CT are less sensitive than bone scintigraphy or PET/CT.

Biopsy

• Preferably taken from a soft tissue mass at the afflicted site, otherwise from an accessible bone where biopsy does not cause lasting impairment of motility or stability
• In case of an isolated lesion, it should be presumed to be a primary tumor unless proven otherwise.

Treatment

The choice of treatment generally depends on the underlying primary malignancy and stage of disease.

• Pain management
• Systemic therapy:
  • Chemotherapy
  • Osteoclast inhibitors (e.g., bisphosphonates): inhibit bone resorption
• Localized tumor radiation
• Surgery
  • If pathologic fractures have occurred or are likely: stabilize and restore function
  • If spinal instability or spinal cord compression has occured or is likely: immediate decompression and stabilization

References:^{[6][21][22][17][23][24]}