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

• Definition
  • Highly malignant bone tumor arising from neuroectodermal cells
  • Some sources suggest that Ewing sarcoma originates from mesenchymal stem cells. ^[1][2]
• Etiology: : associated with various chromosomal translocations of the EWSR1 gene (chromosome 22)
• Epidemiology
  • Incidence: peak at 10–20 years
  • Sex: ♂ > ♀
  • Ethnicity: primarily affects white individuals
• 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

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.

Diagnostics

• Conventional X-ray
  • Lytic bone lesions
  • Onion skin appearance of the periosteum
• Biopsy
  • Anaplastic small-blue-round-cell malignancy
    • Tumor cells resemble lymphocytes.
    • Differential diagnoses include lymphoma and chronic osteomyelitis.
  • Chromosomal translocation t(11;22)(q24;q12); which leads to expression of fusion protein EWS-FLI1
  • Cells contain glycogen accumulations and are usually CD99-positive. ^[3]
• Laboratory findings: ↑ ESR, ↑ LDH, leukocytosis

“Ew, did you feed on 22 onions?”: Ewing sarcoma, femur region, chromosome 22, onion skin appearance.

Treatment ^[4]

• Surgery; (definitive resection) plus neoadjuvant and adjuvant polychemotherapy
• Additionally: radiation therapy

Prognosis

• Extremely aggressive, early metastases
• Usually responsive to chemotherapy
• Five-year survival rate of ∼ 80% for localized disease ^[5]

References:^[6]

Description

• Definition: malignant, osteoid, and bone-forming tumor arising from mesenchymal stem cells (osteoblasts) located in the periosteum
• Etiology
  • Primary osteosarcoma: unknown
  • Secondary osteosarcoma: Paget disease of bone, radiation injury, bone infarction
  • Increased incidence in individuals with retinoblastoma and Li-Fraumeni syndrome
• Epidemiology
  • Incidence: bimodal distribution
    • Primary osteosarcoma: in puberty/adolescence (peak incidence age 10-30 years)
    • Secondary osteosarcoma: advanced age
  • Sex: ♂ > ♀
  • Most common primary bone malignancy
• Localization
  • Primary tumor: metaphyses of long bones (particularly distal femur and proximal tibia)
  • Metastases: lungs , skeletal system, regional lymph nodes

Clinical features

• Frequently first manifests with pain (progressive, worsens at night and with activity)
• Progressive swelling (tissue mass that is tender to palpation; and accompanied by erythema)
• Pathologic fractures
• Limping, decreased range of motion
• Possible B symptoms

Diagnostics ^[7]

• Imaging
  • Conventional x-ray
    • Sunburst appearance of lytic bone lesions and/or Codman triangles
    • Signs of osteolysis adjacent to osteosclerosis (moth-eaten appearance)
  • MRI: assesses the involvement of soft tissue, evaluation in cases of unclear radiographic findings
• Biopsy
  • Pleomorphic, malignant osteoblasts that produce osteoid
  • Osteosarcomas always feature woven bone matrix (compared to chondrosarcomas and fibrosarcomas)
• Laboratory
  • ↑ Alkaline phosphatase
  • ↑ LDH
  • ↑ ESR

Remember to wear your SOCK (Sunburst, Osteosarcoma, Codman, Knee region).

Treatment

• Surgery; (definitive resection) with neoadjuvant and adjuvant polychemotherapy (e.g., a combination of methotrexate, doxorubicin, cisplatin, and ifosfamide)
• Histological examination of the resected bone to evaluate the effect of neoadjuvant chemotherapy (major prognostic factor)

Osteosarcomas are usually resistant to radiation therapy.

Prognosis

• Aggressive course
• Primary osteosarcoma: five-year survival rate of ∼ 70% (usually responsive to treatment)
• Secondary osteosarcoma: poor prognosis (less responsive to treatment)

References:^[8]

Description

• Definition: a malignant tumor arising from mesenchymal cells that produce cartilage
• Etiology
  • Primary chondrosarcoma: unknown
  • Secondary chondrosarcoma: e.g., osteochondroma, Paget disease of bone, radiation
• Epidemiology ^[9]
  • Age: usually > 50 years
  • Sex: ♂ > ♀
• Localization: most common in the medullary cavity of the pelvis, ribs, proximal femur, and proximal humerus

Clinical features

• Deep, dull pain (worsens at night, insidious progression over months to years)
• Local swelling
• Pathological fractures
• Neurovascular disturbances and/or limited range of motion

Diagnostics ^[10]

• Conventional X-ray or CT
  • Osteolysis with a moth-eaten appearance
  • Intralesional calcifications (rings and arcs calcification, popcorn calcification)
  • Endosteal scalloping; and cortical breach with infiltration of soft tissue
• MRI: rim-like contrast enhancement
• Biopsy
  • Malignant chondrocytes
  • Lobulated appearance (hyaline cartilage nodules with peripheral calcification )
  • Grading ^[11]
    • Grade I: low cellularity, mostly chondroid matrix
    • Grade II: increased cellularity, decreased chondroid matrix with localized myxoid changes
    • Grade III: high cellularity, prominent nuclear atypia, myxoid matrix

Treatment

• Surgery (definitive resection)
• Chemotherapy and radiation therapy, possibly as adjuvant therapy or as palliative treatment

Prognosis ^[12]

• Five-year survival rate of 50–85% (depending on the histological grading)
• Late recurrences are possible.
• Regular follow-ups for 10 years are required.

• Description: extremely rare malignancy of the spine and skull
• Epidemiology: typically develops in patients around 50 years
• Localization: sacral spine (∼ 50%) and skull base (∼ 35%) ^[13]
• Treatment: surgery

References:^[14]

Imaging

General approach

• Detection and evaluation of possible primary bone tumors ^[15]
  • Plain radiography (initial test of choice): fast and efficient overview, detection of bone lesions, 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 the metabolic activity of bone lesions
• Detection of metastases: See “Secondary malignancies of the bone (bone metastasis)” below.

Radiographic signs of malignant bone tumors ^[16]

• Margins of the lesion: The more poorly defined the margins of the lesion are, the more rapid is the tumor growth. ^[15]
  • Type I: geographic
  • Type II: moth-eaten appearance
  • Type III: permeative
• Periosteal reactions: reactive periosteal bone synthesis as a result of bone destruction by a malignant process

Types of 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
    • Multiple layers of new bone (onion skin appearance)
    • Indicates rapid tumor growth
  • Spiculated periosteal reaction
    • Spicules (new bone formations) that grow along Sharpey fibers (collagen fibers that anchor the periosteum to the compact bone)
    • 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
  • Occur if continuous periosteal reactions are themselves disturbed by tumor growth
  • Indicate the presence of a particularly aggressive malignant process
  • Codman triangle: develops as a result of the destruction and elevation 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

Differential diagnosis of bone pain in children

Benign bone conditions

• Osteomyelitis
• Giant cell tumor of the bone
• Langerhans cell histiocytosis
• Aneurysmal bone cysts

Growing pains ^[17][18]

• Etiology: unknown
• Epidemiology
  • Affects up to 35% of all children
  • Most commonly seen at 3–12 years of age
• 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 awakening from sleep
  • Pain is not present during the day or activities.
  • May be mild to severe and lasts for a few minutes to several hours; usually resolves by morning
• Diagnostics
  • The diagnosis is clinical.
  • Imaging shows no abnormalities and is not indicated.
• Treatment
  • Reassurance
  • Acetaminophen/NSAIDs and massages during acute pain episodes may alleviate symptoms.
• Prognosis
  • Usually good
  • Most cases resolve spontaneously by late childhood.

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
  • More common than primary bone tumors (∼ 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%) ^[19]
• Classification: based on radiological findings ^[20]
  • Osteoblastic metastasis
    • New bone formation by osteoblasts outweighs osteolytic processes → increase in radiographic density
    • Examples: prostate cancer, small cell lung cancer
  • Osteolytic metastasis
    • Osteolytic processes outweigh new bone formation → decrease in radiographic density
    • Examples: multiple myeloma, thyroid cancer, kidney cancer, melanoma, non-small cell lung cancer
  • Mixed metastasis: e.g., breast cancer, gastrointestinal cancer

Clinical features

• Often no or few symptoms (incidental finding during routine staging of the primary tumor)
• Local pain; and swelling ^[19]
• 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 ^[20]

• Choice of imaging studies depends on:
  • The location of the suspected lesion and the clinical presentation
  • 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)
  • Followed by CT or MRI if a pathological fracture is identified or suspected for operative planning ^[21]
• 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 the 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 the disease. ^[22]

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