Osteosarcoma

Osteosarcoma is a primary malignant tumor of the bone characterized by the production of osteoid or immature bone by the tumor cells. The disease is most common in children and young adults and most frequently affects growth plates of the long bones, although it can involve any bone. Osteosarcoma can present with pain, swelling, and palpable mass, and sometimes with a pathologic fracture. Diagnosis is established with imaging studies and biopsy. Treatment involves systemic chemotherapy and surgical resection. Long-term survival can be expected with appropriate treatment in the absence of macrometastatic disease.

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Overview

Definition

Osteosarcoma is a primary malignant tumor of the bone characterized by the production of osteoid or immature bone by the tumor cells.

Epidemiology

  • Primary malignant bone tumors: 
    • 6th most common neoplasm in children
    • 3rd most common neoplasm in adolescents and young adults
    • Approximately 3,000 primary malignant bone tumors are diagnosed annually in the United States.
    • Approximately 1,500 deaths result from primary malignant bone tumors annually.
  • Osteosarcoma:
    • Most common primary malignancy of the bone 
    • 750–900 cases diagnosed annually in the United States
    • Bimodal age distribution:
      • Most frequently diagnosed in the 2nd or 3rd decade of life
      • Second small peak in adults > 65
    • Males > females

Etiology

  • Acquired genetic abnormalities of tumor suppressor genes and oncogenes (RB, TP53, INK4α, MDM2, CDK4)
  • Risk factors:
    • Paget disease of bone (usually in older adults)
    • Previous radiation treatment
    • Bone infarcts (sickle cell anemia) 
    • Familial syndromes:
      • Retinoblastoma
      • Li-Fraumeni syndrome
      • Rothmund-Thomson syndrome

Pathophysiology and Clinical Presentation

Pathophysiology

  • Cells of origin not definitely established; may be osteoblasts or mesenchymal stem cells
  • Thought to arise from aberrations of normal growth and remodeling secondary to acquired mutations
  • Most commonly occur during adolescent growth spurt and affect growth plates of the fastest-growing bones
  • Therefore, most commonly seen in the metaphysis around the knee (distal femur and proximal tibia)
  • Usually gritty, gray-white tumors
  • Spread extensively in medullary canal and may invade joint spaces
  • Histologic features:
    • Large hyperchromatic nuclei
    • Giant cells
    • Frequent mitoses
    • Vascular invasion
  • Diagnostic feature: formation of new immature bone by the tumor cells
Osteoblastic osteosarcoma

Hematoxylin and eosin stain of osteoblastic osteosarcoma with irregular immature bone deposition by anaplastic tumor cells

Image: “Osteoblastic osteosarcoma” by Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Higashi-ku, Maidashi, Fukuoka, 812-8582, Japan. License: CC BY 2.5, cropped by Lecturio.

Clinical presentation

  • Pain:
    • Localized
    • Usually of a few months’ duration
    • Sometimes follows an injury
    • Waxes and wanes
  • Swelling
  • Decreased range of motion (ROM) 
  • Palpable, tender soft tissue mass on examination
  • Pathologic fractures
  • Relative absence of constitutional symptoms
  • Sites affected (in decreasing order of frequency):
    • Distal femur
    • Proximal tibia
    • Proximal humerus 
    • Middle and proximal femur
    • Other bones
  • Metastases:
    • Present in 10%–20% at presentation
    • Local spread to same bone or adjacent bone 
    • Distant spread: most commonly to lungs

Diagnosis

History

  • Pain and swelling persistent beyond normal time frame associated with trauma
  • Family history of genetic diseases
  • Radiation exposure in older adults

Physical exam

  • Localized extremity swelling/mass
  • Tenderness to palpation

Laboratory studies

  • ↑ Erythrocyte sedimentation rate (ESR)
  • ↑ Alkaline phosphatase (ALP)
  • ↑ Lactate dehydrogenase (LDH) (higher levels correlate with a worse prognosis)

Imaging

  • X-ray: 
    • Characteristic periosteal reaction/elevation known as Codman’s triangle
    • “Sunburst” (spiculated) appearance due to extension through periosteum
  • CT scan:
    • Primary area: for evaluation of the extent of lesion and for surgical planning
    • Chest: to evaluate for pulmonary metastases
  • MRI:
    • The best modality for pre-surgical evaluation of primary lesion
    • Evaluates soft tissue, joint, and neurovascular involvement
  • Bone scan: to evaluate for metastatic or multifocal disease

Biopsy

  • Required for definitive diagnosis
  • Excisional, core needle, or fine needle

Musculoskeletal Tumor Society (MSTS) staging

  • Stage Ⅰ (low grade):
    • A: intracompartmental (does not extend through bone cortex)
    • B: extracompartmental (extends through bone cortex)
  • Stage Ⅱ (high grade):
    • A: intracompartmental
    • B: extracompartmental (majority of high-grade tumors)
  • Stage Ⅲ: distant metastases

Management

Chemotherapy

  • Most patients have occult micrometastases at the time of presentation.
  • Therefore, systemic chemotherapy improves outcomes.
  • Neoadjuvant (preoperative or adjuvant (postoperative) chemotherapy may be utilized.
  • No clear advantage of 1 over the other has been demonstrated.
  • Regimens include methotrexate, doxorubicin, and cisplatin.

Surgery

  • Complete tumor resection (limb sparing when feasible) is the mainstay of treatment.
  • Frequently, resection of the bone and the adjacent joint is required.
  • Depending on the location of the tumor, achieving negative margins may be difficult (e.g., spine osteosarcomas).

Radiation

  • Osteosarcomas are not very radiosensitive.
  • Radiation is sometimes used:
    • As primary therapy for a tumor in a difficult location where surgery would cause significant morbidity
    • As adjuvant treatment for incompletely resected tumors

Prognosis

  • 60%–70% 5-year survival without macrometastases
  • < 20% 5-year survival with distant metastatic disease

Differential Diagnosis

  • Ewing sarcoma: primary bone malignancy composed of poorly differentiated cells that most commonly affects adolescents. Ewing sarcoma presents with localized pain and swelling. Diagnosis is established with imaging and biopsy. Management is based on chemotherapy and surgical resection.
  • Chondrosarcoma: malignant bone tumor of cartilage-producing cells. Most common in older adults. Usually presents as a slow-growing mass associated with dull, achy pain. Diagnosed with imaging and biopsy. Treatment is wide surgical excision.
  • Bone metastases: metastatic bone lesions from primary cancers arising at other sites, most commonly the prostate, breast, and lung. Present with bone pain, pathologic fractures, and constitutional symptoms. Diagnosis is made based on clinical history and imaging. Treatment includes systemic chemotherapy as well as supportive measures aimed at minimizing pain and pathologic fractures.
  • Benign bone tumors: more common than malignant bone tumors; include enchondroma, osteochondroma, non-ossifying fibroma, chondroblastoma, osteoid osteoma, osteoblastoma, periosteal chondroma, giant cell tumor, and chondromyxoid fibroma, among others. Many benign bone tumors, however, may present the risk of malignant transformation. 
  • Osteomyelitis: bone infection most commonly due to pyogenic bacteria in the setting of orthopedic injury or chronic non-healing wound that erodes into bone. Presents with localized pain, signs of inflammation/infection, and fever; can progress to sepsis and limb loss. Treatment is aggressive antibiotic therapy with or without surgical debridement.
  • Orthopedic injury: strains, sprains, growing pains, fractures, etc., are the precipitating events that bring bony tumors to clinical attention. However, a more innocent injury or process may be to blame when considering the possibility of a bony neoplasm. Characterized by localized pain and inflammation/swelling. Diagnosis is usually made clinically, and management is supportive.

References

  1. Hornicek, F., McCarville, B., Agaram, N. (2020). Bone tumors: Diagnosis and biopsy techniques. Retrieved February 21, 2021, from https://www.uptodate.com/contents/bone-tumors-diagnosis-and-biopsy-techniques
  2. Janeway K.A., Maki R. (2021). Chemotherapy and radiation therapy in the management of osteosarcoma. Retrieved March 12, 2021, from https://www.uptodate.com/contents/chemotherapy-and-radiation-therapy-in-the-management-of-osteosarcoma
  3. Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., Loscalzo, J. (2012). Harrison’s Principles of Internal Medicine (18th ed). New York: McGraw Hill Education.
  4. Mehlman C.T. (2020). Osteosarcoma. Retrieved February 26, 2021, from https://emedicine.medscape.com/article/1256857-overview
  5. Robbins and Cotran. (2015). Pathologic Basis of Disease (9th Edition). Pp. 1197–1203.
  6. Wang L.L., Gerbhardt M.C., Rainusso N. (2019). Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology. Retrieved March 12, 2021, from https://www.uptodate.com/contents/osteosarcoma-epidemiology-pathogenesis-clinical-presentation-diagnosis-and-histology

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