Osteosarcoma

Osteosarcoma is a primary malignant tumor of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones characterized by the production of osteoid or immature bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones. Osteosarcoma can present with pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, swelling, and palpable mass, and sometimes with a pathologic fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures. 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones characterized by the production of osteoid or immature bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones by the tumor cells.

Epidemiology

  • Primary malignant bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tumors: 
    • 6th most common neoplasm in children
    • 3rd most common neoplasm in adolescents and young adults
    • Approximately 3,000 primary malignant bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tumors are diagnosed annually in the United States.
    • Approximately 1,500 deaths result from primary malignant bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tumors annually.
  • Osteosarcoma:
    • Most common primary malignancy of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 
    • 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones (usually in older adults)
    • Previous radiation treatment
    • Bone infarcts (sickle cell anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Familial syndromes:
      • Retinoblastoma Retinoblastoma Retinoblastoma is a rare tumor but the most common primary intraocular malignancy of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or nonheritable. 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones by the tumor cells
Osteoblastic osteosarcoma

Hematoxylin and eosin stain of osteoblastic osteosarcoma with irregular immature bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones or adjacent bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 
    • Distant spread: most commonly to lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. 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 Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis

  • Stage Ⅰ (low grade):
    • A: intracompartmental (does not extend through bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones cortex)
    • B: extracompartmental (extends through bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 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 Ewing Sarcoma Ewing sarcoma (ES) is a primary bone malignancy derived from primitive round cells affecting primarily children and teenagers. Ewing sarcoma commonly presents with a painful mass, swelling, and pathologic bone fractures. Ewing Sarcoma: primary bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones malignancy composed of poorly differentiated cells that most commonly affects adolescents. Ewing sarcoma Ewing Sarcoma Ewing sarcoma (ES) is a primary bone malignancy derived from primitive round cells affecting primarily children and teenagers. Ewing sarcoma commonly presents with a painful mass, swelling, and pathologic bone fractures. Ewing Sarcoma presents with localized pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and swelling. Diagnosis is established with imaging and biopsy. Management is based on chemotherapy and surgical resection.
  • Chondrosarcoma Chondrosarcoma Chondrosarcoma is a malignant bone tumor characterized by the production of a cartilaginous matrix. This bone tumor most commonly affects adults over the age of 50. Chondrosarcoma usually presents with a slowly increasing mass (or swelling) with a dull achy pain. Chondrosarcoma: malignant bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tumor of cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage-producing cells. Most common in older adults. Usually presents as a slow-growing mass associated with dull, achy pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Diagnosed with imaging and biopsy. Treatment is wide surgical excision.
  • Bone metastases: metastatic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones lesions from primary cancers arising at other sites, most commonly the prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands, breast, and lung. Present with bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and pathologic fractures.
  • Benign bone tumors Benign bone tumors Benign bone lesions are a group of noncancerous, slow-growing neoplasms that arise from cartilage or bone. These lesions have distinct features, such as endosteal reactions with intraosseous calcification and bone formation. Benign Bone Tumors: more common than malignant bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tumors; include enchondroma, osteochondroma, non-ossifying fibroma, chondroblastoma, osteoid osteoma, osteoblastoma, periosteal chondroma, giant cell tumor, and chondromyxoid fibroma, among others. Many benign bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tumors, however, may present the risk of malignant transformation. 
  • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis: bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones infection most commonly due to pyogenic bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview in the setting of orthopedic injury or chronic non-healing wound that erodes into bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones. Presents with localized pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, signs of inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation/infection, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever; can progress to sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. 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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