Osteosarcoma

Overview

Definition

Osteosarcoma, also called osteogenic sarcoma, is a highly malignant mesenchymal 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. Bones: Structure and Types tumor Tumor Inflammation characterized by the direct production of osteoid Osteoid Bones: Development and Ossification (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. Bones: Structure and Types) by the tumor Tumor Inflammation 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. Bones: Structure and Types 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. Bones: Structure and Types 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. Bones: Structure and Types tumors annually.
• Osteosarcoma:
  • Most common primary malignancy Malignancy Hemothorax 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. Bones: Structure and Types 
  • 800–900 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 Tumor Inflammation suppressor genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure and oncogenes Oncogenes Genes whose gain-of-function alterations lead to neoplastic cell transformation. They include, for example, genes for activators or stimulators of cell proliferation such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of ‘v-‘ before oncogene symbols indicates oncogenes captured and transmitted by retroviruses; the prefix ‘c-‘ before the gene symbol of an oncogene indicates it is the cellular homolog (proto-oncogenes) of a v-oncogene. Carcinogenesis ( RB RB Chlamydia, 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. Bones: Structure and Types (usually in older adults)
  • Previous radiation treatment
  • 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. Bones: Structure and Types infarcts ( sickle cell anemia Sickle cell anemia A disease characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs. It is the clinical expression of homozygosity for hemoglobin S. Sickle Cell Disease) 
  • 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 non-heritable. Retinoblastoma (1,000-fold increased risk of osteosarcoma)
    • Li-Fraumeni syndrome (linked to TP53 mutations)
    • Rothmund-Thomson syndrome

Pathophysiology and Clinical Presentation

Pathophysiology

• Cell of origin not definitively established; likely arises from mesenchymal stem or early osteoprogenitor cells committed to the osteoblastic lineage
• Thought to arise from aberrations of normal growth and remodeling secondary to acquired mutations
• Most commonly occur during adolescent growth spurt Growth spurt Puberty and affect growth plates of the fastest-growing bones
• Therefore, most commonly seen in the metaphysis Metaphysis Bones: Structure and Types around the knee (distal femur and proximal tibia Tibia The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. Knee Joint: Anatomy)
• Usually gritty, gray-white tumors
• Spread extensively in the medullary canal and may extend through the cortex into adjacent soft tissue Soft Tissue Soft Tissue Abscess or invade joint spaces
• Histologic features:
  • Large hyperchromatic nuclei
  • Giant cells Giant cells Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In aids, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Giant Cell Arteritis
  • 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. Bones: Structure and Types by the tumor Tumor Inflammation cells

Clinical presentation

• Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways:
  • Localized, progressive deep aching 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. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways that typically worsens at night and with activity
  • Usually of a few months’ duration
  • Sometimes follows an injury
  • Waxes and wanes
• Swelling Swelling Inflammation
• Decreased range of motion Range of motion The distance and direction to which a bone joint can be extended. Range of motion is a function of the condition of the joints, muscles, and connective tissues involved. Joint flexibility can be improved through appropriate muscle strength exercises. Examination of the Upper Limbs (ROM) 
• Palpable, tender soft tissue Soft Tissue Soft Tissue Abscess mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast on examination
• Pathologic fractures
• Relative absence of constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
• Sites affected (in decreasing order of frequency):
  • Distal femur
  • Proximal tibia Tibia The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. Knee Joint: Anatomy
  • Proximal humerus Humerus Bone in humans and primates extending from the shoulder joint to the elbow joint. Arm: Anatomy 
  • 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. Bones: Structure and Types 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. Bones: Structure and Types 
  • 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: Anatomy

Diagnosis

History

• Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and swelling Swelling Inflammation persistent beyond normal time frame associated with trauma
• Family history Family History Adult Health Maintenance of genetic diseases
• Radiation exposure in older adults

Physical exam

• Localized extremity swelling Swelling Inflammation/ mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
• Tenderness to palpation Palpation Application of fingers with light pressure to the surface of the body to determine consistency of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. Dermatologic Examination

Laboratory studies

• ↑ Erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess ( ESR ESR Soft Tissue Abscess)
• ↑ Alkaline phosphatase (ALP)
• ↑ Lactate dehydrogenase (LDH) (higher levels correlate with a worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas)

Imaging

• X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests:
  • Codman’s triangle: new subperiosteal 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. Bones: Structure and Types formed when the tumor Tumor Inflammation elevates the periosteum Periosteum Thin outer membrane that surrounds a bone. It contains connective tissue, capillaries, nerves, and a number of cell types. Bones: Structure and Types away from the cortex
  • “Sunburst” appearance due to spiculated 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. Bones: Structure and Types formation radiating outward from the cortex into soft tissue Soft Tissue Soft Tissue Abscess
• 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 Soft Tissue Soft Tissue Abscess, joint, and neurovascular involvement
• 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. Bones: Structure and Types scan: to evaluate for metastatic or multifocal Multifocal Retinoblastoma disease

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

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

Musculoskeletal Tumor Tumor Inflammation Society (MSTS) staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. 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. Bones: Structure and Types 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. Bones: Structure and Types cortex)
• Stage Ⅱ (high grade):
  • A: intracompartmental
  • B: extracompartmental (majority of high-grade tumors)
• Stage Ⅲ: distant metastases

Management

Chemotherapy

• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have occult micrometastases at the time of presentation.
• Therefore, systemic chemotherapy improves outcomes.
• For high-grade osteosarcoma, chemotherapy typically begins in the neoadjuvant (preoperative) setting before wide surgical resection; adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination (postoperative) chemotherapy may also be utilized.
• No clear advantage of 1 over the other has been demonstrated.
• Regimens include methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy, doxorubicin, and cisplatin Cisplatin An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These cross links appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the g2 phase of the cell cycle. Alkylating Agents and Platinum.

Surgery

• Complete tumor Tumor Inflammation resection (limb sparing when negative margins can be achieved and function preserved) is the mainstay of treatment.
• Amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation may be required with extensive soft tissue Soft Tissue Soft Tissue Abscess, neurovascular, or joint involvement.
• Depending on the location of the tumor Tumor Inflammation, achieving negative margins may be difficult (e.g., spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy osteosarcomas).

Radiation

• Osteosarcomas are not very radiosensitive.
• Radiation is sometimes used:
  • As primary therapy for a tumor Tumor Inflammation in a difficult location where surgery would cause significant morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status
  • As adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination treatment for incompletely resected tumors

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• 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. Bones: Structure and Types malignancy Malignancy Hemothorax 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 An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and swelling Swelling Inflammation. Diagnosis is established with imaging and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. 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. Bones: Structure and Types tumor Tumor Inflammation of cartilage-producing cells. Most common in older adults. Usually presents as a slow-growing mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast associated with dull, achy pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways. Diagnosed with imaging and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Treatment is wide surgical excision.
• 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. Bones: Structure and Types metastases: metastatic bone lesions Bone Lesions Multiple Myeloma 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. , 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. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, pathologic fractures, and constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Diagnosis is made based on clinical history and imaging. Treatment includes systemic chemotherapy as well as supportive measures aimed at minimizing pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and pathologic fractures.
• Benign Benign Fibroadenoma 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. Bones: Structure and Types 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. Bones: Structure and Types tumors; include enchondroma, osteochondroma, non-ossifying fibroma, chondroblastoma, osteoid osteoma Osteoid Osteoma Benign Bone Tumors, osteoblastoma Osteoblastoma A benign, painful, tumor of bone characterized by the formation of osteoid tissue, primitive bone and calcified tissue. It occurs frequently in the spine of young persons. Benign Bone Tumors, periosteal chondroma, giant cell tumor Tumor Inflammation, and chondromyxoid fibroma, among others. Many benign Benign Fibroadenoma 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. Bones: Structure and Types tumors, however, may present the risk of malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology. 
• 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 infection Bone infection 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 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 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. Bones: Structure and Types. Presents with localized pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, 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 Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock and limb loss. Treatment is aggressive antibiotic therapy with or without surgical debridement Debridement The removal of foreign material and devitalized or contaminated tissue from or adjacent to a traumatic or infected lesion until surrounding healthy tissue is exposed. Stevens-Johnson Syndrome.
• Orthopedic injury: strains, sprains, growing pains, fractures, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC)., are the precipitating events that bring bony tumors to clinical attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment. However, a more innocent injury or process may be to blame when considering the possibility of a bony neoplasm. Characterized by localized pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways 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 Swelling Inflammation. Diagnosis is usually made clinically, and management is supportive.