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Ewing Sarcoma

Ewing sarcoma (ES) is a 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 derived from primitive round cells affecting primarily children and teenagers. Ewing sarcoma commonly presents with a painful mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast, swelling Swelling Inflammation, and pathologic bone fractures Bone fractures Breaks in bones. Bones: Remodeling and Healing. Diagnosis is established with imaging and biopsy. Treatment involves systemic chemotherapy Chemotherapy Osteosarcoma and local control of the tumor Tumor Inflammation with surgical resection or radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma. With proper treatment, the overall 5-year survival is over 70%.

Last updated: Dec 6, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Ewing sarcoma (ES) is a 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 derived from undifferentiated primitive round 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.
    • 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. 
  • Ewing sarcoma:
    • 10%–15% of 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 malignancies
    • Peak incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is in the 2nd decade of life.
    • Men > women
    • Whites are most commonly affected.
    • Manifests in the diaphysis Diaphysis The shaft of long bones. Bones: Structure and Types of long bones Long bones Length greater than width. Bones: Structure and Types and flat bones Flat bones Bones: Structure and Types ( pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy, scapula)

Etiology

  • Mutations result in the proliferation of primitive undifferentiated cells
  • Translocation of ESW and ETS regions (t(11;22)) implicated in > 80% of Ewing sarcomas
  • In addition to ES, the Ewing sarcoma family of tumors also include primitive neuroectodermal tumors and atypical ES.
  • Environmental triggers or congenital Congenital Chorioretinitis associations not identified

Pathophysiology and Clinical Presentation

Pathophysiology

  • Characterized by primitive round cells without differentiation
  • Histologically appears as sheets of round cells with hyperchromatic nuclei and scant cytoplasm
  • May be derived from neural crest cells Neural crest cells Gastrulation and Neurulation, but exact origins are unknown
  • Closely related to primitive neuroectodermal tumors
  • Originates in medullary cavity but invades cortex, 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, and soft tissue Soft Tissue Soft Tissue Abscess
  • Tumor Tumor Inflammation usually contains areas of hemorrhage and extensive necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
Ewing sarcoma on h&e stain

A hematoxylin and eosin (H&E) stained section from an Ewing sarcoma tumor magnified at 400x:
Sheets of small round cells with a high nuclear:cytoplasmic ratio

Image: “Ewing sarcoma” by Center for Children’s Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. License: CC BY 3.0, cropped by Lecturio.

Clinical presentation

  • 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:
    • Aggravated by exercise 
    • Worse at night
    • Can present in many locations
  • Palpable soft tissue Soft Tissue Soft Tissue Abscess mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast:
    • Markedly tender on examination
    • Fixed to 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
    • Accompanied by erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion and swelling Swelling Inflammation
  • Sometimes present with pathologic fracture Pathologic Fracture Chondrosarcoma
  • 10%–20% have constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (often correlate with metastatic disease).
  • Extremely aggressive with early metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis (worst prognostic factor)
  • May metastasize 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, other bones, bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis

Diagnosis

Laboratory studies

  • 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 and Types ( 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 and Types of chronic disease)
  • Increased WBC count
  • Elevated erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess ( ESR ESR Soft Tissue Abscess) and lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma ( LDH LDH Osteosarcoma) (often misdiagnosed as 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)
  • Classic cytogenetic abnormality translocation t(11;22) identified in biopsy specimens

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:
    • Typically 1st imaging test if diagnosis suspected
    • Destructive 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 lesion associated with soft tissue Soft Tissue Soft Tissue Abscess mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
    • Onion skinning due to the lamellated appearance of the periosteal reaction
    • Periosteal displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms can create a Codman triangle.
    • Moth-eaten appearance due to lytic lesion and endosteal scalloping Endosteal Scalloping Chondrosarcoma 
  • Other tests for evaluation of primary and metastatic disease:
    • CT scan: extent of cortical destruction and soft-tissue involvement
    • MRI: best to define the relationship of tumor Tumor Inflammation to vessels and nerves 
    • Bone scan Bone Scan Osteosarcoma
    • PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging scan

Biopsy

  • Definitive diagnosis
  • Open biopsy preferable to core needle
  • Histology: anaplastic small blue round cell sarcoma
  • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy should also be performed to rule out bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis.

Management

Systemic

  • Systemic chemotherapy Chemotherapy Osteosarcoma is the mainstay of treatment.
  • Administered as induction (neoadjuvant) chemotherapy Chemotherapy Osteosarcoma, and additional chemotherapy Chemotherapy Osteosarcoma after local control
  • Regimens include vincristine Vincristine An antitumor alkaloid isolated from vinca rosea. Microtubule and Topoisomerase Inhibitors, doxorubicin, cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants, and dactinomycin Dactinomycin A compound composed of a two cyclic peptides attached to a phenoxazine that is derived from streptomyces parvulus. It binds to DNA and inhibits RNA synthesis (transcription), with chain elongation more sensitive than initiation, termination, or release. As a result of impaired mRNA production, protein synthesis also declines after dactinomycin therapy. Antitumor Antibiotics.

Local treatment

  • Surgical excision:
    • Preferred management method of primary tumor Tumor Inflammation site
    • Goal: limb salvage and minimal disfigurement
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy: Use if surgery is not feasible.
Ewing sarcoma surgery

Ewing sarcoma:
a: Axial section of noncontrast CT scan showing Ewing sarcoma of the right clavicle
b: Photograph showing the resected right clavicle with tumor in situ

Image: “Ewing’s sarcoma of the right clavicle” by Department of Orthopaedics, All India Institute of Medical Sciences, Dr. B. R. A. Institute Rotary Cancer Hospital, Delhi, India. License: CC BY 2.0

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

  • Overall 5-year survival is > 70%.
  • Complete initial response to chemotherapy Chemotherapy Osteosarcoma imparts a better 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.

Differential Diagnosis

  • Osteosarcoma 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: a 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 characterized by the production of 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. Osteosarcoma 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 is most common in children and young adults. Presentation includes pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, swelling Swelling Inflammation, palpable mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast, and pathologic fracture Pathologic Fracture Chondrosarcoma. Diagnosis is suspected on imaging and confirmed with tissue biopsy. Management includes surgical resection and systemic chemotherapy Chemotherapy Osteosarcoma.
  • 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 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: Histology producing cells. 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 is most common in older adults and usually presents as a slowly 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. Diagnosis is based on imaging and biopsy, and 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 metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis: metastatic bone lesions Bone Lesions Multiple Myeloma from primary cancers arising at other sites (commonly 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). Presentation includes 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 fracture Pathologic Fracture Chondrosarcoma, and constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Diagnosis is made based on clinical history and imaging. Treatment includes systemic chemotherapy Chemotherapy Osteosarcoma 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; 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. 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 include enchondroma, osteochondroma, nonossifying 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.
  • 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 nonhealing wound eroding 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. Presentation includes 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. 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 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: strain, sprain, growing pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, 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, 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 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 bony neoplasm. Orthopedic injury is 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, 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, and/or swelling Swelling Inflammation. Diagnosis is usually made clinically and management is supportive.

References

  1. DeLaney T.F., Hornicek F.J., Bahrami A. (2020). Ewing sarcoma family of tumors. Retrieved March 17, 2021, from https://www.uptodate.com/contents/clinical-presentation-staging-and-prognostic-factors-of-the-ewing-sarcoma-family-of-tumors
  2. Gerbhardt M.C., Dubois S.G. (2020). Treatment of the Ewing sarcoma family of tumors. Retrieved March 17, 2021, from https://www.uptodate.com/contents/treatment-of-the-ewing-sarcoma-family-of-tumors
  3. Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., Loscalzo, J. (2012). Harrison’s principles of internal medicine (18th edition.). New York: McGraw Hill Education.
  4. Robbins and Cotran Pathologic Basis of Disease. (2015). 9th Edition. p.1197-1203.
  5. Shaikh H. (2020). Ewing Sarcoma. Retrieved February 26, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/21419/

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