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. Structure of Bones malignancy derived from primitive round cells affecting primarily children and teenagers. Ewing sarcoma commonly presents with a painful mass, swelling, and pathologic 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 fractures. Diagnosis is established with imaging and biopsy. Treatment involves systemic chemotherapy and local control of the tumor with surgical resection or radiation. With proper treatment, the overall 5-year survival is over 70%.

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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. Structure of Bones malignancy 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. 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.
    • 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. 
  • 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. Structure of Bones malignancies
    • Peak incidence is in the 2nd decade of life.
    • Men > women
    • Whites are most commonly affected.
    • Manifests in the diaphysis of long bones and flat bones ( 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, 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 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, but exact origins are unknown
  • Closely related to primitive neuroectodermal tumors
  • Originates in medullary cavity but invades cortex, periosteum, and soft tissue
  • Tumor usually contains areas of hemorrhage and extensive necrosis
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 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:
    • Aggravated by exercise 
    • Worse at night
    • Can present in many locations
  • Palpable soft tissue mass:
    • 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. Structure of Bones
    • Accompanied by erythema and swelling
  • Sometimes present with 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
  • 10%–20% have constitutional symptoms (often correlate with metastatic disease).
  • Extremely aggressive with early 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, other bones, bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow

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 (anemia of chronic disease)
  • Increased WBC count
  • Elevated erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) (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:
    • 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. Structure of Bones lesion associated with soft tissue mass
    • Onion skinning due to the lamellated appearance of the periosteal reaction
    • Periosteal displacement can create a Codman triangle.
    • Moth-eaten appearance due to lytic lesion and endosteal scalloping 
  • 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 to vessels and nerves 
    • Bone scan
    • PET scan

Biopsy

  • Definitive diagnosis
  • Open biopsy preferable to core needle
  • Histology: anaplastic small blue round cell sarcoma
  • Bone marrow biopsy should also be performed to rule out bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow metastasis.

Management

Systemic

  • Systemic chemotherapy is the mainstay of treatment.
  • Administered as induction (neoadjuvant) chemotherapy, and additional chemotherapy after local control
  • Regimens include vincristine, doxorubicin, cyclophosphamide, and dactinomycin.

Local treatment

  • Surgical excision:
    • Preferred management method of primary tumor site
    • Goal: limb salvage and minimal disfigurement
  • Radiation 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

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

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. Structure of Bones tumor 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. Structure of Bones. 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 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, palpable mass, and 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 suspected on imaging and confirmed with tissue biopsy. Management includes surgical resection and systemic chemotherapy.
  • 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. 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 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. Diagnosis is based on imaging and biopsy, and treatment is wide surgical excision.
  • Bone metastasis: 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 (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. Prostate and other Male Reproductive Glands, 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. 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 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, 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; may present the risk of malignant transformation. 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 include enchondroma, osteochondroma, nonossifying fibroma, chondroblastoma, osteoid osteoma, osteoblastoma, periosteal chondroma, giant cell tumor, and chondromyxoid fibroma, among others.
  • 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 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. Structure of Bones. Presentation includes 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. Osteomyelitis 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: strain, sprain, growing 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, 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. are 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 bony neoplasm. Orthopedic injury is 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, 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. 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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