Ewing Sarcoma

Overview

Definition

Ewing sarcoma (ES) is a malignant sarcoma derived from undifferentiated primitive round cells that usually arises in 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 but may be extraosseous. It is biologically distinct from 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 because it does not produce osteoid Osteoid Bones: Development and Ossification.

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; very rare in African American and Asian populations
  • 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

• Caused by recurrent chromosomal translocations involving EWSR1 and an ETS family transcription factor Transcription factor Generic term for proteins necessary for transcription Regulation of Transcription.
• Translocation t(11;22)(q24;q12) resulting in an EWSR1-FLI1 fusion gene Gene 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. Basic Terms of Genetics is present in approximately 85% of cases.
• No clear environmental risk factors or inherited familial cancer syndromes have been 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
• Its exact normal cell of origin remains uncertain, but current classification is molecular rather than based on a presumed neural crest Neural crest The two longitudinal ridges along the primitive streak appearing near the end of gastrulation during development of nervous system (neurulation). The ridges are formed by folding of neural plate. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the neural tube. Hirschsprung Disease origin.
• 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
• Large tumors may contain areas of hemorrhage and necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage

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 20%–25% of cases presenting with metastatic disease at diagnosis, representing a poor 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
• Molecular confirmation through FISH FISH A type of in situ hybridization in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei. Chromosome Testing, PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR), or NGS of an EWSR1 or related FET-ETS fusion is an important part of modern diagnosis.

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, permeative 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 a 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
• Image-guided core needle biopsy Core Needle Biopsy Fibrocystic Change is preferred over open biopsy due to lower morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status.
• Histology: anaplastic small blue round cell sarcoma
• CD99 membranous staining is common but not specific.
• 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 is no longer routinely required in all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship and may be omitted in otherwise localized disease when staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis studies are negative.

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
• The medical approach usually involves the VDC-IE regimen, which is a combination of vincristine Vincristine An antitumor alkaloid isolated from vinca rosea. Microtubule and Topoisomerase Inhibitors, doxorubicin, and 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 alternated with ifosfamide Ifosfamide Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. Alkylating Agents and Platinum and etoposide Etoposide A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the g2 and s phases of the cell cycle. Microtubule and Topoisomerase Inhibitors.

Local treatment

• Wide surgical resection:
  • Preferred management method of the primary tumor Tumor Inflammation site when tumor Tumor Inflammation size and extension Extension Examination of the Upper Limbs allow
  • Goal: limb salvage and minimal disfigurement
• Unlike 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, Ewing sarcoma is very radiosensitive, making 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 an important component of treatment for unresectable tumors or positive margins.

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.