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EWING'S SARCOMA

Introduction

James Ewing first described the tumor that was to be named after him in the 1920s. Ewing sarcoma (ES) is a rare, extremely aggressive bone and soft-tissue cancer most common in the long bones and pelvis, but also occur rarely in the hand (<.2%of Ewing sacroma in hand).3 The most common location in the hand is the metacarpal of the long finger. Approximately 25% of patients have metastases at the time of diagnosis. Hand metastases typically occur in the lung. The diagnosis is largely based on genetic testing for characteristic fusion oncogenes expressed by the tumor. The best prognoses are associated with: location in the distal extremities, soft-tissue tumors, smaller tumors, patient age <15 years, female gender. Overall, outcomes have not improved in 20 years because the mechanism of metastasis is almost completely unknown. Clinical trial results for molecular targeted agents have been disappointing. Immunotherapy approaches show greater promise.

Pathophysiology/Pathogenetics

  • Ewing sarcoma results from malignant transformation of stem and/or progenitor cells of mesoderm and neural crest lineages.
  • EWS-ETS fusion proteins play a critical role in ES oncogenesis.
  • Numerous targets of EWS-ETS–mediated transcriptional activity include a tumor suppressor gene (TGF beta type II receptor) and an inhibitor of insulin-like growth factor I (IGFBP-3).
  • Non-transcriptional activity also is significant, with the proteins binding DNA across the genome.
  • However, genetic approaches may not delineate the molecular basis of metastatic disease Ewing sarcoma.

Related Anatomy

  • Primary sites of bone disease are:
    • Lower extremity (41%)
    • Pelvis (26%)
    • Chest wall (16%)
    • Upper extremity (9%)
    • Spine (6%)
    • Hand and foot (3%)
    • Skull (2%)
  • Most common soft-tissue sites are:
    • Trunk (32%)
    • Extremity (26%)
    • Head and neck (18%)
    • Retroperitoneum (16%)
    • Other (9%)

Incidence

  • The hand is affected in <0.2% of all (bone and soft-tissue) Ewing sarcoma.3
  • Across all age groups in the United States, 1 case of ES occurs per 1 million people.
  • About half of all cases occur between the ages of 10 and 20 years.
  • ES occurs 9 times more often in whites than in African Americans.
  • The gender division is 59% male and 41% female.

Differential Diagnosis

  • Desmoplastic sarcoma
  • Malignant lymphoma
  • Neuroblastoma
  • Poorly differentiated synovial sarcoma
  • Rhabdomyosarcoma
ICD-10 Codes

  • EWING'S SARCOMA

    Diagnostic Guide Name

    EWING'S SARCOMA

    ICD 10 Diagnosis, Single Code, Left Code, Right Code and Bilateral Code

    DIAGNOSISSINGLE CODE ONLYLEFTRIGHTBILATERAL (If Available)
    EWING'S SARCOMA C40.12C40.11 

    ICD-10 Reference

    Reproduced from the International statistical classification of diseases and related health problems, 10th revision, Fifth edition, 2016. Geneva, World Health Organization, 2016 https://apps.who.int/iris/handle/10665/246208

Symptoms
Pain at tumor site
Swelling and/or redness at tumor site (usually considered to be a play- or sports-related injury in children)
Symptoms related to nerve compression from tumor (eg, numbness, tingling)
If metastatic: decreased appetite, fatigue, fever, and weight loss
Typical History

The patient is likely to be an adolescent (50%) or young adult.  The presenting complaint is usually pain. A mass may be palpable. Fever and weight loss may be indicative of metastatic disease. The patient also may mention fatigue. Other symptoms are highly depended on the location of the tumor. 

Positive Tests, Exams or Signs
Work-up Options
Treatment Options
Treatment Goals
  • Preserve life
  • Preserve hand function
  • Maintain quality of life
Conservative
  • For both local and metastatic disease:
    • Pre-surgical, multi-agent, high-dose chemotherapy to eradicate systemic disease 1-5
Operative

     Surgery1-5

  • Bone or tissue grafts to replace disease areas that have been removed
  • Artificial bone implant
  • Thumb salvage by pollicization, free transfer of a toe, wraparound flap from the great toe or distraction lengthening
  • Thumb, finger and multiple ray amputations are often required 1-5
  • Radiotherapy, to treated cancer cells that cannot be removed surgically
  • Adjuvant chemotherapy to prevent recurrence
Complications
  • Fracture
  • Infection
  • Limb-length discrepancy
  • Loss of limb (rare)
  • Toxicity to adjacent healthy organs
  • Death
Outcomes
  • Patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better event-free survival than do patients with larger amounts of viable tumor.
  • Patients with poor response to presurgical chemotherapy are at increased risk of local recurrence.
  • Survival rates are >70% for patients with localized tumors.1-5
  • Overall 5-year survival rates are 59–78% for children aged <15 years old, and 20–60% for adolescents aged 15 to 19 years.1-5
  • Event-free and overall survival rates for patients with metastases are ~20%.
  • For patients who relapse, no standard salvage therapy exists. 
Key Educational Points
  • Radiotherapy may preserve hand structures that would otherwise be lost during surgical resection.
  • Surgery for ES in the hand avoids the complications of stiffness, fibrosis, and radiation sarcoma; however, preservation of hand functionality can be difficult owing to the need to achieve wide excision with negative margins.4,5
  • Without systemic chemotherapy, localized ES almost always recurs at distant sites.3,4,5
  • Systemic chemotherapy is intense and toxic, so survivors experience significant morbidities and shortened life expectancies. 
  • Treatment for ES often harms reproductive function. Cryopreservation of mature or immature oocytes, sperm, and embryo are options for this reproductive-age group.
  • Examples of site-dependent findings:
    • Asymmetrical breath sounds, pleural signs, or rales, if lung metastases
    • Petechiae or purpura due to thrombocytopenia, if bone marrow metastases
References

Cited and New Articles

  1. Biswas B, Bakhshi S.  Management of Ewing sarcoma family of tumors: Current scenario and unmet need. World J Orthop 2016;7(9):527-38. PMID: 27672565
  2. Lawlor ER, Sorensen PH. Twenty years on: what do we really know about Ewing sarcoma and what is the path forward? Crit Rev Oncog 2015;20(3-4):155-71. PMID: 26349414
  3. Ramos-Pascua LR, Fernández-Hernández O, Herráez SS, et al. Ewing sarcoma of the first metacarpal with a 9-year follow-up: case report.  J Hand Surg Am 2013;38:1575-8. PMID: 23809471
  4. Puhaindran ME, Athanasian EA. Malignant and metastatic tumors of the hand. J Hand Surg 2010;35A:1895-1900. PMID: 21050968. 
  5. Athanasian EA. Malignant bone and soft-tissue sarcomas of the hand. J Hand Surg Am 2004; 4(2): 60-72.

Reviews

  1. Lewis TB, Coffin CM, Bernard PS. Differentiating Ewing’s sarcoma from other round blue cell tumors using a RT-PCR translocation panel on formalin-fixed paraffin-embedded tissues. Mod Pathol 2007;20:397-404. PMID: 17334332
  2. Puhaindran ME, Athanasian EA. Malignant and metastatic tumors of the hand. J Hand Surg 2010;35A:1895-1900. PMID: 21050968

Case Report

  1. Ramos-Pascua LR, Fernández-Hernández O, Herráez SS, et al. Ewing sarcoma of the first metacarpal with a 9-year follow-up: case report.  J Hand Surg Am 2013;38:1575-8. PMID: 23809471
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