AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

James Ewing first described Ewing sarcoma in 1921 after observing radiosensitivity in a subgroup of bone tumors. In the early 1980s, Ewing sarcoma and the peripheral primitive neuroectodermal tumor were both found to contain the same reciprocal translocation between chromosomes 11 and 22, t(11;22). Later that decade, similar patterns of biochemical and oncogene expression were observed. These tumors were categorized as the Ewing sarcoma family of tumors because of the shared translocation and the similar cellular physiology. The Ewing sarcoma family of tumors includes Ewing sarcoma, peripheral primitive neuroectodermal tumor, neuroepithelioma, atypical Ewing sarcoma, and Askin tumor (tumor of the chest wall). The tumors in the Ewing sarcoma family are treated similarly on the basis of their clinical presentation (eg, metastatic or localized) rather than their histologic subtype.

Pathophysiology

Tumors in the Ewing sarcoma family are thought to derive from cells of the neural crest, possibly postganglionic cholinergic neurons. The exact cell of origin of the Ewing sarcoma family of tumors is unknown. Research is ongoing to further characterize the biology of the EWS-FLI1 fusion protein and its role in transformation, cell growth, and chemosensitivity. The focus of most research is the fusion protein generated from t(11;22).

Translocation t(11;22) or one of a series of related translocations occurs in more than 95% of the Ewing sarcoma family of tumors. Some argue that, without a translocation, the tumor does not belong to the Ewing sarcoma family. This translocation joins the Ewing sarcoma gene EWS on chromosome 22 to a gene of the ETS family, friend leukemia insertion (FLI1) on chromosome 11 (ie, t[11;22]). The EWS-FLI1 fusion transcript encodes a 68-kDa protein with 2 primary domains. The EWS domain is a potent transcriptional activator, whereas the FLI1 domain contains a highly conserved ETS DNA-binding domain. The EWS-FLI1 fusion protein thus acts as an aberrant transcription factor. EWS-FLI1 transforms mouse fibroblasts, and this transformation requires both the EWS and the FLI1 functional domains to be intact. Therefore, the EWS-FLI1 fusion protein is implicated in the pathogenesis of the Ewing sarcoma family of tumors. However, no data regarding the cause of the translocation are available. Downstream targets that are responsible for EWS-FLI1 transformation are currently under study. 

In any individual patient, t(11;22) fuses one of many observed combinations of exons from EWS and FLI1 to form the fusion message. The most common combination is EWS exon 7 fused to FLI1 exon 6 (type 1 translocation), which occurs in approximately 50-64% of tumors of the Ewing sarcoma family. Retrospective analyses showed that patients who have localized tumors with the 7/6 fusion have a 4-year survival rate of 70%, whereas patients with the other variants have a  4-year survival rate of 20%. This difference may, at least in part, be due to different potencies among the variants in their ability to activate gene transcription.

Frequency

United States

The annual incidence of Ewing sarcoma family tumors from birth to age 20 years is 2.9 cases per million population. Approximately 10% of patients are aged 20-30 years. Cases occurring later than this are infrequent.

Mortality/Morbidity

The survival of patients with Ewing sarcoma family tumors highly depends on the initial manifestation of the disease. Approximately 80% of patients present with localized disease, whereas 20% present with clinically detectable metastatic disease, most often to the lungs, bone, and/or bone marrow. The overall survival rate is 60%; however, for patients with localized disease, the survival rate approaches 70%. Patients with metastatic disease have a long-term survival rate of less than 25%.

Race

The incidence in whites is at least 9 times higher than that in blacks. This finding is in contrast to what is observed osteosarcoma, which has a relatively equal racial distribution. African countries report similar incidences, with a paucity of Ewing sarcoma family of tumors.

Sex

The incidence of Ewing sarcoma family tumors in female individuals is 2.6 cases per million population. The incidence in male individuals is 3.3 cases per million population.

Age

Incidence peaks in the late teenage years. Overall, 27% of cases occur in the first decade of life, 64% of cases occur in the second decade of life, and 9% of cases occur in the third decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients usually present with pain.
• Patients often have a palpable mass.
• Patients with lesions of the long bones can present with a pathologic fracture.
• Back pain may indicate a paraspinal, retroperitoneal, or deep pelvic tumor.
• Systemic symptoms of fever and weight loss can also occur and often indicate metastatic disease.

Physical

• Tumors of the Ewing sarcoma family can occur in virtually any location. Careful examination of painful sites with inspection and palpation is critical.
• Because patients can present with disease close to bone, tumors can result in neuropathic pain. Therefore, a comprehensive neurologic examination to evaluate asymmetric weakness, numbness, or pain is critical.
• Patients with lung metastases can present with asymmetric breath sounds, pleural signs, or rales.
• Patients with clinically significant bone marrow metastases can present with petechiae or purpura due to thrombocytopenia.

Causes

• The cause is unknown.
• Cases are thought to be sporadic. However, the incidence of neuroectodermal and stomach malignancies is increased among family members of patients with tumors of the Ewing sarcoma family.
• Ewing sarcoma family tumors are rarely reported after the treatment of another neoplasm (second malignancy).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No diagnostic blood studies provide pathognomonic or suggestive results to diagnose ESFT.
• Depending on the patient’s age and presenting symptoms, blood tests might be helpful in evaluating other diagnoses. Such tests may include blood cultures, measurement of C-reactive protein levels, and determinations of the CBC count and erythrocyte sedimentation rate.

Imaging Studies

• Evaluation of the primary lesion
• • The priority is to obtain images of the suspected primary lesion or of any region with symptoms.
  • If a bony mass is palpated, plain radiography is indicated.
  • MRI of the region can help in determining the extent of disease. MRI is immediately required if tumors are adjacent to critical neurologic structures, and emergency radiation therapy, surgery, and/or steroids should be considered to prevent nerve damage.
  • CT imaging is helpful to delineate any bony involvement.
• Evaluation for metastases
• • Metastatic evaluation includes chest CT and radioisotope bone scanning.
  • If the initial results suggest that a tumor is likely, chest CT scanning should be performed before surgical biopsy to avoid confusion of this finding with postoperative atelectasis.
  • Most centers now use whole-body body MRI or fluorodeoxyglucose (FDG) positron emission tomography (PET) as sensitive tools to detect metastatic disease. Neither modality is associated with an improved prognosis. However, a general consensus among investigators suggests that localized disease may occur at distal sites because metastatic disease is underdiagnosed, among other reasons.

Procedures

• Biopsy
• • If a lesion of the Ewing sarcoma family of tumors or another tumor is probable, consultation with a pediatric oncologist should be sought before a biopsy is performed.
  •  A biopsy specimen is required for definitive diagnosis.
  • The biopsy specimen should be evaluated by means of routine staining as well as immunohistochemical analysis with antibodies to differentiate the lesion from other small round blue cell tumors, such as rhabdomyosarcoma and lymphoma.
  • Biopsy should be performed after any potential therapy is fully considered because all patients with tumors of the Ewing sarcoma family require some form of definitive local treatment.
  • Inappropriate biopsy or resection often increases patient morbidity or mortality. An example is a biopsy incision that extends outside the tumor resection at the time of definitive surgery. This causes the surgeon to excise additional tumor-contaminated tissue that might have been spared if proper planning occurred prior to a biopsy.
• Cytogenetic and molecular studies
• • Cytogenetic studies should be used to confirm the diagnosis if t(11;22) or a related translocation is found.
  • For standard cytogenetics, fresh tissue should be sent in appropriate media to a cytogenetic laboratory.
• • In addition, a small piece of the tumor should be snap frozen in liquid nitrogen for molecular studies.

Histologic Findings

• Tumors of the Ewing sarcoma family are small, round, blue cell tumors. They can be undifferentiated or differentiated, as reflected in rosette formation.
• Immunohistochemical markers include membranous staining with MIC2 (12E7) antigen (CD99), which is characteristic but not pathognomonic. Muscle, lymphoid, and adrenergic markers should be negative.

Staging

• Staging includes both local imaging to reveal the full extent of tumor prior to therapy and evaluation for distant metastases.
• Local imaging usually includes both MRI and CT scanning (see Imaging Studies). When bone is involved, these are complimentary techniques. For soft-tissue lesions, MRI should be adequate in most cases.
• The evaluation for metastases should include bilateral bone marrow biopsies (some centers obtain multiple cores on each side, but this is not well supported), chest CT scanning, and radionuclide total body scanning, such as technetium-99 scanning (see Procedures). Many centers are now using FDG-PET scanning or total body MRI to look for occult metastases. Although these techniques often produce false-positive results that require biopsy, some findings suggest that locating these occult metastases and providing local therapy (radiation or surgery) improves survival.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The most recent Children's Oncology Group (COG) clinical trial randomized patients between chemotherapy cycles either 2 or 3 weeks apart.^{1, 2} The patients who received chemotherapy had an improved outcome to those who received chemotherapy every 3 weeks. The doses of chemotherapy were similar between the groups and both groups of patients received granulocyte-colony stimulating factor (G-CSF) to support adequate neutrophil counts.

Medical therapy varies slightly among European and North American pediatric oncologists.

• Patients should be treated under the supervision of a pediatric oncologist; staff at a comprehensive pediatric oncology center should direct care.
• A multidisciplinary team should evaluate and treat the patient. The team may include pediatric oncologists, radiation oncologists, surgeons, radiologists, pathologists, nurses, social workers, occupational and/or physical therapists, blood bank specialists, psychologists, school tutors, and pharmacists.
• In-house expertise from infectious disease specialists is often required.
• Treatment lasts 6-9 months and consists of alternating courses of 2 chemotherapeutic regimens: (1) vincristine, doxorubicin, and cyclophosphamide and (2) ifosfamide and etoposide.³
• Management of the primary tumor site is critical to long-term cure. Definitive surgical margins are desirable (eg, removal of fibula, limb salvage with extensive margins).
• In the absence of a minimally morbid surgical procedure, local control may be achieved with radiation therapy. Doses to the tumor and fractionation are site dependent.⁴

Surgical Care

Any surgery should be performed under the supervision of experienced oncologic surgeons specializing in the area of the body where the tumor is found. The specific surgery is highly patient dependent.

Consultations

• Orthopedic surgeon
• • If the patient has a lesion close to bone that is potentially resectable, consultation with an orthopedic oncologist is required biopsy.
  • Biopsy planning is critical because an inappropriately conducted procedure can contaminate tissue planes.
• Neurologist: Lesions close to nerve roots, ganglia, or plexuses might result in neurologic symptoms.
• Pathologist: When a mass is resected from a pediatric patient, a pathologist should be aware of the procedure and the differential diagnosis. This information and involvement is critical for appropriate diagnostic studies to be performed.

Diet

• Patients require close monitoring of their caloric intake during treatment.
• Services of a dietitian are often needed. However, no special diets are required for treatment.

Activity

• Activity limitations depend on the location of primary and metastatic lesions.
• No general restrictions are indicated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Dose intensity is critical in the treatment of tumors of the Ewing sarcoma family. To facilitate maximum dosing of chemotherapeutic agents, anticipatory supportive care is necessary. Neutrophils are stimulated with G-CSF, and fevers are aggressively treated. New symptoms that occur while patients are being treated should be closely evaluated and monitored.

Drug Category: Antineoplastic agents

Cancer chemotherapy is based on an understanding of tumor cell growth and on how drugs affect this growth. After cells divide, they enter a period of growth (G1 phase), followed by DNA synthesis (S phase). The next phase is a premitotic phase (G2 phase), then finally a phase mitotic cell division (M phase).

Rates of cell division vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant ones. This is partly the rationale for current cyclic dosage schedules.

Antineoplastic agents interfere with cellular reproduction. Some agents are specific to the cell cycle, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Category: Uroprotectants

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide or cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Chemotherapy can be administered on an inpatient or outpatient basis, depending on patient tolerance and proximity to the hospital.
• Patients often develop episodes of fever while neutropenic, resulting in 3- to 7-day hospitalizations between cycles of chemotherapy.

Further Outpatient Care

• Chemotherapy care and follow-up
• • Most patients require RBC and platelet support starting approximately 2 months after the start of therapy and continuing to the completion of therapy. Although G-CSF is given for neutrophil support, biweekly CBC counts are necessary.
  • A full physical examination is required before each cycle of chemotherapy and any time suspicious signs or symptoms arise between cycles. Suspicious signs include signs similar to those observed at presentation, as well as unexplained fever or pain.
  • Primary and metastatic sites are evaluated approximately every 10-12 weeks during therapy and every 3-4 months during the first year after therapy.
  • Reevaluations are spaced out gradually for 5-6 years after the completion of therapy. At that time, no further scanning is indicated; however, the patient should have annual follow-up visits to monitor function of the primary site and late effects of therapy.
• Long-term follow-up
• • Late effects from chemotherapy require regular follow-up with a provider trained to evaluate the such sequelae.
  • Recurrence of primary disease is the major risk in the first 10 years after diagnosis.
  • Second malignancy occurs in approximately 1-2% of patients beginning after 5 years after diagnosis. The most common second malignancy is acute myeloid leukemia.
  • Therapeutic toxicities to the heart and kidneys and to the nervous, endocrine, and mental systems should be monitored in patients who had acute toxicity and in those who developed symptoms after therapy.

Transfer

• Patient care during chemotherapy is generally under the direct supervision of the pediatric oncologist. The primary care physician should be kept informed about the patient's progress and complications.
• After therapy is completed, the primary physician should increase his or her involvement in patient care.

Deterrence/Prevention

• No prevention methods are known.

Complications

• Chemotherapy complications
• • Vincristine primarily causes neuropathy, including constipation, myalgias, arthralgias, and cholestasis.
• • Doxorubicin causes myocardial dysfunction and pancytopenia.
• • Cyclophosphamide causes pancytopenia and a dosage-dependent hemorrhagic cystitis.
• • Ifosfamide is similar to cyclophosphamide, although it is associated with an increased incidence of hemorrhagic cystitis, which requires the use of mesna. Patients near the end of therapy occasionally develop the Fanconi syndrome of electrolyte wasting.
• • Etoposide can result in pancytopenia as well as anaphylactic reactions, and it is implicated in the development of second malignancies, particularly acute myelogenous leukemia.
  • In general, combination chemotherapy results in alopecia, nausea, vomiting, and, occasionally, diarrhea. The nutritional and psychologic statuses of patients undergoing this therapy must be closely monitored.
• Surgical complications
• • Surgical complications generally include infection and bleeding.
  • Specific complications are related to the site of surgery and to the patient's overall condition at the time of surgery.
• Radiation complications
• • Complications of radiation therapy are a direct result of the sites of radiation.
  • Patients who receive large pelvic doses of radiation often have increased problems with pancytopenia, malnutrition, and diarrhea.
  • Radiation increases the likelihood of second malignancies, particularly in the radiation field.

Prognosis

• At this time, the only significant factor that determines the prognosis is the presence or absence of metastatic disease.

Patient Education

• Any patient with a malignancy needs extensive education, as does their family.
• For the patient, education includes age and developmentally appropriate information about their disease and its therapy. Patients should be informed about their specific disease and prognosis. Education also includes information about expected complications, particularly fever and its management.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Chemotherapy involves a group of medications with clear and notable risks, both immediate and long-term.
• Obtaining informed consent is required before therapy if the patient will be enrolled in a clinical trial. If no appropriate trial is accruing patients, the oncologist refers to the most recent clinical trial to determine the best therapeutic regimen. A consent form that includes the recommended agents and their adverse effects should be strongly considered in these circumstances.

Special Concerns

• Because these tumors are rare, they are often not considered in a differential diagnosis until biopsy reveals a small, round, blue cell tumor.
• Malignancy is usually in the differential diagnosis before biopsy. For this reason, consultation with a pediatric oncologist is critical.
• These tumors should be considered in the differential diagnosis if a patient aged 10-30 years has a soft tissue or bony mass that causes the physician to consider a neoplasm.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. Jul 15 2004;22(14):2873-6. [Medline].
2. Womer, West, Krailo, Pawel, Dickman. hemotherapy intensification by interval compression in localized Ewing Sarcoma Family Tumors. Seattle, WA: Connective Tissue Oncology Society Annual Meeting; 2007.
3. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. Feb 20 2003;348(8):694-701. [Medline].
4. Dunst J, Jurgens H, Sauer R, Pape H, Paulussen M, Winkelmann W, et al. Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys. Jul 15 1995;32(4):919-30. [Medline].
5. Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries LA, Smith MAS, Gurney JG, et al, eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. Publication 99-4649. Bethesda, MD: National Cancer Institute; 1999:99-110.
6. Meyers PA, Krailo MD, Ladanyi M, Chan KW, Sailer SL, Dickman PS, et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol. Jun 1 2001;19(11):2812-20. [Medline].
7. Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. Mar 15 2001;19(6):1818-29. [Medline].
8. Saylors RL 3rd, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. Aug 1 2001;19(15):3463-9. [Medline].
9. Uren A, Toretsky JA. Ewing's sarcoma oncoprotein EWS-FLI1: the perfect target without a therapeutic agent. Future Oncol. Aug 2005;1(4):521-8. [Medline].

Article Last Updated: Jun 17, 2008