Ewing Sarcoma

Ewing sarcomas are thought to derive from cells of the neural crest, possibly mesenchymal stem cells, via a pathway that might include postganglionic cholinergic neurons. However, the exact cell of origin of the Ewing sarcomas is unknown.

Translocation of EWSR1 (Ewing sarcoma breakpoint region 1) with an ETS (E26 transformation-specific) transcription factor gene occurs in more than 95% of Ewing sarcomas. (Some argue that without a translocation, the tumor does not belong to Ewing sarcoma). The most common translocation seen in about 85% of all Ewing tumor is the t(11;22) translocation. 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]). Alternative translocations include EWS-ERG t(21;22), EWS-ETV t(7;22), and EWS-FEV t(2;22), all of which involve the ETS family protein. Approximately 4% of Ewing sarcomas have been identified as having an intrachromosomal X-fusion leading to BCOR (encoding the BCL6co-repressor) and CCNB3 (encoding the testis-specific cyclin B3).[5]

No data regarding the cause of the chromosomal translocation are available. Downstream targets and protein partners responsible for EWS-FLI1 transformation of cells are numerous; however, any one of these downstream pathways is neither adequate to create a Ewing sarcoma nor is its inhibition adequate to lead to Ewing sarcoma cell death.[6]

Fusion protein

The EWS-FLI1 fusion transcript encodes a 68-kd 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 and has been found to transform mouse fibroblasts if both the EWS and the FLI1 functional domains are intact. The protein has consequently been implicated in the pathogenesis of Ewing sarcoma.

EWS-FLI1 remains the singular most direct target to eliminating Ewing sarcoma tumor cells. A small molecule that binds to EWS-FLI1, YK-4-279, blocks its interaction with a key partner protein, RNA Helicase A (RHA), leading to apoptotic cell death.[7] Other approaches to target EWS-FLI1 have been developed by functional screening assays. While agents identified from these assays may lead to Ewing sarcoma cell death, evidence is inadequate to describe the agents as directly targeting the activity of EWS-FLI1.[8] This distinction is important when considering the potential of nonspecific toxicities and off-target effects of novel agents.

Causes

The cause of tumors in Ewing sarcoma is unknown. Cases are thought to be sporadic, although it has been found that relatives of patients with Ewing sarcoma have an increased incidence of neuroectodermal and stomach malignancies. In rare cases, Ewing sarcomas have been reported as a second malignancy, being found after a patient has been treated for another neoplasm.

Occurrence in the United States

The overall annual incidence of Ewing sarcoma is approximately 1 case per 1 million per year in the United States. The incidence from birth to age 20 years is 2.9 cases per million population. Approximately half of all patients are aged 10-20 years at the time of first diagnosis, making this the second most common primarily malignant bone tumor in children and adolescents. Cases have been reported from birth through 80 years, although very infrequently.

Race-, sex-, and age-related demographics

The incidence of these tumors in Whites is at least 9 times higher than it is in Blacks. This finding contrasts with that observed in osteosarcoma, which has a relatively equal racial distribution. African countries report similar incidences, with a paucity of Ewing sarcoma.

The incidence of Ewing sarcoma in females is 2.6 cases per million population, compared with 3.3 cases per million population in males.

The incidence of these tumors 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, and 9% of cases occur in the third decade.

The most significant factor currently known to determine the prognosis in patients with Ewing sarcoma is the presence or absence of metastatic disease. Primary site of the tumor also is a prognostic factor, with distal extremities being more favorable than those with central or pelvic sites.[9] Age younger than 15 years also seems to be a more favorable prognosis.[9, 10]

Treatment complications

Complications of chemotherapy can include the following:

• 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 - 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

• Combination chemotherapy - Results, in general, in alopecia, nausea, vomiting, and occasionally diarrhea; increased risk of infection from immune suppression; the nutritional and psychological status of patients undergoing this therapy must be closely monitored; effects of chemotherapy such as organ damage, infertility, and risk of secondary malignancy

Surgical complications generally include infection and bleeding. Specific complications are related to the site of the operation and to the patient's overall condition at the time of surgery.

Similarly, the 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. In addition, radiation increases the likelihood of second malignancies, particularly in the radiation field.

Mortality

The survival of patients with Ewing sarcoma depends highly 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 patient survival rate is 60%; for patients with localized disease, however, the survival rate approaches 70%. Patients with metastatic disease have a long-term survival rate of less than 25%.

For the patient, education includes age and developmentally appropriate information about his or her disease, its therapy, and its prognosis. Education also includes information about expected complications, particularly fever and its management. (See Prognosis, Treatment, and Medication.)

For patient information and resources, see the Ewing Sarcoma topic center.

History

Patient history includes the following:

• Patients usually present with pain

• Patients often have a palpable mass

• 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 examination

Ewing sarcoma 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 asymmetrical weakness, numbness, or pain is critical. Patients with lesions of the long bones can present with a pathologic fracture

Clinically significant bone marrow metastases can result in petechiae or purpura due to thrombocytopenia, while patients with lung metastases can present with asymmetrical breath sounds, pleural signs, or rales.

No diagnostic blood studies provide pathognomonic or suggestive results to diagnose Ewing sarcoma. The most important factor that can help a patient with Ewing sarcoma is to be properly diagnosed and have a treatment plan established by an oncologist with significant experience in treating Ewing sarcoma.

Depending on the patient’s age and presenting symptoms, blood tests may be helpful in evaluating other diagnoses. Such tests may include blood cultures, measurement of C-reactive protein levels, a complete blood count (CBC), lactate dehydrogenase (LDH), and the erythrocyte sedimentation rate.

Cytogenetic and molecular studies

Cytogenetic studies should be used to confirm the diagnosis of Ewing sarcoma 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.[11]

Histology

Ewing sarcomas 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.

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. (See the image below.)

Radiograph of an 11-year-old boy with a large Ewing sarcoma in the right pelvic area. Destruction of the bone structure resulted from tumor involvement.

Magnetic resonance imaging (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. Computed tomography (CT) scanning is helpful in delineating any bony involvement.

Metastases

Metastatic evaluation includes chest CT, radioisotopic bone scan, and bilateral bone marrow aspirate and biopsy. If the initial results indicate the probable existence of a tumor, chest CT scanning should be performed before surgical biopsy to avoid confusion of this finding with postoperative atelectasis.

Most centers now use whole-body MRI or fluorodeoxyglucose positron emission tomography (FDG-PET) scanning as sensitive tools to detect metastatic disease. Some studies suggest that FDG-PET[12, 13] may have superiority for detecting metastatic lesions over bone scanning; however, bone scanning may be useful to detect osseous metastases if Ewing sarcoma is sclerotic.[14]

If a lesion of Ewing sarcoma or another tumor is probable, consultation with a pediatric oncologist should be sought before a biopsy is performed. However, a biopsy specimen is required for definitive diagnosis.

The biopsy specimen should be evaluated by means of routine staining, as well as with immunohistochemical analysis with antibodies to differentiate the lesion from other small round blue cell tumors, such as rhabdomyosarcomas and lymphomas.

The biopsy should be performed after any potential therapy is fully considered, because all patients with Ewing sarcoma 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.

Staging includes local imaging to reveal the full extent of tumor prior to therapy, as well as evaluation of the patient for distant metastases.

Local imaging usually includes MRI and CT scanning. When bone is involved, these are complimentary techniques, but 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-99m (99m Tc) scanning. 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 occult metastases and providing local therapy (radiation or surgery) improves survival.

A systematic review found that FDG-PET had a pooled 100% sensitivity and 96% specificity, a positive predictive value of 75%, and a negative predictive value of 100% for the detection of bone marrow metastasis, compared with bone marrow biopsy and aspiration.[15]

Treatment lasts 6-9 months and consists of alternating courses of 2 chemotherapeutic regimens: (1) vincristine, doxorubicin, and cyclophosphamide and (2) ifosfamide and etoposide.[4] 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.

In a pilot study in which standard chemotherapy for newly diagnosed metastatic Ewing sarcoma was combined with low-dose antiangiogenic therapy, Felgenhauer et al found the combination treatment to be “feasible according to protocol definitions” but also determined that it tended to cause toxicity in areas that had received radiation therapy, limiting the protocol’s usefulness. Although 24-month event-free survival in the study was better for patients with isolated pulmonary metastases than it was for historical controls, the investigators pointed out that the study used only a small number of patients and did not include contemporaneous controls.[16]

Chemotherapy interval compression from the standard 3-week therapy to 2 weeks improves outcomes for localized Ewing sarcoma, without increased toxicity, according to a study by the Children's Oncology Group.[17, 18] According to the investigators, patients who received interval compression chemotherapy every 2 weeks had a 5-year event-free survival rate of 73%, compared with 65% in patients 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. No significant increase in therapy-related toxicity due to the extra intensification was reported.[17, 18]

Currently, an open study within the Children’s Oncology Group (AEWS1031) is evaluating the efficacy of adding vincristine, topotecan, and cyclophosphamide to the interval compressed 5-drug backbone for patients with nonmetastatic Ewing sarcoma (NCT01231906).[19]

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.

Surgery and radiation therapy

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). 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.[20, 21]

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.[22]

Recurrent disease

There are no standardized second-line treatment plans for relapsed or refractory Ewing sarcoma. Considerations need to be made depending on site(s) of disease recurrence and prior therapy. Chemotherapy combinations such as vincristine/irinotecan/temozolomide[23] or gemcitabine/docetaxel[24] have been considered in recurrent Ewing sarcoma. Radiation and/or surgery may have a role for local control and disease palliation. Identification and development of targeted therapies for Ewing sarcoma are underway in early clinical trial settings.

Diet

Patients require close monitoring of their caloric intake during treatment. The services of a dietitian are often needed, although no special diets are required for treatment.

Activity

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

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. (Medical therapy varies slightly among European and American pediatric oncologists.)

A multidisciplinary team should evaluate and treat the patient. The team may include, along with pediatric oncologists and in-house infectious disease specialists, the following personnel:

• Radiation oncologists

• Surgeons

• Radiologists

• Pathologists

• Nurses

• Social workers

• Occupational and/or physical therapists

• Blood bank specialists

• Psychologists

• School tutors

• Pharmacists

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.

The following specialists may be consulted:

• Orthopedic surgeon - If the patient has a lesion close to bone that is potentially resectable, consultation with an orthopedic oncologist is required before biopsy; biopsy planning is critical because an inappropriately conducted procedure can contaminate tissue planes

• Neurologist - Lesions close to nerve roots, ganglia, or plexuses may 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 in order for appropriate diagnostic studies to be performed.

Most patients require red blood cell (RBC) and platelet support during therapy. Although granulocyte colony-stimulating factor (G-CSF) is given for neutrophil support, patients most often require a minimum of weekly laboratory evaluations.

A full physical examination is required before each cycle of chemotherapy and any time suspicious signs or symptoms arise between cycles. Suspicious signs include those similar to the signs 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. After 5 years of disease-free remission, no further scanning is indicated; however, the patient should have annual follow-up visits to monitor the function of the primary site and late effects of therapy, preferably in a late-effects clinical setting.

Other posttreatment considerations include the following:

• Late effects from chemotherapy require regular follow-up with a provider trained to evaluate such sequelae

• Recurrence of primary disease is the major risk in the first 10 years after diagnosis.

• A second malignancy occurs in approximately 1-2% of patients beginning 5 years after diagnosis; the most common second malignancy is acute myeloid leukemia.

• Therapeutic toxicities to the heart and kidneys, to the nervous and endocrine systems, and to mental status should be monitored in patients who suffered acute toxicity and in those who developed symptoms after therapy.

Guidelines Contributor: Mrinal M Gounder, MD Attending Physician in Medical Oncology, Sarcoma and Developmental Therapeutics Service, Memorial Sloan-Kettering Cancer Center

Guidelines for the management of Ewing sarcoma have been published by the following organizations:

• National Comprehensive Cancer Network (NCCN) ^[25]
• European Society for Medical Oncology (ESMO) ^[26]

Diagnosis

National Comprehensive Cancer Network (NCCN) guidelines recommend that all patients younger than 40 years of age with abnormal radiographs be referred to an orthopedic oncologist for further workup that includes biopsy. For patients 40 years old or older, the recommended workup includes the following[25] :

• Computed tomography (CT) of the chest, abdomen and pelvis
• Bone scan
• Mammogram and other imaging studies as clinically indicated

Findings of other lesions indicates a non-bone primary tumor. If no other lesions are found, the patient should be referred to an orthopedic oncologist for a biopsy.[25]

European Society for Medical Oncology (ESMO) guidelines recommend followup of an abnormal radiograph with magnetic resonance imaging (MRI) of the whole compartment with adjacent joints. CT scan is recommended only in the case of diagnostic problems or doubt, to provide clearer visualization of calcification, periosteal bone formation, or cortical destruction.[26]

Both guidelines agree that biopsy is required to confirm the diagnosis prior to any surgical procedure and should be performed at a specialized center that will provide the definitive treatment.[25, 26]

Classification

ESMO guidelines recommend specifying the tumor type and subtype according to the 2013 World Health Organization (WHO) classification.[26] Under the WHO classification system, tumors are further classified as benign, intermediate or malignant. Bone sarcomas are classified by group (eg, chondrogenic, osteogenic, fibrohistiocytic, Ewing sarcoma) and further subtyped within each group.[27]

NCCN guidelines recommend that the final pathologic evaluation include assessment of surgical margins as well as the size/dimensions of tumors.[25]

Grading and Staging Systems

A number of staging systems are used for bone tumors. The ESMO guidelines do not provide a specific recommendation for which system should be followed.[26]   NCCN follows both the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) [28] and the Surgical Staging System from the Musculoskeletal Tumor Society (MTS)[29] for staging.[25]

Treatment

NCCN recommendations for treatment of Ewing sarcoma are as follows[25] :

• Enrollment in a clinical trial should be considered when available; in addition, whenever possible patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team
• Multi-agent chemotherapy for at least 12 weeks followed by local control therapy and adjuvant treatment; longer duration of initial chemotherapy can be considered for patients with metastatic disease, based on response
• VAC/IE (vincristine, doxorubicin [Adriamycin], and cyclophosphamide alternating with ifosfamide and etoposide) is the preferred regimen for localized disease
• VAC (vincristine, doxorubicin, and cyclophosphamide) is the preferred regimen for patients with metastatic disease
• Restaging following chemotherapy

ESMO recommends a treatment protocol of three to six cycles of multi-agent chemotherapy (doxorubicin, cyclophosphamide, ifosfamide, vincristine, dactinomycin, and etoposide), followed by local therapy and another six to 10 cycles of chemotherapy. Wide resection is preferred over radiation therapy for local control.[26]

For patients with stable or improved disease after restaging, the NCCN recommends the following[25] :

• Wide excision or definitive radiation therapy with chemotherapy, or amputation in selected cases.
• Postoperative chemotherapy for 28-49 weeks, depending on the type of regimen and the dosing schedule (category 1 for wide excision)
• Postoperative radiation therapy in addition to chemotherapy if surgical margins are positive or very close

For patients with progressive disease after restaging the NCCN recommends radiation therapy with or without surgery for local control and palliation, followed by chemotherapy or best supportive care. Treatment options for relapsed or refractory disease include enrollment in clinical trials or chemotherapy with or without radiation therapy.[25]

As previously mentioned, treatment of Ewing sarcoma lasts 6-9 months and consists of alternating courses of 2 chemotherapeutic regimens: (1) vincristine, doxorubicin, and cyclophosphamide and (2) ifosfamide and etoposide.[4]

Dose intensity is critical in the treatment of these tumors. 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.

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect it. 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), after which comes the final 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 do. 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.

Doxorubicin (Adriamycin)

Multiple mechanisms of action are recognized for doxorubicin (eg, DNA intercalation, topoisomerase-mediated DNA strand breaks, oxidative damage by free radical production).

Cyclophosphamide

This agent exerts its cytotoxic effect through alkylation of DNA, which leads to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA replication.

Vincristine (Vincasar PFS)

Vincristine is a plant-derived vinca alkaloid that acts as mitotic inhibitor by binding tubulin. It inhibits microtubule formation in the mitotic spindle, causing metaphase arrest.

Ifosfamide (Ifex)

Ifosfamide exerts its cytotoxic effect via alkylation of DNA, leading to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA replication.

Etoposide (Toposar)

Etoposide is a glycosidic derivative of podophyllotoxin that exerts its cytotoxic effect by stabilizing normally transient covalent intermediates formed between DNA substrate and topoisomerase II. This results in single- and double-strand DNA breaks.

Class Summary

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.

Mesna (Mesnex)

Mesna inactivates acrolein (the urotoxic metabolite of ifosfamide and cyclophosphamide) and prevents urothelial toxicity without affecting cytostatic activity.