OVERVIEW: What every practitioner needs to know
Are you sure your patient has Ewing sarcoma? What are the typical findings for this disease?
Ewing Sarcoma (EWS) and PNET (primitive neuroectodermal tumors) are known as the ESFT (Ewing Sarcoma Family of tumors.) The “small round blue cell” tumors originate in bone 80% of the time and ~ 20% in soft tissues. ESFT are of uncertain histogenesis.
James Ewing described this tumor in 1921 as an “endothelioma of bone.” Present thinking is that the likely precursor cell is a multipotent mesenchymal stem cell of the bone marrow stroma. Treatment for EWS/PNET tumors is multiagent chemotherapy for several cycles, followed by re-staging, then local control (either surgery, radiation or both) and then continuing chemotherapy for up to a year. Therapy should be initiated only after full staging is complete, and participation in clinical trials is recommended for this rare cancer.
Almost all of the bone and soft tissue tumors of the ESFT share a translocation, and in 85% the translocation is t(11:22)(q24;q12). This translocation results in a chimeric EWS-FLI1 RNA that codes for the transcription protein EWS-FLI1. Other translocations involving the EWS gene and other gene partners have been identified in ESFT tumors (See Figure 1).
The presentation is dependant upon the site of origin. Most commonly there is bone pain, and there may be a mass. The most common site is the pelvis. Typically pelvic lesions present with pain as the mass must be extremely large to be visible or palpable in most patients. Patients with pelvic lesions may also present with symptoms of sciatic nerve pain, usually described as a burning or searing pain radiating from the back or from and down the back of the leg.
EWS/PNET of the spine or paraspinal soft tissue would present with back pain and possibly neurological symptoms related to the level of the lesion.
Chest wall EWS/PNET (also called Askin tumor) may present as chest wall pain, pleural effusion and most often have an associated rib lesion.
Extremity lesions present with pain, there may be a visible mass or asymmetry between the involved and normal extremity.
Patients present with metastatic disease is approximately 20%-25%. The most common site of metastasis is the lung, followed by bone and bone marrow.
Typical findings of Ewing Sarcoma:
A mass, pain, and sometimes systemic symptoms such as fever and weight loss.
The specific symptoms relate to the site of origin of the tumor which can be almost anywhere in the body. Pelvic lesions, chest wall lesions and extremity lesions are the most common sites.
Diagnosis cannot be certain without a biopsy of the lesion.
What other disease/condition shares some of these symptoms?
Other tumors in the same site might present with similar symptoms. For example, osteosarcoma may present with bone pain and a mass. Unlike Ewing sarcoma, osteosarcoma almost never presents with systemic symptoms such as fever.
Chest wall EWS/PNET might be mistaken for a pulmonary infection.
A soft tissue mass would be clinically indistinguishable from any other form of soft tissue sarcoma such as rhabdomyosarcoma or a benign mass in the absence of imaging studies and a biopsy.
Pelvic, vertebral and extremity lesions may present in a matter similar to osteomyelitis. Although osteomyelitis may cause pain, a mass would be distinctly uncommon.
What caused this disease to develop at this time?
There are no known predisposing factors.
Cancer in general is caused by a genetic aberration (or several) in a tumor cell that results in abnormal proliferation.
In ESFT clearly the known translocation and aberrant protein production is part of the disease process, however it is not understood if this is the tumor initiating event or an event that occurs after an undefined “first event.”
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Lab tests are non-specific and variable: one might or might not see mild anemia, elevated ESR, elevated LDH.
Evaluation of liver function, renal function and CBC are required before initiating therapy.
Would imaging studies be helpful? If so, which ones?
Imaging is the most important first step towards diagnosis.
Start with a plain film of the site: if the lesion is a bone lesion you will see periosteal destruction. In long bones the typical lesion is in the diaphysis. Periosteal reaction, bone destruction and an associated soft tissue mass are common findings. If the plain film demonstrates a lesion a magnetic resonance imaging (MRI) +/- gadolinium (See Figure 2) should be the next step to define the extent of the lesion. If MRI not possible, computed tomography (CT) with contrast is indicated.
If there is no bone lesion on plain film, the next step would also be an MRI +/- gadolinium of the site.
An evaluation for metastasis must include a CT of the Chest with contrast and a technitium whole body bone scan and a bone marrow examination. A PET scan may be useful as well. These studies are most often done after the diagnosis is established by tissue biopsy.
Confirming the diagnosis
The diagnosis must be made by tissue biopsy. Ideally the physician performing the biopsy should be an experienced orthopedic oncologist or surgical oncologist (depending on site) who would be equipped to perform definitive surgery. This is to assure that the anatomic placement of the biopsy is done in a manner to preserve limb-sparing options, or options for complete resection at other sites.
The biopsy should be done at an insitution prepared to do the specialized tests required to analyze the tissue such as cytogenetics, FISH and/or PCR for the translocation.
The tissue should be examined by an experienced pathologist.
Fresh tissue if at all possible should be sent for chromosomes and frozen and /or fresh tissue should be sent for correlative studies if at all possible by a clinical oncologist working with cooperative clinical trial groups.
The tumor is a “a small round blue cell tumor” that is immunochemistry + for vimentin, PAS and CD99. Cytogenetics, PCR (polymerase chain reaction) or FISH (florescent in situ hybridization) for an ESFT translocation is essential (See Figure 3).
Although a diagnosis may be established by a fine needle biopsy, open biopsy is recommended in order to obtain sufficient tissue. ESFT often have necrotic areas and it is essential to procure sufficient tissue for histological slides and studies for the translocation.
If you are able to confirm that the patient has Ewing Sarcoma, what treatment should be initiated?
The patient should be referred to an oncologist and an orthopedic or surgical oncologist who both have experience in treating sarcoma patients. As EWS/PNET are more common in young adults often a pediatric oncologist is likely to have the most expertise and experience.
Treatment for EWS/PNET tumors is multiagent chemotherapy for several cycles, followed by re-staging, then local control (either surgery, radiation or both) and then continuing chemotherapy for up to a year.
EWS/PNET cannot be cured with only surgery or radiation or both.
Therapy should be initiated only after full staging is complete, and the patient and/or family understands the planned treatment.
This rare disease is often the subject of clinical trials. If the patient is eligible for a clinical trial, consideration should be given to having the patient treated by a physician partcipating in a trial and able to explain the trial to the family and obtain consent for participation.
The current US standard of care for patients with ESFT that is nonmetastatic is chemotherapy with compressed cycles (i.e. chemotherapy every 2 weeks) with vincristine, cyclophosphamide, doxorubicin (VCD) alternating with Ifosfamide and etoposide (IE).
New combinations of chemotherapy that have been shown to be effective in relapsed patients include the pair of cyclophosphamide and topotecan and the pair of irinotecan and temozolimide. The role of these pairs in the therapy of newly diagnosed patients is in evolution. They are often employed as second line chemotherapy for those who have relapsed despite standard therapy.
New trials of chemotherapy for newly diagnosed patients will likely incorporate one or both of these pairs. There is an open U.S. COG clinical trial for nonmetastic patients with EWS/PNET that compares compressed cycles of VDC/IE to compressed cycles of VDC/IE with cycles of vincristine, topotecan and cyclophosphamide.
In Europe at the current time there is an international trial comparing chemotherapy with vincristine, ifosfamide, doxorubicin and etoposide (VIDE) as initial therapy and compares post local control therapy between vincristine, cyclophosphamide and actinomycin (VAC ) and vincristine, Ifosfamide and acinomycin (VAI) for patients with small (<200 ml) tumors, or tumors with good histological response to chemotherapy.
The standard of care for patients with metastatic tumors is less clear. In European sites patients with high risk tumors (large size, metastatic, poor respone to initial chemotherapy) are eligible for an international trial (EURAMOS). Patients are randomized to post induction therapy with VIDE to either post induction VAI or high dose therapy with Busulfan-Melphalan megatherapy with aurlogous stem cell support.
In the United States, the standard of care for patients with metastatic disease remains compressed cycles every 2 weeks with vincristine, cyclophosphamide, doxorubicin alternating with Ifosfamide and etoposide. Some US centers participate in the EURAMOS randomization noted above for patients with metastases limited to the lungs.
After 9-12 weeks of Induction therapy local control is initiated (the timing is specific to protocol). Although most ESFT are sensitive to radiation, in general the trend has been to avoid radiation if a complete resection is possible. This is owing to late effects of radiation including growth disturbance and second malignancies such as osteosarcoma. Moreover, advances in orthopedic and surgical techniques have increased surgical options for patients. In the United States, radiation is generally reserved for patients with unresectable tumors, or those with positive margins after surgery.
In Europe there is more use of radiation in combination with surgery for large high risk tumors. There is no randomized data to determine the local control course that yields better survival and functional results. There are retrospective reviews which yield conflicting results likely due to selection bias between surgery and radiation. Thus, local control is always individualized.
Radiation to sites of metastatic disease (lungs, bone mets and/or both) is individualized and usually initiated at the end of chemotherapy, or later in the course of chemotherapy to assure chemotherapy is not abrogated by marrow compromise from radiation.
What are the adverse effects associated with each treatment option?
Chemotherapy side effects during treatment include hair loss, anorexia, weight loss, nausea and vomiting, myelosuppression, need for transfusions of blood and/or platelets, epiodes of infection and/or febrile neutropenia, renal and hepatic impairment. Rarely, cumulative doses of doxorubicin may cause cardiac dysfunction. These effects occur in all treatment regimens for EWS/PNET.
Later effects of therapy include cardiac toxicity due to doxorubicin, hemorrhagic cystitis due to Ifosfamide and cyclophospahmide. Renal or liver impairment may occur. Second malignancies may occur. Infertility is more likely with high dose busulfan-melphalan but may occur in lower dose regimens as well.
As side effects of each chemotherapy agent are specific to the agent, these medications should only be given by experts in chemotherapy and after careful discussion with patients and family about each medication. The late effects of chemotherapy are protean and should be discussed with the patient and family as part of long term follow-up and care.
Radiation side effects during therapy may include erythema of the skin and skin breakdown. Other effects are specific to the site of radiation and the radiation therapist should discuss potential side effects with the patient and parent. Late effects from radiation may cause growth disturbance and a finite risk of a secondary cancer, such as a secondary sarcoma.
Surgical side effects in regard to function, cosmetic outcome, pain, and growth and development are also very variable and must be discussed with each patient/parent on an individual basis depending on the surgical options considered.
What are the possible outcomes of Ewing sarcoma?
For patients with localized ESFT who receive compressed therapy with VDC alternating with IE as above, the 4 year even free survival is ~ 80%. It must be noted that statistics are for groups of people and for each specific patient the odds are cure or not. Overall relapse free survival rates in other studies have been reported to be 60-70%.
For patients with pulmonary metastases only the EFS at 5 years is ~50%.
For patients with bone marrow and/or bone metastases and/or pulmonary metastases the EFS is ~20% at 2 years.
What causes this disease and how frequent is it?
The majority of patients are between 14-30 years of age at diagnosis, but EWS/PNET may present at any age.
Ewing Sarcoma Family of Tumors (ESFT) are slightly more commmon in males than females (55% versus 45%) and is relatively rare in people of African or Asian descent compared to Caucasians. The predominance in the non-Caucasian population is not effected by migration, thus, an ill defined hereditary predisposition (albeit a rarely expressed one) is implied.
The incidence of EWS family of tumors in the United States is ~ 2.9/ per one million/ year.
How do these pathogens/genes/exposures cause the disease?
EWS-ETS chromosomal translocations are pathognomonic of ESFT. The EWS-ETS gene rearrangements result in the production of a chimeric fusion protein which appears to be essential for tumorigenesis. The role of additional aberrations and transcription factors is under intensive investigation.
It has been shown that overexpression of FLI1 gene product of the EWS translocation has been shown to promote cell survival, cell transformation and tumorigenesis. EWS-FLI1 acts through a complex transcriptional pathway, yet to be fully understood. It has been shown that in vitro loss of the EWS-FLI1 expression resulted in growth arrest and increase in apoptosis.
Other clinical manifestations that might help with diagnosis and management
What complications might you expect from the disease or treatment of the disease?
Are additional laboratory studies available; even some that are not widely available?
How can Ewing Sarcoma be prevented?
There is no known cause of Ewing Sarcoma/PNET. There are no methods of prophylaxis, it is not induced by behavioral factors.
What is the evidence?
The epidemiology and clinical presentation of this disease is well documented in clinical trials and cancer databases.
The treatment of ESFT is well studied in a series of randomized controlled clinical trials and other single arm clinical trials over a greater than 20-year period.
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Grier, H, Krailo, M, Tarbell. “Addition of ifosfamide and etoposide to standard therapy for Ewing 's sarcoma and primitive neuroectodermal tumor of bone”. N Engl J Med. vol. 348. 2003. pp. 694-701.
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Ongoing controversies regarding etiology, diagnosis, treatment
As there has never been a randomized controlled trial comparing local control (surgery, radiation or both), the treatment remains individualized and empiric. There is debate about the role of surgery alone versus surgery with radiation in high risk patients. There is consensus that after surgery with close or positive margins, radiation should be employed.
There is no consensus on the role of megatherapy with autologous stem cell support in high risk and/or metastatic patients.
There are many appealing new “biologic” agents such as antiangiogenic agents, targeted agents, anti-insulin growth factor receptor monoclonol antibodies, and M-tor inhibitors. The role of these agents and how to integrate them into therapy remains undefined. New clinical trials are being planned that will examine the role of insulin-like growth factor (IGF) receptor antagonists, as there is data that IGF receptors are expressed in EWS/PNET cell lines and tumors. There is also great interest in developing antisense molecules that interfere with EWS-FLI1 function.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has Ewing sarcoma? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has Ewing Sarcoma, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of Ewing sarcoma?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- Other clinical manifestations that might help with diagnosis and management
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can Ewing Sarcoma be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment