ESFT

Ewing’s Sarcoma Family of Tumors (ESFT)

R. Lor Randall, MD, FACS

Director, Sarcoma Services

Chief, SARC Lab

Huntsman Cancer Institute & Primary Children’s Medical Center

University of Utah

What is ESFT?

Ewing’s sarcoma (ES) was first described by James Ewing in 1921 as a “diffuse endothelioma of bone” (Ewing 1921). He observed that this highly aggressive bone cancer was remarkably sensitive to radiation therapy.

Among other things, Dr. Ewing "laid the foundations of what is now known as the Memorial Sloan-Kettering Cancer Centre, building up a strong team of physicians who later distinguished themselves in the various specialities in oncology. His reputation was widespread, his peers referred to him as 'The Chief' and 'Mr. Cancer'." See About James Ewing. Click here to read about sidebars like this.

Since the time of his description, many theories have evolved regarding how these tumors arise. Based on advanced testing techniques called electron microscopy and immunohistochemistry, it is currently believed that the tumor represents a cancer that arises from a primitive cell derived from an embryologic tissue called the neural crest. By the early 1980’s, ES and another malignancy often seen in soft tissues, termed primitive neuroectodermal tumor (PNET), were found to not only have similar features when examined under a microscope but, in greater than 95% of cases (Burchill 2003), also had an identical genetic abnormality called a translocation. PNET is far less common than ES, making up about 10% of combined cases. Subsequently, these two tumors have been grouped into a class of cancers entitled Ewing’s Sarcoma Family of Tumor (ESFT), which also includes neuroepithelioma, atypical ES, and Askin tumor (ES of the chest wall), all of which demonstrate this translocation.

What is a translocation?

A translocation involves the mechanical breakage and reconnection between different chromosomes (Obata 1999). Chromosomes are the cellular storage unit for genes contained within the nucleus or genetic center of the cell and are analogous to a spool with the DNA or genetic message being the thread on the spool. Humans have a duplicate set of 23 for a total of 46 chromosomes in a given cell that carry all of the human genes. In ESFT, the translocation is between chromosomes 11 and 22 and is encrypted as t(11;22). The gene from chromosome 22 encodes a Ewing’s sarcoma gene (EWS) and is involved in the regulation of gene activation. The gene from chromosome 11, termed FLI1, also is involved in the turning on of other genes. Thus, this new fused gene encodes an altered factor that regulates other genes that can give rise to cancers when not acting normally.

An introduction to DNA, RNA and proteins can be found on the Nobel website. After clicking on the above hyperlink, make sure to read the section “Learn how to navigate in the document” to take full advantage of this tutorial.

The Ewing’s sarcoma gene encodes a homologous sequence to the RNA binding site in RNA polymerase II. The FLI product is a transcription factor. Accordingly, in the resultant fusion protein the FLI-1 transcription factor is placed under control of the Ewing’s sarcoma promoter. While other translocations have also been described in Ewing’s/PNET, including t(21:22) and t(7:22), all of the translocations involve the fusion of the EWS gene with an ETS family gene. Click here to read about sidebars like this.

The online Atlas of Genetics and Cytogenetics in Oncology and Haematology contains a webpage summarizing classification and other information about Ewing’s tumors. In particular, see the "Bibliography" section of this webpage and the "Bibliography" of the EWSR1 webpage of the Atlas. Both have extensive references related to translocations in Ewing's sarcoma. Two additional important references are:

	Translocation involving chromosome 22 in Ewing's sarcoma. A cytogenetic study of four fresh tumors, by Aurias A, Rimbaut C, Buffe D, Zucker JM, Mazabraud A., Cancer Genet Cytogenet. 1984 May;12(1):21-5.
	Chromosome translocation in peripheral neuroepithelioma, by Whang-Peng J, Triche TJ, Knutsen T, Miser J, Douglass EC, Israel MA, N Engl J Med. 1984 Aug 30;311(9):584-5.

Who gets ESFT?

ESFT is very rare, arising in just less than 3 per one million people under 20 years of age. In 90% of the cases, ESFT is found in patients between 5 and 25 years of age. After age 25, it is exceptionally rare. About 25% of cases occur before age 10, while 65% arise between ages 10 and 20 years old. Approximately 10% of patients are older than 20 years when they are diagnosed.

If the patient is under 5 years old, the most likely diagnosis is metastatic neuroblastoma.

Boys and young men are affected more frequently than girls and young women. Males also do less well than females. The pelvis is the most common location, followed by the femur, tibia, humerus, and scapula. However, ESFT can be found in any part in the body. Interestingly, ESFT is ten times more common in whites than in blacks. This is true globally.

How does someone with ESFT feel?

People with ESFT will initially complain of a pain and a mass that they notice. Generally, the mass will continue to grow over the course of a few weeks to months. A mass that has been present for many years is unlikely to be an aggressive tumor such as ESFT. Sometimes the tumor eats away the bone and causes a break. Perhaps a quarter of patients will complain of a fever and/or weight loss. People with these complaints should see their primary care doctor who can better evaluate whether a specialist should see the individual.

What tests are needed to figure out if some one has ESFT?

After a doctor asks questions (a history) and performs a physical, he/she may order a radiograph to evaluate the area. On radiographs, ESFT of bone appears as a destructive growth arising in the middle of the bone (diaphysis), see Figure 1.

Figure 1: Pelvic radiograph of a 16 year old girl who had a several month history of right hip pain. If one looks carefully, above the right hip joint, one can appreciate a dark area that corresponds to a destructive tumor above her right hip joint that is better appreciated on a MRI. Figures 2-6 demonstrate a case study of ESFT.

Radiographically ESFT presents as a central lytic tumor of the diaphyseal-metaphyseal bone. It creates extensive permeative destruction of cortical bone, and as it breaks through under the periosteum, it takes on a typical onionskin, multilaminated appearance. Another radiographic feature is the reactive hair-on-end appearance created by bone forming along the periosteal vessels that run perpendicularly between the cortex and the elevated periosteum.

A useful introduction the human skeletal system can be found on the Medical Terminology and Cancer” website of Simon Cotterill (of the University of Newcastle upon Tyne). After clicking on the above hyperlink, click on item 6, The Skeletal System.

Advanced imaging techniques including magnetic resonance imaging (MRI) can help establish the diagnosis, especially when the tumor arises outside the bone (see Figure 2).

Figure 2: MRI demonstrating the aggressive bone tumor. The bright area above the right hip joint indicates a bone tumor that is concerning for a bone sarcoma.

If ESFT is suspected, two additional (staging) tests, will be done to determine if the tumor has spread: a computerized tomography (CT) scan of the lungs and a bone scan. The results of these staging studies help physicians determine treatments and outcomes (prognosis). Certain blood tests may also help to determine the diagnosis. After all of these tests are performed, a sample of the tumor (biopsy) is absolutely necessary to figure out if the problem is truly ESFT.

What does a biopsy entail?

Two types of biopsies are possible: incisional and excisional. Incisional biopsies involve only taking a small sample of the tumor and include needle (closed) and open biopsies. Needle biopsies can be either fine needle or core. Excisional biopsies are performed when the mass is small (< 2 inches) and not next to any vital structures The type of biopsy chosen must be carefully determined after evaluating the size and location of the tumor as well as the age of the patient (Mankin 1996; Simon 1998).

The placement of the biopsy site relative to the location of the tumor and the anatomic structures of the patient is also of critical importance. Small, superficial lesions are amenable to excisonal biopsy. Generally, if a malignant bone tumor is suspected, an excisional biopsy is rarely, if ever utilized. This is due to the fact that the tumor is often large at presentation and that neoadjuvant therapy is usually appropriate prior to definitive resection. If the lesion is most likely benign based upon the preoperative history, physical exam and imaging studies, then at the time of excision a frozen section should be obtained if there is any doubt as to the diagnosis. Primary excision of an expendable bone should only be considered by an experienced musculoskeletal oncologist. Expendable bones may include a rib, clavicle, sternum, ilium, scapular body and perhaps distal ulna.

Most bone tumors of uncertain biologic potential, where there is a significant suspicion for malignancy, are biopsied via an incisional approach. The location of the biopsy site is determined by a thorough prebiopsy assessment of the extent of local disease and its relationship to critical structures such as the neurovascular bundle. This must be determined on a case-by-case basis. It is strongly recommended that the biopsy be performed by the surgeon who will be performing the definitive resection so that the biopsy tract can be ellipsed within the planned surgical incision. At the time of biopsy, the surgeon must be familiar with orthopaedic oncologic principles of flap development, coverage and even amputation, when definitive limb salvage is the proposed plan for a given bone tumor.

Needle (closed) biopsies can potentially expedite the diagnostic process when performed as an outpatient in the doctor’s office. This can be conducted using a local anesthetic and can reduce the cost of the procedure. However, such techniques are generally not recommended for children. Most malignant bone tumors have a soft tissue component on its periphery. Conveniently this is also the most representative tissue. Accordingly, deep deployment of the needle within the tumor is unnecessary and likely to lead to problems such as deep contamination and bleeding. Again the needle biopsy site must be carefully planned so that it may be excised at time of resection. With a well-trained cytopathologist, fine needle biopsy is an option. A 0.7 mm diameter needle is generally used. Up to 90% diagnostic accuracy has been reported, with bone sarcomas exceeding 80% accuracy. The drawback is that insufficient material may be obtained to perform cytogentics, flow cytometry, gene profiling and other tests that may help to establish the diagnosis.

Core biopsies are minimally invasive, can be performed under local anesthesia when appropriate, maintains the architecture of the tissue and can obtain adequate specimen for advanced studies. Diagnostic accuracy for this technique can surpass 95%.

While needle biopsies are intended to faciliate diagnosis they can also lead to a delay. Because no specific diagnosis of a malignancy should be rendered on a frozen analysis, the patient must wait until the results are finalized which may take several days, if special studies are necessary. If the specimen is indeterminate, which can occur in 25-33% of cases, even at experienced centers, then a delay occured.

An open incisional biopsy can potentially be done in the office. However for suspected bone malignancies, it is usually recommended that they be performed in the operating room. Generally, longitudinal incisions are the rule. Transverse incisions potentially contaminate flap planes and can compromise neurovascular structures. During the approach to the tumor, no flaps should be developed to minimize contamination. The area where the tumor is most superficial is preferable unless other factors, such as an overlying vessel or nerve, preclude it. Furthermore, the preoperative imaging may suggest that a specific area within the tumor may be more diagnostic than another. Areas of extensive necrosis and/or hemorrhage can be misleading. Once the tumor is reached, the biopsy should involve the periphery only. Deep sampling is not necessary. A frozen section must be obtained to determine if diagnostic tissue has been retrieved but not to establish the definitive diagnosis. Careful communication with the pathologist should be done preoperatively to clarify the amount of tissue that may be necessary for special studies and any special processing of the tissue once it is explanted. Formaldehyde fixes the tissue, preventing the application of cytogentics and other molecular tests. Furthermore, the tissue rapidly desiccates once outside the body, which also prevents certain advanced tests, so expeditious handling of the specimen is very important.

For those bone tumors that have not violated the cortex, controlled fenestration will be necessary. A trephine is usually adequate but if a larger window is required it is imperative that it be round or oval to minimize stress risers. A pituitary rongeur may then be used to retrieve tissue from within the medullary canal. The bone window may then be impacted back in place and sealed with bone wax. Alternatively, a polymethylmethacrylate plug may be used instead. Hemostasis is of utmost importance. Certain tumors may be quite vascular and meticulous hemostasis may not be possible. In such cases, a drain must be placed, in line with the incision distally, and sewn in place.

The use of tourniquets is controversial. While their use provides for a bloodless approach, they must be let down prior to closure to assure adequate hemostasis. If used, the limb should not be exsanguinated to minimize the risk of tumor embolis.

What other diseases mimic ESFT?

ESFT of bone can frequently masquerade as bone infection and doctors can have trouble initially distinguishing between the two.

ESFT can mimic osteomyelitis because it is a high grade lesion with resultant areas of necrosis, liquefaction may occur which may be mistaken for pus. Furthermore, patients frequently present with systemic symptoms of low grade intermittent fever, elevated white cell count and ESR.

Under the microscope these two diseases can, however, be separated (see Figure 3).

Figure 3: Biopsy of the tumor shows the typical appearance of ESFT when examined under a microscope. The dark blue material within the cells represent the enlarged, active nuclei. The nuclei contain the genetic information necessary for a cell to grow and reproduce, qualities inherent in cancers such as Ewing’s sarcoma.

Microscopically, ESFT demonstrates small round-like cells that predominate in densely packed sheets. Formation of pseudorosettes may also be seen. Immunohistochemistry reveals positive staining for O13 (CD99).

Other cancers that may involve the bones such as osteosarcoma and lymphoma can also be distinguished using the microscope and special studies. Non-cancerous (benign) conditions such as Langerhan’s cell histiocytosis may also look like ESFT. When ESFT arises outside the bone, soft tissue cancers (soft tissue sarcomas), such as rhabdo- and non-rhabdomyosarcomas, must be considered as well. Specialists are readily able to differentiate between these entities.

The Cancer Group Institute’s website contains an overview of bone cancers.

How does ESFT behave?

ESFT is an aggressive cancer with a tendency to recur where it arose (local recurrence) and spread throughout the body (metastasize). Treatment involves three potential types of therapy. For ESFT contained to one area (localized), chemotherapy is used to shrink the tumor and prevent further spread. Subsequently, the patients undergoes surgical removal of the tumor if possible. If surgery is not possible the radiation therapy is used to kill the localized tumor. The patient then receives further chemotherapy. In certain cases, both surgery and radiation are used. In general, for patients treated this way, the average patient has a 5-year survival rate of approximately 70-75%. Unfortunately, 15-25% of ESFT patients, when they initially see their doctor will have disease that has spread elsewhere in their body. For these people, the average survival at five years is 30%. In these patients, chemotherapy and radiation are the primary treatments but surgery may be used as well.

Resection of lung metastasis, if possible, does improve survival.

What are the treatments for ESFT?

The management of ESFT involves physicians from multiple disciplines. It is critical that a patient diagnosed with ESFT is treated at a center very familiar with this disease and that the center has an interdisciplinary team of physicians and allied heath care providers dedicated to this rare but deadly form of cancer (Randall 2004). Advances in chemotherapy (CTx) have significantly improved survival. Surgical removal of the primary tumor generally occurs after a course of initial chemotherapy. Chemotherapy is started first to attack any potential tumor cells that have broken off from the main tumor (metastasized) but have not yet been detected by the staging studies. Furthermore, this gives the surgeon an opportunity to better plan her/his surgery, which can be very involved, see Figure 4.

Figure 4: Plastic model of the pelvis. An artificial metal pelvis was created for her while she was undergoing her initial chemotherapy prior to surgery.

The February 2004 issue of ESUN contains an article entitled, “Treatments for Ewing’s Sarcoma”.

Surgery is then followed by further chemotherapy which may be adjusted depending upon the response of the tumor to the drugs. If the tumor has been highly responsive to the drugs a better outcome may be predicted in some cases. In ESFT, radiation therapy may be used in conjunction or instead of surgery depending upon location and extent of disease. While all aspects of treatment have improved dramatically over the past 30 years, it is a very intensive intervention. Treatment generally lasts a year. In essence, an ESFT patient and his/her family is giving up one year of life to hopefully get the rest of them back.

What drugs are used to treat ESFT?

Chemotherapy (CTx) is a critical part of the treatment for ESFT (Wexler 1996). Prior to CTx, the majority of patients, up to 90%, died when radiation and/or surgery were used exclusively. Certain drugs (cyclophosphamide, actinomycin-D and vincristine) were used in the 1960’s to treat ESFT patients and survival improved. We now know that the drugs doxorubicin, ifosfamide, cyclophosphamide, melphalan and busulfan work the best.

The results of the Intergroup Ewing's Sarcoma Study III randomized patients to treatment with a combination of the 3-drug therapy (vincristine, doxorubicin, and cyclophosphamide) vs. the 5-drug therapy (vincristine, doxorubicin, cyclophosphamide plus ifosfamide and etoposide). As reported in the New England Journal of Medicine in Feb 2003 (Grier et al., 348:694-701), patients receiving five drug therapy had improved survival compared to those receiving three drug therapy (survival 72% vs. 61%, p = 0.01). Based upon this landmark study, the currently accepted chemotherapy regimen for Ewing's sarcoma family of tumors is the 5-drug combination. Although melphalan and busulphan are active agents and have been used with some effectiveness in the context of autologous stem cell transplants for Ewing's sarcoma family of tumors, the extent of myelosuppression they induce render their use prohibitive in routine clinical settings.

Ifosfamide combined with etoposide has been shown to be a very effective combination as well. The schedule by which these drugs are given may also influence survival. The Children’s Oncology Group, a cooperative network of physicians dedicated to childhood cancers such as ESFT, are investigating if the drug regiments can be given more frequently and intensively to help improve survival.

In each issue of ESUN, the Drug News column reviews one or more chemotherapy agents. Vincristine was discussed in the February issue, doxorubicin (also known as adriamycin) was reviewed in the April 2004 issue, and cyclophosphamide (also known as cytoxan) and ifosfamide are discussed in this issue of ESUN.

For cases of ESFT where the tumor has spread to other sites (metastasized), studies investigating the use of bone marrow transplantation are underway to see if survival can be increased. For further information about chemotherapy protocols, the reader is referred to:

Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701.
Rosito P, Mancini AF, Rondelli R, Abate ME, Pession A, Bedei L, Bacci G, Picci P, Mercuri M, Ruggieri P, Frezza G, Campanacci M, Paolucci G. Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer. 1999 Aug 1;86(3):421-8.
Oberlin O, Habrand JL, Zucker JM, Brunat-Mentigny M, Terrier-Lacombe MJ, Dubousset J, Gentet JC, Schmitt C, Ponvert D, Carrie C, et al. No benefit of ifosfamide in Ewing's sarcoma: a nonrandomized study of the French Society of Pediatric Oncology. J Clin Oncol. 1992 Sep;10(9):1407-12.
Ferrari S, Mercuri M, Rosito P, Mancini A, Barbieri E, Longhi A, Rimondini S, Cesari M, Ruggieri P, Di Liddo M, Bacci G.J Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86.Clin Oncol. 2001 Mar 15;19(6):1818-29. Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. J Chemother. 1998 Dec;10 (6):484-91.

What are the side effects of chemotherapy in ESFT?

Conventional chemotherapy treatment for ESFT is not without significant side effects (toxicities). Supportive care in the form of nutritional, psychological, social, occupational and physical therapies, are essential to the well being of the ESFT patient and his or her family. Most patients undergoing chemotherapy for ESFT develop a compromised immune system and are unable to make adequate numbers of white blood cells, the cells that fight infections. A medication called granulocyte-colony stimulating factor (G-CSF) helps the body to generate new white blood cells. Nevertheless, patients often develop fevers and opportunistic infections that can be treated with antibiotics. Platelets, the components of the blood that help stop bleeding, can also be impaired with chemotherapy, necessitating the transfusion of platelets from the blood bank. Anemia, or the loss of red blood cells, which carry oxygen to the tissues, can be corrected by red blood cell transfusion and the use of drugs that stimulate red blood cell formation (erythropoietin). Doxorubicin can affect heart function, so the heart must be carefully monitored during chemotherapy administration. Dexrazoxane is a drug that helps protect the heart during treatment as well. Chemotherapy causes patients to loose their hair (alopecia) which readily grows back after the drugs have been discontinued. Some of the chemotherapies also cause nausea and vomiting but there are a variety of drugs that can help to minimize this. Finally, certain agents have particular side effects that the specialty physicians (oncologists) discuss with each patient and family.

How is the main tumor treated in ESFT?

ESFT is sensitive to radiation treatment. Historically, this has been the modality of choice for the main tumor.

Generally, a dose of 45-50 Gy is administered over a 5 week course to treat local disease.

However, radiation therapy can cause problems as well, including secondary cancers in less than 5% of cases. Therefore, surgical removal of the tumor was implemented to remove the tumor (local control). If, after surgical removal, a small amount of tumor remains behind, then local irradiation is used postoperatively. Some tumors are so big that surgery is not possible. In those cases, radiation treatment is still used to kill the tumor.

What does surgery for ESFT entail?

The surgical management of ESFT has evolved into a sophisticated field, see Figures 5 and 6 (Alman 1995; Gebhardt 1991, Hornicek 1998; Musculo 2000; Clohisy 1994; O’Connor 1996; Weiner 1996; and Randall 2000).

Figure 5: Artificial pelvis next to the pelvis containing the tumor.

Figure 6: Pelvic radiograph after surgery. The metal, artificial hemipelvis has been implanted on the right side.

How the surgery is performed is a matter of how large the tumor is and how far it extends into surrounding tissues. The goal of any cancer operation is to perform a complete removal of the tumor with an additional cuff of normal tissue for safe measure (Sluga 2001). Limb sparing surgery has become the norm with advances in imaging techniques, such as MRI. This, in combination with improved chemotherapy, has enabled the tumor surgeon to obtain local control rates equivalent to amputation. However, in severe cases, where limb salvage may compromise the survival of the patient, amputation may be necessary.

Because of the complexity of the musculoskeletal system, different ways to rebuild the area where the tumor is removed are performed depending upon the site of involvement. Generally, the areas where these tumors arise are the bony pelvis and the large long bones (femur, tibia, humerus). The spine, ribs, hands and feet can also be involved, albeit less frequently. ESFT has the potential to develop in any part of the body however.

How is the body repaired after removal of an ESFT tumor?

Ewing’s sarcoma of bone is the most common form of ESFT. The main ways to rebuild the defect created by removal of the tumor include bone transplants, either from the patient themselves or from a bone bank, and/or metal artificial body parts (endoprosthetics). Which technique is employed is a function of the location of the tumor, age of the patient and types of additional therapies that will be employed (i.e. chemotherapy and/or radiation).

Allografts and endoprosthetics may be used in conjunction as a composite reconstruction. Autogenous bone grafts may be vascularized (e.g. fibula). All three have inherent advantages and disadvantages. Large structural allografts and endoprosthetics should generally be reserved for children older than 8 years. Nonvascularized autografts from the pelvis or other sites may be used in a limited fashion for relatively small defects and work well in children. The advantage is a high incorporation rate but with potential donor site morbidity. Vascularized autografts such as the fibula are attractive because, when successful, the graft incorporates and even may remodel secondary to the forces exerted across it. Again, donor site complications can occur.

Structural allografts have no donor site morbidity. The major drawback to allografts is difficulty incorporating with the host bone (nonunion) and fracture. Their advantage is that they are a biologic solution and if they do heal and do not fracture then they may last the lifetime of the patient. Osteoarticular allografts may be used in the reconstruction of the proximal humerus, distal femur and proximal tibia as well as potentially any joint. Diaphyseal tumors can be reconstructed with intercalary allografts. The physis may sometimes serve as an adequate tumor barrier allowing preservation of the epiphysis and thus the joint surface. This must be carefully assessed preoperatively with MRI. When this is possible the durability and functional outcome will be superior to cases where the joint proper must be sacrificed.

For large structural bone transplants, satisfactory functional results can be anticipated in at least 60-70% of cases and in many cases, depending upon the extent of the repair, can be far better.

Artificial metallic body parts (endoprosthetics) provide an immediate stable reconstruction. These implants are much larger and complex than the standard joint replacements used to treat worn out joints due to arthritis and related conditions. Usually the endoprosthesis is cemented in place with acrylic bone cement (polymethylmethacrylate) but new techniques are available so as to avoid the use of cement. The endoprostheses are made from cobalt, chrome, steel or titanium.

Because ESFT affects children with immature skeletons, endoprosthetics have been designed to mechanically elongate when a growth plate has to be removed to get the tumor out. For such expandable prostheses, most (85%) are still working at 5 years. Expandable prosthetics are available with multiple, varying mechanism for expansion.

For metallic prosthesis, newer cementless, porous ingrowth sytems have been developed but have not yet replaced cement in most centers. A novel prestress compliant fixation device is also now available that obviates the need for long intramedullary stems, thereby avoiding stress shielding. This system is designed to facilitate osseous integration at the bone-implant interface.

Are there any options other than bone grafts and metallic implants for ESFT surgical repair?

In select cases, a patients own body part, such as their lower leg can be transplanted to reconstruct a defect in the thigh. Such surgeries are called rotationplasty and tibial turnup-plasty. Such options are particularly beneficial in the young child (less than 8 years of age) who will experience a significant amount of growth. Rotationplasty utilizes the ankle joint, which is rotated along its long axis 180 degrees, to convert a lower femur amputation level to a below knee amputation. Functionally, rotationplasty compares quite well to other forms of limb salvage in terms of a person's ability to walk (McClenaghan 1990). Additionally, it is far more durable than other forms of reconstruction and retains the lower tibial growth plate for additional growth.

If a joint (e.g. knee) needs to be removed with the tumor, an alternate option to joint reconstruction is a joint fusion (arthrodesis). This involves inducing the bone above and below the joint (e.g. femur and tibia) to grow together resulting in a stiff, immobile “joint.” While fusion remains an option in limb preservation surgery, it is utilized with diminishing frequency as endoprostheses and bone transplants have improved. The advantage to fusion is that once healed, the construct is very durable and may endure heavy labor.

What are the side effects of surgery in ESFT?

Surgery, like chemotherapy, is not without potential side effects. Infections can occur in 10-15% of bone transplants (Mankin 1996; Alman 1995; and Hornicek 1998). Furthermore, the bone transplant may not incorporate (nonunion) in 10-25% of cases where a large transplant is used from a bone bank (Gebhardt 1991; Mankin 1996). Because of these problems, additional surgery may be necessary and the bone transplants may have to be removed. These problems are more likely in patients receiving chemotherapy. Large bone transplants are always at risk for breaking (about 20% of cases) so care must be used throughout the life of the person that survives ESFT. Fractures can be managed by standard techniques but may necessitate graft and or implant removal and replacement.

The draw back of endoprosthetics is that they can eventually loosen and/or the components can wear out. The anticipated five-year survival for large metallic replacements ranges from 50-90% depending upon where it is located (e.g. thigh versus arm) and how large. For expandable endoprostheses some of the mechanisms by which these implants expand may be easily facilitated, yet the longevity of replacement is inversely related to the age of the patient at time of surgery (Ward 1996; Finn 1997; Eckardt 1993; Schiller 1995 and Schindler 1998). The younger the patient the more likely that she or he will suffer a complication related to the reconstruction. Also, like large bone transplants, infections are a significant risk, with rates ranging from 0-35% of cases (Grimer 2000; Wirganowicz 1999; Malawer 1995; Ritschl 1992; and Ward 1997).

The drawbacks of rotationplasty and tibial turnup-plasty relate to body image. In the United States it is not performed very often probably due to societal pressures regarding appearance. Families must undergo extensive presurgical counseling, including viewing images of patients that have undergone the procedure before.

Joint fusion often results in dissatisfied patients because of the lack of motion. It is better tolerated for the shoulder than the lower extremity (Alman 1995; Cheng 1991 and Kneisl 1995).

When should an amputation be performed in ESFT surgery?

In general, contemporary limb sparing surgery results in a permanent removal of the tumor in almost as many cases as when an amputation is performed (Rougraff 1994). Amputation itself does not guarantee absolute tumor eradication. ESFT has the ability to “skip” closer to the central body and not be detected before amputation, resulting in tumor re-growth in the amputation site (Enneking 1975). Currently, MRI is able to image the entire involved area making this is very rare.

Sometimes the tumor involves critical nerves, arteries or veins, structures which may make limb sparing surgery quite risky. When the patient is treated by an experienced Orthopaedic oncologist, contemporary limb salvage surgery does not impart a survival disadvantage. Patients that develop a break in the bone, may or may not be able to undergo limb sparing surgery depending upon the case. The decision to amputate is a complex one and must involve the entire team of health care providers and the family. The age of the patient, location of the tumor, presence or absence of a bone fracture, and the desires of the patient and family must be considered carefully. Finally, because ESFT is radiosensitive, amputation is rarely, if ever, performed.

Functionally, in the upper extremity, amputation leads to very poor results. Accordingly aggressive reconstruction, with vascular and/or nerve grafting as necessary should be done to save even limited hand and wrist function. However, if an adequate margin cannot be obtained then amputation is necessary. In the lower extremity, external hemipelvectomy leads to a particularly poor functional result. A hip disarticulation, at least permits improved sitting although prosthetic use remains poor. For tumors above the proximal tibia, limb salvage with one of the above techniques is preferable to amputation and can potentially give equal functional results. Patients undergoing above knee amputation have increased energy expenditure compared to those undergoing endoprosthetic reconstruction. A knee arthrodesis is intermediate between these two. Tibial diaphyseal lesions often are amenable to limb salvage however for those about the ankle and distal, below knee amputation is generally preferable to limb salvage. In a study evaluating psychosocial adjustment, physical complaints were reported more often in patients undergoing limb salvage, yet amputees tended to have lower self-esteem and experience more social isolation

What new therapies are on the horizon for ESFT?

New drugs are continually in experimental development. In an attempt to tailor drugs more specifically to the specific aberrancies of a given cancer, investigators are now studying particular biologic pathways in cancer development. Because the molecular “signature” for ESFT is the t(11;22) genetic translocation, this has become the main focal point for ESFT researchers (Lessnick 2002). Investigators at Huntsman Cancer Institute as well as other major sarcoma centers are studying the molecular genetics (translocations) and related pathways to see if there are ways to block the formation of ESFT by interrupting the abnormal expression of genes caused by the EWS-FLI1 translocation (see above).

Genetic sequences directed against particular genes, termed “anti-sense” oligonucleotides, are an exciting new technology that may prove beneficial in an array of cancers including ESFT. Anti-sense against the ESFT translocation has been shown to inhibit tumor formation in the lab dish as well as in animals (Ouchida 1995; Kovar 1996; Tanaka 1997; and Lambert 2000) but this technique is still very investigational and much work has yet to be done. Anti-sense oligonucleotides that inhibit a molecule known as insulin-like growth factor 1 (IGF-1) also may prove to be a future biologic agent against ESFT (Scotlandi 2002). The role of tumor growth factor (TGF) beta in the formation of ESFT is also being investigated (Hahm 1999).

Imatinib (Gleevec, STI-571), a small antagonist molecule against cellular messenger systems called tyrosine kinases and platelet derived growth factor (PDGF) may prove useful in certain cases of ESFT (Ricotti 1998 and Landuzzi 2000). Tumor cell suicide via programmed cell death or apoptosis may be facilitated by a molecule entitled tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and may eventually prove to be a biologic therapy that can help to kill ESFT (Mitsiades 2001 and Van Valen 2000). These and other drugs are purely investigational at this point, but with continued support of molecular translational research, these and other agents will hopefully prove effective drugs against ESFT.

The April issue of ESUN had an immunotherapy emphasis (vaccine therapy and antibody therapy). It contains a number of articles on immunotherapy and related clinical trials cited in the Q and A on Immunotherapy. There are additional immunotherapy references in the Clinical Trial News column, in the Odds and Ends column, and a number of immunotherapy resources are discussed in the Research Corner column. Patients with ESFT are potential candidates for some of the clinical trials.

Where else can one learn about ESFT?

This article is a very general overview of ESFT. Interested readers are encouraged to continue their education at the websites listed below:

	CancerIndex Ewing's Sarcoma Webpages
	Cancer Information % Support International Ewing's Sarcoma Webpages
	Huntsman Cancer Center Sarcoma Service Webpages
	Sarcoma Alliance
	Sarcoma Foundation of America
	The Cure our Children Foundation Ewing's Sarcoma Webpages
	The Liddy Shriver Sarcoma Initiative ESUN Newsletter

Also for additional resources and websites see the discussion of Online Sarcoma Support Groups and Sarcoma Communities in the April 2004 issue of ESUN.

Steve Dunn's CancerGuide provides a very useful starting point for undertaking investigations into cancer and cancer-related issues on the Internet. Among other things, he discusses how to research the medical literature and how to use and access medical databases and online resources. He explains the medical research cycle, where to get medical references and describes the various types of papers in the medical literature, and how to find and use a medical library.

A word of caution: while the Internet is a wonderful tool to gain access to information, simply because information appears on the Internet does not necessarily indicate that it is accurate or truthful. Any heath information that you obtain on the internet should be reviewed with your physician.

Feedback and Questions.

We would appreciate receiving any comments or questions regarding the content of this article. Click here to send us a note.

References

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