Ewing sarcoma: current concepts in diagnosisand treatmentJohn G. Kennedy, MD, FRCSI, Peter Frelinghuysen, MD, and Bang H. Hoang, MD

Ewing sarcoma (ES) accounts for about 1% of all child-hood tumors, yet it is the second most common primarymalignant bone tumor, second only to osteosarcoma. Theannual incidence of this disease is approximately 3 newcases per 1,000,000 Caucasians under the age of 21 yearsin the United States. The incidence amongst those ofother race is significantly less [1].

Historically, the prognosis for patients with a diagnosis ofEwing sarcoma was poor. However, with newer chemo-therapeutic strategies, combined with selective surgery,outcome has improved with overall survival approaching80%. As the disease is systemic in nature, many patientshave micrometastases at presentation. These microme-tastases have been targeted by chemotherapy drugs, thusimproving survival. Those patients, however, who haverecognized multiple metastases at presentation or whohave a recurrence continue to have a poor prognosis. It isthis group of patients that newer generation treatmentstrategies will focus on.

Molecular characterizationEwing sarcoma is characterized by the translocation t (11;22) (q24; q12) in up to 85% of cases. Chromosomal trans-locations, identified by polymerase chain reaction, arebecoming increasingly important not only in identifyingfusion proteins, but also by aiding in differentiating Ew-ing sarcoma from other tumors, including childhood neu-roblastoma. In addition, with modern molecular cytoge-netics, translocations are proving to be of prognosticsignificance. The primary genetic alteration in Ewingsarcoma is a specific fusion of EWS with the ETS tran-scription factor FLI1 (90%95%) or ERG (5%10%).Differences in the location of the translocation break-points result in the insertion of different combinations ofexons from EWS and FLI1 or ERG in the final fusionproduct. The most common type of EWS-FLI1 fusion

transcript, type 1, has been shown to be associated witha favorable prognosis independent of tumor size, site, orstage [2].

Secondary genetic alterations in Ewing sarcoma havealso been studied as to their prognostic significance. Al-though the tumor suppressor gene P53 is found rarely inpatients with ES, this particular alteration is associatedwith a poor prognosis. In addition, recent work has es-tablished that there may be a correlation between P53and the cell proliferation nuclear antigen Ki-67 [3]. Bothmarkers have been found to be associated with a pooreroutcome in ES when present. The most frequent sec-ondary molecular genetic alteration found to date in ESis the INK4A deletion [4]. Although there is no clear roledefined yet by the presence of this genetic alteration,clinical trials are ongoing to establish the usefulness ofthis exciting genetic marker.

HER2/Neu gene expression has been seen in breast andother cancers; however, it has not been found conclu-sively to be involved in Ewing sarcoma, although someinvestigators believe it be present in some osteogenicsarcomas. As such, recent enthusiasm for monoclonal an-tibody therapy in patients with refractory ES must betempered with caution [5].

LocationEwing sarcoma is found most frequently in the diaphysisof long bones. The femur is the most common locationfollowed by the tibia, humerus, and fibula bones. Thepelvis is the next most common site, which can give riseto an insidious delayed presentation with a poor progno-sis [6]. The ribs, vertebrae, scapula, and clavicle can alsobe involved. Extraskeletal Ewing sarcoma is rare;however, it can be found in most soft-tissue parts of thebody [7].

Pathology and laboratory studiesAt present, Ewing sarcoma is regarded as a member ofthe primitive neuroectodermal tumor (PNET) family.The gross pathologic description of Ewing sarcoma isone of a soft grey/ white mass with areas of hemorrhageand necrosis. The degree of necrosis is an importantprognostic indicator following resection after neoadju-vant chemotherapy [8].

Ewing sarcoma is a small round cell tumor and as suchrequires differentiation from other similar round cell tu-

Orthopaedic Surgery Service, Department of Surgery, Memorial Sloan-KetteringCancer Center, New York, New York, USA. Affiliated with Weill Medical College ofCornell University.

Address all correspondence to Bang H. Hoang, MD Orthopaedic Surgery Service,Suite A342, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NewYork, NY 10021, USA; e-mail: bhoang@pol.net

Current Opinion in Pediatrics 2003, 15:5357

Abbreviations

PNET primitive neuroectodermal tumor

ISSN 10408703 2003 Lippincott Williams & Wilkins, Inc.

53

mors (Fig. 1). In children, these include neuroblastoma,rhabdomyosarcoma, histiocytosis, small cell osteosar-coma, and osteomyelitis. In adults, it must be differen-tiated from lymphoma, multiple myeloma, and small cellcancer of the lung. The histopathologic picture is one ofmonotonous round cells with small hyperchromatic nu-clei and a complete absence of intracellular material. Cy-toplasm is sparse and the nuclei are large in comparison.Intracellular accumulation of glycogen in Ewing sarcomaconfers a positive acid-Schiff test on these cells. Thediagnosis of Ewing sarcoma has to date largely been oneof clinical and radiologic suspicion confirmed by biopsy.Recent work has been encouraging using fine-needle as-piration (FNA) and immunohistochemistry in the pri-mary and recurrent diagnosis of ES [9]. Typical immu-nohistochemical markers used in the diagnosis of Ewinginclude MIC2, NFP, Vimentin, and HBA-71. The ad-vantages of FNA are that the procedure is rapid, accu-rate, and relatively atraumatic. It may also prevent grossbiopsy error that can occur with conventional intrale-sional biopsy, compromising both the oncological andfunctional end result [10]. More work will need to bedone confirming this method of diagnosis as accuratewith low sampling error before it can be uniformlyadopted.

Laboratory studies used in the diagnosis of Ewing sar-coma and in the evaluation of treatment include an el-evated lactate dehydrogenase (LDH) and alkaline phos-phatase. A fall in the level of LDH is a useful indicatorof the efficacy of the chemotherapeutic regimen. TheLDH level is especially useful as a marker of recurrentdisease [11].

Clinical and radiographic presentationThe clinical presentation of a child with Ewing sarcomais one usually of pain and swelling about the affectedlimb, with mild or moderate erythema. This may mimica playground trauma, and often it is an incidental traumathat may lead to the ultimate diagnosis. Occasionally(1015%) a pathologic fracture, typically of the femur,will lead to the diagnosis [12]. Children may also displaysystemic symptoms, including pyrexia and loss of energy.In those cases where the tumor is in the pelvis, symp-toms and signs will be delayed. These patients typicallypresent with gait abnormalities from root compression,bowel or bladder dysfunction, or back pain [13].

The radiographic features of ES are of a metadiaphysealor diaphyseal lesion in long bones. Typically the lesionwill show the periosteal reaction of a rapidly expandingtumor (Fig. 2). The Codmans triangle, not exclusive toES, is also a valuable diagnostic radiographic sign. Thelesion is typically poorly marginated with permeativepattern of osteolysis. The host bone will often show cor-tical erosion, and often a soft-tissue extension can bevisualized on plain radiograph. This is best appreciatedon magnetic resonance imaging (MRI) where the truenature of the large soft-tissue component of this tumor isseen (Fig. 3). Magnetic resonance imaging is also a usefultool in establishing the true extent of marrow infiltrationof the lesion that may not be appreciated on plain radio-graph (Fig. 4).

Other imaging modalities used in the initial staging andin follow-up posttreatment in Ewing sarcoma includebone scan and chest computed tomography. Recent

Figure 1. Histologic features of Ewing sarcoma

Ewing sarcoma is composed of small round cells with littleor no identifiable matrix. Under high magnification,homogenous cells with uniform nuclei are typical cytologicfeatures of this tumor.

54 Orthopedics

work has suggested that a triple-phase bone scan may bemore advantageous and sensitive than the standardsingle-phase scan used in most institutions [14,15]. Thisis particularly so when evaluating the soft-tissue compo-nent of Ewing sarcomas, which would have been missedif only the delayed bone scan had been performed.

TreatmentTreatment of Ewing sarcoma has evolved so that pa-tients can now expect 60%80% survival when present-ing as a nonmetastatic, nonrecurrent disease. The intro-

duction of chemotherapeutic agents supplanted previousradiotherapy and amputation that were ineffective inprolonging survival. Currently, treatment strategies forEwing sarcoma combine neoadjuvant chemotherapywith surgical resection followed by adjuvant chemo-therapy. The role of radiotherapy is controversial, andmany centers reserve its use for patients with positive orclose margins following local resection.

At present in the United States, the Childrens OncologyGroup coordinates the chemotherapy protocols adminis-tered around the country. Most drug regimens includecombinations of the following drugs: doxorubicin, acti-nomycin, dactinomycin, cyclophosphamide, and vincris-tine. The introduction of ifosfamide into this chemo-therapy protocol was prompted by a comparative studyconducted using two treatment groups. Those patientsin the first group received vincristine, actinomycin, cy-clophosphamide, and doxorubicin. Those patients in thealternate arm of the study received the same drugs inaddition to ifosfamide. The overall 3-year survival forpatients who received ifosfamide was 80% as comparedwith 56% 3-year survival for those patients who receivedthe VAC/Dox combination alone. Additional studies bythe Intergroup Ewing Sarcoma Study Group have shownthat the 5-year event-free survival of patients with Ewingor Ewing family of tumors could be increased with theaddition of ifosfamide and etoposide. In a study of 54newly diagnosed patients treated with vincristine, doxo-rubicin, and cyclophosphamide, the 5-year event-freesurvival was 45%. In the group treated with the additionof ifosfamide and etoposide, this figure increased to 64%[16]. In those patients regarded as poor risk due to largetumor volume, high-dose cyclophosphamide, doxorubi-cin, and vincristine given in a seven-course regimen hasproved to give excellent anti-tumor toxicity in these pre-viously poor responders [17]. In those patients who didnot respond well to first-line chemotherapeutic modali-ties or who experienced a recurrence, the 5-year survivalrates have been poor. A recent study on patients with

Figure 3. The utility of MRI in Ewing sarcoma

Axial T1- (A) and T2-weighted (B) MRI of the distal fibulademonstrating a large soft-tissue mass associated withEwing sarcoma in this location.

Figure 2. Plain radiograph of Ewing sarcoma

Ewing sarcoma of the distal fibula showing abundant periosteal reaction (arrow).

Ewing sarcoma: diagnosis and treatment Kennedy et al. 55

recurrent disease from St. Jude Childrens ResearchHospital demonstrated 17% 5-year postrecurrence sur-vival [18]. However, patients with relapse more than2 years after diagnosis had significantly better outcome.Also, patients with local recurrence alone fared bet-ter than patients with both local and distant recurrences.In this study, lung irradiation appeared to improveoutcomes of patients with isolated pulmonary metasta-sis [18].

Recent work using Irinotecan, an antineoplastic agentthat works by inhibiting topoisomerase, has been encour-aging. In a study of pretreated solid tumors that hadrelapsed, Irinotecan appeared to have promising single-agent activity. This drug is currently being used in casesof recurrence in combination with other active chemo-therapeutic agents and has promise for the future [19].Recent work on insulin-like growth factor (IGF) recep-tors has shown that they play an essential role in thepathogenesis of ES. In a multicenter trial using IGF1receptor antisense agents in nude mice, investigatorshave demonstrated that survival was increased and thattumor formation was delayed compared with those micenot treated with the IGF1 antisense agent. In addition, itwas shown that inhibiting IGF1 receptors enhanced thesensitivity of tumor cells to doxorubicin [20]. IGF1 re-ceptor antisense agents may have a future role in treat-ment strategies in patients with ES, both by reducing themalignant potential of the sarcoma and by augmentingconventional chemotherapeutic agents.

Radiation to the primary tumor in patients with ES hashad reported rates of up to 90% local control, particularly

for distal extremity lesions. The rate decreases for moreaxial and larger lesions. Radiation alone has theoreticaladvantages, the most important being the reduction ofsurgical mortality. Problems associated with radiation,however, include growth arrest, pathologic fractures, andradiation-induced sarcomas. Wagner et al. [12] report that64% of fractures occurring in patients with ES occurredfollowing radiation. The authors caution that when frac-tures do occur following high-dose radiotherapy, a recur-rence or a second malignancy must be suspected.

In an effort to control for adverse effects of high-doseradiation, surgical resection and low dose radiation havebeen investigated as a means of achieving local control.Merchant et al. [21] investigated 25 patients using a me-dian irradiation dose to the primary site of 30 Gy. In thisstudy cohort, no patients had a local recurrence. Twenty-five percent of patients progressed from established me-tastases, and 25% of patients had a distal recurrence.Despite that, however, the investigators found that low-dose radiation is effective in controlling local recurrencewhen combined with wide surgical resection and thatfew complications were experienced.

The ideal interval between surgical resection and com-mencement of radiotherapy has not been fully estab-lished. Early postsurgical radiotherapy must be evalu-ated against cell turnover and wound healing. In a studyof 153 patients who had radiotherapy prior to and follow-ing the 60th postoperative day, Schuck et al. found thatthere was no difference in event-free survival betweenthe two groups at 5 years [22]. In this study, a trend wasseen, however, for improved local control in those pa-tients treated with early onset radiotherapy.

The impact of wide surgical margins on survival in pa-tients with ES has been considerable. Advanced diag-nostic investigative methods including 3D computed to-mography and MRI now allow the establishment ofprecise resection margins preoperatively. In a study of86 patients with ES, the 5-year overall survival for thosepatients treated with wide or radical resection was 60% ascompared with 40% for those patients treated with mar-ginal or intralesional resection [23]. Better diagnosticimaging is also helping establish resection marginsfollowing induction chemotherapy, where the soft-tissuecomponent of ES may have diminished greatly insize. This may facilitate limb-sparing resection and im-prove long-term function without compromising localrecurrence.

At present, the value of stem cell transplant in the treat-ment of ES has not been fully established. High-dosechemotherapy supported by autologous stem cell trans-plants has shown encouraging results; however, there issome concern about long-term treatment outcomes, par-ticularly secondary malignancies [24,25]. This may tem-

Figure 4. Marrow involvement in Ewing sarcoma

Sagittal T1- (A) and T2-weighted (B) MRI reveal the extent of marrow infiltrationwith Ewing sarcoma of the tibial diaphysis.

56 Orthopedics

per the use of stem cell transplantation in the currentformat.

Limb salvage surgery is now the primary goal, once thetumor has been removed, of the orthopaedic oncologist.Newer designs, coupled with modularity of components,are increasing the durability and function of contempo-rary endoprosthesis [26]. The decision for limb-sparingsurgery is still dependent, however, on the stage of thetumor, the feasibility of obtaining a wide margin, and thetumors response to neoadjuvant treatment.

Prognostic indicatorsPrognostic indicators in ES are both laboratory based andclinical. The EWS-FLI1 fusion transcript has beenshown by multivariate analysis to be a true predictor ofoverall survival. In a study of 99 patients in whom iden-tification of the fusion transcript could be performed,those patients with a type 1 fusion had fewer metastasesand longer survival times than those patients with lesscommon fusion types. This prognostic indicator appearsto be independent of clinical factors including tumor siteand size [27]. Recent work has also established that theremay be a correlation between P53 and the cell prolifera-tion nuclear antigen Ki-67 [3]. Both markers have beenfound to be associated with a poorer outcome in ESwhen present, and continued investigation is needed toestablish their role as prognostic markers. Clinical prog-nostic indicators include the histologic response to che-motherapy and the size of the primary tumor. Wunderet al. [8] studied a series of 74 patients with ES treatedwith pre- and postoperative chemotherapy with andwithout radiation following operative resection. Theevent-free survival at 5 years for patients with grade Iresponse was zero and for patients with grade III or IVresponse was 84%, clearly implicating the histologic re-sponse to chemotherapy as a significant prognostic indi-cator.

ConclusionThe overall survival for patients with Ewing sarcoma hasimproved significantly over the past 20 years. Continuedadvances in molecular and genetic analysis, diagnosticimaging as well as chemo- and radiotherapy will un-doubtedly make current survival figures redundant inthe coming years.

References and recommended readingPapers of particular interest, published within the annual period of review,have been highlighted as: Of special interest Of outstanding interest

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Ewing sarcoma: diagnosis and treatment Kennedy et al. 57