sarcoma de edwing

Ewing Sarcoma Family of Tumors

AbstractThe Ewing sarcoma family of tumors (ESFT) consists of a group oftumors characterized by morphologically similar round-cell neo-plasm and by the presence of a common chromosomal transloca-tion. Although rare, such tumors constitute the third most frequentprimary sarcoma of bone after osteosarcoma and chondrosarcoma.ESFT most commonly affects young children and adolescents. Be-cause most patients with clinically apparent localized disease atdiagnosis may also have occult metastatic (ie, systemic) disease,multidrug chemotherapy as well as local disease control with sur-gery and/or radiation therapy are indicated for all patients. Despitemarked improvements in survival during the past 40 years for pa-tients with localized disease, lesser improvements have been seenin patients with metastatic or recurrent disease. A better under-standing of the complex biology of ESFT may lead to the success-ful development of biologically targeted therapies. As the regulatorypathways responsible for transformation, growth, and metastasis ofESFT become more refined, the number of potential therapeutictargets will expand.

Tumors of the Ewing sarcoma fam-ily of tumors (ESFT) are character-ized bymorphologically similar round-cell neoplasms aswell as by the presenceof common chromosomal transloca-tion. In 1918, Stout1 reported a caseof an ulnar nerve tumor composed ofundifferentiated round cells thatformed rosettes; this lesion was sub-sequently defined as primitive neuro-ectodermal tumor (PNET) of soft tis-sue. In 1921, Ewing2 reported a caseof round-cell tumor in the radius of a14-year-old girl as a diffuse endo-thelioma of bone, proposing an en-dothelial derivation (Ewing sarcoma[ES]). Angervall and Enzinger3 re-ported the first case of an ES arisingin soft tissue (ie, extraskeletal ES) in1975. In 1979, Askin et al4reported amalignant small-cell tumor of thethoracopulmonary region (ie, Askintumor) with histologic features simi-lar to those in PNET. In 1984, Jaffe

et al5 described a neuroectodermaltumor of bone, calling it a PNET ofbone.Initially, ESFT were believed to be

biologically distinct. However, basedon their wide spectrum of neural dif-ferentiation (PNET being the mostdifferentiated); their immunohisto-chemical, cytogenetic, and molecularuniformity; and their identicalresponse to Ewing-based chemother-apy regimens, it was determined thatthese sarcomas are related and thatthey originate from unique mesen-chymal stem cells capable of multi-lineage differentiation.6 A commonchromosomal translocation that re-sults in EWS-ETS fusion (betweenthe EWS gene on chromosome 22and an ETS-type gene, most com-monly the FLI1 gene on chromo-some 11) has been implicated in80% to 95% of cases of ES, PNET,and Askin tumor.6,7 Thus, these le-

Aditya V. Maheshwari, MD

Edward Y. Cheng, MD

From the Department ofOrthopaedic Surgery, University ofMinnesota, Minneapolis, MN(Dr. Maheshwari), and theDepartment of Orthopaedic Surgery,Masonic Cancer Center, Universityof Minnesota (Dr. Cheng).Dr. Cheng or an immediate familymember serves as a board member,owner, officer, or committee memberof Musculoskeletal Tumor Society,has received royalties fromInnomed, and has received researchor institutional support from AastromBiosciences and MusculoskeletalTransplant Foundation. NeitherDr. Maheshwari nor an immediatefamily member has receivedanything of value from or ownsstock in a commercial company orinstitution related directly orindirectly to the subject of thisarticle.

J Am Acad Orthop Surg 2010;18:94-107

Copyright 2010 by the AmericanAcademy of Orthopaedic Surgeons.

Review Article

94 Journal of the American Academy of Orthopaedic Surgeons

sions have been grouped as the sameentity, called ESFT. Treatment princi-ples are the same regardless of ana-tomic location. Herein we have cho-sen to focus on ES of the bone.

Epidemiology

Currently, it is believed that ES mostlikely can be ascribed to spontaneousgenetic translocations rather than toexposure to environmental factors ordrugs, mendelian inheritance, dis-ease, or traumatic events.6,8 The inci-dence of secondary ES after radio-therapy (RT) has been reported to be20 years.18-20 Patient age hasdiagnostic importance. In patientsaged >30 years who present withprimary lung disease, small-cellcarcinoma should be excluded. Inyounger patients, alternative diag-

noses must be considered, such aslymphoma/leukemia, rhabdomyosar-coma, medulloblastoma, and neuro-blastoma. ES is more common inmales than in females, with a re-ported ratio of 1.3 to 1.5:1.12-17 Cau-casians are much more frequently af-fected than Asian persons; Africanand African-American persons rarelysuffer from ES.16,17

Esiashvili et al17 searched the Sur-veillance, Epidemiology, and End Re-sults (SEER) database for informa-tion on ES in patients aged 1 through19 years. Based on data reportedfrom 1973 through 2004, the meanannual incidence of ES is 2.9 casesper 1,000,000 population. Of the906 patients with ES, 830 were Cau-casian and 18 were African Ameri-can (91.6% versus 2%, respectively).There was a male preponderance(553 patients [61%]), and 212 caseswere reported in children aged 6 months before the tumor was di-agnosed.27 Delayed diagnosis of pel-vic tumors is particularly commonbecause a mass in that area is notpalpable until it becomes quite large.In another study, 26% of patientswith ES related the onset of symp-toms to minor injury.28 Thirty-fourpercent of patients with ES had apalpable mass at initial presentation.The most frequent initial misdiag-noses in older patients with ES weretendinitis (21%) and sciatica (11%)and, in younger patients, coxitis sim-plex (9%) and osteomyelitis (6%).The mean delay in diagnosis fromthe first medical visit was 19 weeks(range, 1 to 72 weeks). A high indexof suspicion, along with persistentfollow-up and early diagnostic imag-

Aditya V. Maheshwari, MD, and Edward Y. Cheng, MD

February 2010, Vol 18, No 2 95

ing, is helpful in obtaining an earlierdiagnosis.Several factors have been associ-

ated with metastatic disease: thepresence of constitutional symptoms,a shorter interval between the onsetof symptoms and diagnosis, pelviclocation, older age, larger tumors,and a high level of serum lactic dehy-drogenase.29

Imaging Features

Plain RadiographyUnlike osteosarcoma, which usuallyoriginates in the metaphysis, ES ofthe long bones tends to arise fromthe diaphysis or metadiaphysis. Ofthe 206 patients in the IntergroupEwings Sarcoma Study 7299 group,121 (58.7%) presented with lesionslocated in the metadiaphysis, 73(35.4%) with lesions in the diaphy-sis, 11 (5.3%) with lesions in the me-taphysis, and only 1 with a lesion inthe epiphysis (0.5%).25

Typically, ES appears as an ill-defined,permeative, mottled, or focally moth-eaten, destructive intramedullary lesion.Periosteal reaction, with a laminated oronion skin appearance (a prominentmultilayered reaction), is common inES, but it is not pathognomonic. Peri-osteal reactions may be seen, such as asunburst or spiculated pattern (the lat-ter displaying as a perpendicular reac-tion), aswell as theCodman triangle (ie,triangular lifting of the periosteum fromthe bone at the site of detachment).However, these presentations are lesscommon in ES than in osteosarcoma.An ill-defined soft-tissue mass adjacentto the primary bone lesion is very com-mon in ES. Of the 373 patients in theIntergroup Ewings Sarcoma Study7299, common radiographic findings(present in >30%of evaluated cases) in-cluded poor margination (ie, indistinctlesion borders; 96%), soft-tissue com-ponent (80.4%), permeative compo-nent (76.1%), laminated periosteal

reaction (56.6%), and sclerotic compo-nent (39.7%).25 The major radio-graphic differential diagnoses in-cluded osteosarcoma, osteomyelitis,and eosinophilic granuloma.

Advanced Imaging StudiesInitial plain radiographs, particularlyof the pelvis, may appear to be nor-mal, and advanced imaging studiesare needed for tumor localization.MRI provides the most precise defi-nition of the local extent of bone tu-mor, including the degree of expan-sion into the intramedullary region,extent of soft-tissue involvement,and the relationship of the lesion toadjacent neurovascular structures.MRI may also be used to assess re-sponses to neoadjuvant chemother-apy and irradiation. CT is useful forstaging the disease and detectingmacrometastasis. As an adjunct toMRI, CT may also be helpful in tar-get planning for radiation. A techne-tium Tc-99m whole-body bone scanis important in detecting skip or dis-tant metastases; these occur in 10%of patients.10 False-negative bonescans occasionally occur. In conjunc-tion with the aforementioned studies,fluorodeoxyglucose positron emis-sion tomography, thallium-201 scin-tigraphy, and dynamic MRI also maybe used to assess responses after neo-adjuvant therapy.30

Staging

Currently, most commonly usedstaging systems for malignant bonetumors are also applied to ESFT, butthese systems are problematic. Nodalstatus and grade, as defined by theAmerican Joint Committee on Can-cer staging system for sarcoma,31 areirrelevant for ESFT because such tu-mors rarely spread to the lymphnodes. In addition, by definition,these are high-grade tumors.6 Ac-cording to the Enneking staging sys-

tem adopted by the MusculoskeletalTumor Society, almost all ESFT neo-plasms are classified as stage IIBor III.32 Clinically apparent metasta-sis (macrometastasis) has prognos-tic significance, and the stagingwork-up is based on proper imagingof the primary tumor and sites oflikely metastasis, including plain ra-diography and MRI of the primarysite, chest radiography and CT of thelung, bone scanning, and bone mar-row biopsy. Laboratory studies in-clude a complete blood count, anerythrocyte sedimentation rate assay(increased in up to 50% of patients),serum lactate dehydrogenase mea-surement, and baseline chemistries.Additional scans, such as the multi-ple gated acquisition scan, may berequired before initiation of chemo-therapy because of the cardiotoxicityassociated with doxorubicin.

Pathology

Grossly, ESFT presents as a gray-white tumor with a variable amountof necrosis, hemorrhage, or cystformation. Morphologically, ESFTare composed of sheets of smallround cells with a high nuclear-to-cytoplasmic ratio. They are oftenclassified into a group of small, blue,round-cell tumors that include neu-roblastoma, alveolar rhabdomyosar-coma, and lymphoblastic lymphoma.The cells typically have scant, weaklyeosinophilic cytoplasm that usuallycontains glycogen (making them pos-itive on periodic acid-Schiff [PAS]stain), diastase degradable granules,and round nuclei with evenly distrib-uted chromatin and little mitotic ac-tivity (Figure 1). Tumor histologymay range from undifferentiated (ES)to more differentiated (PNET). ThePNET type may exhibit neural differ-entiation under light microscopy (ie,Homer Wright rosettes in >20% oftumor tissue). In addition, neuroen-



docrine differentiation can be ob-served on ultrastructural studies,which visualize the presence of neu-rosecretory granules.Immunohistochemical findings are

helpful in distinguishing ESFT fromother neoplasms. However, theyshould be interpreted alongside cyto-genetic and molecular studies to bemost definitive. CD99 is nearly uni-versally expressed at high levels byESFT cells (95%) (Figure 2), even inthe absence of the characteristic11;22 translocation, but is not spe-cific for this tumor type.10,33 Depend-ing on their neural differentiation,ESFT can also express neuron-specific enolase (NSE), S-100 pro-tein, Leu-7 (ie, CD57), and proteingene product 9.5, as well as neurofil-aments and synaptophysin. ESFTcells are reactive with antivimentinantibodies and, in fewer than onequarter of cases with anticyto-keratin antibodies. In addition, ESFTneoplasms are often PAS-positive,because of the presence of intracellu-lar glycogen, and reticulin-negative.In contrast, lymphomas are PAS-negative and reticulin-positive. Lym-phocyte-derived tumors also stainpositive for leukocyte common anti-gen and other T and B cell markers(eg, CD45, TdT, or both). Neuro-blastoma cells are NSE- and S-100positive; however, unlike their ESFTcounterparts, they are vimentin-negative and neurofilament-positive.Embryonal rhabdomyosarcoma mayexpress CD99, but it also expressesdesmin, myoglobin, and muscle-specific actins (eg, MyoD1, myoge-nin, or both).Genetic studies, along with histo-

pathology and immunochemistry, areessential for diagnosis. At the geneticlevel, ESFT is defined by the presenceof these EWS-ETS fusion gene ar-rangements (Table 1).6,34,35 The rear-rangements of EWS with FLI1 orFLI1-related genes make up >95%of all ESFT; t(11;22)(q24;q12) trans-

location, a chromosomal abnormal-ity specific to ESFT, is detected inapproximately 80% to 95% of cas-es6,34,35 (Figure 3). Recently, the EWSgene has been found to be rear-ranged with still other ETS-likegenes in other cancers, such as clearcell sarcoma (ie, melanoma of softparts [EWS-ATF1]) and desmoplasticsmall round-cell tumor of the abdo-men (EWS-WT1).38,39 Fluorescence insitu hybridization has been reportedto be a more sensitive and reliableancillary technique than reverse-transcription polymerase chain reac-tion for the diagnosis of ESFT informalin-fixed paraffin-embeddedtissue; however, the latter providesadditional information regarding fu-sion transcript subtype and progno-sis.36 These methods are particularlyhelpful in differentiating synovialsarcoma from ESFT because synovialsarcoma usually harbors a well-characterized t(X;18) translocation.1

However, one must be careful, be-cause although the occurrence israre, other tumors (eg, polypheno-typic tumors, rhabdomyosarcomas)have been found to have the EWS-FLI1 transcript.37

Prognosis and PrognosticRisk Factors

It is important to identify the patientat high risk for ESFT and calculatethe prognostic stratification becausedifferent subgroups may require dif-

Ewing sarcoma family of tumorspresent as small round uniformcells with high nucleus-to-cytoplasmic ratio and grow indense, solid sheets (hematoxylin-eosin, original magnification 600).(Courtesy of J. Carlos Manivel,MD, and Michelle Dolan, MD,Minneapolis, MN.)

Figure 1

Strong immunoreactivity for CD99is seen in all tumor cells(immunoperoxidase stain, originalmagnification 600). (Courtesyof J. Carlos Manivel, MD, andMichelle Dolan, MD, Minne-apolis, MN.)

Figure 2

Table 1Chromosomal Translocations in Ewing Sarcoma Family ofTumors6,7,21,34-37

Translocation Gene Fusion Incidence (%)t(11;22)(q24;q12) EWS-FLI1 80-95t(21;22)(q22;q12) EWS-ERG 5-10t(7;22)(p22;q12) EWS-ETV1 Raret(17;22)(q12;q12) EWS-EIAF Raret(2;22)(q33;q12) EWS-FEV Rare



ferent treatment intensities. Al-though the literature differs on theexact impact of individual prognos-tic factors,6,12-15,29 clinically evidentmetastatic disease remains the mostimportant independent prognosticindicator in ESFT. The relative im-portance of tumor site and size as aprognostic factor is diminishing withthe use of modern treatment proto-cols. Recently, analysis of risk factorshas come to include the amount oftumor load (ie, volume, macrome-tastasis pattern, amount of bonemarrow disease by polymerase chainreaction) and the biologic factors (ie,histologic response, gene expression,type of fusion transcript)6,12-15,29 (Ta-ble 2).

Treatment

Most patients with apparently local-ized disease at diagnosis have sub-clinical micrometastatic (ie, systemic)disease; thus, systemic therapy usingmultidrug chemotherapy as well aslocal disease control via surgeryand/or RT is indicated in the treat-ment of all patients (Figure 4). Re-gardless of tumor extent, most pa-

tients receive four to eight cycles ofneoadjuvant chemotherapy.6 There-after, treatment varies based on theeventual resectability of the tumor.With these protocols, event-free sur-vival and overall survival have in-creased to 65% to 82% at 5 years inpatients with localized disease andto 25% to 39% in those with de-tectable metastatic disease atdiagnosis.6,12,17-22,40-45 The correspond-ing 10-year survival rate has been re-ported to be 63% for localized dis-ease and 32% for metastaticdisease.17

ChemotherapyDespite various local control mea-sures, chemotherapy is usually pro-vided both before (ie, neoadjuvant)and after (ie, adjuvant) definitive lo-cal control therapy. The clinical trialsperformed in the past 15 years havebeen undertaken in an attempt to im-prove survival by maximizing thechemotherapy dose per cycle, in-creasing the total number of cyclesprovided, or decreasing the inter-val between cycles (dose-dense ordose intensification therapies)with the addition of granulocyte col-

onystimulating factor. In the UnitedStates, current standard chemothera-peutic agents used include vincris-tine, doxorubicin, and cyclophos-phamide, alternating with ifosfamideand etoposide.22 The mode of admin-istration and dose intensity withincourses differs markedly betweenprotocols. The duration of primarychemotherapy ranges from 6 monthsto approximately 1 year.

Local ControlCurrently, treatment is centered onthe use of neoadjuvant chemother-apy with the goal of eradicating mi-crometastases and reducing the sizeof the primary tumor so as toachieve better tumor demarcationand improve the success of subse-quent local control measures.10 Theprecise indications for local controlin the form of surgical resectionand/or RT are controversial. Thetreatment plan should be individual-ized based on the stage and resect-ability of the tumor.

SurgeryThe role of surgery continues toevolve in the treatment of patientswith ESFT. Careful patient selectionhas led to local failure rates of

viable tumor in the resected speci-men have a worse outcome than pa-tients with complete necrosis. In thethird study of the French Society ofPaediatric Oncology (EW88), event-free survival at 5 years for patientswith 30% viable tu-mor was 75%, 48%, and 20%, re-spectively.46

When surgery is selected, completeresection is required because there isa strong correlation between a posi-tive surgical margin and local recur-

rence.20,54 Patients who are treatedwith adequate margins (ie, wide, rad-ical) have been shown to have better5-year event-free survival than thosewith inadequate margins (ie, intrale-sional, marginal) (58.2% versus46.7%, respectively).54 Overall sur-vival is also better with adequatemargins than with inadequate ones(60.2% versus 40.1%). When posi-tive margins are found, a repeat re-section should be done, when possi-ble. Although the addition of RT hasalso been recommended when resec-

tion margins are microscopicallypositive after an attempted wide ex-cision, planned intralesional debulk-ing procedures followed by RT donot improve local control rates andshould be avoided.40,41

Limb salvage is now possible inmost patients and should be per-formed in cases in which survivalrates are anticipated to be the sameregardless whether amputation isperformed and in cases in which thesalvaged limb is expected to providesatisfactory function with an accept-

Table 2Prognostic Factors for Ewing Sarcoma Family of Tumors6,12-17,20,29,34,40-53

PretreatmentFactor Description

Location Ewing sarcoma family of tumors (ESFT) located in the distal extremities has the best prognosis, followed bythe proximal extremities and then by central or pelvic sites. Cutaneous and subcutaneous lesions tend tohave an indolent course associated with good outcome.

Tumor size andvolume

Tumor size (>8 cm) and volume (>100-200 mL) are adverse prognostic factors. Larger tumors tend to occurin unfavorable sites (eg, pelvis).

Age Patients aged 14 years have the best prognosis of any age group.Sex Females have a better prognosis than males.Laboratory

parametersIncreased serum lactate dehydrogenase levels (LDH >200 IU/L) pretreatment are associated with inferior

prognosis. However, increased LDH levels are correlated with large primary tumors and metastatic disease.Anemia as well as elevated white blood cell counts and erythrocyte sedimentation rate (with constitutionalsymptoms) may indicate extensive disease and poorer prognosis.

Metastases Any metastatic disease is an adverse prognostic factor. Patients with metastatic disease confined to the lunghave a better prognosis than do patients with extrapulmonary metastases (eg, bone, bone marrow). A skipmetastasis in the same bone has a better clinical outcome than does metastasis to another site.

Time to relapse The 5-year survival rate is considerably worse in patients who experience recurrence within 2 years of diag-nosis.

Histopathology Degree of neural differentiation has not been found to be a prognostic factor.Molecular

pathology47-53The EWS-FLI1 translocation associated with ESFT can occur at several potential breakpoints in each of the

genes that join to form the novel segment of DNA. Some variants of the novel gene created by the translo-cation (type 1, EWS exon 7 fused to FLI1 exon 6) have been associated with a more favorable prognosisthan other EWS-FLI1 fusion types independent of tumor size and location. Overexpression of tumor-suppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/neu are associ-ated with poor prognosis in some tumors. The prognosis is better when

Treatment algorithm for Ewing sarcoma family of tumors.6* Consider dose-dense therapy for children (q 2 weeks)IGFR-1 = insulin-like growth factor-1, LDH = lactate dehydrogenase, PET = positron emission tomographyAdapted with permission from Ludwig JA: Ewing sarcoma: Historical perspectives, current state-of-the-art, and opportu-nities for targeted therapy in the future. Curr Opin Oncol 2008;20:412-418.

Figure 4



able risk of complications.55,56 Patho-logic fracture may not preclude sur-gical resection and is not necessarilyassociated with an adverse out-come.10 Conditions for which ampu-tation is likely include extremelylarge tumors involving vital struc-tures, an unmanageable or displacedpathologic fracture, and a lesion inthe ankle or foot. Overall survivalrates are similar whether amputationor limb salvage is performed; in gen-eral, functional outcomes and pa-tient acceptance are better with limbsalvage than with amputation, al-

though complications are more com-mon with limb salvage.55

Many reconstruction options areavailable, including vascularized andnonvascularized autograft reconstruc-tion (eg, fibula, scapula, iliac crest, rib,clavicle), allograft reconstruction,allograft-prosthetic composites, and en-doprosthetic reconstruction, includingexpandable prosthesis, rotationplasty,and amputation.56 The technique se-lected should be tailored to each in-dividual patient (Figures 5 and 6).Because it is usually more durablethan prostheses, biologic precon-

struction is preferable in younger pa-tients. The use of allograft-prostheticcomposites and endoprostheses is ex-pected to increase with continuedimprovement in bioengineering andmetallurgy.

RadiotherapyRT traditionally has been used forlocal disease control in patients withESFT.18,19,57,58 Radiation for local con-trol is recommended for unresectabletumors and when there is a low like-lihood that adequate surgical mar-gins can be achieved. RT may also

A 27-year-old woman presented with pain and an enlarging mass in her right groin region. A, AP radiographdemonstrating a large soft-tissue shadow in the right lower pelvis with marked destruction of the superior and inferiorpubic rami. B, Coronal MRI (TR 5220, TE 44) confirming the presence of a 14.6 12.1 11.0-cm heterogeneousmass with osseous destruction of the entire right superior and inferior pubic rami with involvement of the ischium andextension into the true pelvis and the adductor compartment. C, Coronal F-18 fluorodeoxyglucose positron emissiontomography (FDG-PET) CT scan showing the hypermetabolic mass with a standard uptake value of 8.8. Biopsyconfirmed the diagnosis of Ewing sarcoma, and the patient underwent four cycles of neoadjuvant chemotherapy.D, Coronal MRI (TR 5910, TE 38) study demonstrating a substantial reduction in tumor volume. E, Coronal F-18 FDG-PET CT scan demonstrating minimal hypermetabolic activity. F, AP radiograph following wide local excision of thetumor and reconstruction using an allograft-prosthetic composite. The patient was disease-free at 30-month follow-up,after completing adjuvant chemotherapy.

Figure 5



have a role in improving local dis-ease control in patients with poorchemotherapeutic response.The recommended doses in various

clinical situations have been recentlysummarized in a retrospective reviewof large-group experiences.57 The ir-radiation treatment field should in-

clude the pretreatment tumor volumeplus an adequate margin. A coned-down boost is then administered tothe postinduction chemotherapy vol-ume, also with an adequate margin.Most local treatment failures follow-ing RT alone are within the radiatedfield; thus, a 2- to 3-cm margin be-yond the affected area is usually con-sidered adequate. The dose for localcontrol using radiation alone is 55.8to 60.0 Gy. Typically, 45 Gy is ad-ministered, followed by a boost of10.8 Gy. No adjuvant radiation isnecessary in the setting of adequatemargins and a good histologic re-sponse to prior chemotherapy. Nodifference has been found in overallsurvival regardless whether standardwhole-bone radiation or RT of theinvolved field only is performed.19

Similarly, standard fractionation(180 to 200 cGy/d, 5 days a week) isas effective as hyperfractionation(120 to 160 cGy twice daily); how-ever, hyperfractionation has been re-ported to cause less late toxicity.58

With the increase in long-term sur-vival rates as a result of modern chemo-therapy, the problems of late localrecurrence, functional impairment sec-ondary to radiation complications, andradiation-induced sarcomas have be-come more apparent.59 Radiation-related complications have been re-ported in up to 63% of patients andare most pronounced in skeletallyimmature patients.59 These complica-tions include limb-length discrep-ancy, joint contracture, muscle at-rophy, pathologic fracture, andsecondary malignancies.

Surgery VersusRadiotherapyTraditionally, ES has been treated withchemotherapy and radiation, with re-section reserved for expendablebones.8 Advancements in imagingtechnology and technique have led tobetter planning for both resection

Attempted frog leg view radiograph (A) and axial MRI (TR 2500, TE 70) scan(B) demonstrating cortical involvement with a sunburst type periostealreaction and an associated large soft-tissue mass in the proximalmetadiaphyseal region of the femur in a 15-year-old boy who presented withleft hip pain. Ewing sarcoma was confirmed on biopsy and treatment withneoadjuvant chemotherapy, and the patient underwent wide local resectionand reconstruction using an allograft-prosthetic composite. C and D, APradiographs obtained at 15-year follow-up demonstrating a stable, well-aligned hemiarthroplasty component with a well-healed grafthost bonejunction (arrow in panel D). (Panels A and C reproduced from Ewingssarcoma. Your Orthopaedic Connection. Rosemont, IL, American Academy ofOrthopaedic Surgeons. Available at: http://orthoinfo.aaos.org/topic.cfm?topic=A00082. Accessed September 22, 2009.)

Figure 6



and RT. Many protocols have dem-onstrated superior local control andsurvival with surgery with or with-out RT compared with RT alone(5% to 10% versus 35% local recur-rence).10,12,14,40,49,60,61 One possibleexplanation for the increased sur-vival rate is that tumor resectioneliminates residual clones of chemo-therapy-resistant cells before theyhave a chance to recur locally or tometastasize.10 Selection bias for per-forming surgery on smaller and moresurgically resectable tumors may ex-plain these more favorable results.Conversely, other studies of modernchemotherapy protocols have notedno difference in survival or local fail-ure based on treatment protocol, ra-diation dose, or surgery.62,63

Thus, the question whether to per-form surgery or RT for local controlcannot be answered with confidence.Only level III and IV evidence isavailable, and there is known selec-tion bias in that resectable lesionstend to be operated on. A level I ran-domized trial comparing the twotreatments is not feasible practically;thus, a level II individual compara-tive study will likely be the only andbest evidence possible to answer thisquestion. The trends, however, favorsurgical resection in all cases inwhich the surgeon believes that theprimary tumor can be removedcompletely, particularly in expend-able or surgically reconstructiblesites.10,12,14,40,49,60,61 RT is still used fortumors in anatomic sites in whichwide resection cannot be done, whenthe functional deficit is unacceptableto the patient, when an attempted re-section has unacceptable margins,and when the chemotherapeutic re-sponse has been poor.10

High-dose ChemotherapyWith Stem Cell RescueHigh-dose chemotherapywith hemato-poietic stem cell transplant (HSCT) has

been developed to treat patients at highrisk of relapse following conventionaltreatment. However, the results withthis therapy are difficult to evaluatein the absence of large randomizedtrials with heterogeneous patientgroups.64,65 In one recent study, 33patients with recurrent or progres-sive ES were treated with high-dosechemotherapy and HSCT with andwithout total-body irradiation.64 The2- and 5-year event-free survivalrates were 42.5% and 38.2%, re-spectively. In another study, Meyerset al65 reported 2-year event-free sur-vival to be 20% and concluded thatconsolidation with total-body irradi-ation and high-dose chemotherapywith HSCT did not significantly im-prove survival in patients with ESmetastasized to bone and bone mar-row. Results are often superior forpatients with isolated lung metasta-ses than in those with bone and bonemarrow disease and those with lung,bone, and bone marrow disease. Re-lapse and regimen-related toxicity re-main the main obstacles to success.

Metastatic Ewing SarcomaES has a strong potential to metasta-size. In the SEER study, 26% to 28%of patients presented with distantmacrometastasis.17 More than 10%of patients present with multiplebone metastases at initial diagnosis.10

Although metastases in the lungs,bone, bone marrow, or a combina-tion thereof are detectable in approx-imately 25% of patients, metastasesto lymph nodes, the liver, and thebrain are rare.17,66

Despite advances in the treatmentof localized ES, the prognosis for pa-tients with detectable metastatic dis-ease remains poorer than apparentlylocalized disease.17,67 Standard che-motherapy combined with adequatelocal control measures applied to pri-mary and metastatic sites may resultin complete or partial responses;

however, the 8-year event-free sur-vival is approximately 20%, and theoverall cure rate is 14% to 28%.67 Acure rate of 32% was reported forpatients with lung/pleural metastasesonly. A worse outcome was reportedwithout lung radiation than with it.Patients with only bone/bone mar-row metastases were reported tohave an approximate 20% to 25%cure rate. Patients with combinedlung and bone/bone marrow metas-tases had a cure rate of

curring after 5 years.42,43 Moreover,very few patients who relapse laterthan 5 years after initial diagnosisare salvageable. The prognosis forpatients who relapse >2 years follow-ing completion of primary therapy isbetter than for patients who relapsewhile on their initial chemotherapyregimen or within 2 years of com-pleting primary therapy.13,42,43

The selection of further treatmentdepends on many factors, includingthe site of recurrence and prior treat-ment, as well as individual patientconsiderations. RT to bone lesionsmay provide a palliative effect,whereas radical resection may im-prove outcome.13 Patients with pul-monary metastases should undergowhole-lung irradiation.13 Residualdisease in the lung may be surgicallyremoved. Ifosfamide and etoposideshould be considered for patientswho have not previously receivedthese agents. Second-line drugs suchas topotecan, irinotecan, busulfan,melphalan, thiotepa, and temozolo-mide have also been shown toachieve responses.6,10,64,69 Aggressiveattempts to control the disease, in-cluding myeloablative regimens, maybe warranted.68

Second MalignantNeoplasmsPatients treated for ES show a trend to-ward a higher risk of developing secondmalignancies than do persons in thegeneral population. Treatment-relatedacute myeloid leukemia andmyelodys-plastic syndrome have been reported tooccur in 1% to 2% of survivors of ES,and some dose-intensive regimens ap-pear to be associated with a higher riskof hematologic malignancy.69-73 Treat-ment-related acute myeloid leukemiaand myelodysplastic syndrome arisemost commonly at 2 to 5 years fol-lowing diagnosis. The risk of devel-oping solid tumors appears to begreatest in patients treated with RT,

and sarcomas usually occur withinthe prior radiation field.70,72

The cumulative risk of developinga bone sarcoma following treatmentfor ES is estimated to be 20% at 20years.9 Of the 397 patients with EStreated at the Mayo Clinic during a25-year period, 26 (6.5%) developed29 secondary malignancies: 12 sar-comas, 8 hematologic malignancies,and 9 carcinomas.72 The authors at-tributed sarcoma to RT and hemato-logic malignancy to chemotherapy.The mean latent period for the devel-opment of sarcoma was 10.9 years(range, 1.5 to 32.5 years) and for he-matologic malignancy, 4.8 years(range, 1.7 to 12.9 years). The prog-nosis with carcinoma was better thanwith either sarcoma or hematologicmalignancy. A similar prevalence hasbeen reported by Kuttesch et al,70

who found a 6.5% incidence of sec-ondary sarcoma within the irradi-ated field in ES patients at 20-yearfollow-up. The incidence was dose-dependent; patients who received60 Gy had a 20% incidence of sec-ond malignancy. Those who receiveda dose of 48 to 60 Gy had an inci-dence of 5%, and those who receiveda dose of

ESFT may lead to the successful de-velopment of biologically targetedtherapies. As our understanding ofthe regulatory pathway responsiblefor ESFT transformation, growth,and metastasis becomes more re-fined, the number of potential thera-peutic targets will expand in parallel.

Acknowledgment

The authors would like to thank J.Carlos Manivel, MD, and MichelleDolan, MD, Department of Labora-tory Medicine and Pathology, Uni-versity of Minnesota, Minneapolis,Minnesota, for providing the histo-pathologic slides as well as the kary-otype and fluorescence in situ hy-bridization images used in thisarticle.

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