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PEDIATRIC ONCOLOGY
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THE EWING FAMILY OF TUMORS Ewing’s Sarcoma and Primitive Neuroectodermal Tumors Holcombe E. Grier, MD
The Ewing family of tumors (Ewing’s sarcoma and primitive neuroectoderma1 tumor [PNET]) is the second most common malignant bone tumor (after osteogenic sarcoma) in children and adolescents. These tumors can also occur in soft tissue, presenting in a manner similar to rhabdomyosarcoma. Nearly half of all patients with Ewing’s family tumors are between 10 and 20 years of age, and 70% are under the age of 20, with a slight male predominance. The annual incidence in the United States is 2.1 cases per million children.81A similar incidence of these tumors occurs throughout the world in countries composed mostly of whites or persons of Hispanic origin; however, these tumors are extremely rare in black children and children of Asian rigi in.'^,^ The reason for this striking difference in incidence according to racial background is unknown. Ewing’s tumor was originally described in 1921 by James Ewing as an endotheli0ma.I4 Over the past decade it has become clear that Ewing’s sarcoma, in fact, derives from a primitive neuroectodermal cell with variable differentiation. Classical Ewing’s sarcoma is a poorly differentiated small round blue cell tumor, whereas, on the other end of the scale, PNET shows quite discernible differentiation. Both share the same histochemical staining profile and a unique characteristic translocation t(11;22) or a variation of the same within the tumor cell. Virtually all Ewing’s tumors contain the chromosomal marker.
CAUSE The cause of Ewing’s sarcoma is unknown. Radiation exposure does not appear to be a common cause of Ewing‘s sarcoma. For example, no increased
From the Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston; and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
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incidence occurred after exposure to nuclear fallout in Japan8”The tumor may occur after prior treatment for cancer, including radiotherapyi3; however, the incidence is quite low. In a large study of secondary bone tumors after radiotherapy, 69% of the tumors were osteosarcoma, whereas only 3% were Ewing’s sarcoma.7” Ewing’s sarcoma does not appear to be inherited. The disease has been reported in siblings, but may be a chance i n c i d e n ~ e . ~ In ~ , general, the Ewing family of tumors is not associated with familial cancer syndromes. One study noted an increased risk of neuroectodermal tumors and stomach cancer in relatives of patients with Ewing’s however, this has not yet been confirmed. Most striking, as previously noted, is the extreme rarity of the Ewing family of tumor in Asians and blacks. MOLECULAR GENETICS
Nearly all Ewing’s sarcomas and PNET have a clonal translocation seen in the malignant cells. By far, the most common translocation is between the long arms of chromosomes 11 and 22. This translocation can be found by standard cytogenetics in over 80% of the Ewing family of tumors, and is seen using molecular techniques in over 90‘X.’*, 76, 7‘’ The break point of this common translocation has been cloned; the rearrangement occurs within the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11 (Fig. 1).I0 FLI-1 is a member of the ETS family of transcription factors. These factors encode for transcription activators that bind directly to DNA. The EWS gene is less well
t( 11;22)
EWS-FLI 1
Chr 11
FLI 1
Chr 22
EWS
Chr 21
ERG
t(21;22)
EWS-ERG
Figure 1. The Ewing’s sarcoma (EWS) gene on chromosome 22 contains a putative RNA binding domain. This domain is lost when the gene combines with the ETS-like genes on either chromosome 11 (the most common translocation site in the Ewing family of tumors, where it recombines with the FLI-1 gene) or chromosome 21 (the ERG gene). The recombined genes shown on the top for t(11;22) and on the bottom for t(21;22) retain the DNA binding portion of the ETS-like oncogenes while coming under the control of the EWS promotor.
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characterized but appears to have an RNA binding area. The fusion gene juxtaposes the 5’ sequences of the EWS gene with the 3’ sequences of the FLI-1 gene. The new gene retains the DNA binding of FLI-1 but appears to be under the regulation of the promoters of the EWS gene. The resultant gene can transform NIH 3T3 cells, the classical test for a dominant oncogene.39 The t(11;22) translocation is the most common translocation in Ewing’s sarcoma. The next most common translocation, t(21;22), recombines the EWS A gene on 22 with another ETS-like gene, ERG, on chromosome 21 (Fig. l).b5 third quite rare rearrangement, t(7;22), fuses ETV-1 with EWS2*Recently, the EWS gene has been found to be rearranged with still other ETS-like genes in two other cancers, clear cell sarcoma (also known as melanoma of soft parts) and desmoplastic small round cell tumor of the abdomen (Table l).,, 84 The exact rearrangements within the common t(11;22) and t(21;22) are somewhat variable. The type of rearrangement does not appear to correlate with presenting features but may be of prognostic ~ignificance.~~ Molecular assays are now being used more and more to diagnose Ewing‘s sarcoma and PNET. The reverse transcriptase polymerase chain reaction (RTPCR) assay can be used to look for the translocation within tumor tissue even if more traditional cytogenetics are unsuccessful. Using these techniques, undifferentiated sarcomas can be found to contain a typical Ewing family tran~location.~ One must be careful, because other tumors rarely have been found to have the EWS/FLI-1 transcript.“ 71 A multiplex PCR technique can look at the typical translocation in alveolar rhabdomyosarcoma and the t(11;22) Ewing’s abnormality simultaneously.I2The RT-PCR technique is quite sensitive and can find tumor cells admixed with normal cells at a level well below that detectable by light microscopy. The RT-PCR assay has allowed investigators to find low levels of tumor cells in the bone marrow and even in the blood of patients at diagnosis and during therapy. It is quite clear that the presence of the abnormal transcript is variable among patients at presentation, and prospective trials are looking at the prognostic significance of this ~ariability.~~, 72, 77 PATHOLOGY
Ewing’s sarcoma and PNET belong to the group of neoplasms commonly referred to as small round cell tumors. These include neuroblastoma, rhabdomyosarcoma, and non-Hodgkin’s lymphoma. The differentiation of Ewing’s tumor from the other entities may occasionally be difficult, especially in the soft tissue variants.74The individual cells in Ewing’s sarcoma are round, of moderate size, have clear and frequently quite scant cytoplasm, and round to oval nucleus. Small to moderate areas of necrosis may be present; in addition, dense pyknotic
Table 1. REARRANGEMENTS OF EWS GENE IN HUMAN CANCER Tumor
Ewing’s sarcoma Clear cell sarcoma Desmoplastic small round cell tumor of the abdomen
Rearrangement
ETS Gene Involved
t (11;22)
FLI-1
t (21;22)
ERG
t (7;22) t (10;22) t (1 1;22)
ETV-1 ATF-1 WT-1
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cells indicating apoptosis are often present. Calcification is rare. Classical Ewing’s sarcoma cells are frequently positive for glycogen. Occasionally, the cells in Ewing’s sarcoma can be larger than are those of the typical There is considerable neuroectodermal differentiation in the PNET variant of the Ewing family of t u m o r ~This . ~ differentiation is noted by neural stains (e.g., 5100, neuron-specific enolase) or the presence of rosettes or neural elements on electron microscopy. It remains controversial whether neuroectodermal differentiation predicts a different outcome than does standard histology.21,54, 63, 70 Cell surface staining for the protein product of the pseudo-autosomal gene MIC2 has been particularly helpful in the differentiation of the Ewing family of tumors from other small round cell tumors. The MIC2 protein product is a ubiquitous cellular component but is usually seen in high quantities only in T cells and the Ewing family cells. Two monoclonal antibodies (12E7 and HBA-71, now designated CD99) have been developed and are sometimes referred to as ”Ewing’s 50,58
CLINICAL PRESENTATION
Pain or swelling, or both, at the site of the primary tumor are, by far, the most common presenting symptoms in Ewing’s sarcoma-PNET of bone and soft tissue. Unlike osteosarcoma, patients with Ewing’s sarcoma may also present with systemic signs and symptoms such as weight loss, fever, and increased sedimentation rate. Systemic signs are more common in patients presenting with meta~tases.5~ The presence of systemic symptoms often brings osteomyelitis into the differential diagnosis of patients at the presentation of Ewing’s sarcoma. The proportions of various symptoms at diagnosis as compiled by Green,Is from 10 different series are shown in Table 2. These symptoms may be present for months before medical attention is sought. A delay between the first symptoms and diagnosis is quite common in Ewing’s sarcoma, with one study finding that 50% of patients had symptoms for over 6 months before the tumor was This is particularly true oLpelvic tumors in which the mass is not palpable until it is quite large, if ever. Ewing’s sarcoma-PNET can develop in almost any bone in the body. Unlike osteosarcoma in which long bones are predominantly involved, flat and long bones are about equally represented in the Ewing family of tumors. Table 3 presents the primary sites for over 300 patients treated in the first Intergroup Ewing’s Sarcoma Study (IESS). The pelvic bones as a group are followed by the femur and then the tibia and humerus in frequency of tumor site.32In long bones, Ewing’s sarcoma usually begins in the midshaft, rather than the ends as in osteosarcoma. Plain radiographs tend to show a lytic or mixed lytic and sclerotic lesion (Fig. 2). The classical radiologic appearance of Ewing’s sarcoma is called onion skinning. This effect is caused by parallel laminated periostial formation where the tumor has continued to grow through the reparative attempts of the bone. Soft tissue masses are common in Ewing’s sarcoma, although Table 2. SYMPTOMS AT DIAGNOSIS OF EWING’S SARCOMA OF BONE Local pain Local swelling Fever Paraplegia
84%
63% 28% 3%
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Table 3. DISTRIBUTION OF PRIMARY SITE FOR 303 PATIENTS WITH EWINGS SARCOMA OF BONE Primary Site Pelvic Ilium Sacrum lschium Pubis Lower extremity Femur Fibula Tibia Feet Upper extremity Humerus Forearm Hand Axial Skeletonkibs Face
Figure 2. A Ewing’s sarcoma of the distal fibula with the cIassic permeative bone destruction and laminated elevation of the periosteum (“onion skinning”).
Percent 20 12.5 3.3 3.3 1.7 45.6 20.8 12.2 10.6 2.0 12.9 10.6 2.0 0.3 12.9 2.3
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occasionally a patient may have a large extent of bone involved with minimal mass even on CT scan or MR imaging. MR imaging is clearly the most sensitive technique to show the extent of the tumor in soft tissue and intramedullary extension (Fig. 3)?,25The soft tissue tumor can be quite massive, especially in pelvic primary tumors (Fig. 2). Soft tissue Ewing’s sarcoma-PNET often occurs
Figure 3. Ewing’s sarcoma may present with large masses, particularly when the primary tumor is in the pelvis. Shown here are M R imaging scans of a tumor involving the ischium and pubic bones. A, The dark marrow space on the involved side on this T1-weighted study is contrasted with the lighter marrow signal caused by normal fat on the opposite side. 8, An axial TP-weighted MR imaging view of the tumor shows a bright signal outlining the extensive nature of the tumor.
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near bones and may be difficult to differentiate from primary tumors in bone in some cases. This is particularly true in the chest wall in which the ribs may be the primary site or may be secondarily involved with large masses. The percentage of patients presenting with metastases varies from series to series, but averages about 25Y0.l~Sites of metastases include the lung (approximately half of patients), bone (approximately a quarter), and bone marrow (approximately a fifth).- Metastases to other sites, including the central nervous system are rare except late after relapse. Patients may occasionally present with symptoms from metastatic sites rather than pain at the primary site. STAGING AND PROGNOSIS The staging workup for Ewing’s sarcoma is based on proper imaging of the primary tumor and sites of likely metastases: plain films and MR imaging of the primary site, chest radiographs and CT scan of the lung, bone scan, and bone marrow biopsy. Laboratory studies should include a complete blood count, an erythrocyte sedimentation rate (increased in up to 50% of patients), and baseline chemistries. The tumor biopsy should be done at a center with facilities to provide immunohistochemistry, solid tumor cytogenetics, and other molecular diagnostic techniques. In addition, the biopsy specimen should be taken from a location that will not compromise later surgery or radiotherapy. Needle biopsy can be done while still performing the necessary molecular and immunologic ~ o r k u pNo . ~ widely ~ accepted staging system for Ewing’s sarcoma exists. Prognosis clearly varies with the presence or absence of metastases, and with tumor size. Although the site of the primary tumor has been found to be prognostic, the poorer outcome of pelvic tumors may have more to do with their usual size than with their location. When multivariate analysis was used in a large European trial, location was not a significant factor when size was taken into account.62Table 4 lists prognostic factors found in several Ewing’s tumor trials; many of these overlap. THERAPY
Treatment of Ewing’s sarcoma requires eradication of the tumor at both its presenting site (local control) and the sites of metastatic or micrometastatic Table 4. PROGNOSTIC FACTORS IN EWING’S SARCOMA Prognostic Factors
Negative Factors: Metastases at diagnosis Over 8 cm in longest diameter Large tumor volume Pelvic location High LDH levels Over 17 years of age Neuroectodermal differentiation (controversial) Positive Factors: Good radiologic response to induction chemotherapy Good pathologic response to induction chemotherapy
References
Seen in many studies 23 62
Seen in many studies 17, 60
19,20 21,63, 70 46, 47,52,
8,30,46,66
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disease. Nearly all patients with Ewing's sarcoma have micrometastatic disease (i.e., tumor cells outside the primary site that cannot be detected by standard methods) at the time of diagnosis. This is evidenced by a cure rate of less than 10% when Ewing's sarcoma is treated with radiotherapy or surgery to the local site In addition, as mentioned previously, tumor cells now can be detected, using the sensitive RT-PCR assay, in the bone marrow and blood of patients who are classified as nonmetastatic by conventional tumor-detection methods?', 72, Control of the Primary Tumor
Local control in Ewing's sarcoma is usually attempted with surgery, radiotherapy, or a combination of both to the primary tumor. Local control should almost always be deferred until after initial chemotherapy, allowing for better consideration of surgical options after the tumor volume has been reduced. Tumor control with radiotherapy requires moderately high doses. Standard practices require doses ranging from 5500 to 6000 c G Y . ~ Traditionally, ~ the volume of radiotherapy was to the whole bone; however, a Pediatric Oncology Group (POG) study demonstrated no difference in local control when a volume including the initial tumor extent with an additional 2-cm margin was compared with whole bone radiotherapy." Chemotherapy has improved local control rates in Ewing's sarcoma.2,49, 69 However, attempts to lower radiotherapy doses for tumors that had marked reduction in soft tissue masses from induction chemotherapy led to a higher than expected local failure rate.23 Surgery is an effective way to treat Ewing's sarcoma. The problem with this modality is the morbidity of removing these sometimes very large tumors which often occur in important functional areas. Surgery is clearly indicated in certain circumstances; however, clavicles, ribs, and fibulae, for instance, can sometimes be removed without significant functional loss if the concomitant soft tissue mass is small. The most ipportant factor in choosing local control in Ewing's sarcoma is eradication of the cancer. Several authors have argued from retrospective analyses of patients that surgery improves overall survival in Ewing's and Not all such analyses have agreed with this concl~sion,~~, @ 56, , sarc0ma.3~, nearly all of the studies are biased by a tendency for tumors treated with surgery to be smaller than are those treated with radiotherapy. In one study, the influence of surgery could be explained by size differences using multivariate ana1y~is.I~ Unfortunately, the question has not been subjected to randomized clinical trials and, considering the difficulty of such trials, may never be. Because whether surgery improves survival remains controversial, late effects must also be considered in choosing a local control modality. These late effects include function, appearance, and, most importantly, occurrence of second tumors. The incidence of bone tumors in the irradiated field has varied somewhat from study to study, with estimates ranging from 10% to 30% at 20 years after therapy.?l, 67, 75 However, because the incidence of second bone tumors is likely to be much less if radiation therapy is not used, at our institution we often use surgery if the likelihood is high that the tumor can be completely removed and the function after the resection is predicted to be reasonable.
Chemotherapy The poor outcome with radiotherapy or surgery alone led investigators in the 1960s and 1970s to initiate trials of adjuvant chemotherapy, with lower
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failure rates than had been seen historically.’6, 27, 55 These studies used some combination of vincristine, dactinomycin, and cyclophosphamide (VAC). The IESS begun in the early 1970s demonstrated that the addition of doxorubicin to VAC (albeit with the resulting therapy having a higher dose intensity) improved outcome compared with VAC alone. Interestingly, VAC with prophylactic whole lung radiotherapy had an intermediate outcome compared with VAC alone and VAC with doxorubicin.“ In contrast, a review of the Intergroup Rhabdomyosarcoma Group experience with extraosseous Ewing’s sarcoma did not show an improvement for patients with unresectable disease who received doxorubicin when compared with those who received VAC alone.59This result must be interpreted with caution, however, because since the time these studies were done the classification of soft tissue sarcomas including extraosseous Ewing’s and rhabdomyosarcoma has become more precise using immunohistochemistry, solid tumor cytogenetics, and molecular biologic techniques. About two thirds of these patients with unresectable tumors survive long term, a finding similar to that of unresectable rhabdomyosarcoma in general. A second study done by the IESS, in this case for the group of patients with localized disease excluding pelvic lesions, showed that intensified therapy improved overall results.6 Most other trials of Ewing’s sarcoma have not been randomized; in general, a combination of vincristine, doxorubicin, cyclophosphamide, and dactinomycin produces 5-year event-free survival rates of 50% to 60% for patients presenting without metastases. One must acknowledge that the 5-year survival is not the end of the story because these patients are at risk for late relapse or second tumors.lh,z2, 31 The high response rate of patients with relapsed Ewing’s sarcoma to ifosfamide with or without e t o p ~ s i d e ~ has ~ , ~prompted ~,~’ several groups to add one or both of these agents during the initial therapy for patients presenting without metastases. Results of single arm studies with historical controls have been somewhat confusing. A French study showed no improvement with the addition of ifosfamide and noted increased cardiac toxicity.16 A German study that added ifosfamide to the therapy for high-risk patients showed an improvement for that group compared with historic controls.30Investigators at the National Cancer Institute had similar results when they added ifosfamide and etoposide to a standard regimen.78The Children’s Cancer Group (CCG) and the POG performed a randomized trial comparing a standard treatment of vincristine, doxorubicin, cyclophosphamide, and dactinomycin to an experimental treatment in which patients received the same drugs alternating with ifosfamide and etoposide. At 5 years the event-free survival rate for patients with nonmetatastatic disease on the standard arm was 52% compared with 68% for the patients treated with ifosfamide and etoposide, a highly statistically significant result.19,’” Currently, a combined CCG-POG trial is comparing the previous experimental therapy with a treatment program that intensifies the alkylating agents. The results for patients presenting with metastases has lagged behind that for patients without; most studies show a 5-year event-free survival rate of approximately 25%.’ The addition of ifosfamide and etoposide has not appeared 78 This outcome to improve the outcome for this group of high-risk has led some investigators to use megatherapy with stem-cell rescue in patients with Ewing’s sarcoma metastatic at presentation or in those who develop metastases while on therapy. Two European groups have reported an excellent outcome (>40% event-free survival) with this technique; the German study, in particular, is impressive because the therapy was limited to patients with a very poor p r o g n o s i ~ .However, ~,~ the results from the European BMT (Bone Marrow Transplant) Solid Tumour Registry were quite disappointing and were not
clearly different from those of standard chemotherapy.3sThe efficacy of megatherapy in Ewing‘s sarcoma is not yet clear. Treatment after relapse is extremely difficult in Ewing’s sarcoma if the patient has relapsed while on therapy. Megatherapy is being tried for these patients, as noted previously. Late relapses are not uncommon in Ewing’s sarcoma; however, for these patients retreatment with intensive chemotherapy may produce some long-term survivors.Z2As noted previously, the occurrence of second malignancy is a particularly disturbing phenomenon in Ewing’s sarcoma. These tumors are usually osteogenic sarcoma and occur in the irradiated bone with an incidence that may be as high as 30%.33,67, 75 SUMMARY
There has been an explosion of new knowledge regarding the Ewing family of tumors over the past 5 to 10 years. Classical Ewing’s sarcoma and PNET are now known to be the same tumor with variable differentiation, defined by a translocation between the EWS gene on chromosome 22 with one of three ETSlike genes, especially the FLI-1 gene on chromosome 11. Molecular techniques used to identify this translocation along with the knowledge that the protein product of the MIC2 gene is highly expressed on the cell surface have greatly improved our diagnostic abilities in this family of tumors. Controversy still exists as to whether surgery improves event-free survival when compared with radiotherapy in Ewing‘s sarcoma. The high second tumor rate, if nothing else, has started moving many physicians to preferentially use surgery when the functional results are predicted to be reasonable. The addition of ifosfamide and etoposide to standard therapy in Ewing’s sarcoma has improved survival for patients without metastases at presentation. However, outcome for patients with metastases or who develop metastases while on therapy or shortly thereafter remains poor. Prelimin.ary reports of better outcome with megatherapy are interesting but not yet definitive. The decades ahead will probably see marked changes in therapy for Ewing‘s sarcoma. The unique translocation seen in virtually all of these tumors is a potential target for a ”magic bullet” therapy, because the protein product of this translocation is present only in the malignant cells. Hopefully either immune modulation against this unique protein or further knowledge of how to use antisense genes will move us toward exquisitely targeted therapy in the Ewing family of tumors. References 1. Ambrose IM, Ambrose PF, Strehl S, et al: MIC2 is a specific marker for Ewing’s sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing’s sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 671886, 1991 2. Bacci G, Picci P, Gitelis S, et al: The treatment of localized Ewing’s sarcoma: The experience at the Istituto Ortopedico Rizzoli in 163 cases treated with and without adjuvant chemotherapy. Cancer 49:1561, 1982 3. Barr FG, Chatten J, DCruz CM, et al: Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 273:553, 1995 4. Boyko OB, Cory DA, Cohen MD, et al: MR imaging of osteogenic and Ewing’s sarcoma. Am J Radio1 148:317, 1987
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5. Burdach S, Jurgens H, Peters C, et al: Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing’s sarcoma. J Clin Oncol 11:1482, 1993 6. Burgert OE, Nesbitt ME, Gamsey LA, et al: Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: Intergroup study IESS-11. J Clin Oncol 8:1514, 1990 7. Cangir A, Vietti TJ, Gehan EA, et al: Ewing’s sarcoma metastatic at diagnosis: Results and comparisons of two intergroup Ewing‘s sarcoma studies. Cancer 66887, 1991 8. de Stefani E, Carzoglio J, Deneo Pellegrini H, et al: Ewing’s sarcoma: Value of tumor necrosis as a predictive factor. Bull Cancer 71:16, 1984 9. Dehner LP: Neuroepithelioma (primitive neuroectodermal tumor) and Ewing‘s sarcoma: At least a partial consensus. Arch Pathol Lab Med 118:606, 1994 10. Delattre 0, Zucman J, Melot T, et al: The Ewing family of tumors: A subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:294, 1994 11. Donaldson SS, et al: Tailored radiotherapy for the treatment of Ewing’s sarcoma of bone. Proc Am Soc Ther Radiol Oncol, in press 12. Downing JR, Khandekar A, Shurtleff SA, et al: Multiplex RT-PCR assay for the differential diagnosis of alveolar rhabdomyosarcoma and Ewing’s sarcoma. Am J Pathol 146:626, 1995 13. Dunst J, Jurgens 13, Sauer R, et al: Radiation therapy in Ewing’s sarcoma: An update of the CESS 86 Trial. Int J Radiat Oncol Biol Phys 32:919, 1995 14. Ewing J: Diffuse endothelioma of bone. Proc New York Path Soc 21:17, 1921. Reprinted in Clin Orthop Re1 Res 185:2, 1984 15. Fraumeni JF, Glass AG: Rarity of Ewing’s sarcoma among U S . negro children. Lancet 1:366, 1981 16. Gasparini M, Lombardi F, Ballerini E, et al: Long-term outcome of patients with monostotic Ewing’s sarcoma treated with combined modality. Med Pediatr Oncol 23:406, 1994 17. Gobel V, Jurgens H, Etspuler G, et al: Prognostic significance of tumor volume in localized Ewing’s sarcoma of bone in children and adolescents. Cancer Res Clin Oncol 113:187, 1987 18. Green DM: Diagnosis and Management of Malignant Solid Tumors in Infants and Children. Boston, Martinus Nijhoff Publishing, 1985 19. Grier H, Krailo M, Link M, et al: Improved outcome in non-metastatic Ewing’s sarcoma and PNET of bone with the addition of ifosfamide and etoposide to vincristine, adriamycin, cyclophosphamide, and actinomycin: A Children’s Cancer Group and Pediatric Oncology Group report. Proc Am Soc Clin Oncol 13:421, 1994 20. Grier H, Krailo M, Tarbell N, et al: Adding ifosfamide and etoposide to vincristine, cyclophosphamide, adriamycin, and actinomycin improves outcome in non-metastatic Ewing’s and PNET Update of CCG/POG study. Med Pediatr Oncol27259, 1996 21. Hartman KR, Triche TJ, Miser JS: Prognostic value of histopathology in Ewing’s sarcoma: Long term follow-up of distal extremity primary tumors. Cancer 67163, 1991 22. Hayes FA, Thompson EI, Kumar M, et al: Long-term survival in patients with Ewing’s sarcoma relapsing after completing therapy. Med Pediatr Oncol 15:254, 1987 23. Hayes FA, Thompson EI, Meyer WH, et al: Therapy for localized Ewing’s sarcoma of bone. J Clin Oncol 7208, 1989 24. Hoffer FA, Gianturco LE, Fletcher JA, et al: Percutaneous biopsy of peripheral primitive neuroectodermal tumors and Ewing’s sarcomas for cytogenetic analysis. AJR Am J Roentgen01 162:1141, 1994 25. Hudson TM, Hamlin DJ, Enneking WF, et al: Magnetic resonance imaging of bone and soft tissue tumors: Early experience in 31 patients compared with computed tomography. Skeletal Radiol 13:134, 1985 26. Hustu HO, Pinkel D, Pratt CB: Treatment of clinically localized Ewing‘s sarcoma with radiotherapy and combination therapy. Cancer 30:1522, 1972 27. Jaffe R, Santamaria M, Yunis EJ, et al: The neuroectodermal tumor of bone. Am J Surg Pathol 8:885, 1984 28. Jeon IS, Davis JN, Braun BS, et al: A variant Ewing’s sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene 10:1229,1995
29. Joyce MJ, Harmon DC,Mankin HJ, et al: Ewing’s sarcoma in female siblings. A clinical report and review of the literature. Cancer 53:1959, 1984 30. Jurgens H, Exner U, Kuhl J, et al: High-dose ifosfamide with mesna uroprotection in Ewing’s sarcoma. Cancer Chemother Pharmaco124(suppl):40, 1989 31. Kinsella TJ, Miser JS, Waller B, et al: Long-term follow-up of Ewing’s sarcoma of bone treated with combined modality therapy. Int J Radiat Oncol Biol Phys 20:389, 1991 32. Kissane Jh4,Askin FB, Foulkes M, et al: Ewing’s sarcoma of bone: Clinicopathologic aspects of 303 cases from the Intergroup Ewing’s Sarcoma Study. Hum Pathol 14:773, 1983 33. Kuttesch JF, Jr, Wexler LH, Marcus RB, et al: Second malignancies after Ewing’s sarcoma: Radiation dose-dependency of secondary sarcomas. J Clin Oncol14:2818,1996 34. Ladanyi M, Gerald W: Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Canc Res 542837, 1994 35. Ladenstein R, Lasset C, Pinkerton R, et al: Impact of megatherapy in children with high-risk Ewing’s tumours in complete remission: A report from the EBMT Solid Tumour Registry. Bone Mar Trans 15:697, 1995 36. Li FP, Tu J-T, Liu F-S, et al: Rarity of Ewing’s sarcoma in China. Lancet 1:1255, 1980 37. Magrath I, Sandlund J, Raynor A, et al: A phase 11 study of ifosfamide in the treatment of recurrent sarcomas in young people. Cancer Chemother Pharmacol 18(suppl 2):25, 1986 38. Margrove RC, Rosen G: Radical en bloc excision of Ewing’s sarcoma. Clin Orthop 153:86, 1980 39. May WA, Gishizky ML, Lessnick SL, et al: Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLIl for transformation. Proc Natl Acad Sci 90:5752, 1993 40. Michon J, Hartmann 0, Demeocq F, et al: Consolidation with busulfan and melphalan followed by blood progenitor cell graft in children and young adults with high risk Ewing’s sarcoma: A report of the French Society of Pediatric Oncology. Proc Am SOC Clin Oncol 13414, 1994 41. Miser JS, Kinsella TJ, Triche TJ, et al: Ifosfamide with mesna uroprotection and etoposide: An effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol5:1191, 1987 42. Miser JS, Krailo M, Meyers P, et al: Metastatic Ewing’s sarcoma and primitive neuroectodermal tumor of bone: Failure of new regimens to improve outcome. Proc Am SOC Clin Oncol 15:467, 1996 43. Nascimento AG, Cooper KL, Unni KK, et al: A clinicopathologic study of 20 cases of large-cell (atypical) Ewing’s sarcoma of bone. Am J Surg Pathol 4:29, 1980 44. Nesbit ME, Gehan EA, Burgert 0, et al: Multimodal therapy for the management of primary nonmetastatic Ewing’s sarcoma of bone: A long-term follow-up of the first intergroup study. J Clin Oncol 8:1664, 1990 45. Novakovic B, Goldstein AM, Wexler LH, et al: Increased risk of neuroectodermal tumors and stomach cancer in relatives of patients with Ewing’s sarcoma family of tumors. J Natl Cancer Inst 86:1702, 1994 46. Oberlin 0, Habrand J-L, Zucker JM, et al: No benefit of ifosfamide in Ewing’s sarcoma: A nonrandomized study of the French Society of Pediatric Oncology. J Clin Oncol 10:1407, 1992 47. Oberlin 0, Patte C, Demeocq F, et al: The response to initial chemotherapy as a prognostic factor in localized Ewing’s sarcoma. Eur J Cancer Clin Oncol21:463, 1985 48. OConnor MI, Pritchard DJ: Ewing’s sarcoma. Clin Orthop Re1 Res 262:78, 1991 49. Perez CA, Tefft M, Nesbitt M, et al: The role of radiation therapy in the management of non-metastatic Ewing’s sarcoma of bone. Report of the Intergroup Ewing’s Sarcoma Study. Int J Radiat Oncol Biol Phys 7141, 1981 50. Perlman EJ, Dickman PS, Askin FB, et al: Ewing’s sarcoma: Routine diagnostic utilization of MIC2 analysis: A Pediatric Oncology Group/Children’s Cancer Group Intergroup Study. Hum Pathol25:304, 1994 51. Pfleiderer C, Zoubek A, Gruber 8,et al: Detection of tumour cells in peripheral blood and bone marrow from Ewing tumour patients by RT-PCR. Int J Cancer 64:135, 1995 52. Picci P, Rougraff BT, Bacci G, et al: Prognostic significance of histopathologic response
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to chemotherapy in norunetastatic Ewing‘s sarcoma of the extremities. J Clin Oncol 11:1763, 1993 53. Pilepich MV, Vietti TJ, Nesbit ME, et al: Radiotherapy and combination chemotherapy in advanced Ewing’s sarcoma: Intergroup study. Cancer 471930, 1981 54. Pinto A, Grant LH, Hayes FA, et al: Immunohistochemical expression of neuronspecific enolase and Leu 7 in Ewing‘s sarcoma of bone. Cancer 64:1266, 1989 55. Pomeroy TC, Johnson RE: Prognostic factors in Ewing’s sarcoma. Am J Roentgen01 Radium Ther Nucl Med 123:598, 1975 56. Pritchard DJ: Indications for surgical treatment of localized Ewing’s sarcoma of bone. Clin Orthop 15339, 1980 57. Pritchard DJ, Dahlin DC, Dauphine RT, et al: Ewing’s sarcoma: A clinicopathological and statistical analysis of patients surviving five years or longer. J Bone Joint Surg 5710, 1975 58. Ramani P, Rampling D, Link M: Immunocytochemical study of 12E7 in small roundcell tumours of childhood: An assessment of its sensitivity and specificity. Histopathology 23:557, 1993 59. Raney RB, Asmar L, Newton WA Jr, et al: Ewing’s sarcoma of soft tissues in childhood: A report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 15574, 1997 60. Rosen G, Caparros B, Nirenberg A, et al: Ewing’s sarcoma: Ten-year experience with adjuvant Chemotherapy. Cancer 472204, 1981 61. Sailer SL, Harmon DC, Mankin HJ, et al: Ewing‘s sarcoma: Surgical resection as a prognostic factor. Int J Radiat Oncol Biol Phys 15:43, 1988 62. Sauer R, Jurgens H, Burgers JMV, et al: Prognostic factors in the treatment of Ewing’s sarcoma. Radiother Oncol 10:101, 1987 63. Schmidt D, Hermann C, Jurgens H, et al: Malignant peripheral neuroectodermal tumor and its necessary distinction from Ewing’s sarcoma: A report from the Kiel Pediatric Tumor Registry. Cancer 682251, 1991 64. Scully SP, Temple HT, O’Keefe RJ, et al: Role of surgical resection in pelvic Ewing’s sarcoma. J Clin Oncol 13:2336, 1995 65. Sorensen PH, Lessnick SL, Lopez-Terrada D, et al: A second Ewing‘s sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet 6:146, 1994 66. Sorensen PH, Shimada H, Liu XF, et al: Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing’s sarcoma EWS/FLI1 fusion gene. Cancer Res 55:1385, 1995 67. Strong LC, Herson J, Osbome BM, et al: Risk of radiation-related subsequent malignant tumors in survivors of Ewing’s sarcoma. J Natl Cancer Inst 62:1401, 1979 68. Suit HD: Role of therapeutic radiology in cancer of the bone. Cancer 35:930, 1975 69. Tepper J, Glaubiger D, Lichter A, et al: Local control of Ewing’s sarcoma of bone with radiotherapy and combination Chemotherapy. Cancer 45:1969, 1980 70. Terrier P, Henry-Amar M, Triche TJ, et al: Is neuro-ectodermal differentiation of Ewing’s sarcoma of bone associated with an unfavourable prognosis? Euro J Cancer 31A:307, 1995 71. Thomer P, Chilton-MacNeil S, et a1 Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types. Am J Pathol 148:1125, 1996 72. Toretsky JA, Neckers L, Wexler L H Detection of (11;22)(q24;q12) translocation-bearing cells in peripheral blood progenitor cells of patients with Ewing’s sarcoma family of tumors. J Natl Cancer Inst 87:385, 1995 73. Travis LB, Curtis RE, Hankey BF, et al: Second cancers in patients with Ewing’s sarcoma. Med Ped Oncol 22:296, 1994 74. Triche TJ: Diagnosis of small round cell tumors of childhood. Bull Cancer 75297, 1988 75. Tucker MA, DAngio GJ, Boice JD, Jr, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317588, 1987 76. Turc-Care1 C, Aurias A, Mugneret F, et al: Chromosomes in Ewing’s sarcoma. An
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evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet 32:229, 1988 77. West DC,Crier HE, Swallow MM, et al: Detection of circulating tumor cells in patients with Ewing’s sarcoma and peripheral primitive neuroectodermal tumor. J Clin Oncol 15583, 1997 78. Wexler LH, DeLaney TF, Tsokos M, et a1 Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing’s sarcoma family of tumors. Cancer 78:901, 1996 79. Whang-Peng J, Triche TJ, Knutsen T, et al: Cytogenetic characterization of selected small round cell tumors of childhood. Canc Genet Cytogenet 21:185, 1986 80. Yamamota T, Wakabayashi T Bone tumors among the atomic bomb survivors of Hiroshima and Nagasaki. Acta Pathol Jpn 19:201, 1969 81. Young JL, Jr., Miller RW: Incidence of malignant tumors in U S . children. J Pediatr 86254, 1975 82. Zamora P, Garcia de Paredes ML, Gonzalez-Baron M, et a 1 Ewing’s tumor in brothers. An unusual observation. Am J Clin Oncol9:358, 1986 83. Zoubek A, Dockhom-Dworniczak B, Delattre 0, et al: Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 141245, 1996 84. Zucman J, Delattre 0, Desmaze C, et a1 EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet 4341, 1993 Address reprint requests to Holcombe E. Grier, MD Department of Pediatric Oncology Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115
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0031-3955/97 $0.00
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THE EWING FAMILY OF TUMORS Ewing’s Sarcoma and Primitive Neuroectodermal Tumors Holcombe E. Grier, MD
The Ewing family of tumors (Ewing’s sarcoma and primitive neuroectoderma1 tumor [PNET]) is the second most common malignant bone tumor (after osteogenic sarcoma) in children and adolescents. These tumors can also occur in soft tissue, presenting in a manner similar to rhabdomyosarcoma. Nearly half of all patients with Ewing’s family tumors are between 10 and 20 years of age, and 70% are under the age of 20, with a slight male predominance. The annual incidence in the United States is 2.1 cases per million children.81A similar incidence of these tumors occurs throughout the world in countries composed mostly of whites or persons of Hispanic origin; however, these tumors are extremely rare in black children and children of Asian rigi in.'^,^ The reason for this striking difference in incidence according to racial background is unknown. Ewing’s tumor was originally described in 1921 by James Ewing as an endotheli0ma.I4 Over the past decade it has become clear that Ewing’s sarcoma, in fact, derives from a primitive neuroectodermal cell with variable differentiation. Classical Ewing’s sarcoma is a poorly differentiated small round blue cell tumor, whereas, on the other end of the scale, PNET shows quite discernible differentiation. Both share the same histochemical staining profile and a unique characteristic translocation t(11;22) or a variation of the same within the tumor cell. Virtually all Ewing’s tumors contain the chromosomal marker.
CAUSE The cause of Ewing’s sarcoma is unknown. Radiation exposure does not appear to be a common cause of Ewing‘s sarcoma. For example, no increased
From the Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston; and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
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incidence occurred after exposure to nuclear fallout in Japan8”The tumor may occur after prior treatment for cancer, including radiotherapyi3; however, the incidence is quite low. In a large study of secondary bone tumors after radiotherapy, 69% of the tumors were osteosarcoma, whereas only 3% were Ewing’s sarcoma.7” Ewing’s sarcoma does not appear to be inherited. The disease has been reported in siblings, but may be a chance i n c i d e n ~ e . ~ In ~ , general, the Ewing family of tumors is not associated with familial cancer syndromes. One study noted an increased risk of neuroectodermal tumors and stomach cancer in relatives of patients with Ewing’s however, this has not yet been confirmed. Most striking, as previously noted, is the extreme rarity of the Ewing family of tumor in Asians and blacks. MOLECULAR GENETICS
Nearly all Ewing’s sarcomas and PNET have a clonal translocation seen in the malignant cells. By far, the most common translocation is between the long arms of chromosomes 11 and 22. This translocation can be found by standard cytogenetics in over 80% of the Ewing family of tumors, and is seen using molecular techniques in over 90‘X.’*, 76, 7‘’ The break point of this common translocation has been cloned; the rearrangement occurs within the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11 (Fig. 1).I0 FLI-1 is a member of the ETS family of transcription factors. These factors encode for transcription activators that bind directly to DNA. The EWS gene is less well
t( 11;22)
EWS-FLI 1
Chr 11
FLI 1
Chr 22
EWS
Chr 21
ERG
t(21;22)
EWS-ERG
Figure 1. The Ewing’s sarcoma (EWS) gene on chromosome 22 contains a putative RNA binding domain. This domain is lost when the gene combines with the ETS-like genes on either chromosome 11 (the most common translocation site in the Ewing family of tumors, where it recombines with the FLI-1 gene) or chromosome 21 (the ERG gene). The recombined genes shown on the top for t(11;22) and on the bottom for t(21;22) retain the DNA binding portion of the ETS-like oncogenes while coming under the control of the EWS promotor.
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characterized but appears to have an RNA binding area. The fusion gene juxtaposes the 5’ sequences of the EWS gene with the 3’ sequences of the FLI-1 gene. The new gene retains the DNA binding of FLI-1 but appears to be under the regulation of the promoters of the EWS gene. The resultant gene can transform NIH 3T3 cells, the classical test for a dominant oncogene.39 The t(11;22) translocation is the most common translocation in Ewing’s sarcoma. The next most common translocation, t(21;22), recombines the EWS A gene on 22 with another ETS-like gene, ERG, on chromosome 21 (Fig. l).b5 third quite rare rearrangement, t(7;22), fuses ETV-1 with EWS2*Recently, the EWS gene has been found to be rearranged with still other ETS-like genes in two other cancers, clear cell sarcoma (also known as melanoma of soft parts) and desmoplastic small round cell tumor of the abdomen (Table l).,, 84 The exact rearrangements within the common t(11;22) and t(21;22) are somewhat variable. The type of rearrangement does not appear to correlate with presenting features but may be of prognostic ~ignificance.~~ Molecular assays are now being used more and more to diagnose Ewing‘s sarcoma and PNET. The reverse transcriptase polymerase chain reaction (RTPCR) assay can be used to look for the translocation within tumor tissue even if more traditional cytogenetics are unsuccessful. Using these techniques, undifferentiated sarcomas can be found to contain a typical Ewing family tran~location.~ One must be careful, because other tumors rarely have been found to have the EWS/FLI-1 transcript.“ 71 A multiplex PCR technique can look at the typical translocation in alveolar rhabdomyosarcoma and the t(11;22) Ewing’s abnormality simultaneously.I2The RT-PCR technique is quite sensitive and can find tumor cells admixed with normal cells at a level well below that detectable by light microscopy. The RT-PCR assay has allowed investigators to find low levels of tumor cells in the bone marrow and even in the blood of patients at diagnosis and during therapy. It is quite clear that the presence of the abnormal transcript is variable among patients at presentation, and prospective trials are looking at the prognostic significance of this ~ariability.~~, 72, 77 PATHOLOGY
Ewing’s sarcoma and PNET belong to the group of neoplasms commonly referred to as small round cell tumors. These include neuroblastoma, rhabdomyosarcoma, and non-Hodgkin’s lymphoma. The differentiation of Ewing’s tumor from the other entities may occasionally be difficult, especially in the soft tissue variants.74The individual cells in Ewing’s sarcoma are round, of moderate size, have clear and frequently quite scant cytoplasm, and round to oval nucleus. Small to moderate areas of necrosis may be present; in addition, dense pyknotic
Table 1. REARRANGEMENTS OF EWS GENE IN HUMAN CANCER Tumor
Ewing’s sarcoma Clear cell sarcoma Desmoplastic small round cell tumor of the abdomen
Rearrangement
ETS Gene Involved
t (11;22)
FLI-1
t (21;22)
ERG
t (7;22) t (10;22) t (1 1;22)
ETV-1 ATF-1 WT-1
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cells indicating apoptosis are often present. Calcification is rare. Classical Ewing’s sarcoma cells are frequently positive for glycogen. Occasionally, the cells in Ewing’s sarcoma can be larger than are those of the typical There is considerable neuroectodermal differentiation in the PNET variant of the Ewing family of t u m o r ~This . ~ differentiation is noted by neural stains (e.g., 5100, neuron-specific enolase) or the presence of rosettes or neural elements on electron microscopy. It remains controversial whether neuroectodermal differentiation predicts a different outcome than does standard histology.21,54, 63, 70 Cell surface staining for the protein product of the pseudo-autosomal gene MIC2 has been particularly helpful in the differentiation of the Ewing family of tumors from other small round cell tumors. The MIC2 protein product is a ubiquitous cellular component but is usually seen in high quantities only in T cells and the Ewing family cells. Two monoclonal antibodies (12E7 and HBA-71, now designated CD99) have been developed and are sometimes referred to as ”Ewing’s 50,58
CLINICAL PRESENTATION
Pain or swelling, or both, at the site of the primary tumor are, by far, the most common presenting symptoms in Ewing’s sarcoma-PNET of bone and soft tissue. Unlike osteosarcoma, patients with Ewing’s sarcoma may also present with systemic signs and symptoms such as weight loss, fever, and increased sedimentation rate. Systemic signs are more common in patients presenting with meta~tases.5~ The presence of systemic symptoms often brings osteomyelitis into the differential diagnosis of patients at the presentation of Ewing’s sarcoma. The proportions of various symptoms at diagnosis as compiled by Green,Is from 10 different series are shown in Table 2. These symptoms may be present for months before medical attention is sought. A delay between the first symptoms and diagnosis is quite common in Ewing’s sarcoma, with one study finding that 50% of patients had symptoms for over 6 months before the tumor was This is particularly true oLpelvic tumors in which the mass is not palpable until it is quite large, if ever. Ewing’s sarcoma-PNET can develop in almost any bone in the body. Unlike osteosarcoma in which long bones are predominantly involved, flat and long bones are about equally represented in the Ewing family of tumors. Table 3 presents the primary sites for over 300 patients treated in the first Intergroup Ewing’s Sarcoma Study (IESS). The pelvic bones as a group are followed by the femur and then the tibia and humerus in frequency of tumor site.32In long bones, Ewing’s sarcoma usually begins in the midshaft, rather than the ends as in osteosarcoma. Plain radiographs tend to show a lytic or mixed lytic and sclerotic lesion (Fig. 2). The classical radiologic appearance of Ewing’s sarcoma is called onion skinning. This effect is caused by parallel laminated periostial formation where the tumor has continued to grow through the reparative attempts of the bone. Soft tissue masses are common in Ewing’s sarcoma, although Table 2. SYMPTOMS AT DIAGNOSIS OF EWING’S SARCOMA OF BONE Local pain Local swelling Fever Paraplegia
84%
63% 28% 3%
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Table 3. DISTRIBUTION OF PRIMARY SITE FOR 303 PATIENTS WITH EWINGS SARCOMA OF BONE Primary Site Pelvic Ilium Sacrum lschium Pubis Lower extremity Femur Fibula Tibia Feet Upper extremity Humerus Forearm Hand Axial Skeletonkibs Face
Figure 2. A Ewing’s sarcoma of the distal fibula with the cIassic permeative bone destruction and laminated elevation of the periosteum (“onion skinning”).
Percent 20 12.5 3.3 3.3 1.7 45.6 20.8 12.2 10.6 2.0 12.9 10.6 2.0 0.3 12.9 2.3
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occasionally a patient may have a large extent of bone involved with minimal mass even on CT scan or MR imaging. MR imaging is clearly the most sensitive technique to show the extent of the tumor in soft tissue and intramedullary extension (Fig. 3)?,25The soft tissue tumor can be quite massive, especially in pelvic primary tumors (Fig. 2). Soft tissue Ewing’s sarcoma-PNET often occurs
Figure 3. Ewing’s sarcoma may present with large masses, particularly when the primary tumor is in the pelvis. Shown here are M R imaging scans of a tumor involving the ischium and pubic bones. A, The dark marrow space on the involved side on this T1-weighted study is contrasted with the lighter marrow signal caused by normal fat on the opposite side. 8, An axial TP-weighted MR imaging view of the tumor shows a bright signal outlining the extensive nature of the tumor.
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near bones and may be difficult to differentiate from primary tumors in bone in some cases. This is particularly true in the chest wall in which the ribs may be the primary site or may be secondarily involved with large masses. The percentage of patients presenting with metastases varies from series to series, but averages about 25Y0.l~Sites of metastases include the lung (approximately half of patients), bone (approximately a quarter), and bone marrow (approximately a fifth).- Metastases to other sites, including the central nervous system are rare except late after relapse. Patients may occasionally present with symptoms from metastatic sites rather than pain at the primary site. STAGING AND PROGNOSIS The staging workup for Ewing’s sarcoma is based on proper imaging of the primary tumor and sites of likely metastases: plain films and MR imaging of the primary site, chest radiographs and CT scan of the lung, bone scan, and bone marrow biopsy. Laboratory studies should include a complete blood count, an erythrocyte sedimentation rate (increased in up to 50% of patients), and baseline chemistries. The tumor biopsy should be done at a center with facilities to provide immunohistochemistry, solid tumor cytogenetics, and other molecular diagnostic techniques. In addition, the biopsy specimen should be taken from a location that will not compromise later surgery or radiotherapy. Needle biopsy can be done while still performing the necessary molecular and immunologic ~ o r k u pNo . ~ widely ~ accepted staging system for Ewing’s sarcoma exists. Prognosis clearly varies with the presence or absence of metastases, and with tumor size. Although the site of the primary tumor has been found to be prognostic, the poorer outcome of pelvic tumors may have more to do with their usual size than with their location. When multivariate analysis was used in a large European trial, location was not a significant factor when size was taken into account.62Table 4 lists prognostic factors found in several Ewing’s tumor trials; many of these overlap. THERAPY
Treatment of Ewing’s sarcoma requires eradication of the tumor at both its presenting site (local control) and the sites of metastatic or micrometastatic Table 4. PROGNOSTIC FACTORS IN EWING’S SARCOMA Prognostic Factors
Negative Factors: Metastases at diagnosis Over 8 cm in longest diameter Large tumor volume Pelvic location High LDH levels Over 17 years of age Neuroectodermal differentiation (controversial) Positive Factors: Good radiologic response to induction chemotherapy Good pathologic response to induction chemotherapy
References
Seen in many studies 23 62
Seen in many studies 17, 60
19,20 21,63, 70 46, 47,52,
8,30,46,66
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disease. Nearly all patients with Ewing's sarcoma have micrometastatic disease (i.e., tumor cells outside the primary site that cannot be detected by standard methods) at the time of diagnosis. This is evidenced by a cure rate of less than 10% when Ewing's sarcoma is treated with radiotherapy or surgery to the local site In addition, as mentioned previously, tumor cells now can be detected, using the sensitive RT-PCR assay, in the bone marrow and blood of patients who are classified as nonmetastatic by conventional tumor-detection methods?', 72, Control of the Primary Tumor
Local control in Ewing's sarcoma is usually attempted with surgery, radiotherapy, or a combination of both to the primary tumor. Local control should almost always be deferred until after initial chemotherapy, allowing for better consideration of surgical options after the tumor volume has been reduced. Tumor control with radiotherapy requires moderately high doses. Standard practices require doses ranging from 5500 to 6000 c G Y . ~ Traditionally, ~ the volume of radiotherapy was to the whole bone; however, a Pediatric Oncology Group (POG) study demonstrated no difference in local control when a volume including the initial tumor extent with an additional 2-cm margin was compared with whole bone radiotherapy." Chemotherapy has improved local control rates in Ewing's sarcoma.2,49, 69 However, attempts to lower radiotherapy doses for tumors that had marked reduction in soft tissue masses from induction chemotherapy led to a higher than expected local failure rate.23 Surgery is an effective way to treat Ewing's sarcoma. The problem with this modality is the morbidity of removing these sometimes very large tumors which often occur in important functional areas. Surgery is clearly indicated in certain circumstances; however, clavicles, ribs, and fibulae, for instance, can sometimes be removed without significant functional loss if the concomitant soft tissue mass is small. The most ipportant factor in choosing local control in Ewing's sarcoma is eradication of the cancer. Several authors have argued from retrospective analyses of patients that surgery improves overall survival in Ewing's and Not all such analyses have agreed with this concl~sion,~~, @ 56, , sarc0ma.3~, nearly all of the studies are biased by a tendency for tumors treated with surgery to be smaller than are those treated with radiotherapy. In one study, the influence of surgery could be explained by size differences using multivariate ana1y~is.I~ Unfortunately, the question has not been subjected to randomized clinical trials and, considering the difficulty of such trials, may never be. Because whether surgery improves survival remains controversial, late effects must also be considered in choosing a local control modality. These late effects include function, appearance, and, most importantly, occurrence of second tumors. The incidence of bone tumors in the irradiated field has varied somewhat from study to study, with estimates ranging from 10% to 30% at 20 years after therapy.?l, 67, 75 However, because the incidence of second bone tumors is likely to be much less if radiation therapy is not used, at our institution we often use surgery if the likelihood is high that the tumor can be completely removed and the function after the resection is predicted to be reasonable.
Chemotherapy The poor outcome with radiotherapy or surgery alone led investigators in the 1960s and 1970s to initiate trials of adjuvant chemotherapy, with lower
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failure rates than had been seen historically.’6, 27, 55 These studies used some combination of vincristine, dactinomycin, and cyclophosphamide (VAC). The IESS begun in the early 1970s demonstrated that the addition of doxorubicin to VAC (albeit with the resulting therapy having a higher dose intensity) improved outcome compared with VAC alone. Interestingly, VAC with prophylactic whole lung radiotherapy had an intermediate outcome compared with VAC alone and VAC with doxorubicin.“ In contrast, a review of the Intergroup Rhabdomyosarcoma Group experience with extraosseous Ewing’s sarcoma did not show an improvement for patients with unresectable disease who received doxorubicin when compared with those who received VAC alone.59This result must be interpreted with caution, however, because since the time these studies were done the classification of soft tissue sarcomas including extraosseous Ewing’s and rhabdomyosarcoma has become more precise using immunohistochemistry, solid tumor cytogenetics, and molecular biologic techniques. About two thirds of these patients with unresectable tumors survive long term, a finding similar to that of unresectable rhabdomyosarcoma in general. A second study done by the IESS, in this case for the group of patients with localized disease excluding pelvic lesions, showed that intensified therapy improved overall results.6 Most other trials of Ewing’s sarcoma have not been randomized; in general, a combination of vincristine, doxorubicin, cyclophosphamide, and dactinomycin produces 5-year event-free survival rates of 50% to 60% for patients presenting without metastases. One must acknowledge that the 5-year survival is not the end of the story because these patients are at risk for late relapse or second tumors.lh,z2, 31 The high response rate of patients with relapsed Ewing’s sarcoma to ifosfamide with or without e t o p ~ s i d e ~ has ~ , ~prompted ~,~’ several groups to add one or both of these agents during the initial therapy for patients presenting without metastases. Results of single arm studies with historical controls have been somewhat confusing. A French study showed no improvement with the addition of ifosfamide and noted increased cardiac toxicity.16 A German study that added ifosfamide to the therapy for high-risk patients showed an improvement for that group compared with historic controls.30Investigators at the National Cancer Institute had similar results when they added ifosfamide and etoposide to a standard regimen.78The Children’s Cancer Group (CCG) and the POG performed a randomized trial comparing a standard treatment of vincristine, doxorubicin, cyclophosphamide, and dactinomycin to an experimental treatment in which patients received the same drugs alternating with ifosfamide and etoposide. At 5 years the event-free survival rate for patients with nonmetatastatic disease on the standard arm was 52% compared with 68% for the patients treated with ifosfamide and etoposide, a highly statistically significant result.19,’” Currently, a combined CCG-POG trial is comparing the previous experimental therapy with a treatment program that intensifies the alkylating agents. The results for patients presenting with metastases has lagged behind that for patients without; most studies show a 5-year event-free survival rate of approximately 25%.’ The addition of ifosfamide and etoposide has not appeared 78 This outcome to improve the outcome for this group of high-risk has led some investigators to use megatherapy with stem-cell rescue in patients with Ewing’s sarcoma metastatic at presentation or in those who develop metastases while on therapy. Two European groups have reported an excellent outcome (>40% event-free survival) with this technique; the German study, in particular, is impressive because the therapy was limited to patients with a very poor p r o g n o s i ~ .However, ~,~ the results from the European BMT (Bone Marrow Transplant) Solid Tumour Registry were quite disappointing and were not
clearly different from those of standard chemotherapy.3sThe efficacy of megatherapy in Ewing‘s sarcoma is not yet clear. Treatment after relapse is extremely difficult in Ewing’s sarcoma if the patient has relapsed while on therapy. Megatherapy is being tried for these patients, as noted previously. Late relapses are not uncommon in Ewing’s sarcoma; however, for these patients retreatment with intensive chemotherapy may produce some long-term survivors.Z2As noted previously, the occurrence of second malignancy is a particularly disturbing phenomenon in Ewing’s sarcoma. These tumors are usually osteogenic sarcoma and occur in the irradiated bone with an incidence that may be as high as 30%.33,67, 75 SUMMARY
There has been an explosion of new knowledge regarding the Ewing family of tumors over the past 5 to 10 years. Classical Ewing’s sarcoma and PNET are now known to be the same tumor with variable differentiation, defined by a translocation between the EWS gene on chromosome 22 with one of three ETSlike genes, especially the FLI-1 gene on chromosome 11. Molecular techniques used to identify this translocation along with the knowledge that the protein product of the MIC2 gene is highly expressed on the cell surface have greatly improved our diagnostic abilities in this family of tumors. Controversy still exists as to whether surgery improves event-free survival when compared with radiotherapy in Ewing‘s sarcoma. The high second tumor rate, if nothing else, has started moving many physicians to preferentially use surgery when the functional results are predicted to be reasonable. The addition of ifosfamide and etoposide to standard therapy in Ewing’s sarcoma has improved survival for patients without metastases at presentation. However, outcome for patients with metastases or who develop metastases while on therapy or shortly thereafter remains poor. Prelimin.ary reports of better outcome with megatherapy are interesting but not yet definitive. The decades ahead will probably see marked changes in therapy for Ewing‘s sarcoma. The unique translocation seen in virtually all of these tumors is a potential target for a ”magic bullet” therapy, because the protein product of this translocation is present only in the malignant cells. Hopefully either immune modulation against this unique protein or further knowledge of how to use antisense genes will move us toward exquisitely targeted therapy in the Ewing family of tumors. References 1. Ambrose IM, Ambrose PF, Strehl S, et al: MIC2 is a specific marker for Ewing’s sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing’s sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 671886, 1991 2. Bacci G, Picci P, Gitelis S, et al: The treatment of localized Ewing’s sarcoma: The experience at the Istituto Ortopedico Rizzoli in 163 cases treated with and without adjuvant chemotherapy. Cancer 49:1561, 1982 3. Barr FG, Chatten J, DCruz CM, et al: Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 273:553, 1995 4. Boyko OB, Cory DA, Cohen MD, et al: MR imaging of osteogenic and Ewing’s sarcoma. Am J Radio1 148:317, 1987
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