Extraskeletal Ewing's Sarcoma: Results of Combined Modality Treatment By Timothy J. Kinsella, Timothy J. Triche, Paul S. Dickman, Jose Costa, Joel E. Tepper, and Daniel Glaubiger Eleven patients with extraskeletal Ewing's sarcoma (EES) were treated with combined modality therapy at the National Cancer Institute. The diagnosis of EES was reserved for lesions that were identical to Ewing's sarcoma of bone by light and electron microscopy. Diagnostic work-up to rule out a skeletal primary included bone scan, localized views of adjacent bone, and bone tomography. Seven patients presented with an extremity primary and four patients had a truncal primary. No patients had evidence of metastases at presentation. Patients were treated with combined modality therapy consisting of high-dose local irradiation and vincristine, actinomycin D, and cyclophos- A SOFT TISSUE TUMOR indistinguishable from Ewing's sarcoma of bone by light microscopy was first described by Tefft et al in five young children, all of whom presented with signs and symptoms of epidural cord compression and a paravertebral soft tissue mass.' Later, Angervall and Enzinger reported a larger series of these soft tissue tumors in adolescents and young adults. 2 In their retrospective series of 39 patients whose pathology was referred to the Armed Forces Institute of Pathology (AFIP) between 1957-1969, there also appeared to be a predilection for these tumors to arise in the paravertebral soft tissues as well as the soft tissues of the lower extremity. The prognosis for these patients was poor, with approximately 75% of the patients dying of metastatic disease to lung or bone, often within one year of diagnosis. However, in these series there was marked variation in the staging and treatment and no analysis of local control. Subsequently, several reports have confirmed the histologic findings by light microscopy of the so-called extraskeletal Ewing's sarcoma (EES).Ž" More recently, electron microscopy has shown that these round cells have no discernible cytoskeleton, intracellular collagen, nor collagenous intercellular matrix," unlike more common soft tissue sarcomas. These findings by electron microscopy help to distinguish EES from primitive or undifferentiated rhabdomyosarcoma, neuroblastoma, and lymphoma. The prognosis for EES patients appears markJournal of Clinical Oncology, Vol. 1, No. 8 (August) 1983 phamide chemotherapy following a biopsy or local excision. No attempt was made to excise widely the primary tumor mass. Gross tumors generally responded rapidly to the combined modality treatment. Of 11 patients, seven (64%) remain disease free, with a follow-up of three to seven years from completion of therapy. Long-term local control was established in nine of 11 patients (82%). Autopsy findings on two patients with local failure showed no tumor involvement of adjacent bone. Attempts at gross resections by radical surgical procedures do not routinely appear to be necessary in light of the high local control rates with high-dose irradiation. edly improved in the era of combined modality therapy. In a retrospective review of 26 EES patients treated by the multi-institutional Intergroup Rhabdomyosarcoma Study (IRS), 20 patients achieved a complete response, with 17 patients remaining disease free with a median follow-up of two years (range, 10-110 weeks). 8 A more recent analysis by the IRS of extremity (15 patients) and truncal (six patients) EES patients revealed local control of 76% (16 of 21) and disease-free survival of 71% (15 of 21) with follow-up of three to seven years. 9,10 In a five-year period from 1974-1978, 11 patients with various soft tissue tumors subsequently diagnosed as EES were treated at the National Cancer Institute (NCI). Patients were included for study only after careful review of light and electron microscopic findings employing specific criteria for the identification of EES. 5 These patients were staged and treated with combined modality therapy according to protocol studies designed for Ewing's sarcoma of bone." This From the Radiation Oncology and Pediatric Oncology Branches of the Laboratory of Pathology, Division of Cancer Treatment, National Cancer Institute, Bethesda, Md. Submitted December 29, 1982; accepted April 26, 1983. Address reprint requests to Timothy J. Kinsella, MD, Radiation Oncology Branch, Division of Cancer Treatment, National Cancer Institute, Building 10, Room B3B38, NationalInstitutes of Health, Bethesda, MD 20205. C 1983 by American Society of Clinical Oncology. 0732-183X/83/0108-0006$1.00/0 489 Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. KINSELLA ET AL 490 paper is an analysis of the clinical course of these 11 EES patients treated with high-dose irradiation and combination chemotherapy. METHODS AND MATERIALS The clinical records, diagnostic studies, and pathologic material were reviewed for all patients with the diagnosis of EES seen at the NCI between January 1974 and December 1978. Patients who developed cortical bone changes adjacent to the soft tissue tumor during or shortly after therapy were excluded from analysis. During this five-year period, approximately 75 patients with Ewing's sarcoma and 150 patients with soft tissue sarcoma were referred to the NCI. The routine diagnostic work-up included a chest roentgenogram, lung tomograms (also chest computerized tomographic scans after 1977), bone scan, bone marrow biopsy, and roentgenograms of any suspicious bone adjacent to the soft tissue tumor mass. Occasionally bone tomograms also were done to rule out an osseous primary. Fifteen patients were initially diagnosed as having EES and are the cohort group for this retrospective review. The pathologic diagnosis was determined from formalinfixed, paraffin-embedded tissue stained with hematoxylin and eosin (H&E) and with the periodic acid-Schiff stain (PAS) with and without diastase digestion. In the six more recent cases as well as two additional cases in the cohort that were excluded from the final study group, electron microscopy was also done. Treatment consisted of combined modality therapy by two protocol studies designed for Ewing's sarcoma of bone. II For patients with a soft tissue primary of an extremity, treatment involved local irradiation to the mass and its entire muscle group of origin (5,000 rads at 180-200 rad fractions over five to six weeks) followed by prophylactic lung irradiation (1,500 rads at 150-rad fractions over two weeks) and concomitant chemothera2 py. Chemotherapy consisted of vincristine, 2.0 mg/im ; actino2 mycin D, 2.0 mg/m , and cyclophosphamide, 1,200 mg/m 2; given on day I of a 28-day cycle and repeated for four cycles (VAC). For a soft tissue primary of the trunk, the combined modality therapy was more intensive, based on the poor prognosis for 3 central axis Ewing's sarcoma of bone.12-1 Induction therapy consisted of local irradiation with a generous margin (5 cm) about the primary to 5,000 rads at 180-200 rad fractions with a cone down boost for an additional 500-1,000 rads. Patients also received two to three cycles (every four weeks) of VAC chemotherapy. After a bone marrow storage procedure under general anesthesia, patients received low-dose total-body irradiation (150 rads at 15-rad fractions twice weekly over five weeks) followed by an intensive three-day drug cycle (vincristine, 2.0 mg/m 2 on day 1; doxorubicin, 35 mg/m 2 on days I and 2; 2 cyclophosphamide, 1,200 mg/m on days 1 and 2; and dacarba2 zine, 250 mg/m on days 1, 2, and 3). Autologous bone marrow was reinfused following this intensive cycle. After hematologic recovery, maintenance therapy with vincristine, doxorubicin, cyclophosphamide, and dacarbazine was given to truncal patients on a monthly basis for 12 cycles as tolerated. RESULTS Fifteen patients were initially diagnosed as having EES after referral and work-up at the NCI between January 1974 and December 1978. Four patients were excluded following review of the clinical and pathologic material; two being reclassified as having primitive soft tissue sarcomas and the other two as having Ewing's sarcoma of bone. Of the 11 remaining patients, there were six male and five female patients. The patients' ages ranged from 11 to 31 years with a mean age of 19 years. Seven patients presented with a soft tissue primary in an extremity and four patients had a soft tissue primary involving the trunk. The light and electron microscopic material on six of these 11 patients, as well as 23 other NCI patients, has recently been reviewed.' The H&E and PAS slides were compared in a blinded fashion with similar pathologic material from the 23 other NCI patients including patients with Ewing's sarcoma of bone, alveolar rhabdomyosarcoma, and undifferentiated soft tissue sarcoma. In each case, the light microscopic material from the EES patients was indistinguishable from Ewing's sarcoma of bone (Fig. lA and B). Moreover, we were able to distinguish the EES material from patients with all forms of alveolar rhabdomyosarcoma (Fig. 1D) and undifferentiated soft tissue sarcoma (Fig. IC) by the criteria previously mentioned. Although electron micrographs were available for only eight patients in the cohort and six EES patients, the characteristic features of Ewing's sarcoma of bone (Fig. 2A) were noted in all six cases of EES (Fig. 2B) in a blinded review of approximately 30 cases of Ewing's sarcoma of bone and primitive soft tissue sarcomas similar to the light microscopic review (Fig. 2C and D). The clinical features of the EES patients were presented in Table 1. The patients have been grouped according to the location of the primary soft tissue tumor, i.e., extremity or truncal location. The extremity group is equally divided between upper and lower extremity primaries. One patient (no. 6) presented with a left forearm mass associated with a large axillary nodal mass of similar histology. There were no other cases of nodal metastases at presentation or at relapse. There was considerable variation in the size of the primary tumor in both extremity and truncal patients. In general, patients had a biopsy or local excision of the tumor mass prior to referral. A biopsy was not performed on the adjacent bone. Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. EXTRASKELETAL EWING'S SARCOMA With large tumors, the surgical margins were grossly positive. With the exception of a repeat biopsy for diagnostic purposes, no further surgery to the soft tissue primary was carried out at 491 the NCI prior to initiation of combined modality therapy as outlined. Of the 11 patients, seven (64%) remain disease free with a follow-up of 42-79 months from Fig. 1. Comparison of light micrographs of various sarcomas. (A) Ewing's sarcoma of bone. (B) EES. (C) Soft tissue sarcoma. (D) Primitive rhabdomyosarcoma. The appearance of each of these tumors is remarkably similar. Nuclear size and chromatin pattern is variable, but does not correlate with a specific tumor type. Any of these tumors may show variation in these parameters. Very little if any matrix is discernible in any of these tumors. H&E stain. x 400. Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 492 KINSELLA ET AL Fig. 2. Electron microscopic appearance of each of the tumors in Fig. 1. The tumors are quite dissimilar, especially compared to classic Ewing's sarcoma of bone. (A) Ewing's sarcoma of bone has no matrix, the cells usually contain pools of cytoplasmic glycogen (g), and no cytoplasmic filaments are detectable. (B) EES likewise has no matrix or cytoplasmic filaments, but glycogen is similar in amount and cellular disposition. (C) Unclassified soft tissue sarcomas, like primitive rhabdomyosarcoma, display abundant collagen matrix (coil) and tumor cells are frequently elongated or "spindle cell," as here. Myofilaments of any kind are, however, absent. Glycogen is less frequent and is not seen here. (D) Primitive rhabdomyosarcoma is superficially similar to Ewing's sarcoma of bone and EES, with a similar or even greater amount of glycogen in some cases, but is different in several important respects: collagenous matrix is invariably present about individual cells, the nucleus is often eccentric, and the abundant cytoplasm contains tangled masses of fine filaments (f); these are precursors of myoblast filaments and are biochemically related to rhabdomyosarcoma, but not Ewing's sarcoma of bone or EES. Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. EXTRASKELETAL EWING'S SARCOMA Table 1. Group and Patient No. Clinical Characteristics of 11 Patients With Extraskeletal Ewing's Sarcoma Age (yr) Sex Extremity 1 2 3 4 5 6 16 25 15 18 20 20 M M F M M M 7 32 M 14 F Epidural mass at L4-5 9 16 F 10 21 F 11 11 F Retroperitoneum and pelvis R lateral chest wall Posterior neck mass overlying C6 Truncal 8 493 Primary Location* R forearm L calf L thigh L axilla L thigh L forearm with axillary mass R calf Size (cm) 4 4 8 4 10 2 9 8 X x x x x x x x 4 6 6 3 15 3 & 8 10 3 x 2 Surgery Local excision Incisional biopsy Local excision Local excision Incisional biopsy Local excision & biopsy Incisional biopsy 3 x 3 Excision of mass with dura left intact Laparotomy with biopsy Local excision 3 x 4 Local excision 20 x 15 Pattern of Failure (mo) Local Bone Lung Statust (mo) - - + (16) - NED DOD NED NED NED NED - - + (24) DOD (28) - - (72) (39) (66) (42) (79) (74) NED (48) + + + (0) DOD (16) + + + (10) DOD (14) - - - NED (46) *L, left; R, right. tNED, no evidence of disease; DOD, dead of disease. the initiation of treatment (Table 1). Of seven patients with an extremity primary, two failed in the lung at 16 and 24 months and later died of progressive disease. Of the four patients with a truncal primary, one patient (no. 9) showed evidence of distant metastases in lung and bone during induction therapy and later failed locally. One other patient failed locally and distantly in a synchronous fashion while receiving maintenance therapy. Clinical local control was established in nine of 11 patients (82%). In retrospect, the radiation portals were inadequate in one patient with local failure (no. 9). An autopsy on another patient (no. 2) who died with widely metastatic disease without clinical evidence of local failure, showed a few tumor cells surrounded by extensive fibrosis at the primary site in the area of high-dose irradiation. There was no evidence of adjacent bone involvement in this patient nor in two other patients who had clinical evidence of local failure prior to autopsy. DISCUSSION EES is an uncommon yet distinct clinicopathologic entity that should be considered in the differential diagnosis of a soft tissue tumor occurring in adolescents and young adults. The major differential diagnoses include Ewing's sarcoma of bone with extensive soft tissue extension and an inapparent intraosseous component, undifferentiated or primitive soft tissue sarcoma (including rhabdomyosarcoma), metastatic neuroblastoma, and, rarely, other tumors, such as peripheral neuroepithelioma, mesenchymal chondrosarcoma of soft tissue, hemangiopericytoma, synoviosarcoma, and metastatic oat cell (small cell) carcinoma of the lung. The frequency of EES is difficult to determine. In a five-year period during which our series of 11 patients was generated, approximately 75 patients with Ewing's sarcoma of bone were referred to the NCI. Of 314 soft tissue tumors entered on the IRS protocols from 1972 to 1976, 26 patients were diagnosed with EES (i.e., special types I and 2).8 As in our series, the typical patient is an adolescent or young adult with a soft tissue tumor, most commonly involving an extremity. In the less common truncal primary, there appears to be a predilection for involvement of the paravertebral soft tissues. The histologic diagnosis of EES should be re- Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. 494 served for soft tissue tumors that are identical to Ewing's sarcoma of bone by both light and electron microscopy. Typically, the light microscopy reveals sheets of small round cells with a high nuclear/cytoplasmic ratio. A PAS stain is usually strongly positive with diastase sensitivity, indicating the presence of cytoplasmic glycogen. Extracellular collagen is sparse. The ultrastructural description of EES has been less clearly defined. The electron microscopic criteria used by some authors fail to distinguish EES from the other major differential diagnoses. 4 ,7,14 In a study of the ultrastructural features of Ewing's sarcoma at the NCI, it was found that these cells do not contain a cytoskeleton, intracellular collagen, or collagenous intercellular matrix.5 ,6 These electron microscopic criteria should distinguish EES from its major differential, primitive soft tissue sarcoma and solid areas of alveolar rhabdomyosarcoma. Other tumors, such as neuroblastoma and lymphoma can be excluded by virtue of the absence of dense core granules (neuroblastoma) or the presence of primitive cell-cell attachments (lymphoma). The combination of local high-dose radiation therapy and VAC chemotherapy is effective in the curative treatment of EES. In an attempt to improve the systemic treatment in Ewing's sarcoma,15-17 prophylactic lung irradiation and lowdose total-body irradiation were added to the treatment protocols for extremity and truncal patients, respectively. These systemic adjuvants were added since the typical pattern of failure is metastatic (usually lung), and it was argued that micrometastatic disease may respond to relatively low doses of radiation.' 8 However, recent analysis of these trials in patients with Ewing's sarcoma of bone do not show any clear benefit to these adjuvants over local irradiation and VAC chemotherapy. 184.108.40.206 Overall, our results are quite similar to the IRS reports" '• in that 65%-70% of the patients remain disease free with follow-up of three to seven years. Although the number of patients in these two series is small, the prognosis of EES is as good as or better than Ewing's sarcoma of bone.'17 It should be noted, however, that the histogenesis of EES is as unclear as that of Ewing's sarcoma of bone; 20 a common cellular origin is thus not established. In fact, EES may be histogenetically more closely related to alveo- KINSELLA ET AL lar rhabdomyosarcoma, as suggested by Riopelle and Theriault, who first described alveolar rhabdomyosarcoma,21 and more recently by one of us.6 Despite this, the morphology, clinical evolution, response to treatment, and ultimate prognosis of EES more closely resembles Ewing's sarcoma of bone"• "5- than alveolar rhabdomyosarcoma. 9 10 The location of the primary soft tissue tumor appears to be of major prognostic significance: patients with extremity lesions fare much better than those with truncal lesions, similar to Ewing's sarcoma of bone. 2 "13The exact opposite is found in alveolar rhabdomyosarcoma, where extremity lesions indicate an especially poor prognosis.9'0 Although the chemotherapy for EES is quite 0 similar in our patients and those from the IRS,-• the management of the primary tumor is substantially different. In our series, local control was established in nine of 11 patients (82%), with one local failure being attributed to inadequate radiation fields. Typically, patients had only a local excision or an incisional biopsy prior to referral and no further definitive surgery at the NCI. This is in contrast to the surgical approach recommended by the IRS, where the basic surgical strategy is an attempt at a wide local excision followed by local irradiation only if the margins are positive for tumor, if the local lymph nodes are positive, or if gross residual tumor remains. Only one of the 21 EES patients undergoing surgery in the IRS reports had an adequate wide local excision not requiring postoperative irradiation. 8s-l In comparing the local control and disease-free survival data from the two series, wide local excision does not routinely appear to be necessary and may compromise the functional results when combined with high-dose local irradiation. Thus, the nonsurgical treatment employed at the NCI appears to be as effective in terms of local control and ultimate survival as the surgical intervention combined with radiation and chemotherapy employed by the IRS. In summary, EES appears to be a distinct clinicopathologic entity that can be distinguished from the other common round cell tumors arising in soft tissues of young adults. The light and electron microscopic features appear to be identical to the more common Ewing's sarcoma of bone. The natural history of EES also appears to be similar to Ewing's sarcoma of bone. With Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved. EXTRASKELETAL EWING'S SARCOMA combined modality therapy including high-dose irradiation and combination chemotherapy, the majority of patients are potentially curable. REFERENCES 1. 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Mahoney JP, Ballinger WE, Alexander RW: So-called extraskeletal Ewing's sarcoma: Report of a case with ultrastructural analysis. Am J Clin Pathol 70:926-931, 1978 15. Chan RC, Sutow WW, Lindberg RD, et al: Management and results of localized Ewing's sarcoma. Cancer 43:10011006, 1979 16. Gasparini M, Lombardi F, Gianni C, et al: Localized Ewing's sarcoma: Results of integrated therapy and analysis of failures. Eur J Cancer 17:1205-1209, 1981 17. Perez CA, Tefft M, Nesbit M, et al: The role of radiation therapy in the management of nonmetastatic Ewing's sarcoma of bone. Report of the Intergroup Ewing's Sarcoma Study. Int J Radiat Oncol Biol Phys 7:141-149, 1981 18. Glaubiger DL, Tepper J, Makuch R: Ewing's sarcoma, in Levine AS (ed): Cancer in the Young. New York, Masson, 1982, pp 603-641 19. Kinsella TJ, Glaubiger DL, Deisseroth A, et al: Intensive combined modality therapy including low dose TBI in high risk Ewing's sarcoma patients. Int J Radiat Oncol Biol Phys, 1983 (in press) 20. Dickman PS, Liotta LA, Triche TJ: Ewing's sarcoma: Characterization in established cultures and evidence of its histogenesis. Lab Invest 47:375-382, 1982 21. Riopelle JL, Theriault JP: Le rhabdomyosarcoma alveolaire. Ann Anat Pathol 1:88-111, 1956 Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 1983 American Society of Clinical Oncology. All rights reserved.
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