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Localized Ewing sarcoma of the tibia

Localized Ewing sarcoma of the tibia Ewing sarcoma (ES) is a high-grade malignant primary round cell tumour of bone in which there is commonly extension into extraosseous soft tissues at the time of diagnosis. This report details the clinical, radiological and pathological features of a case of ES of the tibia in which there was extensive osseous involvement but no infiltration beyond the periosteum into surrounding soft tissue. We also record the findings of one other ES case that exhibited similar behaviour. Both cases were male, involved the tibia and had the characteristic t (11;22) (q24;q12) translocation. No recurrence of tumour or metastasis has been seen in these two cases, both of which have had 6 years follow-up. Our findings indicate that there is heterogeneity in the behaviour of ES and show that localized ES is associated with a good prognosis. Keywords: Ewing sarcoma, Bone tumour, Malignant, Prognosis Introduction shaft and metaphysis of the tibial bone with erosion of Ewing sarcoma (ES) is a malignant tumour of bone which the bone cortex, but unusually no involvement of soft is composed of small round tumour cells [1,2]. It accounts tissues beyond the periosteum. We also describe the for 6-8% of all primary malignant bone tumours and pre- findings in one other case of ES of the tibia arising in a dominantly affects children, adolescents and young adults. male that behaved similarly. It occurs rarely in patients older than 30 years and is more common in males than females (1.3:1). ES may arise in Case report any bone. In long bones, the femur and tibia are most Case 1 commonly affected [2]. Patients usually present with pain A 36-year old male presented with a 5 year history of left and swelling but pathological fracture may occur and sided shin pain to his general practitioner. A plain radio- some patients exhibit osteomyelitis-like systemic features. graph taken at the time showed no bone or soft tissue ab- Molecular genetic studies have shown that in over 90% of normality. He presented again a few times with recurrent cases ES tumour cells exhibit a characteristic reciprocal left leg and forefoot discomfort, particularly on exercise, chromosomal translocation ie: t(11;22)(q24;q12) which before, 4 years later, complaining of more persistent severe results in fusion of the EWS gene and the FLI-1 gene [3]. shin pain, including at night. On clinical examination ES is highly aggressive tumour which grows rapidly, there was no bone or soft tissue swelling of the left leg. causing extensive destruction of cancellous and cortical There was no other significant medical history and the pa- bone. In long bones, the tumour commonly involves the tient was otherwise well. Haematological and biochemical diaphysis and metaphysis with the epiphysis affected in investigations were normal, including white cell count, only 2% of cases; radiologically, there is extensive per- ESR and CRP. meative or moth eaten bone destruction and a soft tissue Plain radiographs taken at this time showed a large ex- mass is seen in approximately 90% of cases at the time pansile permeative lytic lesion involving the proximal of diagnosis [4]. This report describes in detail a case of half of tumour of the left tibial diaphysis (Figure 1). MRI ES in which there was extensive ES involvement of the demonstrated an intramedullary lesion showing predo- minantly high signal on the STIR sequence and low sig- * Correspondence: nick.athanasou@ndorms.ox.ac.uk nal on the T1- weighted sequence (Figure 2). The lesion Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal had a mildly heterogeneous appearance with scattered Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX7HE, UK Full list of author information is available at the end of the article areas of ill-defined high signal on the T1 -weighted © 2013 Kashima et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 2 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Figure 1 Case 1: A) Frontal and B) lateral radiographs of the tibia showing an expansile permeative lytic lesion involving the proximal tibial diaphysis. images. The proximal and distal margins of the lesion CT showed no evidence of metastasis. After discussion were well defined. A small nubbin of tumour measuring with the patient, a segmental resection of the tibia to in- 0.5 cm in diameter was seen to extend into the posterior clude the lesion and a margin of uninvolved bone was cortex of the distal third of the lesion. The lesion was carried out. Reconstruction of the defect was carried out otherwise contained within the bone. with a right vascularised free fibular graft and plating Histopathology of a biopsy of the lesion showed a solid with stabilization of the left tibia with a 16 hole AO con- proliferation of tumour cells with plump cytoplasm and dylar plate and screw fixation. round vesicular or hyperchromatic nuclei (Figure 2C). The resected segment of tibia was grossly expanded and Scattered cells had a vacuolated cytoplasm containing had a thickened cortex. Cut surface revealed a large hae- glycogen. Occasional typical mitotic activity was noted. morrhagic tumour 18x4x4cm which filled the medulla of The lesion was well-vascularized. The tumour appeared to the tibial shaft and metaphysis (Figure 3A); the tumour infiltrate between bone trabeculae. Immunohistochemistry did not appear to extend through the bone cortex. Histo- showed strong staining of the tumour cells for vimentin logically, there was a solid proliferation of tumour cells and CD99 (Figure 2D). The tumour cells did not express with small round nuclei containing fine chromatin and cytokeratin, EMA, HMB45, S100, CD45, CD20, CD31, scanty clear or eosinophilic cytoplasm. Tumour cells con- CD34, Factor 8, podoplanin, muscle/smooth muscle actin, tained glycogen and there was little reticulin formation desmin or NB84a. There was a high proliferating fraction within the tumour. The tumour was well- vascularized was noted on KI-67 staining. and there were focal areas of haemorrhage within the Radiological and histological features indicated that tumour. There was infiltration of cancellous bone, much this was an aggressive small round cell tumour that of which was undergoing osteoclastic resorption appeared to be confined to bone. The presence of (Figure 3B). The tumour extended focally into the bone glycogen-containing CD99+ cells pointed to a diagnosis cortex reaching the outer surface but not penetrating of ES [2]. Molecular genetic investigations to confirm an through the periosteum into surrounding soft tissue EWS rearrangement were attempted on the biopsy ma- (Figure 3C). There was no evidence of matrix forma- terial but were unsuccessful. Although the results tion by tumour cells. Cytogenetic investigation using interphase FISH revealed the presence of an EWSR1 pointed to a ES-like round cell tumour of bone, the ab- sence of a soft tissue mass in the face of extensive rearrangement in keeping with a t(11;22)(q24;q12) intraosseous involvement was thought to be unusual for translocation. Taken together, the morphological, immunophenotypic this entity. The patient was also noted to be somewhat outside the typical age range for ES. Staging studies in- and molecular genetic findings indicated this was a case cluding MR of the left lower limb, bone scan and chest of ES which unusually appeared to be effectively Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 3 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Figure 2 Case 1: (A) T1-weighted and B) STIR sagittal MRI images showing a mildly heterogeneous, well-defined, expansile intramedullary lesion that is confined within the bone with the exception of a nubbin of tumour that has breached the posterior cortex (arrowed). (C) Biopsy histology shows a malignant round cell tumour. (D) Tumour cells strongly express CD99. confined to the bone with no periosteal or extraosseous radiological features with extensive bone but limited soft soft tissue involvement. The patient recovered unevent- tissue involvement. Radiological features of this case are fully from the operation. Following surgery he under- shown in Figure 4. The biopsy specimen showed a small went adjuvant chemotherapy includes six cycles of VIDT round cell tumour which had an EWSR1 rearrangement (vincristine, ifosfamide, doxorubicin and toposide). In consistent with a (11;22) (q 24;q12). The patient was given addition, he had radiotherapy to the left leg, 45 Gy in 25 neoadjuvant chemotherapy (EURO-E.W.I.N.G. 99). The fractions with boost to the superior and inferior margins tumour regressed and histopathology of the resected to 54.5 Gy (9 Gy in 5 fractions). He made a good func- specimen showed extensive necrosis of the tumour that tional recovery but developed a proximal non-union of had extensively involved medullary bone and spread to a the vascularised fibular graft 18 months after initial sur- limited extent into overlying deep soft tissue. Six years gery, requiring re-excision of the segment of non-union post-treatment the patient is in complete remission. and refixation with reconstruction using an Ilizarov frame. He has been regularly followed-up for 6 years and Discussion has shown no evidence of recurrence or development The two cases of ES documented in this report are of metastasis. unusual in that they show extensive tumour involvement of the tibial bone but limited (Case 2) or no (Case 1) Case 2 spread of tumour into surrounding soft tissues. Both The above case of ES was widely discussed with pa- case 1, which was not treated prior to surgical resection, thology, oncology and surgical colleagues, one of whom and case 2, which did receive preoperative chemothe- (UD) informed us of one other case of ES of the tibia rapy, have not shown evidence of recurrence or metasta- arising in a 16 year old male that had somewhat similar sis after 6 years follow-up; the localized nature of ES in Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 4 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Figure 3 Case 1: (A) The resected segment of the tibia shows extensive medullary involvement by ES. (B), (C) Histology of the resection showing ES spread through medullary bone and erosion of the bone cortex. these cases, particularly the limited involvement of when the patient was again investigated that ES was extraosseous soft tissue is likely to be significant in re- identified. Biochemical and haematology investigations gard to this good prognostic outcome. were normal over this 4 year period. Imaging studies Most patients with ES present with pain and swelling showed a large permeative tumour in which there was of the affected bone and surrounding soft tissues. In case erosion of cortical bone but no evidence of a significant 1, there was no clinical evidence of swelling but bone soft tissue mass or prominent periosteal reaction; the lat- pain had been noted several years prior to diagnosis. No ter is classically onion skinning in type in ES [1,2]. Case 2 tumour was identified on a plain X-ray when the patient also showed extensive medullary involvement and cortical first complained of bone pain. It was only 4 years later disruption with relatively little soft tissue spread. Figure 4 Case 2: (A) Sagittal image showing a high-signal medullary lesion of the tibial diaphysis. The linear high signal anterior to the tibia represents reactive oedema. (B) T1-weighted axial image showing intramedullary tumour with focal cortical erosion and a minor soft tissue component (arrowed). Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 5 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Histologically, the tumour in case 1 showed typical fea- with other fusion types is controversial, largely due to tures of ES. The tumour cells expressed CD99 and mo- the fact that there is a lack of prognostic information on lecular genetic investigations confirmed an EWSR1 the value of translocation type in a prospectively col- rearrangement. As in most cases of ES, the tumour largely lected trial cohort [16]. It is unclear in the cases pre- involved the medulla of the shaft; unusually there was only sented whether lack of tumour progression is related to focal cortical disruption and the tumour was noted to be a specific EWS-FLI1 fusion. A number of other biomar- entirely subperiosteal with no involvement of surrounding kers, such as tumour size, which have been related to soft tissues. No lymphatics are present in bone and this poor prognosis in ES, did not appear to correlate with was confirmed in the present case, where there was no tumour progression in this case [17]. evidence of podoplanin expression; lymph node metasta- The previously reported cases of ES developing slowly ses, which can occasionally occur in ES, were not seen in over a period of years, taken with the two cases pre- this case but can occur if there is extension of ES outside sented in this report, suggest that there is heterogeneity the bone [5]. in the growth pattern of ES with some tumours exhibit- There are a few reports of relatively low-grade beha- ing a relatively long intraosseous phase; several of these viour of ES, most of which represent rare examples of reported cases were in the tibia [6,7]. Early diagnosis is ES where the tumour is localized to bone and exhibits crucial with regard to disease outcome in ES and other radiological appearances suggestive of a benign lesion, bone sarcomas. The cases presented in this report show such as fibrous dysplasia or a simple cyst of bone [6-8]. that identification of localized ES which has not spread In one of these reports [6], a series of fibrous dysplasia- beyond the confines of the bone compartment is import- like ES of the tibia arising in children was described. ant as it is often associated with a good prognosis. Radiologically these cases did not show marked bone de- Competing interests struction and there was little or no periosteal reaction or The authors declare that they have no competing interests. soft tissue involvement [6]. In case 1 there was permea- tive lysis of the diaphysis with the proximal and distal Authors’ contributions margins of the lesion being well defined. Other cases of All authors read and approved the final manuscript. low-grade ES include a benign cystic lesion of the tibial metaphysis in a 27 year old male [7] and a lytic lesion of Acknowledgement the right humerus in a 24 year old who was initially We would like to thank Chris Lowe for typing the manuscript. This study was supported by EuroBoNet a Network of Excellence and funded by The diagnosed as osteomyelitis [9]. In most of the above European Union and the Oxford NIHR Biomedical Research Unit. cases, as in our cases, ES was largely confined to bone and the prognosis was good. Author details Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Several clinical and pathological features have been Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX7HE, UK. shown to have prognostic value in ES [10-13]. In gen- 2 Department of Pediatric Hematology and Oncology, University Children’s eral, patients younger than 10 years of age have a better Hospital Muenster, Muenster, Germany. treatment response and survival rate than older patients. Received: 21 October 2012 Accepted: 30 January 2013 The tumour site is also thought to be important with Published: 4 February 2013 distal extremity disease having a better prognosis. Tumour volume has been shown to predict survival with References tumours greater than 8 cm in maximum dimension ha- 1. Dorfman H, Cerniak B: Ewing sarcoma and related entities. St Louis: Mosby; 1998:607–642. ving poorer survival. In both case 1 and case 2, the tibia 2. de Alava E, Lessnick L, Sorensen P: Ewing sarcoma. In Pathology & Genetics. was affected and tumour volume was relatively high with Tumours of Soft Tissue and Bone. Edited by Fletcher CDM, Hogendoorn PCW, much of the bone being affected. A significant feature Bridge JA, Mertens F. Lyon: IARC Press; 2013. 3. Lopez-Terrada D: Molecular genetics of small round cell tumors. Semin likely to have contributed to the favourable outcome in Diagn Pathol 1996, 13:242–249. these cases was that the tumour was effectively confined 4. Mirra J: Bone tumours: clinical, radiologic and pathological correlation. to the bone compartment. It has been shown that most Philadelphia: Lea and Febiger; 1989. 5. Edwards JR, Williams K, Kindblom LG, Meis-Kindblom JM, Hogendoorn PC, patients with localized resectable ES (involving both Hughes D, Forsyth RG, Jackson D, Athanasou NA: Lymphatics and bone. bone and soft tissue) have a relatively good prognosis Hum Pathol 2008, 39:49–55. following surgery and multiagent chemotherapy, with 6. Arkader A, Myung KS, Stanley P, Mascarenhas L: Ewing sarcoma of the tibia mimicking fibrous dysplasia. J Pediatr Orthop B 2011, doi:10.1097/ five year survival rates of up to 80% [10,13-15]. Localized BPB.0b013e32834dfe4d. disease grossly confined to bone has been reported to 7. Maheshwari AV, Shinault SS, Robinson PG, Pitcher JD Jr: Cystic presentation have a five year survival rate of 88% compared to 20% of Ewing’s sarcoma with indolent clinico-radiologic behaviour. Acta Orthop Belg 2009, 75:836–841. with extraosseous extension [15]. Whether risk of pro- 8. Sundaram M, Inwards CY, Shives TE, Anderson PM: Ewing’s sarcoma of the gression or relapse associated with non-type 1/non-type humerus mimicking fibrous dysplasia on imaging and biological 2 EWS-FLI1 fusion is higher than the risk associated behavior. Skeletal Radiol 2005, 34:285–289. Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 6 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 9. Tow BP, Tan MH: Delayed diagnosis of Ewing’s sarcoma of the right humerus initially treated as chronic osteomyelitis: a case report. J Orthop Surg 2005, 13:88–92. 10. Bacci G, Toni A, Avella M, Manfrini M, Sudanese A, Ciaroni D, Boriani S, Emiliani E, Campanacci M: Long-term results in 144 localised Ewing’s sarcoma patients treated with combined therapy. Cancer 1989, 63:1477–1486. 11. Kinsella TJ, Miser JS, Waller B, Venzon D, Glatstein E, Weaver-McClure L, et al: Long-term follow-up of Ewing’s sarcoma of bone treated with combined modality therapy. Int J Radiat Oncol Biol Phys 1991, 20:389–395. 12. Mameghan H, Fisher RJ, O’Gorman-Hughes D, Bates EH, Huckstep RL, Mameghan J: Ewing’s sarcoma: long-term follow-up in 49 patients treated from 1967 to 1989. Int J Radiat Oncol Biol Phys 1993, 25:431–438. 13. Ahrens S, Jabar S, Heinecke A, et al: Prognostic significance of tumour volume in a volume adapated treatment strategy for localised Ewing’s sarcoma of bone. Med Pediatr Oncol 1994, 23:221. 14. Hayes FA, Thompson EI, Meyer WH, Kun L, Parham D, Rao B, Jumar M, Hancock M, Parvey L, Magill L, et al: Therapy for localised Ewing’s sarcoma of bone. J Clin Oncol 1989, 7:208–13. 15. Mendenhall CM, Marcus JR, Enneking WE, Springfields DS, Thor TL, Million RR: The prognostic significance of soft tissue extension in Ewing’s sarcoma. Cancer 1983, 51:913–917. 16. Le Deley MC, Delattre O, Schaefer KL, Burchill SA, Koehler G, Hogendoorn PCW, Lion T, Poremba C, Marandet J, Ballet S, Pierron G, Brownhill SC, Nesslbock M, Ranft A, Dirksen U, Oberlin O, Lewis IJ, Craft AW, Jurgens H, Kovar H: Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumour: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 2010, 28:1982–8. 17. van Maldegem AM, Hogendoorn PCW, Hassan AB: The clinical use of biomarkers as prognostic factors in Ewing sarcoma. Clinical Sarcoma Res 2012, 2:7. doi:10.1186/2045-3329-3-2 Cite this article as: Kashima et al.: Localized Ewing sarcoma of the tibia. Clinical Sarcoma Research 2013 3:2. 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Abstract

Ewing sarcoma (ES) is a high-grade malignant primary round cell tumour of bone in which there is commonly extension into extraosseous soft tissues at the time of diagnosis. This report details the clinical, radiological and pathological features of a case of ES of the tibia in which there was extensive osseous involvement but no infiltration beyond the periosteum into surrounding soft tissue. We also record the findings of one other ES case that exhibited similar behaviour. Both cases were male, involved the tibia and had the characteristic t (11;22) (q24;q12) translocation. No recurrence of tumour or metastasis has been seen in these two cases, both of which have had 6 years follow-up. Our findings indicate that there is heterogeneity in the behaviour of ES and show that localized ES is associated with a good prognosis. Keywords: Ewing sarcoma, Bone tumour, Malignant, Prognosis Introduction shaft and metaphysis of the tibial bone with erosion of Ewing sarcoma (ES) is a malignant tumour of bone which the bone cortex, but unusually no involvement of soft is composed of small round tumour cells [1,2]. It accounts tissues beyond the periosteum. We also describe the for 6-8% of all primary malignant bone tumours and pre- findings in one other case of ES of the tibia arising in a dominantly affects children, adolescents and young adults. male that behaved similarly. It occurs rarely in patients older than 30 years and is more common in males than females (1.3:1). ES may arise in Case report any bone. In long bones, the femur and tibia are most Case 1 commonly affected [2]. Patients usually present with pain A 36-year old male presented with a 5 year history of left and swelling but pathological fracture may occur and sided shin pain to his general practitioner. A plain radio- some patients exhibit osteomyelitis-like systemic features. graph taken at the time showed no bone or soft tissue ab- Molecular genetic studies have shown that in over 90% of normality. He presented again a few times with recurrent cases ES tumour cells exhibit a characteristic reciprocal left leg and forefoot discomfort, particularly on exercise, chromosomal translocation ie: t(11;22)(q24;q12) which before, 4 years later, complaining of more persistent severe results in fusion of the EWS gene and the FLI-1 gene [3]. shin pain, including at night. On clinical examination ES is highly aggressive tumour which grows rapidly, there was no bone or soft tissue swelling of the left leg. causing extensive destruction of cancellous and cortical There was no other significant medical history and the pa- bone. In long bones, the tumour commonly involves the tient was otherwise well. Haematological and biochemical diaphysis and metaphysis with the epiphysis affected in investigations were normal, including white cell count, only 2% of cases; radiologically, there is extensive per- ESR and CRP. meative or moth eaten bone destruction and a soft tissue Plain radiographs taken at this time showed a large ex- mass is seen in approximately 90% of cases at the time pansile permeative lytic lesion involving the proximal of diagnosis [4]. This report describes in detail a case of half of tumour of the left tibial diaphysis (Figure 1). MRI ES in which there was extensive ES involvement of the demonstrated an intramedullary lesion showing predo- minantly high signal on the STIR sequence and low sig- * Correspondence: nick.athanasou@ndorms.ox.ac.uk nal on the T1- weighted sequence (Figure 2). The lesion Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal had a mildly heterogeneous appearance with scattered Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX7HE, UK Full list of author information is available at the end of the article areas of ill-defined high signal on the T1 -weighted © 2013 Kashima et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 2 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Figure 1 Case 1: A) Frontal and B) lateral radiographs of the tibia showing an expansile permeative lytic lesion involving the proximal tibial diaphysis. images. The proximal and distal margins of the lesion CT showed no evidence of metastasis. After discussion were well defined. A small nubbin of tumour measuring with the patient, a segmental resection of the tibia to in- 0.5 cm in diameter was seen to extend into the posterior clude the lesion and a margin of uninvolved bone was cortex of the distal third of the lesion. The lesion was carried out. Reconstruction of the defect was carried out otherwise contained within the bone. with a right vascularised free fibular graft and plating Histopathology of a biopsy of the lesion showed a solid with stabilization of the left tibia with a 16 hole AO con- proliferation of tumour cells with plump cytoplasm and dylar plate and screw fixation. round vesicular or hyperchromatic nuclei (Figure 2C). The resected segment of tibia was grossly expanded and Scattered cells had a vacuolated cytoplasm containing had a thickened cortex. Cut surface revealed a large hae- glycogen. Occasional typical mitotic activity was noted. morrhagic tumour 18x4x4cm which filled the medulla of The lesion was well-vascularized. The tumour appeared to the tibial shaft and metaphysis (Figure 3A); the tumour infiltrate between bone trabeculae. Immunohistochemistry did not appear to extend through the bone cortex. Histo- showed strong staining of the tumour cells for vimentin logically, there was a solid proliferation of tumour cells and CD99 (Figure 2D). The tumour cells did not express with small round nuclei containing fine chromatin and cytokeratin, EMA, HMB45, S100, CD45, CD20, CD31, scanty clear or eosinophilic cytoplasm. Tumour cells con- CD34, Factor 8, podoplanin, muscle/smooth muscle actin, tained glycogen and there was little reticulin formation desmin or NB84a. There was a high proliferating fraction within the tumour. The tumour was well- vascularized was noted on KI-67 staining. and there were focal areas of haemorrhage within the Radiological and histological features indicated that tumour. There was infiltration of cancellous bone, much this was an aggressive small round cell tumour that of which was undergoing osteoclastic resorption appeared to be confined to bone. The presence of (Figure 3B). The tumour extended focally into the bone glycogen-containing CD99+ cells pointed to a diagnosis cortex reaching the outer surface but not penetrating of ES [2]. Molecular genetic investigations to confirm an through the periosteum into surrounding soft tissue EWS rearrangement were attempted on the biopsy ma- (Figure 3C). There was no evidence of matrix forma- terial but were unsuccessful. Although the results tion by tumour cells. Cytogenetic investigation using interphase FISH revealed the presence of an EWSR1 pointed to a ES-like round cell tumour of bone, the ab- sence of a soft tissue mass in the face of extensive rearrangement in keeping with a t(11;22)(q24;q12) intraosseous involvement was thought to be unusual for translocation. Taken together, the morphological, immunophenotypic this entity. The patient was also noted to be somewhat outside the typical age range for ES. Staging studies in- and molecular genetic findings indicated this was a case cluding MR of the left lower limb, bone scan and chest of ES which unusually appeared to be effectively Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 3 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Figure 2 Case 1: (A) T1-weighted and B) STIR sagittal MRI images showing a mildly heterogeneous, well-defined, expansile intramedullary lesion that is confined within the bone with the exception of a nubbin of tumour that has breached the posterior cortex (arrowed). (C) Biopsy histology shows a malignant round cell tumour. (D) Tumour cells strongly express CD99. confined to the bone with no periosteal or extraosseous radiological features with extensive bone but limited soft soft tissue involvement. The patient recovered unevent- tissue involvement. Radiological features of this case are fully from the operation. Following surgery he under- shown in Figure 4. The biopsy specimen showed a small went adjuvant chemotherapy includes six cycles of VIDT round cell tumour which had an EWSR1 rearrangement (vincristine, ifosfamide, doxorubicin and toposide). In consistent with a (11;22) (q 24;q12). The patient was given addition, he had radiotherapy to the left leg, 45 Gy in 25 neoadjuvant chemotherapy (EURO-E.W.I.N.G. 99). The fractions with boost to the superior and inferior margins tumour regressed and histopathology of the resected to 54.5 Gy (9 Gy in 5 fractions). He made a good func- specimen showed extensive necrosis of the tumour that tional recovery but developed a proximal non-union of had extensively involved medullary bone and spread to a the vascularised fibular graft 18 months after initial sur- limited extent into overlying deep soft tissue. Six years gery, requiring re-excision of the segment of non-union post-treatment the patient is in complete remission. and refixation with reconstruction using an Ilizarov frame. He has been regularly followed-up for 6 years and Discussion has shown no evidence of recurrence or development The two cases of ES documented in this report are of metastasis. unusual in that they show extensive tumour involvement of the tibial bone but limited (Case 2) or no (Case 1) Case 2 spread of tumour into surrounding soft tissues. Both The above case of ES was widely discussed with pa- case 1, which was not treated prior to surgical resection, thology, oncology and surgical colleagues, one of whom and case 2, which did receive preoperative chemothe- (UD) informed us of one other case of ES of the tibia rapy, have not shown evidence of recurrence or metasta- arising in a 16 year old male that had somewhat similar sis after 6 years follow-up; the localized nature of ES in Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 4 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Figure 3 Case 1: (A) The resected segment of the tibia shows extensive medullary involvement by ES. (B), (C) Histology of the resection showing ES spread through medullary bone and erosion of the bone cortex. these cases, particularly the limited involvement of when the patient was again investigated that ES was extraosseous soft tissue is likely to be significant in re- identified. Biochemical and haematology investigations gard to this good prognostic outcome. were normal over this 4 year period. Imaging studies Most patients with ES present with pain and swelling showed a large permeative tumour in which there was of the affected bone and surrounding soft tissues. In case erosion of cortical bone but no evidence of a significant 1, there was no clinical evidence of swelling but bone soft tissue mass or prominent periosteal reaction; the lat- pain had been noted several years prior to diagnosis. No ter is classically onion skinning in type in ES [1,2]. Case 2 tumour was identified on a plain X-ray when the patient also showed extensive medullary involvement and cortical first complained of bone pain. It was only 4 years later disruption with relatively little soft tissue spread. Figure 4 Case 2: (A) Sagittal image showing a high-signal medullary lesion of the tibial diaphysis. The linear high signal anterior to the tibia represents reactive oedema. (B) T1-weighted axial image showing intramedullary tumour with focal cortical erosion and a minor soft tissue component (arrowed). Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 5 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 Histologically, the tumour in case 1 showed typical fea- with other fusion types is controversial, largely due to tures of ES. The tumour cells expressed CD99 and mo- the fact that there is a lack of prognostic information on lecular genetic investigations confirmed an EWSR1 the value of translocation type in a prospectively col- rearrangement. As in most cases of ES, the tumour largely lected trial cohort [16]. It is unclear in the cases pre- involved the medulla of the shaft; unusually there was only sented whether lack of tumour progression is related to focal cortical disruption and the tumour was noted to be a specific EWS-FLI1 fusion. A number of other biomar- entirely subperiosteal with no involvement of surrounding kers, such as tumour size, which have been related to soft tissues. No lymphatics are present in bone and this poor prognosis in ES, did not appear to correlate with was confirmed in the present case, where there was no tumour progression in this case [17]. evidence of podoplanin expression; lymph node metasta- The previously reported cases of ES developing slowly ses, which can occasionally occur in ES, were not seen in over a period of years, taken with the two cases pre- this case but can occur if there is extension of ES outside sented in this report, suggest that there is heterogeneity the bone [5]. in the growth pattern of ES with some tumours exhibit- There are a few reports of relatively low-grade beha- ing a relatively long intraosseous phase; several of these viour of ES, most of which represent rare examples of reported cases were in the tibia [6,7]. Early diagnosis is ES where the tumour is localized to bone and exhibits crucial with regard to disease outcome in ES and other radiological appearances suggestive of a benign lesion, bone sarcomas. The cases presented in this report show such as fibrous dysplasia or a simple cyst of bone [6-8]. that identification of localized ES which has not spread In one of these reports [6], a series of fibrous dysplasia- beyond the confines of the bone compartment is import- like ES of the tibia arising in children was described. ant as it is often associated with a good prognosis. Radiologically these cases did not show marked bone de- Competing interests struction and there was little or no periosteal reaction or The authors declare that they have no competing interests. soft tissue involvement [6]. In case 1 there was permea- tive lysis of the diaphysis with the proximal and distal Authors’ contributions margins of the lesion being well defined. Other cases of All authors read and approved the final manuscript. low-grade ES include a benign cystic lesion of the tibial metaphysis in a 27 year old male [7] and a lytic lesion of Acknowledgement the right humerus in a 24 year old who was initially We would like to thank Chris Lowe for typing the manuscript. This study was supported by EuroBoNet a Network of Excellence and funded by The diagnosed as osteomyelitis [9]. In most of the above European Union and the Oxford NIHR Biomedical Research Unit. cases, as in our cases, ES was largely confined to bone and the prognosis was good. Author details Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Several clinical and pathological features have been Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX7HE, UK. shown to have prognostic value in ES [10-13]. In gen- 2 Department of Pediatric Hematology and Oncology, University Children’s eral, patients younger than 10 years of age have a better Hospital Muenster, Muenster, Germany. treatment response and survival rate than older patients. Received: 21 October 2012 Accepted: 30 January 2013 The tumour site is also thought to be important with Published: 4 February 2013 distal extremity disease having a better prognosis. Tumour volume has been shown to predict survival with References tumours greater than 8 cm in maximum dimension ha- 1. Dorfman H, Cerniak B: Ewing sarcoma and related entities. St Louis: Mosby; 1998:607–642. ving poorer survival. In both case 1 and case 2, the tibia 2. de Alava E, Lessnick L, Sorensen P: Ewing sarcoma. In Pathology & Genetics. was affected and tumour volume was relatively high with Tumours of Soft Tissue and Bone. Edited by Fletcher CDM, Hogendoorn PCW, much of the bone being affected. A significant feature Bridge JA, Mertens F. Lyon: IARC Press; 2013. 3. 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Maheshwari AV, Shinault SS, Robinson PG, Pitcher JD Jr: Cystic presentation have a five year survival rate of 88% compared to 20% of Ewing’s sarcoma with indolent clinico-radiologic behaviour. Acta Orthop Belg 2009, 75:836–841. with extraosseous extension [15]. Whether risk of pro- 8. Sundaram M, Inwards CY, Shives TE, Anderson PM: Ewing’s sarcoma of the gression or relapse associated with non-type 1/non-type humerus mimicking fibrous dysplasia on imaging and biological 2 EWS-FLI1 fusion is higher than the risk associated behavior. Skeletal Radiol 2005, 34:285–289. Kashima et al. Clinical Sarcoma Research 2013, 3:2 Page 6 of 6 http://www.clinicalsarcomaresearch.com/content/3/1/2 9. Tow BP, Tan MH: Delayed diagnosis of Ewing’s sarcoma of the right humerus initially treated as chronic osteomyelitis: a case report. J Orthop Surg 2005, 13:88–92. 10. 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J Clin Oncol 1989, 7:208–13. 15. Mendenhall CM, Marcus JR, Enneking WE, Springfields DS, Thor TL, Million RR: The prognostic significance of soft tissue extension in Ewing’s sarcoma. Cancer 1983, 51:913–917. 16. Le Deley MC, Delattre O, Schaefer KL, Burchill SA, Koehler G, Hogendoorn PCW, Lion T, Poremba C, Marandet J, Ballet S, Pierron G, Brownhill SC, Nesslbock M, Ranft A, Dirksen U, Oberlin O, Lewis IJ, Craft AW, Jurgens H, Kovar H: Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumour: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 2010, 28:1982–8. 17. van Maldegem AM, Hogendoorn PCW, Hassan AB: The clinical use of biomarkers as prognostic factors in Ewing sarcoma. Clinical Sarcoma Res 2012, 2:7. doi:10.1186/2045-3329-3-2 Cite this article as: Kashima et al.: Localized Ewing sarcoma of the tibia. Clinical Sarcoma Research 2013 3:2. 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Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Feb 4, 2013

References