Ewing sarcoma (ES) is a malignant tumour of bone which is composed of small round tumour cells [1, 2]. It accounts for 6-8% of all primary malignant bone tumours and predominantly affects children, adolescents and young adults. It occurs rarely in patients older than 30 years and is more common in males than females (1.3:1). ES may arise in any bone. In long bones, the femur and tibia are most commonly affected [2]. Patients usually present with pain and swelling but pathological fracture may occur and some patients exhibit osteomyelitis-like systemic features. Molecular genetic studies have shown that in over 90% of cases ES tumour cells exhibit a characteristic reciprocal chromosomal translocation ie: t(11;22)(q24;q12) which results in fusion of the EWS gene and the FLI-1 gene [3].
ES is highly aggressive tumour which grows rapidly, causing extensive destruction of cancellous and cortical bone. In long bones, the tumour commonly involves the diaphysis and metaphysis with the epiphysis affected in only 2% of cases; radiologically, there is extensive permeative or moth eaten bone destruction and a soft tissue mass is seen in approximately 90% of cases at the time of diagnosis [4]. This report describes in detail a case of ES in which there was extensive ES involvement of the shaft and metaphysis of the tibial bone with erosion of the bone cortex, but unusually no involvement of soft tissues beyond the periosteum. We also describe the findings in one other case of ES of the tibia arising in a male that behaved similarly.
Case report
Case 1
A 36-year old male presented with a 5 year history of left sided shin pain to his general practitioner. A plain radiograph taken at the time showed no bone or soft tissue abnormality. He presented again a few times with recurrent left leg and forefoot discomfort, particularly on exercise, before, 4 years later, complaining of more persistent severe shin pain, including at night. On clinical examination there was no bone or soft tissue swelling of the left leg. There was no other significant medical history and the patient was otherwise well. Haematological and biochemical investigations were normal, including white cell count, ESR and CRP.
Plain radiographs taken at this time showed a large expansile permeative lytic lesion involving the proximal half of tumour of the left tibial diaphysis (Figure 1). MRI demonstrated an intramedullary lesion showing predominantly high signal on the STIR sequence and low signal on the T1- weighted sequence (Figure 2). The lesion had a mildly heterogeneous appearance with scattered areas of ill-defined high signal on the T1 -weighted images. The proximal and distal margins of the lesion were well defined. A small nubbin of tumour measuring 0.5 cm in diameter was seen to extend into the posterior cortex of the distal third of the lesion. The lesion was otherwise contained within the bone.
Histopathology of a biopsy of the lesion showed a solid proliferation of tumour cells with plump cytoplasm and round vesicular or hyperchromatic nuclei (Figure 2C). Scattered cells had a vacuolated cytoplasm containing glycogen. Occasional typical mitotic activity was noted. The lesion was well-vascularized. The tumour appeared to infiltrate between bone trabeculae. Immunohistochemistry showed strong staining of the tumour cells for vimentin and CD99 (Figure 2D). The tumour cells did not express cytokeratin, EMA, HMB45, S100, CD45, CD20, CD31, CD34, Factor 8, podoplanin, muscle/smooth muscle actin, desmin or NB84a. There was a high proliferating fraction was noted on KI-67 staining.
Radiological and histological features indicated that this was an aggressive small round cell tumour that appeared to be confined to bone. The presence of glycogen-containing CD99+ cells pointed to a diagnosis of ES [2]. Molecular genetic investigations to confirm an EWS rearrangement were attempted on the biopsy material but were unsuccessful. Although the results pointed to a ES-like round cell tumour of bone, the absence of a soft tissue mass in the face of extensive intraosseous involvement was thought to be unusual for this entity. The patient was also noted to be somewhat outside the typical age range for ES. Staging studies including MR of the left lower limb, bone scan and chest CT showed no evidence of metastasis. After discussion with the patient, a segmental resection of the tibia to include the lesion and a margin of uninvolved bone was carried out. Reconstruction of the defect was carried out with a right vascularised free fibular graft and plating with stabilization of the left tibia with a 16 hole AO condylar plate and screw fixation.
The resected segment of tibia was grossly expanded and had a thickened cortex. Cut surface revealed a large haemorrhagic tumour 18x4x4cm which filled the medulla of the tibial shaft and metaphysis (Figure 3A); the tumour did not appear to extend through the bone cortex. Histologically, there was a solid proliferation of tumour cells with small round nuclei containing fine chromatin and scanty clear or eosinophilic cytoplasm. Tumour cells contained glycogen and there was little reticulin formation within the tumour. The tumour was well- vascularized and there were focal areas of haemorrhage within the tumour. There was infiltration of cancellous bone, much of which was undergoing osteoclastic resorption (Figure 3B). The tumour extended focally into the bone cortex reaching the outer surface but not penetrating through the periosteum into surrounding soft tissue (Figure 3C). There was no evidence of matrix formation by tumour cells. Cytogenetic investigation using interphase FISH revealed the presence of an EWSR1 rearrangement in keeping with a t(11;22)(q24;q12) translocation.
Taken together, the morphological, immunophenotypic and molecular genetic findings indicated this was a case of ES which unusually appeared to be effectively confined to the bone with no periosteal or extraosseous soft tissue involvement. The patient recovered uneventfully from the operation. Following surgery he underwent adjuvant chemotherapy includes six cycles of VIDT (vincristine, ifosfamide, doxorubicin and toposide). In addition, he had radiotherapy to the left leg, 45 Gy in 25 fractions with boost to the superior and inferior margins to 54.5 Gy (9 Gy in 5 fractions). He made a good functional recovery but developed a proximal non-union of the vascularised fibular graft 18 months after initial surgery, requiring re-excision of the segment of non-union and refixation with reconstruction using an Ilizarov frame. He has been regularly followed-up for 6 years and has shown no evidence of recurrence or development of metastasis.
Case 2
The above case of ES was widely discussed with pathology, oncology and surgical colleagues, one of whom (UD) informed us of one other case of ES of the tibia arising in a 16 year old male that had somewhat similar radiological features with extensive bone but limited soft tissue involvement. Radiological features of this case are shown in Figure 4. The biopsy specimen showed a small round cell tumour which had an EWSR1 rearrangement consistent with a (11;22) (q 24;q12). The patient was given neoadjuvant chemotherapy (EURO-E.W.I.N.G. 99). The tumour regressed and histopathology of the resected specimen showed extensive necrosis of the tumour that had extensively involved medullary bone and spread to a limited extent into overlying deep soft tissue. Six years post-treatment the patient is in complete remission.