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Lower Back Pain and Mass in a 13-Year-Old Girl

Ricchetti, E T, MD*; Erol, B, MD; Stern, J, MD; Russo, P, MD§; States, L, MD; Dormans, J P, MD

Clinical Orthopaedics and Related Research®: January 2005 - Volume 430 - Issue - p 248-257
doi: 10.1097/01.blo.0000128641.53637.c9
Orthopaedic • Radiology • Pathology Conference: CME ARTICLE
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From the *Medical Student, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA; †Attending Physician, Marmara University Hospital, Istanbul, Turkey; ‡Clinical Assistant Professor, Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA; §Director, Anatomic Pathology, Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA; ^Attending Physician in Radiology, Department of Radiology, The Children’s Hospital of Philadelphia, Philadelphia, PA; and the ¶Chief, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA.

These materials are available on CORRONLINE for continuing medical educational credit.

The authors have disclosed that they have no financial interests in or relationships with any commercial companies pertaining to this educational activity.

Correspondence to: John P. Dormans, MD, Chief, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, 2nd Floor Wood Center, 34th & Civic Blvd., Philadelphia, PA 19104-4399; Phone: 215-590-1534; Fax: 215-590-1501; E-mail: dormans@email.CHOP.edu.

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LEARNING OBJECTIVES

On completion of this activity, the reader should be able to:

  1. prepare a differential diagnosis and diagnostic algorithm for patients with primary mesenchymal malignancies of the axial skeleton;
  2. identify an appropriate staging evaluation; and
  3. organize and plan a multimodality treatment program.
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HISTORY AND PHYSICAL EXAMINATION

A 13 year-old girl reported lower back pain, particularly on the left side, for approximately 6 months before presenting to our institution. The pain initially was thought to be muscle strain secondary to playing basketball, and plain radiographs were read as normal. However, the pain increased recently with the patient reporting occasional episodes of numbness and tingling in her upper left leg, extending to the midthigh. A week before presentation, a painful mass on the left side of the patient’s lower back was seen. A review of plain radiographs revealed a possible lesion in the lumbar spine. Magnetic resonance imaging (MRI) was done and revealed a paraspinal mass arising from the lumbar vertebral bodies. The patient was referred to our institution for additional evaluation.

The patient had no previous major illnesses, injuries, or surgeries and no evidence of urinary retention, urinary incontinence, constipation, diarrhea, or constitutional symptoms, such as weight loss, fatigue, fever, sweats, chills, nausea, and vomiting. The patient was the product of a full-term, uncomplicated pregnancy, and her developmental and family histories were noncontributory.

On physical examination, the patient’s gait was normal. A 7.0 × 8.0 cm, firm, immobile, tender soft tissue mass was present to the left of lumbar spine levels L1-L3. There was no erythema or increased warmth over the area of the mass. Neurovascular examination was normal. Her abdomen was soft and nontender without masses or hepatosplenomegaly. There was no evidence of lymphadenopathy. The remainder of the physical examination was normal.

Laboratory tests revealed a normal white blood cell count, hemoglobin, platelet count, and complete chemistry panel. Lactic dehydrogenase was elevated at 1309 U/L (normal, 380-640 U/L).

Plain radiographs of the chest showed a possible nodule in the right lung. Computed tomography scans of the chest and bone scan of the entire body confirmed the presence of the right lung nodule and showed additional bony lesions in the thoracolumbar spine. The radiograph of the chest, CT, bone scan, and the plain radiographs and MRI scans of the lumbar spine are shown in Figures 1 to 6.

Fig 1.

Fig 1.

Fig 2.

Fig 2.

Fig 3.

Fig 3.

Fig 4.

Fig 4.

Fig 5.

Fig 5.

Fig 6.

Fig 6.

Based on the history, physical findings, and imaging studies, what is the differential diagnosis?

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IMAGING INTERPRETATION

The AP radiograph (Fig 1) of the lumbar spine shows an abnormality of the third lumbar vertebrae. There is loss of the normal outline of the left pedicle and left transverse process (arrows). The margins of the lesion are ill-defined. Slight loss of height of the left lateral aspect of the vertebral body also is seen. There is no evidence of an obvious paraspinal soft tissue mass or other lesions along the spine. The coronal T2-weighted magnetic resonance scan (Fig 2) shows the predominantly high signal, heterogenous mass arising from the third lumbar vertebrae. The vertebral lesion replaces normal bone marrow diffusely. An associated large, lobulated soft tissue mass (M) is seen arising out of the left lateral aspect of this vertebral body, with displacement of the left psoas muscle. Additional areas of increased signal intensity representing other foci are evident in the twelfth thoracic vertebrae (white arrow) and the left pedicles of the fourth and fifth lumbar vertebrae (black arrows). An area of mildly increased signal intensity in the central marrow of the second lumbar vertebrae (arrowhead) also likely represents another focus. The sagittal T2-weighted scan (Fig 3) shows the same diffuse marrow replacement of the third lumbar vertebrae and the associated soft tissue mass (M) and invasion of the epidural space (arrows). Mildly increased signal intensity is seen in the posterior aspect of the fifth lumbar vertebrae (arrowhead). A technetium-99 bone scan of the entire body also characterizes the bone lesions. The posterior view (Fig 4) shows increased radiotracer uptake at multiple levels in the thoracolumbar spine in addition to the primary L3 lesion (arrow), including the eleventh thoracic through the fifth lumbar vertebrae, and a focus in the first thoracic vertebrae (arrowhead). The posterior, left eleventh thoracic rib also has abnormal radiotracer activity (arrow). The AP radiograph (Fig 5) of the chest shows a possible nodule (arrow) in the right lower lung field. A CT scan of the chest (Fig 6) confirms the presence of a large (1 × 1 cm) soft tissue nodule (arrow) in the right lower lobe representing a lung lesion.

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DIFFERENTIAL DIAGNOSIS

Ewing’s sarcoma or primitive neuroectodermal tumor (PNET)

  • Osteosarcoma
  • Rhabdomyosarcoma
  • Lymphoma
  • Acute leukemia

After presentation to our institution, an incisional biopsy of the flank mass with an intraoperative frozen section was done. The photomicrographs from the permanent sections are shown in Figures 7 to 9. Bone marrow sampling of the right and left posterior iliac crest also was done at the time of biopsy.

Fig 7.

Fig 7.

Fig 8.

Fig 8.

Fig 9.

Fig 9.

Based on the history, physical findings, radiographic studies, and histologic pictures, what is the diagnosis and how should this lesion be treated?

See page 254 for diagnosis and treatment.

Continuation of ORP Conference from page 253.

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HISTOLOGIC EVALUATION

The specimen consisted of multiple fragments of tan-pink tissue. Histologic examination showed sheets of cohesive, small round cells with hyperchromatic nuclei and little cytoplasm infiltrating skeletal muscle (Figs 7, 8). Immunohistochemistry revealed a characteristic strong perimembranous staining with CD-99 (MIC2) (Fig 9). Vimentin stain also was positive. The presence of an EWS-FLI1 translocation, t(11;22), was confirmed by RT-PCR assay on frozen tissue. Muscle, epithelial cell, and hematopoietic markers were negative. Bone marrow specimens from the right and left iliac crests revealed hypocellular bone marrow with trilineage hematopoiesis. There was no evidence of tumor, lymphoid aggregate, granuloma, or other abnormality.

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DIAGNOSIS

Metastatic Ewing’s sarcoma

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TREATMENT AND DISCUSSION

The clinical, radiographic, and pathologic findings in the current patient were consistent with the diagnosis of Ewing’s sarcoma of the spine with metastases. In general, primary tumors of the spine are rare in children, representing less than 5% of skeletal tumors in this age group.9 The differential diagnosis in the current patient with metastases included other malignant bone and soft tissue tumors of childhood and adolescence that can present with spinal involvement, such as osteosarcoma, rhabdomyosarcoma, lymphoma, and leukemia. Ultimately, these other tumors were ruled out on histologic evaluation through a combination of morphologic appearance, the presence of markers consistent with Ewing’s sarcoma (MIC2 and vimentin), and the characteristic chromosomal translocation, t(11;22), of Ewing’s Sarcoma. For example, although osteosarcoma is the most common primary malignant bone tumor of childhood, with 10% found in the axial skeleton,9 the classic histologic features of this tumor (large, sarcomatous, pleomorphic spindle cells in the presence of osteoid matrix) were not seen in the current patient.15 Rhabdomyosarcoma, lymphoma, and leukemia were excluded in a similar manner. Acute leukemia is the most common childhood cancer, with acute lymphoblastic leukemia being the most likely to present with bone involvement. However, bone marrow aspiration in the current patient did not show the typical leukemic blast cells and the patient’s CBC was normal.

Ewing’s sarcoma first was described as a diffuse endothelioma of the bone by James Ewing in 1921.10 Since that time, the understanding of this neoplasm has increased tremendously. The Ewing’s family of tumors now describes a group of small round cell tumors of neuroectodermal origin.25 This group includes not only Ewing’s sarcoma, but also related tumors such as PNET, Askin’s tumor (a variant of Ewing’s sarcoma or PNET in the thoracopulmonary region), and possibly several other sarcomas. Although the etiology remains unknown, approximately 90-95% of Ewing’s sarcomas are characterized by the presence of the reciprocal t(11;22)(q24;q12) translocation, as seen in the current case. The other 5-10% of cases have a t(21;22)(q22;q12) translocation.20 Either rearrangement joins the EWS gene (chromosome 22) with one of several genes encoding structurally related transcription factors, most often FLI1 (chromosome 11) or ERG (chromosome 21). The result is a fusion gene that may act as an oncogene, promoting tumor growth through a chimeric transcript, and transcriptional deregulation.6,12,20

Ewing’s sarcoma represents approximately 3% of all malignancies in pediatric patients and is the second most common (30%) bone malignancy in patients younger than 21 years, following osteosarcoma (60%).4,25 Vertebral involvement by Ewing’s sarcoma typically is secondary to metastases from other primary sites. Primary vertebral tumors are uncommon,17 accounting for only 3.5-10% of all cases of Ewing’s sarcoma,3,13,21,25,27 although Ewing’s sarcoma is the most common primary malignant spinal bone tumor in children.14 Only three cases of primary Ewing’s sarcoma of the spine were seen at our institution in the most recent 10-year review.9 Because of the rarity of spinal lesions, much of the data on these patients are available only through case reports and small series. Four larger series have examined this subset of tumors in more depth to define the clinical characteristics and prognostic factors.3,13,21,25 Many of the findings are similar to those seen in nonvertebral tumors.

The median age at the time of diagnosis for primary vertebral Ewing’s sarcoma ranges from 12-19.5 years. There seems to be a stronger male predilection in primary spinal tumors than in nonspinal tumors,7 possibly as high as 2:1. The most common primary tumor site is distal, either in the sacrum or lumbar vertebrae. The most common presenting complaint is pain, either local or radiating, seen in 94-100% of patients. Neurologic deficits are seen in 50-94% of patients at presentation because of nerve compression by the tumor, and include sensory and motor deficits and neurogenic bladder or bowel problems in patients with distal tumors.3,13,21,25 Patients with sacral lesions typically have a longer duration of symptoms before diagnosis than patients with proximal lesions.13,21,25 In terms of tumor extension, one study reported a higher likelihood of bone (55%) and cerebral (20%) metastasis in primary spinal tumors, with only 25% of metastases to the lungs.3 This is in contrast to nonspinal primary lesions, where pulmonary metastases predominate (50%) and central nervous system (CNS) metastases are rare.11,22 The current patient had lung and bone metastases.

Ewing’s sarcoma can be recognized and assessed radiographically through plain radiographs, MRI, and CT scans. The initial imaging study in a suspected bone malignancy should be plain radiography. The majority of Ewing’s sarcoma are purely lytic lesions, regardless of location.3,8,13 These lytic lesions typically have an ill-defined, permeative, or moth-eaten appearance with intramedullary destruction and often are associated with an overlying soft tissue mass. Periosteal bone formation along the diaphysis, either in an onion skin (lamellar) or sunburst (radiating) appearance, is a classic finding. Cortical thickening and sclerosis are very common in Ewing’s sarcoma and a concave defect on the bone surface, known as saucerization, can be seen frequently on either plain radiographs or MRI secondary to a subperiosteal mass.8

Although the diagnosis of Ewing’s sarcoma frequently is suggested by plain radiographs alone, radiographs often do not correctly define the full extent of a lesion, particularly in the spine.8,19 Magnetic resonance imaging and CT scanning provide a more accurate evaluation of the size of a lesion, with MRI considered the most sensitive modality and the radiographic test of choice for diagnosis, local staging, and surgical planning.16,18 Additional work up for staging purposes in Ewing’s sarcoma involves obtaining a CT scan of the chest and technetium bone scan before biopsy, and a bone marrow sampling at the time of biopsy to detect distant metastases.20,24

Radiographic imaging is a valuable tool in the differential diagnosis of Ewing’s sarcoma, but definitive diagnosis requires a pathologic specimen. In addition to typical histologic evaluation, cytogenetic and immunohistochemical analyses also are useful in distinguishing Ewing’s sarcoma from other small round cell tumors of childhood. More traditional staining markers include periodic acid Schiff (PAS) staining, used to detect the presence of glycogen in Ewing’s sarcoma cells, and vimentin, an intermediate filament and the most consistently positive immunohistochemical marker in Ewing’s sarcoma, seen in 80-90% of cases.8,26 Newer techniques have helped to additionally define Ewing’s sarcoma and have become an important part of diagnosis, including the RT-PCR assay used to detect the classic t(11;22) translocation in the current patient.12 For example, a majority of Ewing’s sarcomas produce a cell surface glycoprotein product of the MIC2 gene, p30/32 MIC2. This antigen is detected by monoclonal antibody staining in a characteristic strong perimembranous pattern and can be identified in approximately 90% of Ewing’s sarcoma.8,26 MIC2 can be present in other tumors, but usually is seen at high levels only in T cells and Ewing’s sarcoma cells.8,12

Ewing’s sarcoma is a very aggressive tumor with high rates of local recurrence and distant metastasis, suggesting that this typically is a systemic disease, with micrometastatic foci even if only presenting locally. The modern treatment philosophy of Ewing’s sarcoma, therefore, involves a multimodal approach. Neoadjuvant chemotherapy initially is used to reduce the size of the presenting tumor and metastatic or micrometastatic lesions, followed by local control through surgery and radiation, and postoperative or postradiation adjuvant chemotherapy to prevent and control systemic spread.15 Multiagent chemotherapy for patients with nonmetastatic, resectable disease has increased 5-year survival rates from 5-70%.1,2,26 The most commonly used agents are vincristine, cyclophosphamide, doxorubicin, ifosfamide, and etoposide. The effectiveness of chemotherapy for metastatic disease has not been as profound. Five-year survival rates are approximately 25-30% and have not improved with the addition of ifosfamide and etoposide.5,8,12

Surgical excision is one of the methods of local control in Ewing’s sarcoma. The goal of surgery for spinal lesions should be complete tumor excision with stable reconstruction of the vertebral column.9 However, techniques include complete, subtotal, or partial resection with or without laminectomy, depending on tumor size, site, resectability, and the severity of neurologic symptoms.3,13,21,25 Conventional methods typically have involved intralesional, piecemeal resection; but newer, more aggressive surgical techniques using extralesional resection with wider surgical margins have shown success.23 Despite its benefits, surgery can be associated with significant morbidity, particularly if tumors are large or in important functional areas, and prognosis remains poor in metastatic disease.12 The use of laminectomy in spinal malignancies is controversial because of the risk of postlaminectomy kyphosis and spinal instability.13

Radiation therapy is another method of local control, particularly useful if the likelihood of complete resection is low, often the case in spinal and extensive pelvic lesions, or in surgically nonexpendable sites.3,13,20,21,25 Radiation is used with an understanding of its significant associated risks, such as secondary malignancies (particularly osteosarcoma), growth disturbance, pathologic fractures, and spinal cord injury in vertebral tumors.3,20,21 These risks may be exacerbated in young children.

New evolving techniques in treatment include immunotherapeutic approaches that target the Ewing’s sarcoma translocation or other Ewing’s sarcoma cell markers, and high dose chemotherapy with or without total body irradiation for relapsing or metastatic disease.15,20 High dose therapy has shown a significant survival advantage in nonmetastatic disease and evidence suggests that higher doses of chemotherapy with or without radiation also may be more likely to eradicate aggressive metastatic disease and micrometastatic foci.26 High dose therapy is myeloablative, requiring the collection of stem cells before treatment and subsequent stem cell reinfusion after treatment to restore bone marrow function.

The presence of metastases at diagnosis is an important prognostic factor in patients with Ewing’s sarcoma. Patients with metastases continue to have dismal outcomes despite treatment improvements. Another adverse factor is large tumor volumes (in one series defined as greater than 8 cm).12,25,26 Studies disagree on whether tumor location is an independent adverse factor or if size is a confounding variable, but it seems that the prognosis for a primary vertebral lesion is no worse than the prognosis for a nonspinal primary tumor.12,13,21,25,26 The difference with spinal lesions, however, is that local control with surgery is more challenging and in some cases impossible to achieve without increased risk of paralysis or other nerve damage. Chemotherapy-induced tumor necrosis is another important prognostic factor in patients with Ewing’s sarcoma. It is a major independent predictor of overall and relapse-free survival, with the degree of necrosis appearing to positively correlate with the rate of disease-free survival.8,20,24,26

Because of the presence of pulmonary and bone metastases at diagnosis, the current patient had treatment involving high dose chemotherapy and radiation therapy with the hope of improving prognosis. Treatment consisted of five cycles of neoadjuvant chemotherapy (vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide), with peripheral stem cell harvest performed after the third cycle. Local radiation therapy was delivered after neoadjuvant chemotherapy. The patient then proceeded with two more cycles of high dose chemotherapy approximately 6 weeks apart, with stem cell transplantation after each cycle and total body irradiation after the second cycle, to eliminate known residual disease. The patient had a good initial chemotherapeutic response, with radiographic resolution of her pulmonary and rib metastases, radiographic improvement in her primary L3 tumor, and no new bone metastases. The patient went into remission for approximately 6 months after treatment, but had a local relapse of tumor at the L3, L4, and L5 vertebrae. Based on the location of the patient’s tumor recurrence and the high risk associated with surgical and/or further radiation treatment, the patient was placed on palliative chemotherapy with etoposide and was symptom free 18 months after the original diagnosis.

Ewing’s sarcoma represents the second most common bone malignancy of childhood and adolescents, but primary vertebral lesions are rare. Patients with spinal lesions commonly present with pain and neurologic deficits because of their vertebral location. Magnetic resonance imaging is a valuable tool in the differential diagnosis of Ewing’s sarcoma, but definitive diagnosis requires a pathologic specimen. The use of modern molecular and immunohistochemical techniques have become integral to the diagnosis of these tumors. Treatment of Ewing’s sarcoma is multimodal, with newer techniques for relapsing or metastatic disease involving high dose chemotherapy and total body irradiation followed by bone marrow or stem cell transplantation. Important prognostic factors for Ewing’s sarcoma include metastasis at presentation and chemotherapy-induced tumor necrosis, but the prognosis of primary vertebral lesions seems to be no worse than the prognosis for nonspinal primary tumors.

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References

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