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DOI: 10.1055/s-0038-1676125
Ewing's Sarcoma and Primary Osseous Lymphoma: Spectrum of Imaging Appearances
Abstract
Ewing's sarcoma (ES) is a rare, highly malignant anaplastic stem cell tumor. Histologically, the tumor consists of uniform densely packed small monomorphic cells with round nuclei. The typical appearance at hematoxylin and eosin (H&E) staining is small blue round cells without any matrix formation. On conventional radiography, ES typically presents as a permeative lesion in the diaphysis of a long bone in a child. A large soft tissue component is another characteristic feature, best depicted by magnetic resonance imaging.
Primary osseous lymphomas are most commonly highly malignant B-cell lymphomas. At H&E histologic staining, the tumor stroma consists of diffuse round-cell infiltrates that resembles the appearance of ES. Although there is no typical imaging appearance of an osseous lymphoma, it should be considered in an adult presenting with a Lodwick grade II or III lesion in the metaphysis or diaphysis of a large long bone, the pelvis, or the vertebral column. Histologic confirmation is mandatory.
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Keywords
Ewing's Sarcoma - primary osseous lymphoma - radiography - magnetic resonance imaging - reviewEwing's Sarcoma
Definition
Ewing's sarcoma (ES) is a rare, highly malignant anaplastic stem cell tumor of neuroectodermal origin, also classified as round-cell sarcoma, to which the primitive neuroectodermal tumors also belong. It mainly arises from the bone.[1]
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Demography
ES represents ∼ 7 to 10% of all malignant bone tumors and affects mainly children and adolescents. The mean age is 15 years, and the age peak is 9 to 25 years. However, rarely children and elderly people may be affected. In a series of 64 patients, patient ages ranged between 7 and 67 years.[2] In Germany, the annual incidence is 120 new cases in a general population of 80 million. Boys are 1.5 to 2.4 times more often affected than girls.[2] In children, ES is the second most common primary malignant bone tumor after osteosarcoma.
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Clinical Manifestations
Symptoms consist of nonspecific, non–exercise-related pain in the area of the tumor and swelling. General symptoms such as fever, fatigue, loss of appetite, and weight may appear more frequently than in other malignant bone tumors.[1]
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Localization
ES mainly is localized in the long bones of the extremities and most commonly within the diaphysis close to the metaphysis. The most commonly affected bone is the femur (25%) ([Fig. 1]), followed by the tibia (11%) ([Fig. 2]), humerus (11%), and pelvic bones (11%) ([Fig. 3]).[1] Other localizations are the fibula (7%) ([Figs. 4] and [5]) and ribs (6%) ([Fig. 5]). ES can virtually involve all bones of the body and may also involve extraskeletal sites ([Fig. 1]). An isolated involvement of the soft tissue (extraskeletal ES) was observed in 1.5% of all cases in a series of 64 patients.[2] Compared with osteosarcoma, flat bones are more often affected in ES. Rarely, a bicentric ES or synchronous involvement of multiple bones may be seen ([Fig. 6]), whereas transarticular spread can rarely be seen in sacroiliac joints.[3] Up to 15% of all ES cases are localized in the vertebral column, with the lumbar spine and the sacrum as the most commonly affected; the location of ES tends to follow the distribution of red marrow. The mean age at initial clinical presentation is 19.3 years, slightly higher than the mean age of ES of the extremity bones.[4] Metastases of ES affecting the vertebral column are more common than a primary ES of the spine.[5]
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Pathology
Macroscopically, the tumor has the aspect of fish flesh. At histology, the tumor consists of uniform densely packed small monomorphic cells with round nuclei that are generally larger than in primary osseous lymphoma. The typical appearance at hematoxylin and eosin (H&E) staining is small blue round cells without any matrix formation ([Fig. 2]). At immunostaining, an expression of the cellular surface antigen CD99, a product of the MIC-2 gene, is characteristic. The characteristic reciprocal translocation between chromosome 11 and 22 (t[11;22]), which affects in 85% the EWS and FLI1 gene, can be confirmed by using break- apart fluorescence in situ hybridization ([Fig. 2]).[1] [6] [7]
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Imaging
Conventional radiography (CR) reveals an aggressive osteolytic lesion with a wide zone of transition and with a moth-eaten or permeative pattern in most cases.[8] In a series of 64 patients, most tumors were mixed lytic-sclerotic (in 75%) and purely lytic in 25%.[2] Complex periosteal reactions like onion-skinned, spiculae, “sunburst,” or Codman's triangle can be seen ([Fig. 5]) in 27 to 50% of all cases.[2] Onion-skinned or multi-lamellated periosteal reactions may be encountered in 25% of cases. Computed tomography (CT) is more sensitive than CR to detect bony destruction in anatomically complex regions such as the vertebral column and the pelvic bones due to the lack of superimposition. In flat bones such as the pelvic bones, ES may have a predominantly sclerotic appearance ([Fig. 3]) that overall represents ∼ 10% of cases. The reason for the sclerotic appearance is mainly necrotic bony changes because tumor-related formation of new bone is not a histologic feature of ES.[1]
Magnetic resonance imaging (MRI) is the method of choice for local staging because it demonstrates the true tumor extension ([Figs. 4], [5], [6], [7]). The MRI protocol has to cover the entire tumor extent as well as the adjacent joints and the entire bone where the tumor originates because skip lesions ([Fig. 5]), which when present have great influence on the treatment planning, are frequent. Skip metastases at initial presentation were present in 14% of all cases in a series of 64 patients.[2] The signal intensity of the tumor tissue of the ES is hypointense on T1-weighted images and hyperintense on T2-weighted images. A large soft tissue component is highly characteristic (96% of all cases),[8] showing marked contrast enhancement.[2] Focal areas of cortical destruction are frequent (92% of all cases),[8] allowing continuity between the intraosseous and extraosseous components ([Figs. 5], [6], [7]). This continuity is also commonly seen as subtle channels extending through the cortex at MRI, a finding that reflects the underlying pathologic appearance[8] because the communication between the medullary canal and soft tissue components may be through focal cortical destruction or more commonly through permeation of the cortical haversian canal system and along neurovascular channels with small nests of tumor cells.[8] Extraskeletal ES commonly demonstrates a nonspecific radiologic appearance of a large soft tissue mass affecting the paraspinal region or lower extremity,[8] and it may be occult on CR ([Fig. 1]). Another imaging characteristic that may occur in ES as well as osseous lymphoma is the so-called wraparound sign. This means that the cortex at T2-weighted images appears regularly hypointense, although there is a large soft tissue component that appears to be wrapped around the bone. This is believed to be due to the permeative growth of the tumor so that the calcified bone is not destroyed to a major extent ([Figs. 4], [5], [6], [7]).
Because ES most often metastasizes hematogenously into the lung (although lymphatic and osseous spread may also occur but is rare; the incidence of regional node involvement is ∼ 3% in skeletal ES[9]), staging consists of CT of the thorax and abdomen as well as bone scintigraphy or positron emission tomography (PET) using fluorodeoxyglucose (FDG) as a tracer to detect or exclude metastases. In 25% of all cases, there are metastases present at the time of diagnosis of ES. According to the EWING 2008 study,[10] initial imaging of ES consists of MRI for local staging, chest CT, whole-body scintigraphy, and FDG-PET. After completion of imaging, the final diagnosis will be verified at histology and by genetic markers from biopsy material. Biopsy should be performed in a dedicated sarcoma treatment center.[11]
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Differential Diagnosis
In general, all tumors consisting of small round blue cells may have similar imaging features. The main differential diagnoses consist of osteolytic osteosarcoma and small-cell osteosarcoma in children and adolescents, osteomyelitis in all age groups, and non-Hodgkin's lymphoma in adulthood.[12] In children, unifocal Langerhans cell histiocytosis is another differential, but the periosteal reaction is often less aggressive, and an eosinophilic granuloma may have a sequestrum. In the spine, ES may mimic spondylitis because of its high signal intensity in T2-weighted images,[4] [13] whereas in the rare case of sacroiliac joint involvement, it should be distinguished from septic sacroiliitis ([Fig. 7]).[3]
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Therapy and Treatment Monitoring
Treatment is interdisciplinary and consists of induction chemotherapy and local therapy with subsequent chemotherapy and/or radiation therapy within multicentric study protocols.[14] [15] Such multicentric study protocols are, for instance, the EURO-EWING 99 (six cycles of induction chemotherapy followed by local therapy, and adjuvant chemotherapy using different regimens according to the individual patient's risk factors) or the EURO-EWING 2008 study ([Figs. 4] and [6]).[16] [17] For the latter, neoadjuvant chemotherapy with histopathologic assessment of tumor response to induction neoadjuvant chemotherapy, followed by local therapy like surgical tumor resection and reconstruction, and optionally followed by radiation therapy is recommended. Radiation therapy alone as local therapy is the therapy of choice whenever surgery is not possible but has the drawback of a higher local recurrence rate. A second chemotherapy phase as adjuvant chemotherapy is followed in a risk-adapted way. The success of neoadjuvant chemotherapy is assessed locally by using CR and MRI and FDG-PET (according to EURO-EWING 2008) to assess therapy response and local recurrence ([Fig. 4]).
Dynamic contrast-enhanced MRI may help differentiate residual or recurrent tumor from posttherapeutic changes because tumor tissue enhances early and more rapidly during the first pass of contrast, whereas reactive tissue resulting from posttherapeutic changes enhances later and more slowly.[18] Low-dose CT of the chest is recommended in adults for pulmonary follow-up; in children a chest radiograph may be enough. Most relapses occur in the first 3 years of follow-up; late relapses have rarely been observed even after ≥ 15 years. Follow-up intervals should be 2 to 3 months during the first 3 years, 6 months until 5 years, and at least once yearly thereafter according to the clinical recommendations of the European Society for Medical Oncology.[19] Overall, the 5-year-survival rate is ∼ 64% (up to 75% in those patients who present without known metastases).[20] [21] Age, tumor volume, and extent of metastatic spread are relevant risk factors.[15]
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Primary Osseous Lymphoma
Definition
Lymphomas are a heterogeneous group of primary neoplasms of the lymphoid tissue. Malignant lymphocytes normally accumulate in the lymph nodes, causing lymph node disease. Occasionally they may spread to the blood (leukemic phase) or infiltrate organs outside the lymphoid tissue. Lymphomas may be classified as Hodgkin's disease or non-Hodgkin's lymphoma. Among all cases of lymphoma, 40 to 50% involve the skeletal system, generally from metastatic disease. Non-Hodgkin's lymphoma affects bones more commonly than Hodgkin's lymphoma, either as primary or secondary. Hodgkin's lymphoma, characterized by involvement of Reed-Sternberg cells, most commonly presents with progressive painless enlargement of peripheral lymph nodes, especially around the cervical region. At the time of diagnosis, osseous involvement is uncommon, and even in the late stages only 9 to 35% of cases have any bony involvement. Rarely Hodgkin's lymphoma presents as an osseous lesion without involvement of lymph nodes.[22] Primary osseous lymphoma (primary lymphoma of bone [PLB]) has to be distinguished from a secondary bone involvement by lymphomas arising from visceral organs or lymph nodes. The primary non-Hodgkin's lymphoma of the bone is an aggressively growing tumor consisting of malignant lymphatic cells that affects a single bone with or without regional lymphadenopathy. The polyostotic PBL is defined as multifocal but exclusive involvement of the skeleton, whereas the disseminated lymphoma affects various organs with or without secondary involvement of the skeleton.[23] Thus for the correct categorization of an osseous lymphoma, the radiologist's role is to exclude simultaneous extraosseous manifestations of lymphoma at other localizations. Primary osseous lymphomas are most commonly highly malignant B-cell lymphomas.[24]
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Demography
PLB is an uncommon clinical entity and a rare presentation of non-Hodgkin's lymphoma. It can occur at any age, but it has a wide age peak between 30 and 60 years.[24] [25] An overall median age of 45 years (range: 7–87 years) was reported in a study on 119 patients with a female-to-male ratio of 1:1.53.[25] PLBs represent 3 to 5% of all malignant bone tumors, 4 to 5% of extranodal lymphoma, and < 1% of all non-Hodgkin's lymphoma.[26] Diffuse large B-cell lymphoma (DLBCL) accounts for most cases of primary osseous lymphomas. DLBCL usually associates with single bone involvement, whereas the less frequent types, like B-lymphoblastic lymphoma, are associated with multifocal involvement. Primary osseous lymphoma is uncommon in children and adolescents.[27]
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Clinical Manifestations
The leading symptom is local pain. General symptoms such as fever, night sweats, and fatigue that appear frequently in extraskeletal lymphomas are typically not frequently observed in PLBs.
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Localization
Approximately 50% of all PLBs are localized within the skeleton of the trunk and skull; the other 50% are situated in the long bones, especially the femur ([Fig. 8]); in general, bones containing red marrow are affected. Of the latter, two thirds are localized at the metaphysis and one third at the diaphysis. Epiphyseal involvement is rare.[28] About 80% of PLBs are observed unifocally within the bone ([Fig. 9]).[24] In a 2014 study, the femur was the most commonly involved single site in PLBs, whereas those with multifocal bone lesions most frequently presented with spine disease ([Figs. 8] and [10]).[29] Secondary lymphomas also favor the spine and should be distinguished from primary multifocal lymphoma.[30]
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Pathology
PLBs have an indistinct tumor margin and show an invasive diffuse growth pattern. The bony cortex nearly always is infiltrated and also mostly penetrated. The pattern of extensive marrow disease and surrounding soft tissue masses but without extensive cortical destruction was reported nearly exclusively in round-cell tumors such as PLB, multiple myeloma, and ES.[31] An explanation for this finding is the spread of tumor cells from the marrow through small vascular channels that run through the cortex into the surrounding soft tissue.[31] On H&E histologic staining, the tumor stroma consists of diffuse round-cell infiltrates. This aspect resembles the appearance of ES. The diffuse infiltrates cause secondary bone resorption. At immunohistochemical analysis, nearly all lymphomas express common leukocyte antigen and B-cell markers like CD20 ([Fig. 10]).[31]
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Imaging
On CR or CT, PLBs may appear as solitary osteolytic or multiple osteolytic lesions with an aggressive destruction pattern ([Fig. 9]). Similar to ES, the permeative and moth-eaten destructive pattern is an indication of the presence of a tumor consisting of small or round cells. The periosteal reaction, reported in ∼ 60% of cases, is often aggressive and may be complex.[31] CT may be useful to demonstrate bony destruction and, if present, a sclerosing pattern within the spine and pelvis ([Fig. 11]). Osteosclerotic changes may be observed as well; however, predominant osteosclerosis is unusual in primary osseous non-Hodgkin's lymphomas.[24] [32] A sequestrum within a lucent lesion occasionally is seen and is optimally visualized on CT, although it is a nonspecific finding.[31]
In the spine, the often multisegmental lesions may appear osteolytic or mixed osteolytic and sclerotic ([Fig. 10]). Although osseous lymphoma was classically considered in the differential diagnosis of an ivory vertebra, this is a relatively rare occurrence.[33] [34] The mixed sclerotic-lytic type is more common in secondary lymphomas and after treatment.[30] However, radiographic findings may be very subtle even in the presence of aggressive appearance on other imaging modalities ([Fig. 12]).[31] [35] MRI, similar to ES, is the method of choice for the work-up of symptomatic areas and especially in the case of suspected compression of the spinal cord or spinal nerves. The signal behavior itself is nonspecific and may also show a diffuse or focal replacement of normal bone marrow, as could be seen in multiple myeloma ([Fig. 12]).
Lymphoma of the deep soft tissues usually reveals long cones of intramuscular or intermuscular tumor, again best depicted by MRI. Cortical destruction allowing communication between the intraosseous and soft tissue components may be subtle with small striations of extension.[36] Similar to ES, a wraparound sign may be observed consisting of an often large soft tissue component encasing the bone while the cortical bone appears preserved on MRI ([Fig. 13]). In reality, the tumor has penetrated the cortex in a permeative way.
Contrast-enhanced CT should be used for staging and detection of other organ manifestations ([Fig. 14]). A bone scintigraphy may demonstrate the local osseous involvement and other bony manifestations of the lymphoma. The sensitivity to detect multifocal disease is lower than that of whole-body MRI. FDG-PET is well suitable for staging and treatment monitoring, but whole-body MRI (including diffusion-weighted imaging) may also be used for this purpose ([Fig. 9]); both have similar performance for the detection of bone marrow involvement.[37] [38]
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Differential Diagnosis
For differential diagnosis, the patient's age is the crucial parameter. Typical differential diagnoses in young patients include ES, unifocal Langerhans cell histiocytosis, and osteolytic osteosarcoma. In elderly patients, typical differential diagnoses comprise metastases (for instance of small-cell tumors like bronchial carcinoma), fibrosarcoma, and osteomyelitis. In aggressive osteomyelitis with a Lodwick grade II or III appearance,[39] [40] clinical presentation may favor inflammation. For confirmation of the final diagnosis, biopsy sampling and imaging correlation is always mandatory ([Figs. 13], [15], and [16]).
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Therapy and Treatment Monitoring
The mainstay of treatment is polychemotherapy ([Fig. 13]) and radiotherapy.[24] [31] Surgery is only indicated in case of complications, such as for instance in the case of pathologic fractures[41] or spinal cord compression with neurologic deficits. The most common chemotherapy regimen for aggressive non-Hodgkin's lymphoma is cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisone/prednisolone (CHOP). It was recently reported that primary osseous DLBCL had a 3- and 5-year progression-free survival of 61.2% and 46.9%, respectively, and 5- and 10-year overall survival of 81.1% and 74.7%, respectively. Multivariate analysis identified soft tissue extension and the International Prognostic Index score as the most important unfavorable prognostic factors.[29] Also, multifocality was also significantly associated with a worse progression-free survival and overall survival, and the authors concluded that multifocal bone involvement is more similar to secondary bone lymphoma in characteristics and survival rather than unifocal bone disease, and thus it should be better classified and treated similar to the secondary bone lymphomas.[42] Extraskeletal involvement and older age are adverse prognostic factors. For systemic lymphoma with bone involvement, disease-free 5-year survival is 44%.[25] [43]
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Conclusion
The typical manifestation of ES is a permeative lesion in the diaphysis of a long bone in a child. However, the imaging appearance in projection radiography may be diverse, and ES has been called the chameleon of the bone tumors. Extraskeletal ES may be missed on CR and will best be depicted by MRI. There is no single characteristic imaging appearance of an osseous lymphoma. An osseous lymphoma should be considered in the differential diagnosis when encountering in an adult a Lodwick grade II or III osteolytic lesion in the metaphysis or diaphysis of a large long bone, the pelvis, or the vertebral column that may be accompanied to a greater or lesser extent by sclerotic bony changes. Similar to ES, PLB may also be called the chameleon of the bone tumors. In general, permeative and moth-eaten destructive patterns of the bone are a hint for a small- or round-cell tumor. Histologic confirmation should always be sought. Because patients with remarkably normal-appearing CR may show distinct abnormalities on MRI or bone scintigraphy, in patients with persisting symptoms but negative CR, further assessment with a more sensitive modality, such as MRI, is essential.
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Die Autoren geben an, dass kein Interessenkonflikt besteht.
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Address for correspondence
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References
- 1 Freyschmidt J, Ostertag H. Ewing's sarcoma, fibrogenic tumors, giant cell tumor, hemangioma of bone : radiology and pathology [in German]. Radiologe 2016; 56 (06) 520-535
- 2 Peersman B, Vanhoenacker FM, Heyman S. , et al. Ewing's sarcoma: imaging features. JBR-BTR 2007; 90 (05) 368-376
- 3 Jordanov MI, Block JJ, Gonzalez AL, Green NE. Transarticular spread of Ewing sarcoma mimicking septic arthritis. Pediatr Radiol 2009; 39 (04) 381-384
- 4 Ilaslan H, Sundaram M, Unni KK, Dekutoski MB. Primary Ewing's sarcoma of the vertebral column. Skeletal Radiol 2004; 33 (09) 506-513
- 5 Rodallec MH, Feydy A, Larousserie F. , et al. Diagnostic imaging of solitary tumors of the spine: what to do and say. Radiographics 2008; 28 (04) 1019-1041
- 6 Delattre O, Zucman J, Melot T. , et al. The Ewing family of tumors—a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 1994; 331 (05) 294-299
- 7 Lessnick SL, Ladanyi M. Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu Rev Pathol 2012; 7: 145-159
- 8 Murphey MD, Senchak LT, Mambalam PK, Logie CI, Klassen-Fischer MK, Kransdorf MJ. From the radiologic pathology archives: Ewing sarcoma family of tumors: radiologic-pathologic correlation. Radiographics 2013; 33 (03) 803-831
- 9 Applebaum MA, Goldsby R, Neuhaus J, DuBois SG. Clinical features and outcomes in patients with Ewing sarcoma and regional lymph node involvement. Pediatr Blood Cancer 2012; 59 (04) 617-620
- 10 Study in localized and disseminated Ewing sarcoma. https://clinicaltrials.gov/ct2/show/NCT00987636 . Accessed September 2, 2018
- 11 Lalam R, Bloem JL, Noebauer-Huhmann IM. , et al. ESSR consensus document for detection, characterization, and referral pathway for tumors and tumorlike lesions of bone. Semin Musculoskelet Radiol 2017; 21 (05) 630-647
- 12 McCarville MB, Chen JY, Coleman JL. , et al. Distinguishing osteomyelitis from Ewing sarcoma on radiography and MRI. AJR Am J Roentgenol 2015; 205 (03) 640-650 ; quiz 651
- 13 Kloth JK, Wolf M, Rehnitz C, Lehner B, Wiedenhöfer B, Weber MA. Radiological diagnostics of spinal tumors. Part 1: general tumor diagnostics and special diagnostics of extradural tumors [in German]. Orthopade 2012; 41 (08) 595-607
- 14 Haeusler J, Ranft A, Boelling T. , et al. The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 2010; 116 (02) 443-450
- 15 Potratz J, Dirksen U, Jürgens H, Craft A. Ewing sarcoma: clinical state-of-the-art. Pediatr Hematol Oncol 2012; 29 (01) 1-11
- 16 Ladenstein R, Pötschger U, Le Deley MC. , et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010; 28 (20) 3284-3291
- 17 AWMF guideline to Ewing's sarcoma (in children and adolescents) of the German Society of Pediatric and Adolescent Medicine (DGKJ). In: AWMF online (state 2014, valid until June 1, 2019). https://www.awmf.org/uploads/tx_szleitlinien/025-006l_S1_Ewing_Sarkome_Kinder_Jugendliche_2014-06.pdf . Accessed August 12, 2018
- 18 Vilanova JC, Baleato-Gonzalez S, Romero MJ, Carrascoso-Arranz J, Luna A. Assessment of musculoskeletal malignancies with functional MR imaging. Magn Reson Imaging Clin N Am 2016; 24 (01) 239-259
- 19 Paulussen M, Bielack S, Jürgens H, Casali PG. ; ESMO Guidelines Working Group. Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 (Suppl. 04) 140-142
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