|Year : 2014 | Volume
| Issue : 2 | Page : 377-380
Primary Ewing's sarcoma of the cranium: Case series and review of literature
Kalpathi Krishnamani1, Thota Narender Kumar1, Linga Vijay Gandhi1, Digumarti Raghunadharao1, Gundeti Sadashivudu1, Uppin Megha2
1 Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, India
|Date of Web Publication||14-Jul-2014|
Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082
Source of Support: None, Conflict of Interest: None
Primary Ewing's sarcoma (EWS) of the cranium is extremely rare. It accounts for <1% of cases. We retrospectively analyzed our EWS cases to determine those which had a primary cranial involvement. Out of a total of 332 cases of EWS registered between the years 2000 and 2011, 7 were of the primary cranial involvement. Treatment modalities included surgery, chemotherapy, and radiotherapy (RT), as indicated. The follow-up ranged from 8 months to 7.5 years. In our study, parieto-occipital region was the commonest site. Most patients presented with localized disease and swelling of the scalp. Excision followed by chemotherapy or RT appears to have good survival rates. At a median follow-up of 32.2 months, only one patient had a recurrence, and was successfully salvaged with second line chemotherapy. These cases illustrate that a multi-disciplinary approach in patients with EWS of the cranium results in a good outcome.
Keywords: Chemotherapy, cranium, Ewing′s sarcoma
|How to cite this article:|
Krishnamani K, Kumar TN, Gandhi LV, Raghunadharao D, Sadashivudu G, Megha U. Primary Ewing's sarcoma of the cranium: Case series and review of literature. J Can Res Ther 2014;10:377-80
|How to cite this URL:|
Krishnamani K, Kumar TN, Gandhi LV, Raghunadharao D, Sadashivudu G, Megha U. Primary Ewing's sarcoma of the cranium: Case series and review of literature. J Can Res Ther [serial online] 2014 [cited 2020 Jan 24];10:377-80. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/377/136663
| > Introduction|| |
Primary Ewing's sarcoma (EWS) of the cranium is rare. Most of the available literature is from case reports. Paulus et al.  in their study on 2500 biopsy proven brain tumors encountered only one case of primary EWS of the skull. In this retrospective analysis over an 11-year period, seven cases of primary EWS of the skull were identified. There are only eight case reports of intracranial extension of primary cranial EWS. In our series, two children had an intracranial extension.
| > Case report|| |
Of a total of 332 patients with a diagnosis of ESFT between 2000 and 2011, there were six children with primary cranial involvement. The male to female ratio was 1.3:1. The age of the children ranged between 1 and 17 years. Parieto-occipital region was the commonest site of involvement, occurring in four children. One child each had involvement of the cavernous sinus, sphenoid bone, and baso-frontal region. Three children presented with a scalp swelling [Figure 1] and [Figure 2]. Proptosis was the presenting feature in two children. Of the remaining two, one each presented with squint and symptoms of raised intracranial pressure and facial nerve palsy. Squint as a presenting feature has not been reported till date. To the best of our knowledge this is the first report of a child presenting with squint. In our series, two children had an intracranial extension [Figure 3].
|Figure 1: Lateral radiograph of skull showing ill-defined lytic lesion in posterior parietal bone with spiculated periosteal reaction and soft tissue component|
Click here to view
|Figure 2: (a, b) Sagittal computed tomography images showing large lesion in parieto-occipital region causing destruction of skull bone with large extra-dural and extra-cranial soft tissue component|
Click here to view
|Figure 3: Large intensely enhancing soft tissue lesion involving all the paranasal sinuses (a) with intracranial extension (b) causing extensive bone destruction (c)|
Click here to view
Localized presentation was seen in six children. Excision of the tumor was performed in six children. Histopathology was suggestive of small round cells exhibiting CD99 positivity [Figure 4],[Figure 5] and [Figure 6]. Post-operative radiotherapy (RT) was given in two children. Six children received adjuvant chemotherapy. Vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide VAC/IE regimen was the common protocol used in our patients. Lomustine CCNU/vincristine and cis-platinum was used in one patient who had a local recurrence. The schedule of the agents used is as follows: VAC alternating with IE q 3 weekly; vincristine - 1.4 mg/m 2 D1, doxorubicin - 75 mg/m 2 D1, cyclophosphamide - 1200 mg/m 2 D1, ifosfamide - 1.8 g/m 2 D1-5, and etoposide - 100 mg/m 2 D1-5. CCNU - 75 mg/m 2 D1, cisplatin - 60 mg/m 2 D1, and vincristine - 1.4 mg/m 2 D1 and D8 q 4 weekly.
|Figure 4: Uniform small round cells with rosette formation (H and E, ×100)|
Click here to view
|Figure 5: Cells show scant cytoplasm and round to oval nuclei with finely granular chromatin (H and E, ×400)|
Click here to view
|Figure 6: Immunohistochemistry with CD 99 shows positivity in tumor cells (×100) (a, b)|
Click here to view
The median follow-up in our study is 32.2 months. Six children are under regular follow-up ranging from 8 months to 7.5 years. One child expired before initiation of therapy. One child had a recurrence at 6 years after initial presentation and was successfully treated with second-line chemotherapy [Table 1].
| > Discussion|| |
First described by James Ewing in 1921, EWS comprises 11% of all bone tumors. The peak incidence is between the age groups of 5 and 15 years.  The male to female ratio is 1.6:1.  Diaphysis is the commonest site of involvement although metaphyses may be involved in 25% of the cases.
Primary EWS of the cranium is rare accounting for <1% of cases.  In tumors of the skull vault, frontal, parietal, and temporal bones are the commonest sites of occurrence accounting for 28%, 22%, and 11%, respectively. Vohra recorded eight cases of EWS involving the skull bone while describing the radiologic manifestations in 156 cases of EWS.  Pritchard and Coley reported three cases each among 234 and 149 cases of EWS respectively. ,
Case reports describing the clinical characteristics, radiologic manifestations and treatment modalities are the largest source of available literature on this subject. Syed has reported a case of EWS of the calvarium that presented with mass effect. 
Headache and localized swelling are the common modes of presentation. Features of raised intracranial tension is seen in cases of intracranial involvement. , Involvement or extension into orbit and nasopharynx leads to proptosis and nasal stuffiness respectively. Non-specific symptoms include fever, weight loss and decreased appetite, usually in advanced disease. Abnormal laboratory findings may include elevated Lactate dehydrogenase (LDH) and Alkaline phosphatase (ALP). LDH is a surrogate of tumor burden and usually falls with effective treatment.
Primary EWS of the skull presents with osteolytic lesion with soft tissue component on X-ray.  Similar osteolytic lesions are seen in eosinophilic granuloma, fibrous dysplasia, aneurysmal bone cyst, osteoclastoma and metastases.
Imaging with computed tomography (CT) scan and magnetic resonance imaging (MRI) provide information regarding the size, extent and involvement of dura and parenchyma. On an MRI, the mass is hypo- to iso-intense on T1W and iso- or hyper-intense on T2W with heterogeneous enhancement on contrast. CT scan is useful to delineate bone involvement. CT scan reveals an iso-hyperdense mass which enhances with contrast. Chest X-rays and CT scans of chest are useful in detecting pulmonary metastases. Radioisotope bone scan is necessary to rule out metastases. Bone scans also help in detecting early recurrence as reported in one study. 
Histological examination reveals a homogenous population of small cells with fibro vascular stroma with scant cytoplasm and round to oval vesicular nuclei. The cytoplasm contains glycogen. These cells are positive for vimentin, CD99, and negative for desmin, Leucocyte common antigen (LCA) and synaptophysin differentiating it from other small round cell tumors like rhabdomyosarcoma, lymphoma and neuroblastoma. More than 95% tumors of EWS family express the adhesion receptor CD99 on the cell membranes. Identification of EWS rearrangements using Flourosence in situ hybridization (FISH) or Reverse transcriptase polymerase chain reaction or RT-PCR is useful in differentiating EWS from other round cell tumors.  Most cases have a balanced translocation between chromosomes 11 and 22 which fuses portions of EWS gene on chromosome 22q12 with FLI1 gene on 11q24. Other translocations observed are t (21;22) which results in the fusion between EWS and ERG gene and t (7;22) which is due to fusion between EWS and ETV1 located on chromosome 7p22. 
Good prognostic factors include longer duration of symptoms (>6 months), female gender, absence of systemic symptoms, absence of metastases at diagnosis, peripheral location of tumor, tumor <8 cm, small cell histology, initial LDH <170 IU/L, White blood count (WBC) <7000/cu mm, lymphocyte count <2000, and platelet <400,000/cu mm. 
Multimodal therapy is the treatment of choice in cranial EWS. Total or subtotal excision of the mass followed by post-operative RT and chemotherapy gives good results with a 2-5 year disease-free survival of 50-80%. , Most studies suggest radical excision of the lesion, but this may not be possible when there is involvement of technically difficult areas like the petrous region and clivus. When the tumor affects the cranial bone, surgical resection is necessary. This helps to decompress vital neural structures and decrease the primary tumor mass. Post-operative chemotherapy with a four-drug regimen using vincristine, cyclophosphamide, actinomycin D, and doxorubicin is considered superior to the three-drug regimen of vincristine, cyclophosphamide, and doxorubicin. , RT as the sole treatment is indicated in inoperable cases of skull, spine, and sacrum. EWS of the calvarium generally has a good prognosis following multi-modal treatment. RT is indicated to reduce or prevent loco regional recurrences. It is used as an adjuvant after incomplete excision or positive microscopic margins. Most of our cases had parietal bone involvement. Complete excision with negative margins was possible in these cases, hence RT was not employed. In the one case, the patient's relatives refused RT, hence RT was not given. Pre-operative chemotherapy followed by surgery followed by post-operative chemotherapy and RT gives good results in extra-cranial EWS. This helps to downstage the tumor and obviates the need for large surgical fields and closure of large defects. Primary EWS of the cranium rarely metastasizes. Development of metastases is the main factor in treatment failure.
Peripheral PNETs differ from central PNETs in that the former have a better prognosis.  CD99 positivity is seen in cranial EWS and not in central PNET's. Translocation studies may be used to differentiate between the two. The chromosomal translocation t (11;22) is observed in peripheral PNETs and is quite characteristic. It is not seen in central PNETs. In contrast to medulloblastoma the occurrence of isochromosome 17q is very rare in peripheral PNETs. Treatment protocols used in these two entities are different.
Cranial EWS behaves differently when compared to their peripheral counterparts. They differ in clinical presentation, radiological picture, low incidence of metastases, propensity to involve dura often, treatment, and outcome. The reason may be due to the putative cell of origin or may lie at the molecular level. The mesenchymal stem cell is proposed as the cell of origin for this family of tumors, but there could be other cell types which may give rise to this tumor based on its ability to occur at multiple sites.  Differences are observed even within cranial EWS in that the calvarial and meningeal variety do better than the skull base lesions.
In our study, parieto-occipital region was the commonest site of involvement. Most patients presented with localized disease and swelling of the scalp. Excision followed by chemotherapy or RT appears to have good survival rates. At a median follow-up in our study of 32.2 months, only one patient had a recurrence, and was successfully salvaged with second line chemotherapy.
| > References|| |
|1.||Paulus W, Slowik F, Jellinger K. Primary intracranial sarcomas: Histopathological features of 19 cases. Histopathology 1991;18:395-402. |
|2.||Pritchard DJ, Dahlin DC, Dauphine RT, Taylor WF, Beabout JW. Ewing′s sarcoma. A clinicopathological and statistical analysis of patients surviving five years or longer. J Bone Joint Surg Am 1975;57:10-6. |
|3.||Dahlin D. Ewing′s tumor Bone Tumours: General Aspects and Data on 6221 Cases. 3 rd ed. Springfield, IL: Charles C. Thomas; 1978. p. 278. |
|4.||Desai KI, Nadkarni TD, Goel A, Muzumdar DP, Naresh KN, Nair CN. Primary Ewing′s sarcoma of the cranium. Neurosurgery 2000;46:62-8. |
|5.||Vohra VG. Roentgen manifestations in Ewing′s sarcoma. A study of 156 cases. Cancer 1967;20:727-33. |
|6.||Coley BL.: Neoplasms of Bone and related Conditions. New York: Paul B Hoeber 1949. p. 297-318. |
|7.||BA Syed. Primary intracranial ewings sarcoma of calvarium presenting as acute neurosurgical emergency. Case report and literature review. Pan Arab J Neurosurg 1999;3:1. |
|8.||Agrawal A, Dulani R, Mahadevan A, Vagaha SJ, Vagha J, Shankar SK. Primary Ewing′s sarcoma of the frontal bone with intracranial extension. J Cancer Res Ther 2009;5:208-9. |
|9.||Kuzeyli K, Aktürk F, Reis A, Cakir E, Baykal S, Pekínce A, et al. Primary Ewing′s sarcoma of the temporal bone with intracranial, extracranial and intraorbital extension. Case report. Neurosurg Rev 1997;20:132-4. |
|10.||Steinbok P, Flodmark O, Norman MG, Chan KW, Fryer CJ. Primary Ewing′s sarcoma of the base of the skull. Neurosurgery 1986;19:104-7. |
|11.||Yildizhan A, Gezen F. Primary Ewing′s sarcoma of the skull: Follow-up with bone scanning. Neurosurg Rev 1992;15:225-9. |
|12.||Lam DS, Li CK, Cheng LL, Teo JG, Chik KW, Kwan WH, et al. Primary orbital Ewing′s sarcoma: Report of a case and review of the literature. Eye (Lond) 1999;13:38-42. |
|13.||Salunke PS, Gupta K, Malik V, Kumar N, Henke LE, Cai C, et al. Primary Ewing′s sarcoma of cranial bones: Analysis of ten patients. Acta Neurochir (Wien) 2011;153:1477-85. |
|14.||Alvarez-Berdecia A, Schut L, Bruce DA. Localized primary intracranial Ewing′s sarcoma of the orbital roof. Case report. J Neurosurg 1979;50:811-3. |
|15.||Dunst J, Sauer R. Therapy of Ewing′s sarcoma. Strahlenther Onkol 1993;169:695-708. |
|16.||Bhatoe HS, Deshpande GU. Primary cranial Ewing′s sarcoma. Br J Neurosurg 1998;12:165-9. |
|17.||Dedeurwaerdere F, Giannini C, Sciot R, Rubin BP, Perilongo G, Borghi L, et al. Primary peripheral PNET/Ewing′s sarcoma of the dura: A clinicopathologic entity distinct from central PNET. Mod Pathol 2002;15:673-8. |
|18.||Salunke PS, Gupta K, Pfeifer JD. The cell of origin of cranial Ewings sarcoma: The dilemma persists. Acta Neurochir (Wein) 2012;154:567-8. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]