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��ࡱ�>��	46����123�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�	��:�bjbj����	4ΐΐ�+���������������������85��4��7�555���� d7777777$X9��;;7�!!!;7��55�P7 �(�(�(!��5�5�12�(!7�(�(�*+5�������-����%��*�1p7<�7�*,�<�&��<++��<�,�!!�(!!!!!;7;7<'`!!!�7!!!!���������������������������������������������������������������������<!!!!!!!!!�	�:	Successful multimodality treatment and long-term follow-up of a primary spinal epithelioid hemangioendothelioma

Tsitsopoulos PP1*, Anestis DM1, Nikolaidou C2, Venizelos I2, Tsonidis CA1, Tsitsopoulos PD1


1 Department of Neurosurgery Hippokratio General Hospital, Aristotle University Faculty of Medicine, Thessaloniki, Greece
 
2 Department of Pathology, Hippokratio General Hospital, Thessaloniki, Greece 

* Corresponding author:
Parmenion P. Tsitsopoulos, MD, PhD.
Department of Neurosurgery
Hippokratio General Hospital
Aristotle University Faculty of Medicine
49 Konstantinoupoleos str., 54642
Thessaloniki
Greece
e-mail: par_tsits@yahoo.gr
Tel: +3(0)2310892332, Fax: 011+3(0)2310992945

Abstract
Introduction: Epithelioid hemangioendothelioma (EHE) is an unusual vascular tumor which is rarely found in the spine. It has metastatic potential and unpredictable behavior. The choice of treatment remains controversial with the role of radiotherapy and chemotherapy still not clearly established.
Case presentation: The case of a 63-year-old female patient with a spinal EHE that presented with gradually deteriorating paraparesis and sensory deficits is reported. Radiologic work-up revealed the presence of a mid-thoracic vertebral mass which extended epidurally and into the thoracic cavity. She underwent laminectomy and removal of the epidural mass. Postoperatively, she was further treated with intravascular embolization and stereotactic radiosurgery. These resulted in significant reduction of the tumor. Histopathologic analysis confirmed the diagnosis of EHE. Seven years later, she remained symptom-free with no evidence of tumor recurrence on Magnetic Resonance Imaging.
Conclusion: Selective surgical excision combined with embolization and stereotactic radiosurgery may be effective in treating spinal EHEs obviating the need for an extensive surgery. To our knowledge, this is the first such case reported in the literature.

Keywords  
Epithelioid hemangioendothelioma; Spine tumor; Surgery; Embolization; Stereotactic radiosurgery; Multimodality treatment; Outcome
Introduction    
     Epithelioid hemangioendothelioma (EHE) of the spine is a very rare entity. This term was initially proposed to describe an unusual tumor of soft tissue having an epithelioid appearance and often an angiocentric location, with a clinical course intermediate between benign hemangioma and angiosarcoma  ADDIN EN.CITE <EndNote><Cite><Author>Weiss</Author><Year>1982</Year><RecNum>39</RecNum><DisplayText>[1]</DisplayText><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weiss, S. W.</author><author>Enzinger, F. M.</author></authors></contributors><titles><title>Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma</title><secondary-title>Cancer</secondary-title><alt-title>Cancer</alt-title></titles><periodical><full-title>Cancer</full-title><abbr-1>Cancer</abbr-1></periodical><alt-periodical><full-title>Cancer</full-title><abbr-1>Cancer</abbr-1></alt-periodical><pages>970-81</pages><volume>50</volume><number>5</number><edition>1982/09/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Basement Membrane/pathology/ultrastructure</keyword><keyword>Carcinoma/*pathology/ultrastructure</keyword><keyword>Diagnosis, Differential</keyword><keyword>Endothelium/pathology/ultrastructure</keyword><keyword>Extremities/blood supply</keyword><keyword>Hemangioendothelioma/*pathology/ultrastructure</keyword><keyword>Humans</keyword><keyword>Lymphatic Metastasis</keyword><keyword>Microscopy, Electron</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Soft Tissue Neoplasms/*pathology/ultrastructure</keyword><keyword>Veins</keyword></keywords><dates><year>1982</year><pub-dates><date>Sep 1</date></pub-dates></dates><isbn>0008-543X (Print)&#xD;0008-543X (Linking)</isbn><accession-num>7093931</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/7093931</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_1" \o "Weiss, 1982 #39" 1]. Therefore, EHE is a histologically distinct group of vascular tumors of endothelial origin, with a low-grade malignant endothelial appearance, generally demonstrating a less aggressive course compared to angiosarcoma  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_2" \o "Errani, 2012 #12" 2-4].
     Reported spinal cases are few in number and follow-up periods short. Most cases have been subjected to extensive surgery. Therefore, prognosis and choice of optimal management remain unclear. A case of a spinal EHE that was treated successfully with selective surgery, embolization and stereotactic radiosurgery is presented.


Case Report

History � Clinical examination
      A previously healthy 63-year-old female presented with a 20-day history of pain, gait disturbances and progressive paraparesis. Her history was negative for trauma. Clinical examination revealed tenderness in the mid-thoracic spine, restricted spinal motion, symmetrical weakness in all muscle groups of the lower limbs (+3/5), increased tendon reflexes, sensory disturbances in the form of pin-prick and pallesthesia loss as well as paresthetic numbness with a sensory level at Th9-Th10. Laboratory tests were within normal limits.

Radiologic investigation 
     She underwent Magnetic Resonance Imaging (MRI) scan, which revealed a bony lesion at Th7 extending to the epidural space, compressing the dural sac and spinal cord left posterolaterally. The lesion also extended to the adjacent levels as well as to the left rib, the paravertebral soft tissue area and the thoracic cavity (Figure 1). Total body radiologic workup did not reveal any additional lesions. The differential diagnosis mainly included hemangioma and other vertebral tumors of vascular origin.

Treatment
     She was operated with laminectomy from Th6 to Th8 and removal of the epidural mass. Significant bleeding from the tumor was encountered during surgery. Thoracic surgeons did not recommend surgery for the part extending to the thoracic cavity. Postoperatively, she immediately improved clinically, expressing better muscle strength in the lower limbs and recovered sensation. She was mobilized with a brace and discharged from the department on day 7.
     One month later, she was referred to a specialized intravascular therapy department to embolize the remaining lesion. Through selective catheterization of the left Th7 intercostal artery, two tumor feeding arteries were found and embolized with NBCA (N-butyl-2-cyanoacrylate). The successful outcome of the procedure was confirmed with control angiography (Figure 2). The residual tumor showed additional size reduction. 
     One year after her initial admission, she was further treated with stereotactic radiosurgery (CyberKnife, Accuray, Sunnyvale, CA). The residual tumor was subjected to a single dose of 2100 cGy (Figure 3). No procedure-related complications were noted. Consecutive MRIs showed additional regression in tumor�s size.

Outcome 
     At the last follow-up, at 7 years, she remained neurologically intact, fully mobilized, with no imaging signs of kyphosis, instability or tumor progression on MRI. After the combined treatment, the residual tumor remained significantly reduced, with its size showing no change compared to previous examinations (Figure 4).

Pathology 
     Pathologic examination indicated a vascular lesion consisting of anastomosing vessels of variable size. Vascular channels were lined with endothelial cells of epithelioid appearance with mildly to moderately atypical cytology. Between them, normal bone marrow cells could be observed. Mitoses were absent. Immunohistochemical staining showed positivity for CD34 thus confirming the endothelial nature of the lesion (Figure 5).

Discussion
     Primary malignant vascular tumors of bone are unusual (<1%). Osseous EHEs, as a subtype of this category, are even less common,  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Brennan, 2001 #7" 5,  HYPERLINK \l "_ENREF_6" \o "Kleer, 1996 #24" 6] with tibia (25%), femur (20%), metatarsals (15%), fibula (10%) and humerus (10%) most commonly affected  ADDIN EN.CITE <EndNote><Cite><Author>Liu</Author><Year>2011</Year><RecNum>48</RecNum><DisplayText>[7]</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liu, Q.</author><author>Miao, J.</author><author>Lian, K.</author><author>Huang, L.</author><author>Ding, Z.</author></authors></contributors><auth-address>Department of Orthopaedic Surgery, the Affiliated Southeast Hospital of Xiamen University, Orthopaedic Trauma Center of PLA, Zhangzhou, 363000, PR China.</auth-address><titles><title>Multicentric epithelioid hemangioendothelioma involving the same lower extremity: a case report and review of literature</title><secondary-title>Int J Med Sci</secondary-title><alt-title>International journal of medical sciences</alt-title></titles><periodical><full-title>Int J Med Sci</full-title><abbr-1>International journal of medical sciences</abbr-1></periodical><alt-periodical><full-title>Int J Med Sci</full-title><abbr-1>International journal of medical sciences</abbr-1></alt-periodical><pages>558-63</pages><volume>8</volume><number>7</number><edition>2011/10/01</edition><keywords><keyword>Bone Neoplasms/*diagnosis/pathology/radiography</keyword><keyword>Bones of Lower Extremity/pathology/radiography</keyword><keyword>Female</keyword><keyword>Hemangioendothelioma, Epithelioid/*diagnosis/pathology/radiography</keyword><keyword>Humans</keyword><keyword>Lower Extremity/pathology/radiography</keyword><keyword>Middle Aged</keyword><keyword>Peroneal Nerve/pathology</keyword></keywords><dates><year>2011</year></dates><isbn>1449-1907 (Electronic)&#xD;1449-1907 (Linking)</isbn><accession-num>21960748</accession-num><work-type>Case Reports&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21960748</url></related-urls></urls><custom2>3180772</custom2><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_7" \o "Liu, 2011 #48" 7]. Primary spinal EHE is extremely rare  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Kopniczky, 2008 #3" 8,  HYPERLINK \l "_ENREF_9" \o "Kabukcuoglu, 2006 #22" 9]. To our knowledge, 39 cases of spinal EHE that underwent surgery have been reported in the literature  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "de Singly, 2011 #10" 10-12]. The most common presentation is regional involvement in several contiguous vertebral bodies  ADDIN EN.CITE <EndNote><Cite><Author>Boutin</Author><Year>1996</Year><RecNum>6</RecNum><DisplayText>[13]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boutin, R. D.</author><author>Spaeth, H. J.</author><author>Mangalik, A.</author><author>Sell, J. J.</author></authors></contributors><auth-address>Department of Radiology, University of New Mexico, School of Medicine, Albuquerque 87131-53362, USA.</auth-address><titles><title>Epithelioid hemangioendothelioma of bone</title><secondary-title>Skeletal Radiol</secondary-title><alt-title>Skeletal radiology</alt-title></titles><periodical><full-title>Skeletal Radiol</full-title><abbr-1>Skeletal radiology</abbr-1></periodical><alt-periodical><full-title>Skeletal Radiol</full-title><abbr-1>Skeletal radiology</abbr-1></alt-periodical><pages>391-5</pages><volume>25</volume><number>4</number><edition>1996/05/01</edition><keywords><keyword>Adult</keyword><keyword>Bone Neoplasms/*diagnosis/pathology/radiography</keyword><keyword>Hemangioendothelioma, Epithelioid/*diagnosis/pathology/radiography</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Neoplasms, Multiple Primary/*diagnosis/pathology/radiography</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>1996</year><pub-dates><date>May</date></pub-dates></dates><isbn>0364-2348 (Print)&#xD;0364-2348 (Linking)</isbn><accession-num>8738008</accession-num><work-type>Case Reports</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8738008</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Boutin, 1996 #6" 13]. 
     There are no specific radiologic findings since EHE usually presents as an expansive osteolytic process (solitary or multiple) on both plain radiographs and Computed Tomography (CT) scan. The MRI findings are equally controversial, with usually low to intermediate signal intensity on T1-weighted images, intermediate (less likely) to high signal intensity on T2-weighted and homogenous contrast enhancement  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_9" \o "Kabukcuoglu, 2006 #22" 9,  HYPERLINK \l "_ENREF_14" \o "Larochelle, 2006 #25" 14]. Despite the lack of specific findings, CT and MRI are crucial for identifying the scale of bony destruction and cord compression  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_13" \o "Boutin, 1996 #6" 13,  HYPERLINK \l "_ENREF_15" \o "Bollinger, 1994 #5" 15]. It must be noted that patients diagnosed with EHE should be thoroughly evaluated with chest, abdomen and pelvis CT, bone scintigraphy and a complete skeletal survey due to the tumor�s tendency to present with multifocal osseous and visceral lesions  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "Zbojniewicz, 2010 #40" 16].
     From the pathological perspective, the diagnosis of EHE can be difficult. It is critical to identify and confirm the endothelial nature of the lesion  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Aquilina, 2005 #4" 17]. The tumor consists of short strands, cords or solid parts of rounded to slightly spindled eosinophilic endothelial cells  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Christodoulou, 2008 #9" 18]. Immunohistochemical analysis is usually positive for factor VIII related antigen, CD31, CD34 and vimentin  ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2009</Year><RecNum>32</RecNum><DisplayText>[19]</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, C. G.</author><author>Jia, N. Y.</author><author>Yu, H. Y.</author><author>Liu, H. M.</author><author>Wang, J.</author></authors></contributors><auth-address>Department of Radiology, ShangHai Changzheng Hospital, Second Military Medical University, Shanghai, China, 200003.</auth-address><titles><title>Epithelioid hemangioendothelioma of thoracic vertebra: a case report (2008: 11b)</title><secondary-title>Eur Radiol</secondary-title><alt-title>European radiology</alt-title></titles><periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></periodical><alt-periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></alt-periodical><pages>517-20</pages><volume>19</volume><number>2</number><edition>2009/01/21</edition><keywords><keyword>Back Pain</keyword><keyword>Bone Neoplasms/pathology/*radiography</keyword><keyword>Contrast Media/pharmacology</keyword><keyword>Female</keyword><keyword>Gadolinium DTPA/pharmacology</keyword><keyword>Hemangioendothelioma, Epithelioid/pathology/*radiography</keyword><keyword>Humans</keyword><keyword>Thoracic Vertebrae/pathology/*radiography</keyword><keyword>Tomography, X-Ray Computed/methods</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1432-1084 (Electronic)&#xD;0938-7994 (Linking)</isbn><accession-num>19153746</accession-num><work-type>Case Reports</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19153746</url></related-urls></urls><electronic-resource-num>10.1007/s00330-008-1035-5</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_19" \o "Wang, 2009 #32" 19]. In addition, cytokeratin immunoreaction can be also seen in some cases  ADDIN EN.CITE <EndNote><Cite><Author>Gokhan</Author><Year>2006</Year><RecNum>19</RecNum><DisplayText>[20]</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gokhan, G. A.</author><author>Akyuz, M.</author><author>Gurer, I. E.</author><author>Tuncer, R.</author></authors></contributors><auth-address>Department of Pathology, Akdeniz University Faculty of Medicine, Antalya, Turkey. guzidegokhan@akdeniz.edu.tr</auth-address><titles><title>Epithelioid hemangioendothelioma derived from the spine region: case report and review of the literature</title><secondary-title>Wien Klin Wochenschr</secondary-title><alt-title>Wiener klinische Wochenschrift</alt-title></titles><periodical><full-title>Wien Klin Wochenschr</full-title><abbr-1>Wiener klinische Wochenschrift</abbr-1></periodical><alt-periodical><full-title>Wien Klin Wochenschr</full-title><abbr-1>Wiener klinische Wochenschrift</abbr-1></alt-periodical><pages>358-61</pages><volume>118</volume><number>11-12</number><edition>2006/07/21</edition><keywords><keyword>Adult</keyword><keyword>Diagnosis, Differential</keyword><keyword>Hemangioendothelioma, Epithelioid/*diagnosis</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Rare Diseases/diagnosis</keyword><keyword>Soft Tissue Neoplasms/*diagnosis</keyword><keyword>Spinal Neoplasms/*diagnosis</keyword></keywords><dates><year>2006</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0043-5325 (Print)&#xD;0043-5325 (Linking)</isbn><accession-num>16855926</accession-num><work-type>Case Reports&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16855926</url></related-urls></urls><electronic-resource-num>10.1007/s00508-006-0582-5</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_20" \o "Gokhan, 2006 #19" 20]. Differential diagnosis mainly includes metastatic carcinoma, melanoma, hemangioma, angiosarcoma and multiple myeloma among other pathologies  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Chau, 2001 #8" 21,  HYPERLINK \l "_ENREF_22" \o "Themistocleous, 2005 #30" 22].
     Because of the small number of cases and the uncertain role of chemotherapy and radiotherapy, a widely accepted treatment of those tumors does not exist and thus, general oncologic principles are applied. The surgeon should aim for an adequate spinal cord decompression with maximal safe tumor resection and maintenance of spinal column stability. Occasionally, this is followed by adjuvant treatment with radiotherapy being the most frequent choice  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Kleer, 1996 #24" 6,  HYPERLINK \l "_ENREF_17" \o "Aquilina, 2005 #4" 17]. Recently, volumetric intensity-modulated arc radiotherapy has been proposed as a treatment alternative  ADDIN EN.CITE <EndNote><Cite><Author>Guy</Author><Year>2014</Year><RecNum>51</RecNum><DisplayText>[23]</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Guy, J.B.</author><author>Trone, J.C.</author><author>Chargani, C.</author><author>Falk, A.T.</author><author>Khodri, M.</author><author>Magn�, N.</author></authors></contributors><titles><title>Epithelioid hemangioendothelioma of the spine treated with RapidArc volumetric-modulated radiotherapy</title><secondary-title>Med Dosim</secondary-title></titles><periodical><full-title>Med Dosim</full-title></periodical><pages>242-5</pages><volume>39</volume><number>3</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Guy, 2014 #51" 23]. Embolization prior to surgical treatment is not unusual, considering the vascular nature of these tumors  ADDIN EN.CITE <EndNote><Cite><Author>Gokhan</Author><Year>2006</Year><RecNum>19</RecNum><DisplayText>[20]</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gokhan, G. A.</author><author>Akyuz, M.</author><author>Gurer, I. E.</author><author>Tuncer, R.</author></authors></contributors><auth-address>Department of Pathology, Akdeniz University Faculty of Medicine, Antalya, Turkey. guzidegokhan@akdeniz.edu.tr</auth-address><titles><title>Epithelioid hemangioendothelioma derived from the spine region: case report and review of the literature</title><secondary-title>Wien Klin Wochenschr</secondary-title><alt-title>Wiener klinische Wochenschrift</alt-title></titles><periodical><full-title>Wien Klin Wochenschr</full-title><abbr-1>Wiener klinische Wochenschrift</abbr-1></periodical><alt-periodical><full-title>Wien Klin Wochenschr</full-title><abbr-1>Wiener klinische Wochenschrift</abbr-1></alt-periodical><pages>358-61</pages><volume>118</volume><number>11-12</number><edition>2006/07/21</edition><keywords><keyword>Adult</keyword><keyword>Diagnosis, Differential</keyword><keyword>Hemangioendothelioma, Epithelioid/*diagnosis</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Rare Diseases/diagnosis</keyword><keyword>Soft Tissue Neoplasms/*diagnosis</keyword><keyword>Spinal Neoplasms/*diagnosis</keyword></keywords><dates><year>2006</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0043-5325 (Print)&#xD;0043-5325 (Linking)</isbn><accession-num>16855926</accession-num><work-type>Case Reports&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16855926</url></related-urls></urls><electronic-resource-num>10.1007/s00508-006-0582-5</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_20" \o "Gokhan, 2006 #19" 20].  Although the role of chemotherapy is not yet well defined,  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Christodoulou, 2008 #9" 18,  HYPERLINK \l "_ENREF_21" \o "Chau, 2001 #8" 21] it is probably an accepted option for widely disseminated disease, with occasionally encouraging results  ADDIN EN.CITE <EndNote><Cite><Author>Boutin</Author><Year>1996</Year><RecNum>6</RecNum><DisplayText>[13]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boutin, R. D.</author><author>Spaeth, H. J.</author><author>Mangalik, A.</author><author>Sell, J. J.</author></authors></contributors><auth-address>Department of Radiology, University of New Mexico, School of Medicine, Albuquerque 87131-53362, USA.</auth-address><titles><title>Epithelioid hemangioendothelioma of bone</title><secondary-title>Skeletal Radiol</secondary-title><alt-title>Skeletal radiology</alt-title></titles><periodical><full-title>Skeletal Radiol</full-title><abbr-1>Skeletal radiology</abbr-1></periodical><alt-periodical><full-title>Skeletal Radiol</full-title><abbr-1>Skeletal radiology</abbr-1></alt-periodical><pages>391-5</pages><volume>25</volume><number>4</number><edition>1996/05/01</edition><keywords><keyword>Adult</keyword><keyword>Bone Neoplasms/*diagnosis/pathology/radiography</keyword><keyword>Hemangioendothelioma, Epithelioid/*diagnosis/pathology/radiography</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Neoplasms, Multiple Primary/*diagnosis/pathology/radiography</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>1996</year><pub-dates><date>May</date></pub-dates></dates><isbn>0364-2348 (Print)&#xD;0364-2348 (Linking)</isbn><accession-num>8738008</accession-num><work-type>Case Reports</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8738008</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Boutin, 1996 #6" 13]. Bevacizumab, a recombinant humanized VEGF (vascular endothelial growth factor) antibody, has also been tried  ADDIN EN.CITE <EndNote><Cite><Author>Trautmann</Author><Year>2011</Year><RecNum>58</RecNum><DisplayText>[24]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Trautmann, K.</author><author>Bethke, A.</author><author>Ehninger, G.</author><author>Folprecht, G.</author></authors></contributors><titles><title>Bevacizumab for recurrent hemangioendothelioma</title><secondary-title>Acta Oncol</secondary-title></titles><periodical><full-title>Acta Oncol</full-title></periodical><pages>153-4</pages><volume>50</volume><number>1</number><edition>2010/10/19</edition><keywords><keyword>Angiogenesis Inhibitors/*therapeutic use</keyword><keyword>Antibodies, Monoclonal/*therapeutic use</keyword><keyword>Antibodies, Monoclonal, Humanized</keyword><keyword>Female</keyword><keyword>Fractures, Spontaneous/etiology/surgery</keyword><keyword>Hemangioendothelioma, Epithelioid/*drug therapy/pathology/surgery</keyword><keyword>Humans</keyword><keyword>Laminectomy</keyword><keyword>Lumbar Vertebrae/pathology/surgery</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Neoplasm Recurrence, Local/*drug therapy</keyword><keyword>Spinal Fusion</keyword><keyword>Spinal Neoplasms/complications/*drug therapy/pathology/surgery</keyword><keyword>Treatment Outcome</keyword><keyword>Vascular Endothelial Growth Factor A/*antagonists &amp; inhibitors</keyword><keyword>Young Adult</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1651-226X (Electronic)&#xD;0284-186X (Linking)</isbn><accession-num>20950228</accession-num><work-type>Case Reports&#xD;Letter</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20950228</url></related-urls></urls><electronic-resource-num>10.3109/0284186X.2010.498829</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_24" \o "Trautmann, 2011 #58" 24].
     The behavior and prognosis of EHEs remain unpredictable. Despite attempts to predict the outcome on the basis of their histologic features (nuclear atypia, mitotic activity, necrosis)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_9" \o "Kabukcuoglu, 2006 #22" 9], it seems that visceral involvement is the most important factor  ADDIN EN.CITE <EndNote><Cite><Author>Kleer</Author><Year>1996</Year><RecNum>24</RecNum><DisplayText>[6]</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kleer, C. G.</author><author>Unni, K. K.</author><author>McLeod, R. A.</author></authors></contributors><auth-address>Section of Surgical Pathology, Mayo Clinic, Rochester, MN 55905, USA.</auth-address><titles><title>Epithelioid hemangioendothelioma of bone</title><secondary-title>Am J Surg Pathol</secondary-title><alt-title>The American journal of surgical pathology</alt-title></titles><periodical><full-title>Am J Surg Pathol</full-title><abbr-1>The American journal of surgical pathology</abbr-1></periodical><alt-periodical><full-title>Am J Surg Pathol</full-title><abbr-1>The American journal of surgical pathology</abbr-1></alt-periodical><pages>1301-11</pages><volume>20</volume><number>11</number><edition>1996/11/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Age Distribution</keyword><keyword>Aged</keyword><keyword>Bone Neoplasms/chemistry/*pathology/radiography/therapy</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Hemangioendothelioma, Epithelioid/chemistry/*pathology/radiography/therapy</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Survival Rate</keyword></keywords><dates><year>1996</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0147-5185 (Print)&#xD;0147-5185 (Linking)</isbn><accession-num>8898834</accession-num><work-type>Case Reports</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8898834</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_6" \o "Kleer, 1996 #24" 6] rather than the histological grading system  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_15" \o "Bollinger, 1994 #5" 15]. Multifocal bone involvement was initially associated with better prognosis,  ADDIN EN.CITE <EndNote><Cite><Author>Gokhan</Author><Year>2006</Year><RecNum>19</RecNum><DisplayText>[20]</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gokhan, G. A.</author><author>Akyuz, M.</author><author>Gurer, I. E.</author><author>Tuncer, R.</author></authors></contributors><auth-address>Department of Pathology, Akdeniz University Faculty of Medicine, Antalya, Turkey. guzidegokhan@akdeniz.edu.tr</auth-address><titles><title>Epithelioid hemangioendothelioma derived from the spine region: case report and review of the literature</title><secondary-title>Wien Klin Wochenschr</secondary-title><alt-title>Wiener klinische Wochenschrift</alt-title></titles><periodical><full-title>Wien Klin Wochenschr</full-title><abbr-1>Wiener klinische Wochenschrift</abbr-1></periodical><alt-periodical><full-title>Wien Klin Wochenschr</full-title><abbr-1>Wiener klinische Wochenschrift</abbr-1></alt-periodical><pages>358-61</pages><volume>118</volume><number>11-12</number><edition>2006/07/21</edition><keywords><keyword>Adult</keyword><keyword>Diagnosis, Differential</keyword><keyword>Hemangioendothelioma, Epithelioid/*diagnosis</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Rare Diseases/diagnosis</keyword><keyword>Soft Tissue Neoplasms/*diagnosis</keyword><keyword>Spinal Neoplasms/*diagnosis</keyword></keywords><dates><year>2006</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0043-5325 (Print)&#xD;0043-5325 (Linking)</isbn><accession-num>16855926</accession-num><work-type>Case Reports&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16855926</url></related-urls></urls><electronic-resource-num>10.1007/s00508-006-0582-5</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_20" \o "Gokhan, 2006 #19" 20] but this is no longer widely accepted  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Aquilina, 2005 #4" 17,  HYPERLINK \l "_ENREF_21" \o "Chau, 2001 #8" 21].
     Our case is particularly noteworthy because a unique treatment strategy was applied, with the patient subjected to selective surgical intervention, followed by intravascular embolization and stereotactic radiosurgery. Although embolization succeeded in reducing residual tumor�s size, it did not manage to occlude all feeding arteries. Therefore, it was decided to go further to stereotactic radiosurgery as an adjuvant strategy to treat the remaining lesion and avert future recurrence. It should be noted however that, due to lack of clear-cut results from the literature, the role of stereotactic radiosurgery in these lesions remains unclear. To our knowledge, this is the first case where the three aforementioned modalities were applied in a patient with spinal EHE. Subjection to a larger operation which was common in most previously published cases was avoided. The patient did not show any signs of recurrence on MRI during the follow-up period and the tumor almost totally disappeared. The clinical result was also excellent since, after 7 years, she remained fully mobilized, neurologically intact and symptom-free. 

Conclusions
     Given the lack of a universally accepted treatment, EHE�s rarity and unpredictable behavior, total tumor resection should be at first hand pursued. An individualized treatment plan should be followed. However, there are cases where selective surgery combined with embolization and stereotactic radiosurgery can be equally effective obviating the need for an extensive operation. 

Conflict of interest
     The authors report no conflict of interest related to this study.
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Figure Legends

Figure 1: Left T1-weighted Magnetic Resonance Imaging (MRI) of the spine with gadolinium demonstrating a bony lesion at Th7 extending epidurally and compressing the spinal cord. Right T2-weigthed MRI of the thoracic spine showing the extension of the mass from the vertebral body and spinal canal to the left rib, the paravertebral soft and the thoracic cavity. 
Figure 2: Digital Substraction Angiography (DSA) showing the selective catheterization of the left Th7 intercostal artery and the embolization with N-butyl-2-cyanoacrylate (NBCA). 
Figure 3: Planning of Stereotactic Radiosurgery with Cyber Knife. The residual tumor was subjected to a single dose of 2100 cGy.
Figure 4: Left & Right Postoperative MRI of the spine 7 years after surgery showing significant reduction of the residual tumor with no signs of local recurrence.
Figure 5: Histopathological images. Upper left Lesion of vascular nature, composed of a proliferation of variously sized anastomosing vessels (H&EX100). Upper right The vascular channels were lined by endothelial cells with epithelioid morphology. Between the channels, normal bone marrow cells were observed (H&EX200). Lower left Some endothelial cells formed the lining of the vascular channels and some were arranged in small nests, cords and short strands. The endothelial cells were plump and epithelioid in appearance, medium in size and rounded to polygonal in shape. The nuclei were rounded, vesicular with focal mild atypia. Mitoses were absent (H&EX400). Lower right The neoplastic cells were positive with CD34 antibobies, thus confirming their endothelial nature. Immunohistochemical stain X 400.










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�L�$�ydh�xEƀ��*�gds4>�����������2�3�4�5�6�8�9�:������������־�˺��h�:�h�'CCJaJmHnHuh@Oh�:�CJaJjh@Oh�:�CJUaJhS�jhS�Uh [4h�x�CJaJmH	sH	21�h:p-���. ��A!��"��#��$��%�������sD���y������K�	_ENREF_1.D<EndNote><Cite><Author>Errani</Author><Year>2012</Year><RecNum>12</RecNum><DisplayText>[2-4]</DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Errani, C.</author><author>Vanel, D.</author><author>Gambarotti, M.</author><author>Alberghini, M.</author><author>Picci, P.</author><author>Faldini, C.</author></authors></contributors><auth-address>Ortopedia Generale, Orthopaedic Service, Istituto Ortopedico Rizzoli, Rizzoli-Sicilia, Bagheria, Italy. ostantino.errani@ior.it</auth-address><titles><title>Vascular bone tumors: a proposal of a classification based on clinicopathological, radiographic and genetic features</title><secondary-title>Skeletal Radiol</secondary-title><alt-title>Skeletal radiology</alt-title></titles><periodical><full-title>Skeletal Radiol</full-title><abbr-1>Skeletal radiology</abbr-1></periodical><alt-periodical><full-title>Skeletal Radiol</full-title><abbr-1>Skeletal radiology</abbr-1></alt-periodical><pages>1495-507</pages><volume>41</volume><number>12</number><edition>2012/09/21</edition><keywords><keyword>Bone Neoplasms/*classification/*diagnosis</keyword><keyword>Diagnostic Imaging/*methods</keyword><keyword>Humans</keyword><keyword>Neoplasms, Vascular Tissue/*classification/*diagnosis</keyword></keywords><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1432-2161 (Electronic)&#xD;0364-2348 (Linking)</isbn><accession-num>22993209</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22993209</url></related-urls></urls><electronic-resource-num>10.1007/s00256-012-1510-6</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Jo</Author><Year>2014</Year><RecNum>45</RecNum><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="5psx5wsvdrz5wcer2pa5tetpteapt09pt2ft">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jo, V. 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