10.1007/s11060-009-9973-6</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.16890" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-9973-6</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Topic Review</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Primary gliosarcoma: key = clinical and=20 pathologic distinctions from glioblastoma with implications as a unique=20 oncologic entity </DIV> <P class=3DAuthorGroup>Seunggu J. Han<SUP>1</SUP>,=20 Isaac Yang<SUP>1</SUP>, Tarik Tihan<SUP>2</SUP>,=20 Michael D. Prados<SUP>1</SUP> and=20 Andrew T. Parsa<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#ContactOfAuthor5"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/1272768840581111/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurological Surgery, = University=20 of California at San Francisco, 505 Parnassus Ave., San Francisco, = CA 94117, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Pathology, University of = California at San Francisco, San Francisco, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor5></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/1272768840581111/contact.gif" = border=3D0></TD> = <TD><STRONG>Andrew </STRONG><STRONG>T. </STRONG><STRONG>Parsa</= STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:ParsaA@neurosurg.ucsf.edu">ParsaA@neurosurg.ucsf.edu</A></= TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>6 January 2009 <STRONG>Accepted:=20 </STRONG>6 July 2009 <STRONG>Published online:=20 </STRONG>18 July 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>This report presents = the=20 historical experience, clinical presentation, treatment, prognosis, and=20 pathogenesis of gliosarcoma described to date in the English literature. = PubMed=20 query of term =93gliosarcoma=94 was performed, followed by a rigorous = review of=20 cited literature. Articles selected for analysis included: (1) case = reports of=20 gliosarcoma, (2) review articles of gliosarcoma, and (3) studies of the=20 pathogenesis or genetics of gliosarcoma in humans. Our review identified = 219=20 cases of gliosarcoma in 34 reports and eight articles addressing the=20 pathogenesis. Survival in larger series ranged 4=9611.5 months. = Features=20 unique to gliosarcoma compared to glioblastoma (GBM) include their = temporal lobe=20 predilection, potential to appear similar to a meningioma at surgery, = repeated=20 reports of extracranial metastases, and infrequency of EGFR mutations. = Published=20 experience is limited to small case series, and the pathogenesis remains = unclear. Clinical and pathologic characteristics distinct from GBM = suggest that=20 they may warrant specific treatment, separate from conventional GBM = therapy.=20 </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Gliosarcoma - = ;Primary=20 gliosarcoma - Review </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <DIV class=3DPara> <DIV class=3D"">Gliosarcoma was initially described by Stroebe in 1895 = as a brain=20 neoplasm consisting of both glial and mesenchymal components [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR1">1</A></CITE>].=20 This biphasic tumor subsequently gained general acceptance from detailed = histological analyses of Feigen and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 Due to lack of specific and uniform diagnostic criteria however, the = term=20 gliosarcoma was also applied to tumors of glial origin that have taken = on=20 mesenchymal phenotypes, such as the ability to produce reticulin and = collagen=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>].=20 Over time, these tumors were understood as distinct entities, one being = a tumor=20 of glial origin taking on mesenchymal characteristics, termed = desmoplastic=20 glioma or glioma with desmoplastic metaplasia, the other entity being a = tumor=20 with distinct gliomatous and sarcomatous components, termed gliosarcoma=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR4">4</A></CITE>].=20 The 2007 World Health Organization classification scheme places primary=20 gliosarcoma (PGS) as a grade IV neoplasm and a variant of glioblastoma=20 multiforme (GBM) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR5">5</A></CITE>].=20 The current accepted definition of PGS is a well-circumscribed lesion = with=20 clearly identifiable biphasic glial and metaplastic mesenchymal = components=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR6">6</A></CITE>].=20 Histologically, the glial component fulfills the cytologic criteria of = GBM, and=20 the mesenchymal component may show a wide variety of morphologies with = origins=20 from fibroblastic, cartilaginous, osseous, smooth and striated muscle, = or=20 adipose cell lineage. The current definition, however, lacks pathologic=20 consensus, particularly regarding the relative predominance of a single = element.=20 As clinical and pathologic features of PGS continue to be elucidated, = more=20 rigorous diagnostic criteria must be considered. The current = classification of=20 PGS as a variant of GBM reflects the fact that they are often treated in = the=20 same manner; however anecdotal evidence suggests that PGS are distinct = from GBM.=20 In this report we review the published English language literature to = highlight=20 the unique clinical and pathologic features of PGS (Figs. <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Fig1">1</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Fig2">2</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Fig3">3</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_9973_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/1272768840581111/MediaObjects/= 11060_2009_9973_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Histology = of=20 gliosarcoma. <B>a</B> 200=D7. Immunohistochemical staining for vascular = marker=20 CD31, demonstrating focal perinuclear positivity in many of the tumor = cells.=20 Positive staining vascular endothelium serves as internal control. = <B>b</B>=20 200=D7. Focal strong membranous staining of tumor cells with CD34 = antibody.=20 Positive staining within vascular endothelium serves as internal = control.=20 <B>c</B> 200=D7. Focal weak cytoplasmic staining with GFAP antibody in = tumor=20 cells. This suggests a glial origin. <B>d</B> Hematoxylin and eosin = stain, 200=D7.=20 Vascular endothelial proliferation and myxoid and chondromatous area in = a=20 gliosarcoma. The tumor cells show focal myxoid change and epithelioid = morphology=20 </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_9973_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/1272768840581111/MediaObjects/= 11060_2009_9973_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 2 </SPAN>Morphology of=20 gliosarcoma <B>a</B> Smear preparation, hematoxylin and eosin stain, = 100=D7.=20 Portion of the tumor showing sarcomatous, spindle morphology. Other = potential=20 differentiation includes osseous, vascular, skeletal muscle, and adipose = phenotypes. <B>b</B> GFAP, 100=D7. The sarcomatous component is GFAP = negative=20 <B>c</B> 400=D7. The basement membrane is highlighted by Laidlaw = Reticulin=20 impregnation in the sarcomatous component of the tumor. Reticulin shows = thick=20 uniform atypical appearance </DIV> <HR> <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2009_9973_Fig3_HTML.jpg=20 src=3D"http://www.springerlink.com/content/1272768840581111/MediaObjects/= 11060_2009_9973_Fig3_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 3 </SPAN>Neuroimaging of a=20 gliosarcoma before surgery. Gadolinium-enhanced T1-weighted axial images = of the=20 patient=92s left sided temporal lobe gliosarcoma </DIV> <HR> </DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <P class=3D"">Articles were identified through a PubMed query using the = keyword=20 =93gliosarcoma=94. The cited references of the sources were also = searched. 757=20 citations reported to date were screened using our inclusion criteria. = Articles=20 selected for analysis included: (1) case reports or series of = gliosarcoma=20 patients, (2) review articles of gliosarcoma, or (3) experiments = studying the=20 pathogenesis or genetics of gliosarcoma in humans. The search yielded 34 = case=20 series and reports meeting our criteria and included a total of 219 = cases of=20 PGS. Majority of these published series included cases of gliosarcoma = based on=20 the WHO criteria for gliosarcoma. </P></DIV> <DIV class=3D""><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Pathogenesis</DIV> <P class=3D"">The pathogenesis of gliosarcoma has been a topic of = controversy and=20 currently remains unknown. In addition, there has been no detailed study = to date=20 that focuses on genetic and pathologic differences between PGS and = secondary=20 gliosarcoma. Early reports suggested that the sarcomatous components = originated=20 from neoplastic transformation of hyperplastic blood vessels commonly = found in=20 high grade gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>].=20 This =93collision tumor=94 concept was supported by early descriptions = by Feigin of=20 hyperplastic vessels and perivascular arrangement of sarcomatous = elements in=20 gliosarcoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR7">7</A></CITE>].=20 Studies showing histological reactivity of the sarcomatous component to = vascular=20 endothelial markers such as factor VIII, von Willebrand factor and CD34 = also=20 provided support for this hypothesis [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR8">8</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR10">10</A></CITE>].=20 However, a number of other studies followed that failed to discover the = presence=20 of endothelial markers in the sarcomatous elements [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR11">11</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR13">13</A></CITE>].=20 </P> <P class=3D"">An alternative theory that has recently gained favor = points to a=20 monoclonal origin of both components of gliosarcoma, with sarcomatous = component=20 originating via aberrant mesenchymal differentiation of the malignant = glioma.=20 Biernat and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR14">14</A></CITE>]=20 first demonstrated identical p53 mutations in gliomatous and sarcomatous = components. Reis and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR15">15</A></CITE>]=20 discovered identical PTEN mutations, p53 nuclear accumulation, p16 = deletion, and=20 CDK4 amplifications in both tumor areas. Other authors followed, = describing that=20 both components of gliosarcoma shared common genetic alterations and = chromosomal=20 imbalances of the type classically described in GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR17">17</A></CITE>].=20 These alterations included gains on chromosomes 7, 9q, 20q, and X, and = losses on=20 chromosomes 10, 9p, and 13q [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR17">17</A></CITE>].=20 Studies found, however, a much lower frequency of EGFR amplification in=20 gliosarcoma than found in primary GBM. While EGFR is amplified in up to = half of=20 primary GBMs, the rate of amplification is much lower in gliosarcoma (8% = in=20 small series) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>].=20 Gliosarcomas were also found to have a fewer number of chromosomes = involved in=20 imbalances, suggesting a higher level of genomic stability in = gliosarcomas=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>].=20 Although, there is currently a paucity of data supporting these genetic = markers=20 to be of prognostic value, detailed future clinicopathologic studies = will=20 continue to elucidate their role in tumorigenesis, progression, and = clinical=20 management of gliosarcomas. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <HR> <DIV class=3Dheading2>Clinical characteristics</DIV> <P class=3D"">Gliosarcomas are rare and have an incidence 1.8=962.8% = that of GBMs=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 Similar to other glial based tumors, PGS affects adults in the sixth to = seventh=20 decade of life, with a significantly higher proportion found in men than = in=20 women (M:F ratio 1.4=961.8:1) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 The presenting signs and symptoms reported are consistent with those of = a=20 rapidly expanding intracranial tumor, including aphasia, headache, = hemiparesis,=20 seizures, and cognitive decline, depending on its location. The clinical = similarities to GBM have led many authors to conclude that these tumors = are=20 clinically indistinguishable [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR19">19</A></CITE>].=20 However, there are a number of important and distinct features of PGS = that=20 suggest that it is a separate entity. </P> <P class=3D"">The striking features of PGS that distinguish it from GBM = include=20 its location and its differential radiographic and gross appearance. = Gliosarcoma=20 is almost never found infratentorially and the majority of the reports = describe=20 its temporal lobe predilection [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>]=20 while a few report a higher incidence in the frontal lobe [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>].=20 The published experience describes two distinct appearances of PGS = grossly at=20 operation. The early case series by Feigin and Morantz noted the gross=20 appearance of PGS were often firm, well-circumscribed masses commonly = found at=20 the periphery in contact with the dura mater, falx cerebri or the skull=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 However, the series by Perry and colleagues reported that most cases of=20 gliosarcoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>]=20 were diffusely infiltrating with ill defined margins (exact proportions = not=20 given). In contrast the series by Parekh and colleagues found only 2 of = 15 cases=20 had such characteristics on gross appearance [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>].=20 These three series illustrate the variety of potential appearances of = PGS,=20 despite the use of the same diagnostic criteria described by the WHO. = </P> <P class=3D"">The findings on imaging are also variable. On computed = tomography=20 (CT), the lesions can appear with large necrotic areas and heterogenous = contrast=20 enhancement, similar to that of GBMs, or as hyperdense lesions with = well-defined=20 margins and homogenous enhancement, mimicking the appearance of a = meningioma=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR24">24</A></CITE>].=20 In a small case series of five patients, Maiuri and colleagues [<CITE><A = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR24">24</A></CITE>]=20 reported that PGS resembling meningiomas on CT appeared similar to = meningiomas=20 on gross pathology as well. However, this correlation was not found in a = subsequent report that included 15 patients with PGS who received = surgical=20 resection [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>].=20 Of the 14 patients who were imaged by CT, only 3 showed homogenous = enhancement,=20 similar to a meningioma. Of 15 tumors that were excised, 13 showed firm = lesions=20 with well demarcated margins, and two were necrotic and infiltrating = with ill=20 defined borders. Detailed descriptions of appearance on Magnetic = Resonance=20 Imaging (MRI) are lacking, as the majority of large case series were = reported=20 during the era when CT was the primary method of imaging. Hence, reports = of=20 clinical correlation with findings on MRI are also lacking. Recent case = reports=20 show that findings on MRI are similar to those on CT, with masses having = heterogeneous enhancement and sharply demarcated or irregular borders = [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR19">19</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR30">30</A></CITE>].=20 A prominent and common feature of gliosarcomas seen on MRI is marked = peritumoral=20 edema [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 The difficulty in establishing the diagnosis of PGS radiologically = underscores=20 the importance of establishing methods to make the diagnosis=20 histopathologically. The variability of radiographic and pathologic=20 presentations of gliosarcoma suggests a potential need for an update of = the WHO=20 criteria reflecting these potential clinical subtypes. </P> <P class=3D"">Despite its variable appearance, initial data have = supported uniform=20 aggressive treatment of PGS. Morantz and Feigin as well as Parekh and = colleagues=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>]=20 warn that an attempt to shell out PGS that resemble meningiomas will = likely=20 result in persistence of tumor tissue with subsequent recurrence. = Currently, a=20 reasonable approach to these tumors is an attempt at gross total = resection when=20 possible. However unlike GBM, there currently are no well controlled = studies to=20 support the advantage of a gross total resection of PGS over biopsy or = subtotal=20 resection followed by adjuvant therapy. </P></DIV> <DIV class=3D""><A name=3DSec5></A> <HR> <DIV class=3Dheading2>Metastasis</DIV> <P class=3D"">Extracranial metastases from cerebral gliomas, including = GBM, are=20 very rare, while the propensity for gliosarcomas to metastasize is well=20 established. Even in the early days of Feigin, several authors reported = cases of=20 metastatic foci that contained admixtures of both gliomatous and = sarcomatous=20 elements [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR31">31</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR32">32</A></CITE>].=20 The presence of these metastases was a large contribution to the premise = that=20 PGS are a clinically separate entity from GBM and truly biphasic in = nature.=20 Smith and colleages [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR33">33</A></CITE>]=20 in the largest metastatic case series to date of seven cases of = gliosarcomas,=20 observed that in two cases, the metastatic foci were composed solely of = the=20 sarcomatous component. Other case reports followed with similar findings = of=20 sarcomatous elements alone in metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR34">34</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR36">36</A></CITE>].=20 These observations have generated the belief that the metastatic = potential of=20 gliosarcoma is due to the sarcoma component and ultimately reflects the = strong=20 propensity of sarcomatous neoplasms to disseminate hematogenously. </P> <P class=3D"">Most extracranial metastases of gliosarcoma are located in = the lung=20 and liver, and there are reports of metastatic foci in cervical lymph = nodes,=20 spleen, adrenal glands, kidneys, oral mucosa, skin, bone marrow, skull, = ribs,=20 and spine [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR31">31</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR40">40</A></CITE>].=20 Intramedullary metastasis to the cervical spine has also been observed = [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR41">41</A></CITE>].=20 There is a rare case of widespread extracranial metastases with = intravascular=20 tumor emboli, which is also consistent with the concept that gliosarcoma = metastasize via a hematogenous route [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec6></A> <HR> <DIV class=3Dheading2>Treatment</DIV> <DIV class=3DPara> <DIV class=3D"">Treatment modalities described for gliosarcoma include = tumor=20 resection, postoperative radiation therapy, and chemotherapy with = nitrosureas,=20 misonidazole, dacarbazine, mithramycin, ametophterin, thalidomide, = temozolomide,=20 irinotecan, vincristine, cisplatin, or doxorubicin [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR42">42</A></CITE>].=20 The majority of information on PGS therapy is derived from published = case=20 series. Typically the described therapeutic modality is based on the = prevailing=20 treatment for GBM that has demonstrated benefits in randomized trials. = In an=20 early series of 24 cases by Morantz and colleagues, all 24 patients = underwent=20 surgical resection, 18 patients received radiation therapy, and nine = patients=20 received chemotherapy (mithramycin and ametophterin) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 The distribution of treatment modalities described in other larger case = series=20 are similar with the majority of patients having undergone surgical = resection, a=20 smaller portion having received therapeutic radiation, and a few having = received=20 a wide range of chemotherapeutic agents (Table <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Clinical = data on=20 gliosarcoma reported in large case series </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Study, year, ref. no.</P></TH> <TH align=3Dleft> <P class=3D"">Pts</P></TH> <TH align=3Dleft> <P class=3D"">Mean age</P></TH> <TH align=3Dleft> <P class=3D"">Surgical resection (no)</P></TH> <TH align=3Dleft> <P class=3D"">Radiation (no)</P></TH> <TH align=3Dleft> <P class=3D"">Total dose (Gy)</P></TH> <TH align=3Dleft> <P class=3D"">Fractionation</P></TH> <TH align=3Dleft> <P class=3D"">Chemotherapy no, (agents)</P></TH> <TH align=3Dleft> <P class=3D"">Survival (median, months)</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Morantz, 1976 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">24</P></TD> <TD align=3Dleft> <P class=3D"">54</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">18</P></TD> <TD align=3Dleft> <P class=3D"">50=9660</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">9 (mithramycin, ametophterin)</P></TD> <TD align=3Dleft> <P class=3D"">4 (GS all)</P> <P class=3D"">7 (GS surgery + RT)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Meis, 1991 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">26</P></TD> <TD align=3Dleft> <P class=3D"">50%</P> <P class=3D"">>60</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">45=9681</P></TD> <TD align=3Dleft> <P class=3D"">CF, HF, AF</P></TD> <TD align=3Dleft> <P class=3D"">17 (nitrosureas, dacarbazine, misonidazole)</P></TD> <TD align=3Dleft> <P class=3D"">8.3</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Perry, 1995 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">32</P></TD> <TD align=3Dleft> <P class=3D"">66</P></TD> <TD align=3Dleft> <P class=3D"">31</P></TD> <TD align=3Dleft> <P class=3D"">12</P></TD> <TD align=3Dleft> <P class=3D"">50</P></TD> <TD align=3Dleft> <P class=3D"">CF</P></TD> <TD align=3Dleft> <P class=3D"">6 (nitrosureas)</P></TD> <TD align=3Dleft> <P class=3D"">6.25 (GS all)</P> <P class=3D"">11.5 (GS surgery + RT)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Parekh, 1995 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">17</P></TD> <TD align=3Dleft> <P class=3D"">52</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">16</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">3 (NM)</P></TD> <TD align=3Dleft> <P class=3D""><24 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sarkar, 1997 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">29</P></TD> <TD align=3Dleft> <P class=3D"">42</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">40=9660</P></TD> <TD align=3Dleft> <P class=3D"">CF</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D""><18 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Galanis, 1998 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">18</P></TD> <TD align=3Dleft> <P class=3D"">56%</P> <P class=3D"">>60</P></TD> <TD align=3Dleft> <P class=3D"">16</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">60=9665</P></TD> <TD align=3Dleft> <P class=3D"">CF</P></TD> <TD align=3Dleft> <P class=3D"">18 (nitrosureas)</P></TD> <TD align=3Dleft> <P class=3D"">8.75</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lutterbach, 2001 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">12</P></TD> <TD align=3Dleft> <P class=3D"">56</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">42=9654</P></TD> <TD align=3Dleft> <P class=3D"">AHF, HypoF</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">11.5</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>NM</I> not mentioned, <I>GS</I> gliosarcoma, = <I>RT</I>=20 radiotherapy, <I>CF</I> conventional fractionation, <I>HF</I>=20 hyperfractionation, <I>AF</I> accelerated fractionation, <I>AHF</I> = accelerated=20 hyperfractionation, <I>HypoF</I> hypofractionation </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D"">Adapted from Lutterbach et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>]=20 </DIV></DIV></DIV></DIV></DIV> <P class=3D"">The total dose delivered in radiotherapy ranged from 45 to = 81 Gy in these reports. Because the role of radiation in prolonging = survival in GBM has been well established, many of the previously = mentioned=20 authors implemented postoperative radiotherapy for all patients with = PGS,=20 despite lack of evidence for its benefit at the time [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 The small body of evidence in observational and cohort studies available = now=20 supports the benefit of radiotherapy in gliosarcoma. An interesting = recent case=20 report describes recurrence of only the sarcomatous component of a PGS = after=20 boron neutron capture therapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR26">26</A></CITE>].=20 This case raises the possibility of differential sensitivities to = radiation of=20 the gliomatous and sarcomatous elements, although due to the technique = of boron=20 neutron capture therapy, differential accumulation of boron compounds in = the=20 glioma component is an alternative explanation. </P> <P class=3D"">Although chemotherapy with temozolomide is now standard of = care for=20 GBM, the precise role of chemotherapy remains uncertain for PGS. Morantz = and=20 colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>]=20 observed a modest increase in survival for PGS patients when = chemotherapy with=20 mithramycin and ametophterin (dose not reported) was added to = postsurgical=20 radiation alone (36, 33 weeks respectively, no <I>P</I> value = given). Other=20 authors did not offer chemotherapy to study participants, citing its ill = defined=20 role [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].=20 </P> <P class=3D"">Currently, there is very little data regarding the = response of=20 gliosarcoma to novel therapies that are being developed and studied for=20 malignant gliomas, such as immunotherapy and cancer vaccine therapies. = Most=20 trials with malignant glioma include gliosarcoma as a variant of GBM, = and roles=20 of novel therapies in management of gliosarcoma becomes difficult to = parse out=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR44">44</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Prognosis</DIV> <DIV class=3DPara> <DIV class=3D"">PGS has a poor prognosis with median survival in = untreated=20 patients of 4 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 For patients who underwent treatment described in case series with 10 = patients=20 or more (<I>N</I> =3D 154), the median survival was between = 6.25 and=20 11.5 months per cohort (Table <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].=20 Although a number of series suggested a slightly better prognosis for = PGS than=20 for GBMs, four studies that included a matched GBM control group failed = to show=20 a statistically significant difference in survival (all four studies = predate the=20 currently accepted radiotherapy with concurrent and adjuvant = temozolomide=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR45">45</A></CITE>],=20 as treatment for GBM, Table <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Tab2">2</A>).=20 Meis and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>]=20 found that median survival was 8.3 months for PGS patients compared = to=20 9.6 months for GBM patients (not statistically significant), = Galanis and=20 colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>]=20 reported gliosarcoma patients had median survival of 8.75 months = and the=20 matched controls with GBM had median survival of 8.6 months (not=20 statistically significant), Lutterbach and colleagues found median = actuarial=20 survival to be 11.5 months for the group with gliosarcoma, and=20 8.1 months for the control group with GBM = (<I>P</I> =3D 0.36)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 Miller and Perry [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR6">6</A></CITE>]=20 observed median survivals of 7.6 months for gliosarcoma group and=20 9.3 months for the matched GBM controls = (<I>P</I> =3D 0.33).<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Survival = of=20 gliosarcoma compared to glioblastoma multiforme </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Study, year, ref. no.</P></TH> <TH align=3Dleft> <P class=3D"">Number, GS/GBM</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Median survival GS (months)</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Median survival matched GBM (months)</P></TH> <TH align=3Dleft> <P class=3D""><I>P</I> </P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Meis, 1991 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">26/1453 (1.8%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.6</P></TD> <TD align=3Dleft> <P class=3D"">Non significant</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Galanis, 1998 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">18/748 (2.4%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.75</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.6</P></TD> <TD align=3Dleft> <P class=3D"">Non significant</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lutterbach, 2001 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">12/420 (2.9%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">11.5</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.1</P></TD> <TD align=3Dleft> <P class=3D"">0.36</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Miller, 2007 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR6">6</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">10/453 (2.2%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">7.6</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.3</P></TD> <TD align=3Dleft> <P class=3D"">0.33</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">In a series of five gliosarcoma patients, Maiuri and = colleagues=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR24">24</A></CITE>]=20 noted an association of longer survival with radiologic appearance = similar to=20 that of a meningioma and prevalence of the sarcomatous element on = histology.=20 Cervoni and Celli [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR26">26</A></CITE>]=20 also found in six patients that there was increased survival in patients = with=20 PGS that resembled meningiomas, and had dominance of the sarcomatous = component=20 in comparison with those that did not (14 vs. 7 months, no <I>P</I> = value=20 given). </P> <P class=3D"">The benefit of radiation therapy on survival of patients = was=20 described by Perry and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>],=20 as radiation treated patients had median survival of 10.6 months, = compared=20 to 6.25 months in patients not treated with radiation=20 (<I>P</I> < 0.025). The effect of chemotherapy has only = been=20 commented on by Morantz and colleagues showing a modest improvement in = survival.=20 Strong evidence supporting the benefit of chemotherapy for PGS patients = is=20 lacking. </P> <P class=3D"">One peculiar case of a patient with prolonged survival has = been=20 described by Winkler and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR30">30</A></CITE>].=20 A 61-year-old patient with PGS experienced a recurrence 20 years = after=20 initial diagnosis and treatment with repeated histological confirmation. = During=20 the 2 years following recurrence, she underwent multiple = resections,=20 radiotherapy, radiosurgery, and intracavitary radioimmunotherapy, and = ultimately=20 passed away 22 years after initial diagnosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Future direction of pathogenesis and clinical=20 management</DIV> <P class=3D"">Current hypotheses on the pathogenesis of PGS include (1) = GBM=20 promoting differentiation of local or circulating mesenchymal stem cells = into=20 sarcoma, (2) sarcoma cells converting local or circulating stem cells = into=20 differentiating into GBM, (3) one stem cell lineage ultimately giving = rise to=20 both GBM and sarcoma, and (4) differentiated glial cells of GBM undergo=20 dedifferentiation and give rise to the sarcoma. The concept of sarcoma = induction=20 by GBM is consistent with the early hypothesis of Feigin based on = hyperplasia of=20 vasculature seen in GBMs [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>].=20 Alternatively, primary CNS sarcomas have been reported, and the sarcoma = may=20 induce malignant transformation in glial cells, resulting in = gliosarcoma. This=20 hypothesis could be explored by experiments co-culturing sarcomas and = glial=20 cells and observing for possible malignant changes in glia. The last two = hypotheses, suggesting a monoclonal origin of both parts of gliosarcoma, = have=20 been tested in experiments identifying common genetic alterations in = each cell=20 type [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR17">17</A></CITE>].=20 However, in the case of PGS, there is the possibility that = transformations to=20 glioma and sarcoma may involve different genetic mutations. Considering = the=20 current evidence to date, the monoclonal origin hypothesis seems the = most=20 likely, or at least the most frequent method of pathogenesis; however, = further=20 investigation is necessary elucidate the exact mechanism of pathogenesis = in=20 gliosarcoma. </P> <P class=3D"">Future clinical trials of malignant glioma would likely = benefit from=20 considering gliosarcoma as a unique entity, in order to limit = confounding by the=20 potential differential characteristics between gliosarcoma and other = gliomas in=20 prognostic markers as well as response to novel therapies. However,=20 comprehensive large prospective studies of gliosarcoma remain = challenging due to=20 the rarity of these tumors. </P></DIV> <DIV class=3D""><A name=3DSec9></A> <HR> <DIV class=3Dheading2>Conclusions</DIV> <P class=3D"">PGS represents a clinically challenging group of tumors, = due to its=20 rarity, poor prognosis, and the limited experience in published = literature. Many=20 of its clinical and pathogenetic characteristics remain to be revealed, = and=20 there is much room for future studies focusing on these biphasic tumors. = The=20 current reported literature does provide a number of distinguishing = clinical and=20 pathogenetic features of PGS to suggest they are indeed separate = entities from=20 GBMs. These differences include gliosarcomas=92 temporal lobe = predilection, their=20 potential to appear similar to a meningioma grossly at operation, their=20 increased metastatic potential, and the infrequency of EGFR mutation. = Evidence=20 for survival and efficacy of treatments is also limited due to the = difficulty of=20 conducting prospective trials. However, properly designed studies are = necessary=20 to optimize their management by considering their differential clinical = behavior=20 and pathogenesis from GBM. Although the precise etiology of PGS remains = unknown,=20 the interplay of glioma and sarcoma genesis requires further = investigation to=20 reveal potential targets for clinical applications. </P></DIV> <DIV class=3DAcknowledgments><SPAN class=3DAcknowledgmentsHeading>Open=20 Access </SPAN><SPAN class=3D"">This article is distributed = under the=20 terms of the Creative Commons Attribution Noncommercial License which = permits=20 any noncommercial use, distribution, and reproduction in any medium, = provided=20 the original author(s) and source are credited.</SPAN></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Stroebe H (1895) Ueber Entstehung und Bau der=20 Gehirnglioma. Beitr Pathol Anat Allg Pathol 19:405=96486 = </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Feigin I, Gross SW (1954) Sarcoma arising in=20 glioblastoma of the brain. 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From: Subject: 10.1007/s11060-009-9973-6 Date: Sun, 23 Aug 2009 10:05:15 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0065_01CA23D9.35CC3050" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0065_01CA23D9.35CC3050 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/1272768840581111/fulltext.html 10.1007/s11060-009-9973-6</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.16890" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-9973-6</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Topic Review</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Primary gliosarcoma: key = clinical and=20 pathologic distinctions from glioblastoma with implications as a unique=20 oncologic entity </DIV> <P class=3DAuthorGroup>Seunggu J. Han<SUP>1</SUP>,=20 Isaac Yang<SUP>1</SUP>, Tarik Tihan<SUP>2</SUP>,=20 Michael D. Prados<SUP>1</SUP> and=20 Andrew T. Parsa<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#ContactOfAuthor5"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/1272768840581111/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurological Surgery, = University=20 of California at San Francisco, 505 Parnassus Ave., San Francisco, = CA 94117, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Pathology, University of = California at San Francisco, San Francisco, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor5></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/1272768840581111/contact.gif" = border=3D0></TD> = <TD><STRONG>Andrew </STRONG><STRONG>T. </STRONG><STRONG>Parsa</= STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:ParsaA@neurosurg.ucsf.edu">ParsaA@neurosurg.ucsf.edu</A></= TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>6 January 2009 <STRONG>Accepted:=20 </STRONG>6 July 2009 <STRONG>Published online:=20 </STRONG>18 July 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>This report presents = the=20 historical experience, clinical presentation, treatment, prognosis, and=20 pathogenesis of gliosarcoma described to date in the English literature. = PubMed=20 query of term =93gliosarcoma=94 was performed, followed by a rigorous = review of=20 cited literature. Articles selected for analysis included: (1) case = reports of=20 gliosarcoma, (2) review articles of gliosarcoma, and (3) studies of the=20 pathogenesis or genetics of gliosarcoma in humans. Our review identified = 219=20 cases of gliosarcoma in 34 reports and eight articles addressing the=20 pathogenesis. Survival in larger series ranged 4=9611.5 months. = Features=20 unique to gliosarcoma compared to glioblastoma (GBM) include their = temporal lobe=20 predilection, potential to appear similar to a meningioma at surgery, = repeated=20 reports of extracranial metastases, and infrequency of EGFR mutations. = Published=20 experience is limited to small case series, and the pathogenesis remains = unclear. Clinical and pathologic characteristics distinct from GBM = suggest that=20 they may warrant specific treatment, separate from conventional GBM = therapy.=20 </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Gliosarcoma - = ;Primary=20 gliosarcoma - Review </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <DIV class=3DPara> <DIV class=3D"">Gliosarcoma was initially described by Stroebe in 1895 = as a brain=20 neoplasm consisting of both glial and mesenchymal components [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR1">1</A></CITE>].=20 This biphasic tumor subsequently gained general acceptance from detailed = histological analyses of Feigen and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 Due to lack of specific and uniform diagnostic criteria however, the = term=20 gliosarcoma was also applied to tumors of glial origin that have taken = on=20 mesenchymal phenotypes, such as the ability to produce reticulin and = collagen=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>].=20 Over time, these tumors were understood as distinct entities, one being = a tumor=20 of glial origin taking on mesenchymal characteristics, termed = desmoplastic=20 glioma or glioma with desmoplastic metaplasia, the other entity being a = tumor=20 with distinct gliomatous and sarcomatous components, termed gliosarcoma=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR4">4</A></CITE>].=20 The 2007 World Health Organization classification scheme places primary=20 gliosarcoma (PGS) as a grade IV neoplasm and a variant of glioblastoma=20 multiforme (GBM) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR5">5</A></CITE>].=20 The current accepted definition of PGS is a well-circumscribed lesion = with=20 clearly identifiable biphasic glial and metaplastic mesenchymal = components=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR6">6</A></CITE>].=20 Histologically, the glial component fulfills the cytologic criteria of = GBM, and=20 the mesenchymal component may show a wide variety of morphologies with = origins=20 from fibroblastic, cartilaginous, osseous, smooth and striated muscle, = or=20 adipose cell lineage. The current definition, however, lacks pathologic=20 consensus, particularly regarding the relative predominance of a single = element.=20 As clinical and pathologic features of PGS continue to be elucidated, = more=20 rigorous diagnostic criteria must be considered. The current = classification of=20 PGS as a variant of GBM reflects the fact that they are often treated in = the=20 same manner; however anecdotal evidence suggests that PGS are distinct = from GBM.=20 In this report we review the published English language literature to = highlight=20 the unique clinical and pathologic features of PGS (Figs. <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Fig1">1</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Fig2">2</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Fig3">3</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_9973_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/1272768840581111/MediaObjects/= 11060_2009_9973_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Histology = of=20 gliosarcoma. <B>a</B> 200=D7. Immunohistochemical staining for vascular = marker=20 CD31, demonstrating focal perinuclear positivity in many of the tumor = cells.=20 Positive staining vascular endothelium serves as internal control. = <B>b</B>=20 200=D7. Focal strong membranous staining of tumor cells with CD34 = antibody.=20 Positive staining within vascular endothelium serves as internal = control.=20 <B>c</B> 200=D7. Focal weak cytoplasmic staining with GFAP antibody in = tumor=20 cells. This suggests a glial origin. <B>d</B> Hematoxylin and eosin = stain, 200=D7.=20 Vascular endothelial proliferation and myxoid and chondromatous area in = a=20 gliosarcoma. The tumor cells show focal myxoid change and epithelioid = morphology=20 </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_9973_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/1272768840581111/MediaObjects/= 11060_2009_9973_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 2 </SPAN>Morphology of=20 gliosarcoma <B>a</B> Smear preparation, hematoxylin and eosin stain, = 100=D7.=20 Portion of the tumor showing sarcomatous, spindle morphology. Other = potential=20 differentiation includes osseous, vascular, skeletal muscle, and adipose = phenotypes. <B>b</B> GFAP, 100=D7. The sarcomatous component is GFAP = negative=20 <B>c</B> 400=D7. The basement membrane is highlighted by Laidlaw = Reticulin=20 impregnation in the sarcomatous component of the tumor. Reticulin shows = thick=20 uniform atypical appearance </DIV> <HR> <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2009_9973_Fig3_HTML.jpg=20 src=3D"http://www.springerlink.com/content/1272768840581111/MediaObjects/= 11060_2009_9973_Fig3_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 3 </SPAN>Neuroimaging of a=20 gliosarcoma before surgery. Gadolinium-enhanced T1-weighted axial images = of the=20 patient=92s left sided temporal lobe gliosarcoma </DIV> <HR> </DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <P class=3D"">Articles were identified through a PubMed query using the = keyword=20 =93gliosarcoma=94. The cited references of the sources were also = searched. 757=20 citations reported to date were screened using our inclusion criteria. = Articles=20 selected for analysis included: (1) case reports or series of = gliosarcoma=20 patients, (2) review articles of gliosarcoma, or (3) experiments = studying the=20 pathogenesis or genetics of gliosarcoma in humans. The search yielded 34 = case=20 series and reports meeting our criteria and included a total of 219 = cases of=20 PGS. Majority of these published series included cases of gliosarcoma = based on=20 the WHO criteria for gliosarcoma. </P></DIV> <DIV class=3D""><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Pathogenesis</DIV> <P class=3D"">The pathogenesis of gliosarcoma has been a topic of = controversy and=20 currently remains unknown. In addition, there has been no detailed study = to date=20 that focuses on genetic and pathologic differences between PGS and = secondary=20 gliosarcoma. Early reports suggested that the sarcomatous components = originated=20 from neoplastic transformation of hyperplastic blood vessels commonly = found in=20 high grade gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>].=20 This =93collision tumor=94 concept was supported by early descriptions = by Feigin of=20 hyperplastic vessels and perivascular arrangement of sarcomatous = elements in=20 gliosarcoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR7">7</A></CITE>].=20 Studies showing histological reactivity of the sarcomatous component to = vascular=20 endothelial markers such as factor VIII, von Willebrand factor and CD34 = also=20 provided support for this hypothesis [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR8">8</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR10">10</A></CITE>].=20 However, a number of other studies followed that failed to discover the = presence=20 of endothelial markers in the sarcomatous elements [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR11">11</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR13">13</A></CITE>].=20 </P> <P class=3D"">An alternative theory that has recently gained favor = points to a=20 monoclonal origin of both components of gliosarcoma, with sarcomatous = component=20 originating via aberrant mesenchymal differentiation of the malignant = glioma.=20 Biernat and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR14">14</A></CITE>]=20 first demonstrated identical p53 mutations in gliomatous and sarcomatous = components. Reis and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR15">15</A></CITE>]=20 discovered identical PTEN mutations, p53 nuclear accumulation, p16 = deletion, and=20 CDK4 amplifications in both tumor areas. Other authors followed, = describing that=20 both components of gliosarcoma shared common genetic alterations and = chromosomal=20 imbalances of the type classically described in GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR17">17</A></CITE>].=20 These alterations included gains on chromosomes 7, 9q, 20q, and X, and = losses on=20 chromosomes 10, 9p, and 13q [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR17">17</A></CITE>].=20 Studies found, however, a much lower frequency of EGFR amplification in=20 gliosarcoma than found in primary GBM. While EGFR is amplified in up to = half of=20 primary GBMs, the rate of amplification is much lower in gliosarcoma (8% = in=20 small series) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>].=20 Gliosarcomas were also found to have a fewer number of chromosomes = involved in=20 imbalances, suggesting a higher level of genomic stability in = gliosarcomas=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR16">16</A></CITE>].=20 Although, there is currently a paucity of data supporting these genetic = markers=20 to be of prognostic value, detailed future clinicopathologic studies = will=20 continue to elucidate their role in tumorigenesis, progression, and = clinical=20 management of gliosarcomas. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <HR> <DIV class=3Dheading2>Clinical characteristics</DIV> <P class=3D"">Gliosarcomas are rare and have an incidence 1.8=962.8% = that of GBMs=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 Similar to other glial based tumors, PGS affects adults in the sixth to = seventh=20 decade of life, with a significantly higher proportion found in men than = in=20 women (M:F ratio 1.4=961.8:1) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 The presenting signs and symptoms reported are consistent with those of = a=20 rapidly expanding intracranial tumor, including aphasia, headache, = hemiparesis,=20 seizures, and cognitive decline, depending on its location. The clinical = similarities to GBM have led many authors to conclude that these tumors = are=20 clinically indistinguishable [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR19">19</A></CITE>].=20 However, there are a number of important and distinct features of PGS = that=20 suggest that it is a separate entity. </P> <P class=3D"">The striking features of PGS that distinguish it from GBM = include=20 its location and its differential radiographic and gross appearance. = Gliosarcoma=20 is almost never found infratentorially and the majority of the reports = describe=20 its temporal lobe predilection [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>]=20 while a few report a higher incidence in the frontal lobe [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>].=20 The published experience describes two distinct appearances of PGS = grossly at=20 operation. The early case series by Feigin and Morantz noted the gross=20 appearance of PGS were often firm, well-circumscribed masses commonly = found at=20 the periphery in contact with the dura mater, falx cerebri or the skull=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 However, the series by Perry and colleagues reported that most cases of=20 gliosarcoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>]=20 were diffusely infiltrating with ill defined margins (exact proportions = not=20 given). In contrast the series by Parekh and colleagues found only 2 of = 15 cases=20 had such characteristics on gross appearance [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>].=20 These three series illustrate the variety of potential appearances of = PGS,=20 despite the use of the same diagnostic criteria described by the WHO. = </P> <P class=3D"">The findings on imaging are also variable. On computed = tomography=20 (CT), the lesions can appear with large necrotic areas and heterogenous = contrast=20 enhancement, similar to that of GBMs, or as hyperdense lesions with = well-defined=20 margins and homogenous enhancement, mimicking the appearance of a = meningioma=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR24">24</A></CITE>].=20 In a small case series of five patients, Maiuri and colleagues [<CITE><A = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR24">24</A></CITE>]=20 reported that PGS resembling meningiomas on CT appeared similar to = meningiomas=20 on gross pathology as well. However, this correlation was not found in a = subsequent report that included 15 patients with PGS who received = surgical=20 resection [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>].=20 Of the 14 patients who were imaged by CT, only 3 showed homogenous = enhancement,=20 similar to a meningioma. Of 15 tumors that were excised, 13 showed firm = lesions=20 with well demarcated margins, and two were necrotic and infiltrating = with ill=20 defined borders. Detailed descriptions of appearance on Magnetic = Resonance=20 Imaging (MRI) are lacking, as the majority of large case series were = reported=20 during the era when CT was the primary method of imaging. Hence, reports = of=20 clinical correlation with findings on MRI are also lacking. Recent case = reports=20 show that findings on MRI are similar to those on CT, with masses having = heterogeneous enhancement and sharply demarcated or irregular borders = [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR19">19</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR30">30</A></CITE>].=20 A prominent and common feature of gliosarcomas seen on MRI is marked = peritumoral=20 edema [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 The difficulty in establishing the diagnosis of PGS radiologically = underscores=20 the importance of establishing methods to make the diagnosis=20 histopathologically. The variability of radiographic and pathologic=20 presentations of gliosarcoma suggests a potential need for an update of = the WHO=20 criteria reflecting these potential clinical subtypes. </P> <P class=3D"">Despite its variable appearance, initial data have = supported uniform=20 aggressive treatment of PGS. Morantz and Feigin as well as Parekh and = colleagues=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>]=20 warn that an attempt to shell out PGS that resemble meningiomas will = likely=20 result in persistence of tumor tissue with subsequent recurrence. = Currently, a=20 reasonable approach to these tumors is an attempt at gross total = resection when=20 possible. However unlike GBM, there currently are no well controlled = studies to=20 support the advantage of a gross total resection of PGS over biopsy or = subtotal=20 resection followed by adjuvant therapy. </P></DIV> <DIV class=3D""><A name=3DSec5></A> <HR> <DIV class=3Dheading2>Metastasis</DIV> <P class=3D"">Extracranial metastases from cerebral gliomas, including = GBM, are=20 very rare, while the propensity for gliosarcomas to metastasize is well=20 established. Even in the early days of Feigin, several authors reported = cases of=20 metastatic foci that contained admixtures of both gliomatous and = sarcomatous=20 elements [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR31">31</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR32">32</A></CITE>].=20 The presence of these metastases was a large contribution to the premise = that=20 PGS are a clinically separate entity from GBM and truly biphasic in = nature.=20 Smith and colleages [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR33">33</A></CITE>]=20 in the largest metastatic case series to date of seven cases of = gliosarcomas,=20 observed that in two cases, the metastatic foci were composed solely of = the=20 sarcomatous component. Other case reports followed with similar findings = of=20 sarcomatous elements alone in metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR34">34</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR36">36</A></CITE>].=20 These observations have generated the belief that the metastatic = potential of=20 gliosarcoma is due to the sarcoma component and ultimately reflects the = strong=20 propensity of sarcomatous neoplasms to disseminate hematogenously. </P> <P class=3D"">Most extracranial metastases of gliosarcoma are located in = the lung=20 and liver, and there are reports of metastatic foci in cervical lymph = nodes,=20 spleen, adrenal glands, kidneys, oral mucosa, skin, bone marrow, skull, = ribs,=20 and spine [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR31">31</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR40">40</A></CITE>].=20 Intramedullary metastasis to the cervical spine has also been observed = [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR41">41</A></CITE>].=20 There is a rare case of widespread extracranial metastases with = intravascular=20 tumor emboli, which is also consistent with the concept that gliosarcoma = metastasize via a hematogenous route [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec6></A> <HR> <DIV class=3Dheading2>Treatment</DIV> <DIV class=3DPara> <DIV class=3D"">Treatment modalities described for gliosarcoma include = tumor=20 resection, postoperative radiation therapy, and chemotherapy with = nitrosureas,=20 misonidazole, dacarbazine, mithramycin, ametophterin, thalidomide, = temozolomide,=20 irinotecan, vincristine, cisplatin, or doxorubicin [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR42">42</A></CITE>].=20 The majority of information on PGS therapy is derived from published = case=20 series. Typically the described therapeutic modality is based on the = prevailing=20 treatment for GBM that has demonstrated benefits in randomized trials. = In an=20 early series of 24 cases by Morantz and colleagues, all 24 patients = underwent=20 surgical resection, 18 patients received radiation therapy, and nine = patients=20 received chemotherapy (mithramycin and ametophterin) [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 The distribution of treatment modalities described in other larger case = series=20 are similar with the majority of patients having undergone surgical = resection, a=20 smaller portion having received therapeutic radiation, and a few having = received=20 a wide range of chemotherapeutic agents (Table <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Clinical = data on=20 gliosarcoma reported in large case series </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Study, year, ref. no.</P></TH> <TH align=3Dleft> <P class=3D"">Pts</P></TH> <TH align=3Dleft> <P class=3D"">Mean age</P></TH> <TH align=3Dleft> <P class=3D"">Surgical resection (no)</P></TH> <TH align=3Dleft> <P class=3D"">Radiation (no)</P></TH> <TH align=3Dleft> <P class=3D"">Total dose (Gy)</P></TH> <TH align=3Dleft> <P class=3D"">Fractionation</P></TH> <TH align=3Dleft> <P class=3D"">Chemotherapy no, (agents)</P></TH> <TH align=3Dleft> <P class=3D"">Survival (median, months)</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Morantz, 1976 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">24</P></TD> <TD align=3Dleft> <P class=3D"">54</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">18</P></TD> <TD align=3Dleft> <P class=3D"">50=9660</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">9 (mithramycin, ametophterin)</P></TD> <TD align=3Dleft> <P class=3D"">4 (GS all)</P> <P class=3D"">7 (GS surgery + RT)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Meis, 1991 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">26</P></TD> <TD align=3Dleft> <P class=3D"">50%</P> <P class=3D"">>60</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">45=9681</P></TD> <TD align=3Dleft> <P class=3D"">CF, HF, AF</P></TD> <TD align=3Dleft> <P class=3D"">17 (nitrosureas, dacarbazine, misonidazole)</P></TD> <TD align=3Dleft> <P class=3D"">8.3</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Perry, 1995 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">32</P></TD> <TD align=3Dleft> <P class=3D"">66</P></TD> <TD align=3Dleft> <P class=3D"">31</P></TD> <TD align=3Dleft> <P class=3D"">12</P></TD> <TD align=3Dleft> <P class=3D"">50</P></TD> <TD align=3Dleft> <P class=3D"">CF</P></TD> <TD align=3Dleft> <P class=3D"">6 (nitrosureas)</P></TD> <TD align=3Dleft> <P class=3D"">6.25 (GS all)</P> <P class=3D"">11.5 (GS surgery + RT)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Parekh, 1995 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR21">21</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">17</P></TD> <TD align=3Dleft> <P class=3D"">52</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">16</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">NM</P></TD> <TD align=3Dleft> <P class=3D"">3 (NM)</P></TD> <TD align=3Dleft> <P class=3D""><24 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sarkar, 1997 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">29</P></TD> <TD align=3Dleft> <P class=3D"">42</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">40=9660</P></TD> <TD align=3Dleft> <P class=3D"">CF</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D""><18 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Galanis, 1998 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">18</P></TD> <TD align=3Dleft> <P class=3D"">56%</P> <P class=3D"">>60</P></TD> <TD align=3Dleft> <P class=3D"">16</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">60=9665</P></TD> <TD align=3Dleft> <P class=3D"">CF</P></TD> <TD align=3Dleft> <P class=3D"">18 (nitrosureas)</P></TD> <TD align=3Dleft> <P class=3D"">8.75</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lutterbach, 2001 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">12</P></TD> <TD align=3Dleft> <P class=3D"">56</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">All</P></TD> <TD align=3Dleft> <P class=3D"">42=9654</P></TD> <TD align=3Dleft> <P class=3D"">AHF, HypoF</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">11.5</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>NM</I> not mentioned, <I>GS</I> gliosarcoma, = <I>RT</I>=20 radiotherapy, <I>CF</I> conventional fractionation, <I>HF</I>=20 hyperfractionation, <I>AF</I> accelerated fractionation, <I>AHF</I> = accelerated=20 hyperfractionation, <I>HypoF</I> hypofractionation </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D"">Adapted from Lutterbach et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>]=20 </DIV></DIV></DIV></DIV></DIV> <P class=3D"">The total dose delivered in radiotherapy ranged from 45 to = 81 Gy in these reports. Because the role of radiation in prolonging = survival in GBM has been well established, many of the previously = mentioned=20 authors implemented postoperative radiotherapy for all patients with = PGS,=20 despite lack of evidence for its benefit at the time [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 The small body of evidence in observational and cohort studies available = now=20 supports the benefit of radiotherapy in gliosarcoma. An interesting = recent case=20 report describes recurrence of only the sarcomatous component of a PGS = after=20 boron neutron capture therapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR26">26</A></CITE>].=20 This case raises the possibility of differential sensitivities to = radiation of=20 the gliomatous and sarcomatous elements, although due to the technique = of boron=20 neutron capture therapy, differential accumulation of boron compounds in = the=20 glioma component is an alternative explanation. </P> <P class=3D"">Although chemotherapy with temozolomide is now standard of = care for=20 GBM, the precise role of chemotherapy remains uncertain for PGS. Morantz = and=20 colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>]=20 observed a modest increase in survival for PGS patients when = chemotherapy with=20 mithramycin and ametophterin (dose not reported) was added to = postsurgical=20 radiation alone (36, 33 weeks respectively, no <I>P</I> value = given). Other=20 authors did not offer chemotherapy to study participants, citing its ill = defined=20 role [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].=20 </P> <P class=3D"">Currently, there is very little data regarding the = response of=20 gliosarcoma to novel therapies that are being developed and studied for=20 malignant gliomas, such as immunotherapy and cancer vaccine therapies. = Most=20 trials with malignant glioma include gliosarcoma as a variant of GBM, = and roles=20 of novel therapies in management of gliosarcoma becomes difficult to = parse out=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR44">44</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Prognosis</DIV> <DIV class=3DPara> <DIV class=3D"">PGS has a poor prognosis with median survival in = untreated=20 patients of 4 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>].=20 For patients who underwent treatment described in case series with 10 = patients=20 or more (<I>N</I> =3D 154), the median survival was between = 6.25 and=20 11.5 months per cohort (Table <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].=20 Although a number of series suggested a slightly better prognosis for = PGS than=20 for GBMs, four studies that included a matched GBM control group failed = to show=20 a statistically significant difference in survival (all four studies = predate the=20 currently accepted radiotherapy with concurrent and adjuvant = temozolomide=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR45">45</A></CITE>],=20 as treatment for GBM, Table <A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#Tab2">2</A>).=20 Meis and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>]=20 found that median survival was 8.3 months for PGS patients compared = to=20 9.6 months for GBM patients (not statistically significant), = Galanis and=20 colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>]=20 reported gliosarcoma patients had median survival of 8.75 months = and the=20 matched controls with GBM had median survival of 8.6 months (not=20 statistically significant), Lutterbach and colleagues found median = actuarial=20 survival to be 11.5 months for the group with gliosarcoma, and=20 8.1 months for the control group with GBM = (<I>P</I> =3D 0.36)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>].=20 Miller and Perry [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR6">6</A></CITE>]=20 observed median survivals of 7.6 months for gliosarcoma group and=20 9.3 months for the matched GBM controls = (<I>P</I> =3D 0.33).<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Survival = of=20 gliosarcoma compared to glioblastoma multiforme </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Study, year, ref. no.</P></TH> <TH align=3Dleft> <P class=3D"">Number, GS/GBM</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Median survival GS (months)</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Median survival matched GBM (months)</P></TH> <TH align=3Dleft> <P class=3D""><I>P</I> </P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Meis, 1991 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR22">22</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">26/1453 (1.8%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.6</P></TD> <TD align=3Dleft> <P class=3D"">Non significant</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Galanis, 1998 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR20">20</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">18/748 (2.4%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.75</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.6</P></TD> <TD align=3Dleft> <P class=3D"">Non significant</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lutterbach, 2001 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR18">18</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">12/420 (2.9%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">11.5</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">8.1</P></TD> <TD align=3Dleft> <P class=3D"">0.36</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Miller, 2007 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR6">6</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">10/453 (2.2%)</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">7.6</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.3</P></TD> <TD align=3Dleft> <P class=3D"">0.33</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">In a series of five gliosarcoma patients, Maiuri and = colleagues=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR24">24</A></CITE>]=20 noted an association of longer survival with radiologic appearance = similar to=20 that of a meningioma and prevalence of the sarcomatous element on = histology.=20 Cervoni and Celli [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR26">26</A></CITE>]=20 also found in six patients that there was increased survival in patients = with=20 PGS that resembled meningiomas, and had dominance of the sarcomatous = component=20 in comparison with those that did not (14 vs. 7 months, no <I>P</I> = value=20 given). </P> <P class=3D"">The benefit of radiation therapy on survival of patients = was=20 described by Perry and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>],=20 as radiation treated patients had median survival of 10.6 months, = compared=20 to 6.25 months in patients not treated with radiation=20 (<I>P</I> < 0.025). The effect of chemotherapy has only = been=20 commented on by Morantz and colleagues showing a modest improvement in = survival.=20 Strong evidence supporting the benefit of chemotherapy for PGS patients = is=20 lacking. </P> <P class=3D"">One peculiar case of a patient with prolonged survival has = been=20 described by Winkler and colleagues [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR30">30</A></CITE>].=20 A 61-year-old patient with PGS experienced a recurrence 20 years = after=20 initial diagnosis and treatment with repeated histological confirmation. = During=20 the 2 years following recurrence, she underwent multiple = resections,=20 radiotherapy, radiosurgery, and intracavitary radioimmunotherapy, and = ultimately=20 passed away 22 years after initial diagnosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR43">43</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Future direction of pathogenesis and clinical=20 management</DIV> <P class=3D"">Current hypotheses on the pathogenesis of PGS include (1) = GBM=20 promoting differentiation of local or circulating mesenchymal stem cells = into=20 sarcoma, (2) sarcoma cells converting local or circulating stem cells = into=20 differentiating into GBM, (3) one stem cell lineage ultimately giving = rise to=20 both GBM and sarcoma, and (4) differentiated glial cells of GBM undergo=20 dedifferentiation and give rise to the sarcoma. The concept of sarcoma = induction=20 by GBM is consistent with the early hypothesis of Feigin based on = hyperplasia of=20 vasculature seen in GBMs [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR2">2</A></CITE>].=20 Alternatively, primary CNS sarcomas have been reported, and the sarcoma = may=20 induce malignant transformation in glial cells, resulting in = gliosarcoma. This=20 hypothesis could be explored by experiments co-culturing sarcomas and = glial=20 cells and observing for possible malignant changes in glia. The last two = hypotheses, suggesting a monoclonal origin of both parts of gliosarcoma, = have=20 been tested in experiments identifying common genetic alterations in = each cell=20 type [<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/1272768840581111/fulltext.htm= l#CR17">17</A></CITE>].=20 However, in the case of PGS, there is the possibility that = transformations to=20 glioma and sarcoma may involve different genetic mutations. Considering = the=20 current evidence to date, the monoclonal origin hypothesis seems the = most=20 likely, or at least the most frequent method of pathogenesis; however, = further=20 investigation is necessary elucidate the exact mechanism of pathogenesis = in=20 gliosarcoma. </P> <P class=3D"">Future clinical trials of malignant glioma would likely = benefit from=20 considering gliosarcoma as a unique entity, in order to limit = confounding by the=20 potential differential characteristics between gliosarcoma and other = gliomas in=20 prognostic markers as well as response to novel therapies. However,=20 comprehensive large prospective studies of gliosarcoma remain = challenging due to=20 the rarity of these tumors. </P></DIV> <DIV class=3D""><A name=3DSec9></A> <HR> <DIV class=3Dheading2>Conclusions</DIV> <P class=3D"">PGS represents a clinically challenging group of tumors, = due to its=20 rarity, poor prognosis, and the limited experience in published = literature. Many=20 of its clinical and pathogenetic characteristics remain to be revealed, = and=20 there is much room for future studies focusing on these biphasic tumors. = The=20 current reported literature does provide a number of distinguishing = clinical and=20 pathogenetic features of PGS to suggest they are indeed separate = entities from=20 GBMs. These differences include gliosarcomas=92 temporal lobe = predilection, their=20 potential to appear similar to a meningioma grossly at operation, their=20 increased metastatic potential, and the infrequency of EGFR mutation. = Evidence=20 for survival and efficacy of treatments is also limited due to the = difficulty of=20 conducting prospective trials. However, properly designed studies are = necessary=20 to optimize their management by considering their differential clinical = behavior=20 and pathogenesis from GBM. Although the precise etiology of PGS remains = unknown,=20 the interplay of glioma and sarcoma genesis requires further = investigation to=20 reveal potential targets for clinical applications. </P></DIV> <DIV class=3DAcknowledgments><SPAN class=3DAcknowledgmentsHeading>Open=20 Access </SPAN><SPAN class=3D"">This article is distributed = under the=20 terms of the Creative Commons Attribution Noncommercial License which = permits=20 any noncommercial use, distribution, and reproduction in any medium, = provided=20 the original author(s) and source are credited.</SPAN></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Stroebe H (1895) Ueber Entstehung und Bau der=20 Gehirnglioma. Beitr Pathol Anat Allg Pathol 19:405=96486 = </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Feigin I, Gross SW (1954) Sarcoma arising in=20 glioblastoma of the brain. 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FONT-SIZE: 12pt; FONT-FAMILY: Arial, Helvetica, sans-serif } P.HeadSec6 { FONT-STYLE: italic; FONT-FAMILY: Arial, Helvetica, sans-serif } P.HeadSec7 { FONT-FAMILY: Arial, Helvetica, sans-serif; TEXT-DECORATION: underline } .HeadList { MARGIN-TOP: 1em; FONT-STYLE: italic } A:link { COLOR: #ff0000 } A:active { COLOR: #ff0000 } A:visited { COLOR: #5f5f5f } TR.header { BACKGROUND: #d6d6d6 } TR.BibSectionHeading { FONT-SIZE: 12pt } H1 { FONT-SIZE: 20pt; COLOR: #444444; FONT-FAMILY: Arial, Helvetica, = sans-serif } H2 { FONT-SIZE: 16pt; FONT-FAMILY: Arial, Helvetica, sans-serif } H3 { FONT-FAMILY: Arial, Helvetica, sans-serif } H4 { FONT-FAMILY: Arial, Helvetica, sans-serif } H5 { FONT-SIZE: 12pt; FONT-FAMILY: Arial, Helvetica, sans-serif } ------=_NextPart_000_0065_01CA23D9.35CC3050--