10.1007/s11060-009-0044-9</TIT= LE> <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18852"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0044-9</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Case Report</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Multiple extracranial = metastases from=20 secondary glioblastoma multiforme: a case report and review of the = literature=20 </DIV> <P class=3DAuthorGroup>Li Zhen<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#ContactOfAuthor1"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/n32607m373340186/contact.gif">= </A></SUP>,=20 Cheng Yufeng<SUP>1</SUP>, Shao Zhenyu<SUP>1</SUP> and=20 Xiang Lei<SUP>2</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, Qilu = Hospital, Shandong University, Jinan, 250012,=20 China</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, Qilu = Hospital,=20 Shandong University, Jinan, 250012, = China</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/contact.gif">= </TD> = <TD><STRONG>Li </STRONG><STRONG>Zhen</STRONG><STRONG></STRONG><BR><S= TRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:lizhen_cn@163.com">lizhen_cn@163.com</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>16 May 2009 <STRONG>Accepted:=20 </STRONG>26 October 2009 <STRONG>Published online:=20 </STRONG>7 November 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>Extracranial = metastasis of=20 glioblastoma multiforme (GBM) is very rare, in spite of very aggressive = tumor=20 behavior and being documented in only a few patients. In this article we = present=20 a 25-year-old man with secondary glioblastoma associated with = extracranial=20 progression and distant metastasis. He was diagnosed by magnetic = resononce (MR)=20 with an intracranial lesion in the right parietofrontal region, which = was=20 subsequently resected. Histology revealed a diffuse astrocytoma (grade = II). The=20 tumor recurred 1 year later and the patient received a second = craniotomy. A=20 diagnosis of GBM was made. After radiotherapy, he presented with right = cervical=20 lymph node metastases. The cytomorphological features supported a = diagnosis of=20 metastatic glioblastoma multiforme. The neck dissection was made and = histology=20 confirmed the fine needle aspiration diagnosis of glioblastoma = multiforme. MR=20 with diffusion-weighted imaging revealed right cervical lymph node = metastases=20 and multi-bone metastases (mainly pelvic bone) 3 weeks later. </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Glioblastoma=20 multiforme - Extracranial metastasis - Secondary=20 glioblastoma - Prognosis </P> <DIV class=3DFulltext> <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P>Glioblastoma multiforme is a highly aggressive intracranial malignant = tumor=20 and has the highest fatality rate of all primary central nervous system = (CNS)=20 malignancies [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR1">1</A></CITE>].=20 The prognosis remains very poor, with most patients dying within = 1 year=20 after diagnosis. Glioblastomas may develop de novo (primary = glioblastomas) or=20 through progression from low-grade or anaplastic astrocytomas (secondary = glioblastomas). Primary and secondary glioblastoma constitute distinct = disease=20 subtypes, affecting patients of different age and developing through = different=20 genetic pathways. Secondary glioblastomas evolve slowly through = progression from=20 low-grade diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma = (WHO=20 grade III). Glioblastomas usually spread by local growth and = infiltration.=20 Extracranial metastasis of this tumor is very rare, despite its highly = malignant=20 nature. We report a case of secondary glioblastoma that metastasized to = the=20 right cervical lymph nodes and bone. </P></DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Case report</DIV> <DIV class=3DPara> <DIV>A 25-year-old man had a 10-day history of left facial and upper = limber=20 anesthesia. On neurological examination, the myodynamia of the left = upper limb=20 was IV. Magnetic resonance (MR) showed a right parietofrontal lobe mass=20 measuring 5 =D7 4.6 =D7 4 cm with long T1 and = long T2=20 signal (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig1">1</A>).=20 The verge of the tumor was well defined without obvious peritumoral = edema. A=20 nodular-enhanced mass was identified in the right parietal lobe = (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig1">1</A>).=20 Craniotomy was performed with gross total resection on October 8, 2007. = Upon=20 macroscopic examination of the operation material, there were many = tissue=20 specimens, measured together 7 =D7 6 =D7 4 cm. = These tissue=20 specimens were hemorrhagic, irregular, soft and grey=96white on the cut = surface.=20 The histopathological diagnosis reported a diffuse astrocytoma (grade = II)=20 (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig2">2</A>).=20 The patient did not take any adjuvant therapy after surgery. = Immunohistochemical=20 results showed that the tumor cells were weakly positive for p53 and = epidermal=20 growth factor receptor (EGFR) (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig3">3</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Gd-enhanced coronal=20 T1-weighted MR images before first operation demonstrating a = nodular-enhanced=20 mass in the right parietofrontal region </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 2 </SPAN>Pathologic findings=20 of first operation showing diffuse astrocytoma (WHO grade II) = (<I>left</I>:=20 H&E, =D7200; <I>right</I>: H&E, =D7400) </DIV> <HR> <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig3_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig3_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 3 </SPAN>Biopsy = specimen taken=20 from the first craniotomy showing immunopositive cells for p53 = (<B>a</B>), EGFR=20 (<B>b</B>) (=D7200) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>One year later, the patient was admitted to the hospital on = November 9,=20 2008, complaining of weakness in left arm, and left hemiparesis. MR = showed a=20 recurrent lesion at the location of the first operation,=20 4 =D7 3 =D7 2 cm in diameter with clear dense = contrast=20 enhancement (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig4">4</A>).=20 The tumor was homogeneous post-gadolinium enhancement with surrounding = edema. A=20 second craniotomy revealed a malignant neoplasm on frozen section and on = final=20 pathological evaluation and a diagnosis of GBM was made (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig5">5</A>).=20 Pathological examination of the second operation material revealed the = tissue=20 specimens together measured 3 =D7 3 =D7 1.5 cm. = The tissue=20 specimens were soft and grey on the cut surface just the same as those = in the=20 first operation. Pathological studies revealed that there was no = mesenchymal=20 formation with typical sarcomatous components, which were composed of=20 spindle-shaped sarcomatous elements. Immunohistochemical results showed = that the=20 tumor cells were positive for p53, EGFR (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig6">6</A>),=20 O-6-methylguanine-DNA methyltransferase (MGMT), syn, CD56, Ki-67, = negative for=20 CD3, CD99, glial fibrillary acidic protein (GFAP), S-100, vascular = endothelial=20 growth factor (VEGF), Vimentin, Leu-7, Olig-2, Nestin, Neu-N. The = patient was=20 treated with 5100 cGy/17F of external beam radiation therapy after = surgery.=20 <DIV class=3DFigure><A name=3DFig4></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig4_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig4_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 4 </SPAN>Gd-enhanced coronal=20 T1-weighted MR images of the brain before the second operation revealing = a=20 recurrence at the location of the first operation with patchy = surrounding edema=20 </DIV> <HR> <DIV class=3DFigure><A name=3DFig5></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig5_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig5_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 5 </SPAN>Pathologic findings=20 of the second operation revealing intracranial glioblastoma with = variable=20 histologic features, mitosis, endothelial proliferation, and necrosis=20 (<I>left</I>: H&E, =D7100; <I>right</I>: H&E, =D7400) </DIV> <HR> <DIV class=3DFigure><A name=3DFig6></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig6_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig6_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 6 </SPAN>Biopsy = specimen taken=20 from the second craniotomy showing immunopositive cells for p53 = (<B>a</B>), EGFR=20 (<B>b</B>) (=D7200) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>Two months later, the patient returned with a 2.0-cm subcutaneous = mass in=20 the right cervical. There was no improvement with antibiotics for = 7 days.=20 Contrast-enhanced computerized tomography (CT) showed that there was = extensive=20 adenopathy in the deep cervical (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig7">7</A>).=20 Fine-needle aspiration biopsy revealed a GBM (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig8">8</A>).=20 Neck dissection was made 1 month later with histological = confirmation of=20 the diagnosis and 22 lymph nodes were found tumor invasive of total 27 = resected=20 lymph nodes (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig9">9</A>).=20 Immunohistochemically, the tumor cells were strongly positive for p53, = EGFR=20 (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig10">10</A>)=20 and syn, the same as that of the second craniotomy. We also determined = S100=20 (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig10">10</A>),=20 epithelial membrane antigen (EMA), and Vimentin immunodetection, which = represent=20 sarcomatous components in these samples. None of them was positive. The = other=20 immunohistochemical findings revealed that the tumor cells were negative = for=20 GFAP, CK, CD2, CD35, CK19, smooth muscle actin (SMA), and Desmin. The = diagnosis=20 of gliosarcoma was excluded since reticulin stains disclosed a little = reticulin=20 fiber around the nests of tumor rather than the tumor cells = (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig11">11</A>).=20 <DIV class=3DFigure><A name=3DFig7></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig7_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig7_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 7 </SPAN>Contrast-enhanced=20 transaxial CT showing lymph node in right cervical area (<I>arrow</I>) = </DIV> <HR> <DIV class=3DFigure><A name=3DFig8></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig8_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig8_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 8 </SPAN>Fine-needle=20 aspiration smear from metastatic glioblastoma in cervical lymph node.=20 Photomicrograph shows that metrocyte infiltrated into the lymphocytes in = the=20 cervical soft tissue (H&E, =D71000) </DIV> <HR> <DIV class=3DFigure><A name=3DFig9></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig9_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig9_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 9 </SPAN>Pathologic findings=20 of biopsy specimen taken from neck dissection, confirmed as glioblastoma = (<I>left</I>: H&E, =D7100; <I>right</I>: H&E, =D7400) </DIV> <HR> <DIV class=3DFigure><A name=3DFig10></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig10_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig10_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 10 </SPAN>Biopsy = specimen=20 taken from neck dissection showing immunopositive cells for p53 = (<B>a</B>), EGFR=20 (<B>b</B>), and immunonegative cells for S100 (<B>c</B>) (=D7200) </DIV> <HR> <DIV class=3DFigure><A name=3DFig11></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig11_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig11_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 11 </SPAN>Reticulin stains=20 disclosed a few reticulin fiber around nests of tumor rather than tumor = cells=20 (=D7400) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>Two lymph nodes were found again in the right cervical 3 weeks = later.=20 MR with diffusion-weighted imaging revealed right cervical lymph node = metastases=20 and multi-bone metastases (mainly pelvic bone) (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig12">12</A>).=20 The patient is currently in the hospital again ready to receive systemic = chemotherapy.=20 <DIV class=3DFigure><A name=3DFig12></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig12_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig12_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 12 </SPAN>Whole-body MR with=20 diffusion-weighted imaging revealed right cervical lymph node metastases = and=20 multi-bone metastases (mainly pelvic bone) (<I>arrows</I>) </DIV> <HR> </DIV></DIV></DIV> <DIV><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P>The diagnosis of secondary glioblastoma requires clinical = (neuroimaging) or=20 histological (bioptic) evidence of a development from a less malignant=20 astrocytoma. In this article, the secondary glioblastoma was confirmed = by=20 clinical, morphological, and histological studies. According to the = studies,=20 only 5% of all glioblastomas were secondary glioblastomas with = histopathological=20 evidence of a precursor low-grade or anaplastic astrocytoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR3">3</A></CITE>].=20 The median survival of secondary glioblastoma patients was = 7.8 months,=20 significantly longer than that of primary glioblastoma patients=20 (4.7 months; <I>P</I> =3D 0.003). The patient in our case = report=20 has survived for 17 months since the first operation. </P> <P>It is widely known that secondary glioblastoma occurs with LOH on = chromosome=20 17p strongly correlated with <I>p53</I> mutations and is often seen in = younger=20 patients, whereas primary glioblastoma is characterized by higher = frequencies of=20 EGFR amplification and LOH on chromosome 10 and is common in older = patients. It=20 has been reported that mutations of <I>p53</I> occur in more than 65% of = secondary GBM samples [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR4">4</A></CITE>],=20 such mutations were seen in all samples of our case obtained at three=20 operations. However, immunopositive for EGFR were also observed in our = case. The=20 <I>p53</I> mutation with concomitant EGFR gene amplification was hardly = observed=20 in secondary glioblastomas. However, Yoon KS et al. reported = immunoreactivities=20 for EGFR were noted in 66.7% of primary glioblastomas and in 9.5% of = secondary=20 glioblastomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR5">5</A></CITE>].=20 Watanabe et al. reported that only one out of 20 secondary glioblastomas = showed=20 the <I>p53</I> mutation with concomitant EGFR overexpression [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR6">6</A></CITE>].=20 In the present case, <I>p53</I> was weakly positive in the samples = obtained at=20 the first operation and strongly positive in the samples obtained at the = second=20 operation and neck dissection, EGFR was also positive in all samples, = but the=20 positive rates were increased at the third operation. To our knowledge, = it is=20 the first report of a secondary glioblastoma with EGFR overexpression = and the=20 <I>p53</I> mutation associated with multiple extracranial metastases. = </P> <P>Glioblastoma multiforme can easily metastasize to the neuroaxial = (meninges or=20 spinal cord) spread by way of the cerebrospinal fluid (CSF), but = extracranial=20 metastases are much rarer. Based on the findings of autopsies, the = incidence of=20 CSF spread in glioblastomas was about 20% [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR8">8</A></CITE>].=20 Although extracranial metastases of glioblastomas occur in <1% of = cases,=20 glioblastomas account for about two-thirds of the neuroepithelial tumors = that=20 metastasize extracranially [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR9">9</A></CITE>].=20 The lungs, pleura, lymph nodes, bone marrow, bone, and liver are the = most common=20 sites of extracranial metastases. In a review of literature of = extracranial=20 metastases of astrocytomas and glioblastomas, distribution of metastasis = was as=20 follows: 43 (59.7%) lungs and pleura, 37 (51.4%) lymph nodes, 22 (30.5%) = bone,=20 16 (22.2%) liver, five heart, three adrenal gland, two each in the = kidneys,=20 diaphragm and mediastinum and one each in the pancreas, thyroid gland, = and=20 peritoneum [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR10">10</A></CITE>].=20 Among the lymph node metastases, 62% were situated in the cervical = areas, often=20 ipsilateral to the site of craniotomy but sometimes bilateral [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR10">10</A></CITE>].=20 In our case report, ipsilateral cervical lymph node metastases were = found in the=20 patient. It recurred in the ipsilateral cervical after neck dissection, = and the=20 contralateral cervical remained negative. Regarding bone metastases, the = vertebral spine (73%) was the most common site of involvement, followed = by the=20 ribs (23%), sternum (18%), skull (14%), and acetabulum (9%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR10">10</A></CITE>].=20 However, our patient in this case showed pelvic diffuse bone = involvement. </P> <P>The exact mechanism of metastases is still not well understood, = although=20 several hypotheses have been advanced and some experimental studies have = been=20 performed. Extracranial metastases of glioblastomas usually occur after = surgery=20 in which the tumor cells may find an access to the lymphatics via dural = or scalp=20 extension through the surgical defect [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR11">11</A></CITE>].=20 The tumor can also spread extracranial though the opening of the = intracerebral=20 vessels with surgical intervention [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR12">12</A></CITE>].=20 Spreading to the peritoneum via shunts is the third most common = metastatic=20 pathway [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR13">13</A></CITE>].=20 Our patient developed right cervical lymph node metastases and bone = metastases=20 at the same time after second craniotomy. The pathways of extracranial=20 metastases in our case may include lymphatic spread and hematogenous = spread of=20 glioblastoma. </P> <P>However, these mechanisms do not account for the occurrence of = extraneural=20 metastases in all patients, because there are cases of extracranial = metastases=20 of glioblastoma without previous surgical intervention [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR16">16</A></CITE>].=20 These cases might be interpreted as a CSF or blood spreading of tumor = cells. It=20 seems probable that the glioblastoma spreads outside the skull through = the=20 venous system, after having gained entrance to it either at the dural or = intracerebral level [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR17">17</A></CITE>].=20 </P> <P>Management of glioblastoma usually includes surgical excision, = followed by=20 radiation therapy. Sometimes chemotherapy is given in combination with = radiation=20 or as an adjuvant treatment either before or after surgery [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR18">18</A></CITE>].=20 Particularly in young patients a combined triple therapy can prolong the = time of=20 survival significantly. Soft-tissue metastases sometimes decrease in = size in=20 dramatic fashion with systemic chemotherapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR19">19</A></CITE>].=20 We decided to introduce chemotherapeutic agents to this patient because = the=20 tumor has scattered extensively. Being a highly aggressive malignant = tumor, the=20 prognosis of glioblastomas is very poor, even though surgical procedure, = radiation therapy, and chemotherapy are all used. </P></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>Kelly KA, Kirkwood JM, Kapp DS (1984) = Glioblastoma=20 multiforme: pathology, natural history and treatment. 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Clin Exp Neurol 23:111=96117<BR><A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaL1c%252Fisl2gsQ%253D%253D&md5=3D42569d87f90f91bb8811bbd5cb2142a7"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2822301"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>15.</TD> <TD><A name=3DCR15></A>Hulbanni S, Goodman PA (1976) Glioblastoma = multiforme=20 with extraneural metastases in the absence of previous surgery. = Cancer=20 37:1577=961583<BR><A=20 = href=3D"http://dx.doi.org/10.1002/1097-0142(197603)37:3%3C1577::AID-CNCR2= 820370348%3E3.0.CO;2-0"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaE287mt12itQ%253D%253D&md5=3Da6d2a2afe0a3dd5dfb952940e0f8d275"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D177171"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>16.</TD> <TD><A name=3DCR16></A>Gamis AS, Egelhoff J, Roloson G, Young J, = Woods GM,=20 Newman R, Freeman AI (1990) Diffuse bony metastases at = presentation in a=20 child with glioblastoma multiforme. A case report (abstract). = Cancer=20 66(1):180=96184<BR><A=20 = href=3D"http://dx.doi.org/10.1002/1097-0142(19900701)66:1%3C180::AID-CNCR= 2820660132%3E3.0.CO;2-M"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaK3c3otlyitg%253D%253D&md5=3D455db12948ba1d0f535e0e2f15c0b570"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2162242"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>17.</TD> <TD><A name=3DCR17></A>Anzil A (1970) Glioblastoma multiforme with=20 extracranial metastases in the absence of previous craniotomy. = Case=20 report. J Neurosurg 33:88=9694<BR><A=20 href=3D"http://dx.doi.org/10.3171/jns.1970.33.1.0088" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaE3c3ivFGntA%253D%253D&md5=3Dbf37a3cc4449aba4146c7f19260c4542"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D4316740"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>18.</TD> <TD><A name=3DCR18></A>Zappia JJ, Wolf GT (1992) Cervical metastatic = glioblastoma multiforme. Arch Otolaryngol Head Neck Surg = 118:755=96756<BR><A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaK38zivFSltw%253D%253D&md5=3Dfa3802ff6e6b55296a2f30c64b70827e"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D1320896"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>19.</TD> <TD><A name=3DCR19></A>Steinbok P, Dolman CL, Goldie JH (1985) = Variation in=20 response to CCNU of glioblastoma multiforme in brain and cervical = lymph=20 node: case report. J Neurosurg 62:918=96921<BR><A=20 href=3D"http://dx.doi.org/10.3171/jns.1985.62.6.0918" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaL2M3htVWitw%253D%253D&md5=3Da4d078d2b430a189b112c694a8f5c002"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2987441"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR></TBODY></TABLE></DIV></BODY></HTML> 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From: Subject: 10.1007/s11060-009-0044-9 Date: Sun, 15 Nov 2009 15:52:14 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_00B4_01CA660B.99B0BA90" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_00B4_01CA660B.99B0BA90 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/n32607m373340186/fulltext.html 10.1007/s11060-009-0044-9</TIT= LE> <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18852"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0044-9</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Case Report</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Multiple extracranial = metastases from=20 secondary glioblastoma multiforme: a case report and review of the = literature=20 </DIV> <P class=3DAuthorGroup>Li Zhen<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#ContactOfAuthor1"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/n32607m373340186/contact.gif">= </A></SUP>,=20 Cheng Yufeng<SUP>1</SUP>, Shao Zhenyu<SUP>1</SUP> and=20 Xiang Lei<SUP>2</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, Qilu = Hospital, Shandong University, Jinan, 250012,=20 China</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, Qilu = Hospital,=20 Shandong University, Jinan, 250012, = China</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/contact.gif">= </TD> = <TD><STRONG>Li </STRONG><STRONG>Zhen</STRONG><STRONG></STRONG><BR><S= TRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:lizhen_cn@163.com">lizhen_cn@163.com</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>16 May 2009 <STRONG>Accepted:=20 </STRONG>26 October 2009 <STRONG>Published online:=20 </STRONG>7 November 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>Extracranial = metastasis of=20 glioblastoma multiforme (GBM) is very rare, in spite of very aggressive = tumor=20 behavior and being documented in only a few patients. In this article we = present=20 a 25-year-old man with secondary glioblastoma associated with = extracranial=20 progression and distant metastasis. He was diagnosed by magnetic = resononce (MR)=20 with an intracranial lesion in the right parietofrontal region, which = was=20 subsequently resected. Histology revealed a diffuse astrocytoma (grade = II). The=20 tumor recurred 1 year later and the patient received a second = craniotomy. A=20 diagnosis of GBM was made. After radiotherapy, he presented with right = cervical=20 lymph node metastases. The cytomorphological features supported a = diagnosis of=20 metastatic glioblastoma multiforme. The neck dissection was made and = histology=20 confirmed the fine needle aspiration diagnosis of glioblastoma = multiforme. MR=20 with diffusion-weighted imaging revealed right cervical lymph node = metastases=20 and multi-bone metastases (mainly pelvic bone) 3 weeks later. </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Glioblastoma=20 multiforme - Extracranial metastasis - Secondary=20 glioblastoma - Prognosis </P> <DIV class=3DFulltext> <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P>Glioblastoma multiforme is a highly aggressive intracranial malignant = tumor=20 and has the highest fatality rate of all primary central nervous system = (CNS)=20 malignancies [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR1">1</A></CITE>].=20 The prognosis remains very poor, with most patients dying within = 1 year=20 after diagnosis. Glioblastomas may develop de novo (primary = glioblastomas) or=20 through progression from low-grade or anaplastic astrocytomas (secondary = glioblastomas). Primary and secondary glioblastoma constitute distinct = disease=20 subtypes, affecting patients of different age and developing through = different=20 genetic pathways. Secondary glioblastomas evolve slowly through = progression from=20 low-grade diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma = (WHO=20 grade III). Glioblastomas usually spread by local growth and = infiltration.=20 Extracranial metastasis of this tumor is very rare, despite its highly = malignant=20 nature. We report a case of secondary glioblastoma that metastasized to = the=20 right cervical lymph nodes and bone. </P></DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Case report</DIV> <DIV class=3DPara> <DIV>A 25-year-old man had a 10-day history of left facial and upper = limber=20 anesthesia. On neurological examination, the myodynamia of the left = upper limb=20 was IV. Magnetic resonance (MR) showed a right parietofrontal lobe mass=20 measuring 5 =D7 4.6 =D7 4 cm with long T1 and = long T2=20 signal (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig1">1</A>).=20 The verge of the tumor was well defined without obvious peritumoral = edema. A=20 nodular-enhanced mass was identified in the right parietal lobe = (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig1">1</A>).=20 Craniotomy was performed with gross total resection on October 8, 2007. = Upon=20 macroscopic examination of the operation material, there were many = tissue=20 specimens, measured together 7 =D7 6 =D7 4 cm. = These tissue=20 specimens were hemorrhagic, irregular, soft and grey=96white on the cut = surface.=20 The histopathological diagnosis reported a diffuse astrocytoma (grade = II)=20 (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig2">2</A>).=20 The patient did not take any adjuvant therapy after surgery. = Immunohistochemical=20 results showed that the tumor cells were weakly positive for p53 and = epidermal=20 growth factor receptor (EGFR) (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig3">3</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Gd-enhanced coronal=20 T1-weighted MR images before first operation demonstrating a = nodular-enhanced=20 mass in the right parietofrontal region </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 2 </SPAN>Pathologic findings=20 of first operation showing diffuse astrocytoma (WHO grade II) = (<I>left</I>:=20 H&E, =D7200; <I>right</I>: H&E, =D7400) </DIV> <HR> <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig3_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig3_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 3 </SPAN>Biopsy = specimen taken=20 from the first craniotomy showing immunopositive cells for p53 = (<B>a</B>), EGFR=20 (<B>b</B>) (=D7200) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>One year later, the patient was admitted to the hospital on = November 9,=20 2008, complaining of weakness in left arm, and left hemiparesis. MR = showed a=20 recurrent lesion at the location of the first operation,=20 4 =D7 3 =D7 2 cm in diameter with clear dense = contrast=20 enhancement (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig4">4</A>).=20 The tumor was homogeneous post-gadolinium enhancement with surrounding = edema. A=20 second craniotomy revealed a malignant neoplasm on frozen section and on = final=20 pathological evaluation and a diagnosis of GBM was made (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig5">5</A>).=20 Pathological examination of the second operation material revealed the = tissue=20 specimens together measured 3 =D7 3 =D7 1.5 cm. = The tissue=20 specimens were soft and grey on the cut surface just the same as those = in the=20 first operation. Pathological studies revealed that there was no = mesenchymal=20 formation with typical sarcomatous components, which were composed of=20 spindle-shaped sarcomatous elements. Immunohistochemical results showed = that the=20 tumor cells were positive for p53, EGFR (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig6">6</A>),=20 O-6-methylguanine-DNA methyltransferase (MGMT), syn, CD56, Ki-67, = negative for=20 CD3, CD99, glial fibrillary acidic protein (GFAP), S-100, vascular = endothelial=20 growth factor (VEGF), Vimentin, Leu-7, Olig-2, Nestin, Neu-N. The = patient was=20 treated with 5100 cGy/17F of external beam radiation therapy after = surgery.=20 <DIV class=3DFigure><A name=3DFig4></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig4_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig4_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 4 </SPAN>Gd-enhanced coronal=20 T1-weighted MR images of the brain before the second operation revealing = a=20 recurrence at the location of the first operation with patchy = surrounding edema=20 </DIV> <HR> <DIV class=3DFigure><A name=3DFig5></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig5_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig5_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 5 </SPAN>Pathologic findings=20 of the second operation revealing intracranial glioblastoma with = variable=20 histologic features, mitosis, endothelial proliferation, and necrosis=20 (<I>left</I>: H&E, =D7100; <I>right</I>: H&E, =D7400) </DIV> <HR> <DIV class=3DFigure><A name=3DFig6></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig6_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig6_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 6 </SPAN>Biopsy = specimen taken=20 from the second craniotomy showing immunopositive cells for p53 = (<B>a</B>), EGFR=20 (<B>b</B>) (=D7200) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>Two months later, the patient returned with a 2.0-cm subcutaneous = mass in=20 the right cervical. There was no improvement with antibiotics for = 7 days.=20 Contrast-enhanced computerized tomography (CT) showed that there was = extensive=20 adenopathy in the deep cervical (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig7">7</A>).=20 Fine-needle aspiration biopsy revealed a GBM (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig8">8</A>).=20 Neck dissection was made 1 month later with histological = confirmation of=20 the diagnosis and 22 lymph nodes were found tumor invasive of total 27 = resected=20 lymph nodes (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig9">9</A>).=20 Immunohistochemically, the tumor cells were strongly positive for p53, = EGFR=20 (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig10">10</A>)=20 and syn, the same as that of the second craniotomy. We also determined = S100=20 (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig10">10</A>),=20 epithelial membrane antigen (EMA), and Vimentin immunodetection, which = represent=20 sarcomatous components in these samples. None of them was positive. The = other=20 immunohistochemical findings revealed that the tumor cells were negative = for=20 GFAP, CK, CD2, CD35, CK19, smooth muscle actin (SMA), and Desmin. The = diagnosis=20 of gliosarcoma was excluded since reticulin stains disclosed a little = reticulin=20 fiber around the nests of tumor rather than the tumor cells = (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig11">11</A>).=20 <DIV class=3DFigure><A name=3DFig7></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig7_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig7_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 7 </SPAN>Contrast-enhanced=20 transaxial CT showing lymph node in right cervical area (<I>arrow</I>) = </DIV> <HR> <DIV class=3DFigure><A name=3DFig8></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig8_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig8_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 8 </SPAN>Fine-needle=20 aspiration smear from metastatic glioblastoma in cervical lymph node.=20 Photomicrograph shows that metrocyte infiltrated into the lymphocytes in = the=20 cervical soft tissue (H&E, =D71000) </DIV> <HR> <DIV class=3DFigure><A name=3DFig9></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig9_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig9_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 9 </SPAN>Pathologic findings=20 of biopsy specimen taken from neck dissection, confirmed as glioblastoma = (<I>left</I>: H&E, =D7100; <I>right</I>: H&E, =D7400) </DIV> <HR> <DIV class=3DFigure><A name=3DFig10></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig10_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig10_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 10 </SPAN>Biopsy = specimen=20 taken from neck dissection showing immunopositive cells for p53 = (<B>a</B>), EGFR=20 (<B>b</B>), and immunonegative cells for S100 (<B>c</B>) (=D7200) </DIV> <HR> <DIV class=3DFigure><A name=3DFig11></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig11_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig11_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 11 </SPAN>Reticulin stains=20 disclosed a few reticulin fiber around nests of tumor rather than tumor = cells=20 (=D7400) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>Two lymph nodes were found again in the right cervical 3 weeks = later.=20 MR with diffusion-weighted imaging revealed right cervical lymph node = metastases=20 and multi-bone metastases (mainly pelvic bone) (Fig. <A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#Fig12">12</A>).=20 The patient is currently in the hospital again ready to receive systemic = chemotherapy.=20 <DIV class=3DFigure><A name=3DFig12></A><IMG=20 alt=3DMediaObjects/11060_2009_44_Fig12_HTML.jpg=20 src=3D"http://www.springerlink.com/content/n32607m373340186/MediaObjects/= 11060_2009_44_Fig12_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 12 </SPAN>Whole-body MR with=20 diffusion-weighted imaging revealed right cervical lymph node metastases = and=20 multi-bone metastases (mainly pelvic bone) (<I>arrows</I>) </DIV> <HR> </DIV></DIV></DIV> <DIV><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P>The diagnosis of secondary glioblastoma requires clinical = (neuroimaging) or=20 histological (bioptic) evidence of a development from a less malignant=20 astrocytoma. In this article, the secondary glioblastoma was confirmed = by=20 clinical, morphological, and histological studies. According to the = studies,=20 only 5% of all glioblastomas were secondary glioblastomas with = histopathological=20 evidence of a precursor low-grade or anaplastic astrocytoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR3">3</A></CITE>].=20 The median survival of secondary glioblastoma patients was = 7.8 months,=20 significantly longer than that of primary glioblastoma patients=20 (4.7 months; <I>P</I> =3D 0.003). The patient in our case = report=20 has survived for 17 months since the first operation. </P> <P>It is widely known that secondary glioblastoma occurs with LOH on = chromosome=20 17p strongly correlated with <I>p53</I> mutations and is often seen in = younger=20 patients, whereas primary glioblastoma is characterized by higher = frequencies of=20 EGFR amplification and LOH on chromosome 10 and is common in older = patients. It=20 has been reported that mutations of <I>p53</I> occur in more than 65% of = secondary GBM samples [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR4">4</A></CITE>],=20 such mutations were seen in all samples of our case obtained at three=20 operations. However, immunopositive for EGFR were also observed in our = case. The=20 <I>p53</I> mutation with concomitant EGFR gene amplification was hardly = observed=20 in secondary glioblastomas. However, Yoon KS et al. reported = immunoreactivities=20 for EGFR were noted in 66.7% of primary glioblastomas and in 9.5% of = secondary=20 glioblastomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR5">5</A></CITE>].=20 Watanabe et al. reported that only one out of 20 secondary glioblastomas = showed=20 the <I>p53</I> mutation with concomitant EGFR overexpression [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR6">6</A></CITE>].=20 In the present case, <I>p53</I> was weakly positive in the samples = obtained at=20 the first operation and strongly positive in the samples obtained at the = second=20 operation and neck dissection, EGFR was also positive in all samples, = but the=20 positive rates were increased at the third operation. To our knowledge, = it is=20 the first report of a secondary glioblastoma with EGFR overexpression = and the=20 <I>p53</I> mutation associated with multiple extracranial metastases. = </P> <P>Glioblastoma multiforme can easily metastasize to the neuroaxial = (meninges or=20 spinal cord) spread by way of the cerebrospinal fluid (CSF), but = extracranial=20 metastases are much rarer. Based on the findings of autopsies, the = incidence of=20 CSF spread in glioblastomas was about 20% [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR8">8</A></CITE>].=20 Although extracranial metastases of glioblastomas occur in <1% of = cases,=20 glioblastomas account for about two-thirds of the neuroepithelial tumors = that=20 metastasize extracranially [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR9">9</A></CITE>].=20 The lungs, pleura, lymph nodes, bone marrow, bone, and liver are the = most common=20 sites of extracranial metastases. In a review of literature of = extracranial=20 metastases of astrocytomas and glioblastomas, distribution of metastasis = was as=20 follows: 43 (59.7%) lungs and pleura, 37 (51.4%) lymph nodes, 22 (30.5%) = bone,=20 16 (22.2%) liver, five heart, three adrenal gland, two each in the = kidneys,=20 diaphragm and mediastinum and one each in the pancreas, thyroid gland, = and=20 peritoneum [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR10">10</A></CITE>].=20 Among the lymph node metastases, 62% were situated in the cervical = areas, often=20 ipsilateral to the site of craniotomy but sometimes bilateral [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR10">10</A></CITE>].=20 In our case report, ipsilateral cervical lymph node metastases were = found in the=20 patient. It recurred in the ipsilateral cervical after neck dissection, = and the=20 contralateral cervical remained negative. Regarding bone metastases, the = vertebral spine (73%) was the most common site of involvement, followed = by the=20 ribs (23%), sternum (18%), skull (14%), and acetabulum (9%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR10">10</A></CITE>].=20 However, our patient in this case showed pelvic diffuse bone = involvement. </P> <P>The exact mechanism of metastases is still not well understood, = although=20 several hypotheses have been advanced and some experimental studies have = been=20 performed. Extracranial metastases of glioblastomas usually occur after = surgery=20 in which the tumor cells may find an access to the lymphatics via dural = or scalp=20 extension through the surgical defect [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR11">11</A></CITE>].=20 The tumor can also spread extracranial though the opening of the = intracerebral=20 vessels with surgical intervention [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR12">12</A></CITE>].=20 Spreading to the peritoneum via shunts is the third most common = metastatic=20 pathway [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR13">13</A></CITE>].=20 Our patient developed right cervical lymph node metastases and bone = metastases=20 at the same time after second craniotomy. The pathways of extracranial=20 metastases in our case may include lymphatic spread and hematogenous = spread of=20 glioblastoma. </P> <P>However, these mechanisms do not account for the occurrence of = extraneural=20 metastases in all patients, because there are cases of extracranial = metastases=20 of glioblastoma without previous surgical intervention [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR16">16</A></CITE>].=20 These cases might be interpreted as a CSF or blood spreading of tumor = cells. It=20 seems probable that the glioblastoma spreads outside the skull through = the=20 venous system, after having gained entrance to it either at the dural or = intracerebral level [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR17">17</A></CITE>].=20 </P> <P>Management of glioblastoma usually includes surgical excision, = followed by=20 radiation therapy. Sometimes chemotherapy is given in combination with = radiation=20 or as an adjuvant treatment either before or after surgery [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR18">18</A></CITE>].=20 Particularly in young patients a combined triple therapy can prolong the = time of=20 survival significantly. Soft-tissue metastases sometimes decrease in = size in=20 dramatic fashion with systemic chemotherapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/n32607m373340186/fulltext.htm= l#CR19">19</A></CITE>].=20 We decided to introduce chemotherapeutic agents to this patient because = the=20 tumor has scattered extensively. Being a highly aggressive malignant = tumor, the=20 prognosis of glioblastomas is very poor, even though surgical procedure, = radiation therapy, and chemotherapy are all used. </P></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>Kelly KA, Kirkwood JM, Kapp DS (1984) = Glioblastoma=20 multiforme: pathology, natural history and treatment. 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Brain Pathol 6:217=96223<BR><A=20 href=3D"http://dx.doi.org/10.1111/j.1750-3639.1996.tb00848.x"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaK2s%252FhslKlsw%253D%253D&md5=3D8260c9899b59217a5ec8c6ff5b31e1c4"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D8864278"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>7.</TD> <TD><A name=3DCR7></A>Erlich SS, Davis RL (1978) Spinal subarachnoid = metastasis from primary intracranial glioblastoma multiforme. = Cancer=20 42:2854=962864<BR><A=20 = href=3D"http://dx.doi.org/10.1002/1097-0142(197812)42:6%3C2854::AID-CNCR2= 820420647%3E3.0.CO;2-4"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaE1M%252Fotl2huw%253D%253D&md5=3Dbc53bcc93dfe74c6e1a4f7443bbb14f2"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D215298"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>8.</TD> <TD><A name=3DCR8></A>Yung WA, Horten BC, Shapiro WR (1980) = Meningeal=20 gliomatosis: a review of 12 cases. Ann Neurol 8:605=96608<BR><A=20 href=3D"http://dx.doi.org/10.1002/ana.410080610" = target=3D_blank><IMG border=3D0=20 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaL3M7lvVKquw%253D%253D&md5=3D5aa4948df31154b9d5f6aa1809a66f79"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D6260012"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>9.</TD> <TD><A name=3DCR9></A>Smith DR, Hardman JM, Earle KM (1969) = Metastasizing=20 neuroectodermal tumors of the central nervous system. J Neurosurg=20 31:50=9658<BR><A = href=3D"http://dx.doi.org/10.3171/jns.1969.31.1.0050"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaF1M3js12nsg%253D%253D&md5=3Db7718aabca92dbc237ae761b7c7ea555"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D4307543"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>10.</TD> <TD><A name=3DCR10></A>Pasquier B, Pasquier D, N=92Golet A, Panh MH, = Couderc P=20 (1980) Extraneural metastases of astrocytomas and glioblastomas. = Cancer=20 45:112=96125<BR><A=20 = href=3D"http://dx.doi.org/10.1002/1097-0142(19800101)45:1%3C112::AID-CNCR= 2820450121%3E3.0.CO;2-9"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaL3c%252FovFOitA%253D%253D&md5=3D03f30756f2f8692ffdcb663e2d833252"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D6985826"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>11.</TD> <TD><A name=3DCR11></A>Campora RG, Salaverri CO, Ramirez FV, = Villadiego MS,=20 Davidson HG (1993) Metastatic glioblastoma multiforme in cervical = lymph=20 nodes: report of a case with diagnosis by fine needle aspiration. = Acta=20 Cytol 37:938=96942 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>12.</TD> <TD><A name=3DCR12></A>Wallace CJ, Forsyth PA, Edwards DR (1996) = Lymph node=20 metastases from glioblastoma multiforme. AJNR Am J Neuroradiol=20 17:1929=961931<BR><A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaK2s%252Fosl2nsA%253D%253D&md5=3Dd8586560ea33ffa8a2485627dea32217"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D8933881"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>13.</TD> <TD><A name=3DCR13></A>Gonz=E1lez C=E1mpora R, Otal Salaverri C, = V=E1zquez Ramirez=20 F, Salguero Villadiego M, Galera Davidson H (1993) Metastatic = glioblastoma=20 multiforme in cervical lymph nodes. Report of a case with = diagnosis by=20 fine needle aspiration. Acta Cytol 37:938=96942<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D8249517"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>14.</TD> <TD><A name=3DCR14></A>Brew BJ, Garrick R (1987) Gliomas presenting = outside=20 the central nervous system. Clin Exp Neurol 23:111=96117<BR><A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaL1c%252Fisl2gsQ%253D%253D&md5=3D42569d87f90f91bb8811bbd5cb2142a7"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2822301"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>15.</TD> <TD><A name=3DCR15></A>Hulbanni S, Goodman PA (1976) Glioblastoma = multiforme=20 with extraneural metastases in the absence of previous surgery. = Cancer=20 37:1577=961583<BR><A=20 = href=3D"http://dx.doi.org/10.1002/1097-0142(197603)37:3%3C1577::AID-CNCR2= 820370348%3E3.0.CO;2-0"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaE287mt12itQ%253D%253D&md5=3Da6d2a2afe0a3dd5dfb952940e0f8d275"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D177171"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>16.</TD> <TD><A name=3DCR16></A>Gamis AS, Egelhoff J, Roloson G, Young J, = Woods GM,=20 Newman R, Freeman AI (1990) Diffuse bony metastases at = presentation in a=20 child with glioblastoma multiforme. A case report (abstract). = Cancer=20 66(1):180=96184<BR><A=20 = href=3D"http://dx.doi.org/10.1002/1097-0142(19900701)66:1%3C180::AID-CNCR= 2820660132%3E3.0.CO;2-M"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaK3c3otlyitg%253D%253D&md5=3D455db12948ba1d0f535e0e2f15c0b570"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2162242"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>17.</TD> <TD><A name=3DCR17></A>Anzil A (1970) Glioblastoma multiforme with=20 extracranial metastases in the absence of previous craniotomy. = Case=20 report. J Neurosurg 33:88=9694<BR><A=20 href=3D"http://dx.doi.org/10.3171/jns.1970.33.1.0088" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaE3c3ivFGntA%253D%253D&md5=3Dbf37a3cc4449aba4146c7f19260c4542"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D4316740"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>18.</TD> <TD><A name=3DCR18></A>Zappia JJ, Wolf GT (1992) Cervical metastatic = glioblastoma multiforme. Arch Otolaryngol Head Neck Surg = 118:755=96756<BR><A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaK38zivFSltw%253D%253D&md5=3Dfa3802ff6e6b55296a2f30c64b70827e"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D1320896"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>19.</TD> <TD><A name=3DCR19></A>Steinbok P, Dolman CL, Goldie JH (1985) = Variation in=20 response to CCNU of glioblastoma multiforme in brain and cervical = lymph=20 node: case report. J Neurosurg 62:918=96921<BR><A=20 href=3D"http://dx.doi.org/10.3171/jns.1985.62.6.0918" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaL2M3htVWitw%253D%253D&md5=3Da4d078d2b430a189b112c694a8f5c002"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2987441"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/n32607m373340186/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR></TBODY></TABLE></DIV></BODY></HTML> 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