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VOLUME 32 NUMBER 22 AUGUST 1 2014

JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y

bital changes (Fig 2A, arrows) that were initially attributed to postop-
Glioblastoma Multiforme Metastasis Outside erative changes, infection, or residual tumor.
the CNS: Three Case Reports and Possible Within 5 weeks, there was clear progression, indicating residual
Mechanisms of Escape GBM outside the CNS, with involvement of the sphenoid bone, soft
tissues of the masticator space and extraconal orbit (Fig 2B, arrows)
with resulting proptosis. Three months later, postcontrast T1w MRI
Introduction
revealed a necrotic-enhancing posterior superficial parotid mass (Fig
Primary brain and CNS tumor incidence is approximately 19 per
2C, arrow) that was found to be a GBM nodal metastasis. Four months
100,000 individuals per year in the United States compared with seven
later, postcontrast computed tomography revealed tumor in the lower
per 100,000 individuals worldwide.1,2 Worldwide this accounts for 2%
neck lymph nodes (Fig 2D, arrow); left hemi-neck nodal and parotid
of all primary tumors and 7% of years of life lost from cancer before
dissection revealed GBM involvement in four of 23 lymph nodes.
the age of 70 years.1,2 Glioblastoma multiforme (GBM) is also the
Despite multiple reresections, radiation therapies, and receiving
most aggressive brain tumor with poor prognosis; patients with GBM
multiple chemotherapies (including temozolomide, paclitaxel, carbo-
have a median survival time of about 14 months.3-10
platin, cisplatin, irinotecan, and cetuximab), the patient survived
GBM metastases outside the CNS are rare, so therapeutic expe-
22 months.
rience with these types of tumors is limited.11-15 Normally the brain is
Patient 3. This patients case has been reported previously12;
immunologically and anatomically separated from the body by the
however, the mechanism of GBM metastasis was not clear. Briefly, a
blood brain barrier. Herein, we present the cases of three patients with
30-year-old pregnant woman with a long history of headaches pre-
GBM with extra-CNS metastasis. The variety of metastasis locations
sented with a generalized seizure. MRI revealed a GBM in the left
demonstrated in these cases helps to illustrate the various mechanism
frontal lobe that encased a small venule from the superior sagittal
and corresponding risk factors that allow GBM to escape the CNS.
sinus, causing perivascular thickening and diffusion restriction (Figs
3A through 3C, arrows), shown on axial T2-weighted (Fig 3A) and
Case Reports
Patient 1. A 51-year-old man presented with a general seizure. diffusion-weighted (Fig 3B) images as well as apparent diffusion coef-
Magnetic resonance imaging (MRI) revealed a lesion in the left ficient map (Fig 3C). The mass, found to be a GBM at resection, was
parieto-occipital lobe (Figs 1A and 1B). Coronal T1-weighted post- diffusion-restricted and demonstrated heterogeneous contrast en-
contrast (Fig 1A) and axial T2-weighted cranial MRI (Fig 1B) demon- hancement and partially cystic portions on postcontrast imaging (not
strated an enhancing left parietal mass involving small venules from shown). The tumor was resected and the pregnancy terminated. The
the superior sagittal sinus (Figs 1A and 1B, arrows). The patient was patient underwent chemoradiotherapy with temozolomide, but the
diagnosed with a mixed diffuse glioma and underwent subtotal resec- tumor recurred within 3 months. The patient then underwent rere-
tion of the tumor and postoperative radiochemotherapy. The tumor section and received chemotherapy with sorafenib and erlotinib.
progressed, and 5 years after diagnosis, the patient underwent Seven months after diagnosis, MRI revealed a soft tissue mass in the
contrast-enhanced fluorescence imaging guided tumor reresection temporalis muscles near the craniotomy site (Fig 3D, arrow). Eleven
with a subsequent diagnosis of GBM. Two years later, follow-up MRI months later, sagittal postcontrast T1-weighted MRI revealed an en-
revealed recurrent tumor. After completing radiochemotherapy, the hancing parietal mass in the skull posterior to the resection cavity that
patient was hospitalized for progressive dyspnea. Chest X-ray revealed was found to be a GBM metastasis (Fig 3E, arrow) and a lesion in the
a pleural effusion requiring thoracic drainage. Axial contrast- L5 vertebra that was found to be a spindle cell neoplasm, presumably
enhanced computed tomography demonstrated an ill-defined 4-cm GBM related (3F, arrow). The patient survived 28 months.
mass in the left lower lung lobe (Fig 1C, arrow) and pleural metastases
(Figs 1C and 1E, arrowheads) with infiltration of the chest wall and Discussion
destruction of a ventrolateral left rib (Fig 1E, asterisks). The wide variety of locations of the metastases (bone, nodes,
The pleural lesion was biopsied, and histologic examination of lung, soft tissues, glands) relates to the varying mechanisms for GBM
the biopsy sample (Fig 1D, hematoxylin and eosin staining, 200 to escape the CNS. GBM can easily metastasize within the neuroaxis
original magnification) revealed a malignant astrocytic glioma. (ie, the meninges or spinal cord) by way of the CSF; indeed, autopsy
The patient underwent additional radiochemotherapy with con- studies have revealed that GBM metastases in the neuroaxis occur in
comitant temozolomide. He completed radiotherapy but died 4 approximately 20% of GBM patients,16 which may relate to overex-
weeks later. pression of glial fibrillary acidic protein.17 Eighteen percent of GBM
Patient 2. A 24-year-old man who had undergone resection of a grow in transplanted organs,18,19 indicating their metastatic potential.
left temporal GBM involving the greater wing of the sphenoid bone However, extracranial/extra-CNS GBM metastases occur in only
with invasion of the middle cranial fossa at an outside facility pre- about 0.4% to 2.0% of patients with GBM, although GBMs account
sented with anxiety and headaches. Postoperative MRI revealed on for approximately two thirds of the neuroepithelial tumors that me-
axial T1w postcontrast images a dural thickening and extraconal or- tastasize extracranially.20,21 Extracranial GBM metastases occur most

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Diagnosis in Oncology

A B

C D

Fig 1.

often in the lungs and pleura (60% of patients) but also in the regional GBM metastasis is the migration of GBM cells via the movement of
lymph nodes (51%), bones (31%), and liver (22%).22,23 CSF through shunts to the peritoneum or pleura.27 However, approx-
Weller et al24 have described the role of basement membranes in imately 10% of glioma metastases outside the neuraxis occur in pa-
the wall of capillaries and arteries (pseudolymphatics) and the nasal tients who have not undergone surgery. This was the case in patient 2,
lymphatics in the lymphatic drainage of the CNS interstitial fluid in whom the GBM invaded the bone directly. Other patients develop
and CSF.24 extracranial metastases within 3 to 6 months after a primary diagnosis
One explanation for the rarity of extracranial GBM metastases is of GBM,28 as was the case for patient 3.
that with a median overall survival duration of 14.6 months,10,25 The blood-brain barrier and the brains lack of a lymphatic drain-
patients with GBM do not survive long enough to develop such me- age system inhibit the spread of GBM cells but other potential path-
tastases.26 Indeed many of the reported cases of extra-CNS spread ways of GBM metastasis to extracranial sites exist. Besides the risk
have longer than average survival times.21 Additionally, glioma metas- factors we listed, additional mechanisms of escape have been postu-
tases outside the neuraxis are most commonly found in patients in lated, including vascular invasion, cranial nerve perineural spread,
whom iatrogenic procedures have generated access from the brain to lymphatic spread, direct invasion, or iatrogenic spread into soft tissue.
extracerebral structures. One clear example of this possible pathway of These mechanisms of escape have been associated with certain

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Hamilton et al

A B

C D

Fig 2.

molecular biomarkers for GBM.21 Given that the most common sites dibular vein a few centimeters away. Once in the parotid gland, the
of GBM metastasis are the lungs, liver, and bone,22,23 the most com- lymphatic system drained the tumor cells to the lower neck lymph
mon mechanism of GBM metastasis outside the CNS/neuraxis is nodes. Alternatively, the tumors invasion of the middle cranial fossa
likely vascular invasion. could have spread tumor cells via the deep facial lymphatic system to a
Our review of the literature revealed no reports of GBM metas- parotid lymph node and subsequently the lower neck lymph nodes, a
tasis to the distal limbs. This indicates that the main vascular route of pattern often seen in skin cancers of the scalp.
GBM metastasis is reflux into the systemic venous system, as valves in In summary, we have presented three patients with extraneural
the peripheral veins prevent such reflux whereas arteries have no GBM metastases illustrating the gamut of expected locations of such
valves and reach the distal limbs. In addition, only a few studies have metastases. Although uncommon, risk factors for extraneural GBM
reported GBM metastases in the portal venous system (ie, metastases metastasis include long survival, iatrogenic procedures, and vascu-
in the pancreas, small bowel, spleen, and/or peripheral liver).20,26,29 lar invasion.
The lack of GBM metastases in the portal venous system may result
from the few functioning portal-caval shunts in otherwise healthy Jackson D. Hamilton
individuals (eg, no liver failure). The University of Texas MD Anderson Cancer Center, Houston, TX
The GBMs in patients 1 and 3 likely metastasized via venous
Marion Rapp, Timo Marcel Schneiderhan,
invasion, given the proximity of the tumor to the venules of the
and Michael Sabel
superior sagittal sinus with probable invasion. In case 1, invasion of the University Dusseldorf, Dusseldorf, Germany
superior sinus venule may have resulted in metastasis returning to
the heart and ending in the pulmonary arteries with spread to the Anne Hayman
pleura or refluxed into the systemic venous system and ended up in the Anatom-e Information Systems, Houston, TX
pleural veins. In case 3, venous invasion may have refluxed into Bat-
Axel Scherer, Patric Kropil, Wilfried Budach,
sons plexus of the spine.
The GBM in patient 2 could have metastasized via multiple Usha Kretschmar, and Peter Arne Gerber
University Dusseldorf, Dusseldorf, Germany
possible pathways. One possibility is that the anterior temporal tumor
invaded the sphenoparietal sinus along the greater sphenoid wing, and Sujit Prabhu and Lawrence E. Ginsberg
tumor cells refluxed into an emissary vein connected to the retroman- The University of Texas MD Anderson Cancer Center, Houston, TX

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Diagnosis in Oncology

A B C

D E F

Fig 3.

Edwin Bolke and Christiane Matuschek 3. Kalokhe G, Grimm SA, Chandler JP, et al: Metastatic glioblastoma: Case
University Dusseldorf, Dusseldorf, Germany presentations and a review of the literature. J Neurooncol 107:21-27, 2012
4. Teplyuk NM, Mollenhauer B, Gabriely G, et al: MicroRNAs in cerebrospinal
fluid identify glioblastoma and metastatic brain cancers and reflect disease
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST activity. Neuro Oncol 14:689-700, 2012
Although all authors completed the disclosure declaration, the following 5. Jezewski D, Parafiniuk D, Nowacki P, et al: Intracerebral metastasis of
author(s) and/or an authors immediate family member(s) indicated a glioblastoma multiforme. Case report and literature review. Ann Acad Med Stetin
financial or other interest that is relevant to the subject matter under 57:59-63; discussion 63-64, 2011
consideration in this article. Certain relationships marked with a U are 6. Templeton A, Hofer S, Topfer M, et al: Extraneural spread of glioblastoma
report of two cases. Onkologie 31:192-194, 2008
those for which no compensation was received; those relationships marked
7. Sawaya R, Hammoud M, Schoppa D, et al: Neurosurgical outcomes in a
with a C were compensated. For a detailed description of the disclosure
modern series of 400 craniotomies for treatment of parenchymal tumors.
categories, or for more information about ASCOs conflict of interest policy, Neurosurgery 42:1044-1055; discussion 1055-1056, 1998
please refer to the Author Disclosure Declaration and the Disclosures of 8. Guckenberger M, Mayer M, Buttmann M, et al: Prolonged survival when
Potential Conflicts of Interest section in Information for Contributors. temozolomide is added to accelerated radiotherapy for glioblastoma multiforme.
Employment or Leadership Position: Anne Hayman, Anatom-e Strahlenther Onkol 187:548-554, 2011
Information Systems (C) Consultant or Advisory Role: None Stock 9. Tai CK, Kasahara N: Replication-competent retrovirus vectors for cancer
Ownership: None Honoraria: Peter Arne Gerber, Roche, Amgen gene therapy. Front Biosci 13:3083-3095, 2008
Research Funding: None Expert Testimony: None Patents: None Other 10. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concom-
Remuneration: None itant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996,
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