Glioblastoma multiforme
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{{DiseaseDisorder infobox |
Name = Glioblastoma multiforme |
ICD10 = {{ICD10|C|71||c|69}} |
ICD9 = {{ICD9|191}} |
ICDO = 9440/3 |
Image = |
Caption = |
OMIM = 137800 |
OMIM_mult = |
MedlinePlus = |
eMedicineSubj = neuro |
eMedicineTopic = 147 |
eMedicine_mult = {{eMedicine2|med|2692}} |
DiseasesDB = 29448 |
MeshID = D005909 |
}}
[[Image:Glioblastoma - MR coronal with contrast.jpg|thumb|right|150px|Image 1a. Coronal [[MRI]] with contrast of a glioblastoma WHO grade IV in a 15-year-old boy]]
[[Image:Glioblastoma - MR sagittal with contrast.jpg|thumb|right|150px|Image 1b. Sagittal [[MRI]] with contrast of a glioblastoma WHO grade IV in a 15-year-old boy]]
[[Image:Glioblastoma (1).jpg|thumb|150px|Glioblastoma (histology slide)]]
'''Glioblastoma multiforme''' ('''GBM''') is the most common and most aggressive type of primary [[brain]] [[tumor]], accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs occur in only 2-3 cases per 100,000 people in Europe and North America.<br />
The standard WHO-2007 name for this brain tumor is “Glioblastoma”<ref>Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P
The 2007 WHO Classification of Tumours of the Central Nervous System
Acta Neuropathol (2007) 114:97-109. [http://www.ncbi.nlm.nih.gov/pubmed/17618441 PMID 17618441]<br />
(See also BrainLife.org: [http://www.brainlife.org/who/2007_classification.htm WHO Classification > 2007 WHO Classification].)<br /> In BrainLife.org: [http://www.brainlife.org/who/classification.htm WHO Classification] are the previous WHO classifications. </ref>.
Treatment can involve [[chemotherapy]], [[radiotherapy]], and [[surgery]], all of which are acknowledged as palliative measures, meaning that they do not provide a cure. Even with complete surgical [[resection]] of the tumor, combined with the best available treatment, the survival rate for GBM remains very low. However, many advances in microsurgery techniques, radiotherapy and chemotherapy are slowly increasing the survival time of patients diagnosed with glioblastoma.
==Symptoms==
{{main|brain tumor}}
Although common symptoms of the disease include [[seizure]], [[nausea]] and [[vomiting]], [[headache]], and [[hemiparesis]], the single most prevalent symptom is a progressive memory, personality, or neurological deficit due to [[temporal lobe|temporal]] and [[frontal lobe]] involvement. The kind of symptoms produced depends highly on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is [[asymptomatic]] until it reaches an enormous size.
==Diagnosis==
In early stages, when viewed with [[MRI]], glioblastoma may mimic more [[benign_tumor | benign]] brain lesions.<ref>{{cite journal |author=Jung TY, Jung S |title=Early neuroimaging findings of glioblastoma mimicking non-neoplastic cerebral lesion |journal=Neurol Med Chir (Tokyo) |volume=47 |issue=9 |pages=424–7 |year=2007 |pmid=17895617 |doi=10.2176/nmc.47.424}}</ref> Diagnosis of a suspected GBM on CT or MRI rests on a [[stereotactic biopsy]] or by a [[craniotomy]], which can, at the same time, remove as much tumor as possible.
==Causes==
GBM is more common in males, although the reason for this is not clear.<ref>{{cite journal |author=Ohgaki H, Kleihues P|title=Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas |journal=J Neuropathol Exp Neurol |volume=64 |pages=479–89 |year=2005 |pmid=15977639}}</ref> Most glioblastoma tumors appear to be sporadic, without any [[genetic predisposition]]. No links have been found between glioblastoma and [[smoking]],<ref>{{cite journal |author=Zheng, T, Cantor KP, Zhang Y, ''et al'' |title=Risk of brain glioma not associated with cigarette smoking or use of other tobacco products in Iowa |journal=Cancer Epidemiol Biomarkers Prev |volume=10 |pages=413–4 |year=2001 |pmid=11319186}}</ref> [[Diet_%28nutrition%29 |diet]],<ref>{{cite journal |author=Huncharek M, Kupelnick B, Wheeler L |title=Dietary cured meat and the risk of adult glioma: a meta-analysis of nine observational studies |journal=J Environ Pathol Toxicol Oncol |volume=22 |pages=129–37 |year=2003 |pmid=14533876 |doi=10.1615/JEnvPathToxOncol.v22.i2.60}}</ref> [[cellular phones]]<ref>{{cite journal |author=Inskip PD, Tarone RE, Hatch EE, ''et al'' |title=Cellular-telephone use and brain tumors |journal=N Engl J Med |volume=344 |pages=79–86 |year=2001 |pmid=11150357 |doi=10.1056/NEJM200101113440201}}</ref> [[electromagnetic fields]],<ref>{{cite journal |author=Savitz DA, Checkoway H, Loomis DP |title=Magnetic field exposure and neurodegenerative disease mortality among electric utility workers |journal=Epidemiology |volume=9 |pages=398–404 |year=1998 |pmid=9647903 |doi=10.1097/00001648-199807000-00009}}</ref> or [[virus|viral]] infection.<ref>{{cite journal |author=Vilchez RA, Kozinetz CA, Arrington AS, ''et al'' |title=Simian virus 40 in human cancers |journal=Am J Med |volume=114 |pages=675–84 |year=2003 |pmid=12798456 |doi=10.1016/S0002-9343(03)00087-1}}</ref> There appears to be a small link between [[ionizing radiation]] and glioblastoma.<ref>{{cite journal |author=Cavenee L |title=High-grade gliomas with chromosome 1p loss |journal=J Neurosurg |volume=92 |pages=1080–1 |year=2000 |pmid=10839286}}</ref>
==Pathogenesis==
Glioblastomas multiforme are characterized by the presence of small areas of [[Necrosis|necrotizing]] [[Tissue (biology)|tissue]] that is surrounded by anaplastic cells (pseudopalisading necrosis). This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from Grade 3 [[astrocytomas]], which do not have these features. Although glioblastoma multiforme can be formed from lower-grade [[astrocytomas]], post-mortem autopsies have revealed that most glioblastomas multiforme are not caused by previous lesions in the brain.
Unlike [[oligodendroglioma]]s, glioblastomas multiforme can form in either the [[gray matter]] or the [[white matter]] of the brain; but most GBM arises from the deep white matter and quickly infiltrate the brain, often becoming very large before producing symptoms. The tumor may extend to the meningeal or [[ventricular]] wall, leading to the high protein content of [[cerebrospinal fluid]] (CSF) (> 100 mg/dL), as well as an occasional [[pleocytosis]] of 10 to 100 cells, mostly [[lymphocyte]]s. [[Malignant]] cells carried in the CSF may spread to the [[spinal cord]] or cause meningeal gliomatosis. However, [[metastasis]] of [[GBM]] beyond the [[central nervous system]] is extremely rare. About 50% of GBM occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the [[cerebrum]] and may exhibit the classic infiltrate across the [[corpus callosum]], producing a butterfly (bilateral) [[glioma]].
The tumor may take on a variety of appearances, depending on the amount of hemorrhage, [[necrosis]], or its age. A CT scan will usually show a nonhomogeneous mass with a hypointense center and a variable ring of enhancement surrounded by [[edema]]. Part of a [[lateral ventricle]] is usually deformed, and both lateral and third ventricles may be displaced.
==Treatment==
It is very difficult to treat glioblastoma due to several complicating factors:<ref name = "pmid12672279">{{cite journal
| author = Lawson HC, Sampath P, Bohan E, ''et al''
| title = Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience
| journal = Journal of Neuro-Oncology
| volume = 83
| issue = 1
| year = 2007
| pages = 61–70
| pmid = 17171441
| doi = 10.1007/s11060-006-9303-1 }}</ref>
* The tumor cells are very resistant to chemotherapy and other conventional therapies
* The brain is susceptible to damage due to therapy
* The brain has a very limited capacity to repair itself
* Many drugs cannot cross the [[blood brain barrier]] to act on the tumor
Treatment of primary brain tumors and brain metastases consists of both symptomatic
and palliative therapies.
===Symptomatic therapy===
Supportive treatment focuses on relieving symptoms and improving the patient’s
neurologic function. The primary supportive agents are [[anticonvulsant]]s and
[[corticosteroid]]s.
*Historically, around ninety percent of patients with glioblastoma underwent anticonvulsant treatment, although is has been estimated that only approximately 40% of patients required this treatment. Recently, it has not been recommended that neurosurgeons administer anticonvulsants prophylactically, and should wait until a seizure occurs before prescribing this medication<ref>{{cite journal |author=Stevens GHJ |title=Antiepileptic therapy in patients with central nervous system malignancies |journal=Current Neurology and Neuroscience Reports |volume=6 |pages=311–318 |year=2006 |pmid=16822352 | doi=10.1007/s11910-006-0024-9}}</ref>. Those receiving [[phenytoin]] concurrent with radiation may have serious skin reactions such as [[erythema multiforme]] and [[Stevens-Johnson syndrome]].
*Corticosteroids, usually [[dexamethasone]] given 4 to 10 mg every 4 to 6 h, can reduce peritumoral edema (through rearrangement of the blood-brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.
===Palliative therapy===
Palliative treatment usually is conducted to improve quality of life and to achieve a longer survival time. It includes surgery, radiation therapy, and chemotherapy. A maximally feasible resection with maximal tumor-free margins ("debulking") is usually performed along with external beam [[radiation]] and [[chemotherapy]].
====Surgery====
Surgery is the first stage of treatment of glioblastoma. An average GBM tumor contains 10<sup>11</sup> cells, which is on average reduced to 10<sup>9</sup> cells after surgery.
It is used to take a section for diagnosis, to remove some of the symptoms of a large mass pressing against the brain, to remove disease before secondary resistance to radiotherapy and chemotherapy, and to prolong survival.
The greater the extent of tumor removal, the longer the survival time. Removal of 98% or more of the tumor has been associated with a significantly longer median survival time than if less than 98% of the tumor is removed.<ref>{{cite journal |author=Lacroix M, Abi-Said D, Fourney DR, ''et al'' |title=A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival |journal=J Neurosurg |volume=95 |issue=2 |pages=190–8 |year=2001 |pmid=11780887 }}</ref> The chances of near-complete initial removal of the tumor can be greatly increased if the surgery is guided by a fluorescent dye known as [[5-aminolevulinic acid]].<ref>{{cite journal |author=Stummer W, Pichimeier U, Meinel T, ''et al'' |title=Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial |journal=The Lancet Oncology |volume=7 |issue=5 |pages=392–401 |year=2006 | pmid=16648043 | doi=10.1016/S1470-2045(06)70665-9}}</ref>
====Radiotherapy====
On average, [[radiotherapy]] after surgery can reduce the tumor size to 10<sup>7</sup> cells. Whole brain radiotherapy does not improve survival when compared to the more precise and targeted three-dimensional conformal radiotherapy.<ref>{{cite journal |author=Showalter T, Andrel J, Andrews D, ''et al'' |title=Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression |journal=International Journal of Radiation OncologyBiologyPhysics, |volume=69 |issue=3 |pages=820–824 |year=2007 | pmid=17499453 | doi=10.1016/j.ijrobp.2007.03.045 }}</ref> A total radiation dose of 60-65 Gy has been found to be optimal for treatment.<ref>{{cite journal
| author = Fulton DS, Urtasun RC, Scott-Brown, I, ''et al''
| title = Increasing radiation dose intensity using hyperfractionation in patients with malignant glioma. Final report of a prospective phase I-II dose response study
| journal = Journal of Neuro-Oncolog
| volume = 14
| issue = 1
| pages = 63–72
| year = 1992
| pmid = 1335044 }}</ref>
[[Boron neutron capture therapy]] has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.
====Chemotherapy====
The standard of care for glioblastoma includes chemotherapy during and after radiotherapy. On average, chemotherapy after surgery and radiotherapy can initially reduce the tumor size to 10<sup>6</sup> cells. The use of [[temozolomide]] both during radiotherapy and for six months post radiotherapy results in a significant increase in median survival with minimal additional toxicity.<ref>{{cite journal |author=Stupp R, Mason WP, van den Bent MJ, ''et al'' |title=Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma |journal=NEJM |volume=352 |issue=10 |pages=987–996 |year=2005 | pmid=15758009 |doi=10.1056/NEJMoa043330 }}</ref> This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial.<ref>{{cite journal |author=Mason WP, Mirimanoff RO, Stupp R, ''et al'' |title=Radiotherapy with Concurrent and Adjuvant Temozolomide: A New Standard of Care for Glioblastoma Multiforme |journal=Progress in Neurotherapeutics and Neuropsychopharmacology |volume=1 |pages=37–52 |year=2006 | doi = 10.1017/S1748232105000054 }}</ref><ref>{{cite web |url=http://www.cancer.gov/clinicaltrials/results/glioblastoma0604 |title=Temozolomide Plus Radiation Helps Brain Cancer - National Cancer Institute |accessdate=2007-09-15 |format= |work=}}</ref><br />
====Recurrences====
Long-term disease-free survival is unlikely, and the tumor will often reappear, usually within 2 cm of the original site, and 10% may develop new lesions at distant sites. More extensive surgery and intense local treatment after recurrence has been associated with improved survival.<ref>{{cite journal
|author=Nieder C, Adama M, Mollsa M and Grosu AL
|title=Therapeutic options for recurrent high-grade glioma in adult patients: Recent advances
|journal=Critical Reviews in Oncology/Hematology
|volume=60
|issue = 3
|pages = 181–193
|year=2006
|pmid=16875833
|doi=10.1016/j.critrevonc.2006.06.007}}</ref>.
==Prognosis==
The median survival time from the time of diagnosis without any treatment is 3 months. Increasing age (> 60 years of age) carries a worse prognostic risk. Death is usually due to [[cerebral edema]] or increased [[intracranial pressure]]. One in twenty of glioblastoma patients survive for more than three years, and approximately one in 5,000 glioblastoma patients survive for decades<ref name="doi101093brainawm204">{{cite journal
|author=Krex D, Klink B, Hartmann C, ''et al''
|title=Long-term survival with glioblastoma multiforme
|journal = Brain
|volume= 130
|issue = 10
|pages = 2596–2606
|year=2007
|pmid=17785346
|doi=10.1093/brain/awm204}}</ref>.
Survival of more than three years has been associated with younger age at diagnosis, a good initial KPS, and MGMT [[methylation]] <ref name="doi101093brainawm204"/>. A DNA test can be conducted on glioblastomas to determine whether or not the [[promoter]] of the MGMT [[gene]] is methylated. Patients with a methylated MGMT promoter have been associated with significantly greater long-term survival than patients with an unmethylated MGMT promoter<ref>{{cite journal
|author = Martinez R, Schackert G, Yaya-Tur R, ''et al''
|title = Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme
|journal = Journal of Neuro-Oncology
|volume= 83
|issue = 1
|pages = 91–93
|year=2007
|pmid=17164975
|doi=10.1007/s11060-006-9292-0}}</ref>. This DNA characteristic is intrinsic to the patient and currently cannot be altered externally.
Long-term survival has also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy<ref name="doi101093brainawm204"/>. However, much remains unknown about why some patients survive longer with glioblastoma.
UCLA Neuro-Oncology publishes [http://www.neurooncology.ucla.edu/Performance/GlioblastomaMultiforme.aspx real-time survival data] for patients with this diagnosis. They are the only institution in the [[United States]] that shows how their patients are performing. They also show a listing of chemotherapy agents used to treat GBM tumors.
According to a 2003 study, glioblastoma multiforme prognosis can be divided into three subgroups dependent on [[Performance_status#Karnofsky_scoring | Karnofsky Performance Score]] (KPS), the age of the patient, and treatment:<ref>{{cite journal |author=Shawl, EG, Seiferheld, W, Scott, C, ''et al'' |title=Re-examining the radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) for glioblastoma multiforme (GBM) patients |journal=International Journal of Radiation Oncology*Biology*Physics |volume=57 |issue=2 |pages=S135–S136 |year=2003 |pmid=15758009 |doi=10.1016/S0360-3016(03)00843-5}}</ref>
{| class="wikitable" style="margin: 1em auto 1em auto"
! RPA class || Definition || Historical Median Survival Time || Historical 1-Year Survival || Historical 3-Year Survival || Historical 5-Year Survival
|-
| align="center" | III || Age <50, [[Performance_status#Karnofsky_scoring | KPS]] >= 90 || align="center" | 17.1 months || align="center" | 70% || align="center" | 20% || align="center" | 14%
|-
|rowspan="2" align="center" | IV || Age < 50, KPS < 90 ||rowspan="2" align="center" | 11.2 months ||rowspan="2" align="center" | 46% || rowspan="2" align="center" | 7% ||rowspan="2" align="center" | 4%
|-
|Age > 50, KPS >= 70, surgical removal with good neurologic function
|-
|rowspan="3" align="center" | V + VI || Age >= 50, KPS >= 70, surgical removal with poor neurologic function || rowspan="3" align="center" | 7.5 months || rowspan="3" align="center" | 28% ||rowspan="3" align="center" | 1% ||rowspan="3" align="center" | 0%
|-
|Age >= 50, KPS >= 70, no surgical removal
|-
|Age >= 50, KPS < 70
|}
==References==
{{Reflist|2}}
==External links==
* [http://www.ninds.nih.gov/disorders/brainandspinaltumors/detail_brainandspinaltumors.htm Brain and Spinal Tumors: Hope Through Research (National Institute of Neurological Disorders and Stroke)]
* [http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&action=search&srchstr=glioblastoma&srch_type=all#top Glioblastoma Images] MedPix Medical Image Database
*[http://rad.usuhs.mil/rad/handouts/jsmirnio/index.html Astrocytoma Radiologic-Pathologic Correlation] AFIP Lectures
* [http://i.cmpnet.com/cancernetwork/handbook/pdf/26brain.pdf Cancer Management: Brain Tumors]
* [http://virtualtrials.com/pdf/williams2007.pdf Treatment Options for Glioblastoma and other Glios]
* [http://nabraintumor.org/ North America Brain Tumor Coalition]
* [http://www.braintumourtrust.co.uk Samantha Dickson Brain Tumour Trust] UK
{{Nervous tissue tumors}}
[[Category:Neurosurgery]]
[[Category:Neurology]]
[[Category:Types of cancer]]
[[de:Glioblastom]]
[[fr:Glioblastome multiforme]]
[[it:Glioblastoma]]
[[la:Glioblastoma multiforme]]
[[ja:膠芽腫]]
[[no:Glioblastoma multiforme]]
[[pl:Glejak wielopostaciowy]]
[[pt:Glioblastoma multiforme]]