Glioblastoma multiforme

Glioblastoma multiforme
Classification and external resources

Coronal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old male.
ICD-10 C71.
ICD-9 191
ICD-O: M9440/3
OMIM 137800
DiseasesDB 29448
eMedicine neuro/147 med/2692
MeSH D005909

Glioblastoma multiforme (GBM) is the most common and most aggressive type of primary brain tumor in humans, involving glial cells and accounting for 52% of all parenchymal 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. According to the WHO classification of the tumors of the central nervous system‎, the standard name for this brain tumor is "glioblastoma"; it presents two variants: giant cell glioblastoma and gliosarcoma. Glioblastomas are also an important brain tumor of the canine, and research is ongoing to use this as a model for developing treatments in humans.[1] Treatment can involve chemotherapy, radiation, radiosurgery, corticosteroids, antiangiogenic therapy, and surgery. [2]

Glioblastoma has a very poor prognosis, despite multimodality treatment consisting of open craniotomy with surgical resection of as much of the tumor as possible, followed by concurrent or sequential chemoradiotherapy, antiangiogenic therapy with bevacizumab, gamma knife radiosurgery, and symptomatic care with corticosteroids. Other than the brainstem gliomas, it has the worst prognosis of any CNS malignancy.

Contents

Signs and symptoms

Main article: 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 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 an asymptomatic condition until it reaches an enormous size.

Causes

GBM is more common in males, although the reason for this is not clear.[3] Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking,[4] diet,[5] cellular phones,[6] or electromagnetic fields.[7] Recently, evidence for a viral cause has been discovered, possibly SV40[8] or cytomegalovirus.[9] There also appears to be a small link between ionizing radiation and glioblastoma.[10] Some also believe that there may be a link between polyvinyl chloride (which is commonly used in construction) and glioblastoma.[11] A recent link cited in the Lancet medical journal links brain cancer to lead exposure in the work place. [12] There is an association of brain tumor incidence and malaria, suggesting that the anopheles mosquito, the carrier of malaria, might transmit a virus or other agent that could cause glioblastoma. [13]

Other risk factors include:[14]

Pathogenesis

Glioblastomas multiforme are characterized by the presence of small areas of necrotizing 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.

There are four subtypes of glioblastoma. 97% of tumours in the ‘classical’ subtype carry extra copies of the Epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of Epidermal growth factor receptor (EGFR), whereas the gene TP53, which is often mutated in glioblastoma, is rarely mutated in this subtype. [15] In contrast, the proneural subtype often has high rates of alterations in TP53, and in PDGFRA, the gene encoding a-type platelet-derived growth factor receptor, and in IDHl, the gene encoding isocitrate dehydrogenase-1. The mesenchyrnal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding Neurofibromatosis type 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types. [16]

GBM usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Less than 10% form more slowly following degeneration of low-grade astrocytoma or anaplastic astrocytoma. These are called secondary GBM and are more common in younger patients (mean age 45 versus 62 years).[17]The tumor may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid (CSF) (> 100 mg/dL), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may spread (rarely) to the spinal cord or cause meningeal gliomatosis. However, metastasis of GBM beyond the central nervous system is extremely unusual. 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 rarely exhibit the classic infiltration 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 inhomogeneous mass with a hypodense center and a variable ring of enhancement surrounded by edema. Mass effect from the tumor and edema may compress the ventricles and cause hydrocephalus.

Cancer cells with stem cell-like properties have been found in glioblastomas (this may be a cause of their resistance to conventional treatments, and high re-occurrence rate).[18]

Diagnosis

Image 1b. Sagittal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old male.
Glioblastoma (histology slide)

When viewed with MRI, glioblastomas often appear as ring-enhancing lesions. The appearance is not specific, however, as other lesions such as abscess, metastasis, tumefactive multiple sclerosis, and other entities may have a similar appearance.[19] Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy or a craniotomy with tumor resection and pathologic confirmation. Because the tumor grade is based upon the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the lesion. Imaging of tumor blood flow using perfusion MRI and measuring tumor metabolite concentration with MR spectroscopy may add value to standard MRI in the diagnosis of glioblastoma, but pathology remains the gold standard

Treatment

It is very difficult to treat glioblastoma due to several complicating factors:[20]

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 anticonvulsants and corticosteroids.

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 is usually performed along with external beam radiation and chemotherapy. Gross total resection of tumor is associated with a better prognosis.

Surgery

Surgery is the first stage of treatment of glioblastoma. An average GBM tumor contains 1011 cells, which is on average reduced to 109 cells after surgery. It is used to take a section for a pathological 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 better. Removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed.[22] 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.[23]

Radiotherapy

On average, radiotherapy after surgery can reduce the tumor size to 107 cells. Whole brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy.[24] A total radiation dose of 60–65 Gy has been found to be optimal for treatment.[25]

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 106 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.[26] This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial.[27][28] Temozolomide seems to work by sensitizing the tumor cells to radiation. [29]

High - doses of temozolomide in high - grade gliomas yield low toxicity but the results are comparable to the standard doses. [30]

The U.S. Food and Drug Administration approved Avastin (bevacizumab) to treat patients with glioblastoma at progression after standard therapy based on the results of 2 studies that showed Avastin reduced tumor size in some glioblastoma patients. In the first study, 28% of glioblastoma patients had tumor shrinkage, 38% survived for at least one year, and 43% survived for at least 6 months without their disease progressing. [31].

Immunotherapy

Relapse of glioblastoma is attributed to the recurrence and persistance of tumor stem cells.[32] In a small trial, a tumor B-cell hybridoma vaccine against tumor stem cells elicited a specific tumor immune reaction thus enhancing immune response to the disease.[33] Larger trials are in progress to further assess this approach to treating glioblastoma.

Recurrences

Long-term disease-free environment is possible, but the tumor usually reappears, often within 3 cm of the original site, and 10-20% may develop new lesions at distant sites. More extensive surgery and intense local treatment after recurrence has been associated with improvement.[34].

Drug development and clinical trials

The compound dichloroacetic acid has recently been investigated as addition to standard therapy (radiotherapy + chemotherapy with temozolomide)[35]. While initial results suggest some effectiveness in patients (four out of five patients survived for more than 18 months), the trial was too small, only five patients, and dichloroacetic acid treatment regime too variable to draw definite conclusions yet.

Prognosis

The median survival time from the time of diagnosis without any treatment is 3 months, but with treatment survival of 1-2 years is common. Increasing age (> 60 years of age) carries a worse prognostic risk. Death is usually due to cerebral edema or increased intracranial pressure. [36]

A good initial Karnofsky Performance Score (KPS), and MGMT methylation are associated with longer survival.[36] 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 benefit than patients with an unmethylated MGMT promoter.[37] This DNA characteristic is intrinsic to the patient and currently cannot be altered externally.

Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy.[36] However, much remains unknown about why some patients survive longer with glioblastoma. Age of under 50 is linked to longer survival in glioblastoma multiforme, as is 98%+ resection and use of temozolomide chemotherapy and better Karnofsky performance scores.

UCLA Neuro-Oncology publishes 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 KPS, the age of the patient, and treatment.[38]

RPA class Definition Historical Median Survival Time Historical 1-Year Survival Historical 3-Year Survival Historical 5-Year Survival
III Age < 50, KPS ≥ 90 17.1 months 70% 20% 14%
IV Age < 50, KPS < 90 11.2 months 46% 7% 4%
Age > 50, KPS ≥ 70, surgical removal with good neurologic function
V + VI Age ≥ 50, KPS ≥ 70, surgical removal with poor neurologic function 7.5 months 28% 1% 0%
Age ≥ 50, KPS ≥ 70, no surgical removal
Age ≥ 50, KPS < 70

References

  1. ↑ Lipsitz D, Higgins RJ, Kortz GD, et al. (November 2003). "Glioblastoma multiforme: clinical findings, magnetic resonance imaging, and pathology in five dogs". Vet. Pathol. 40 (6): 659–69. doi:10.1354/vp.40-6-659. PMID 14608019. http://www.vetpathology.org/cgi/pmidlookup?view=long&pmid=14608019. 
  2. ↑ Gina Kolata and Lawrence K. Altman, M.D. (August 27, 2009). "Kennedy Case Shows Progress and Obstacles in Cancer Fight". New York Times. http://www.nytimes.com/2009/08/28/health/28brain.html. 
  3. ↑ Ohgaki H, Kleihues P (2005). "Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas". J Neuropathol Exp Neurol 64 (6): 479–89. PMID 15977639. 
  4. ↑ Zheng, T, Cantor KP, Zhang Y, et al. (2001). "Risk of brain glioma not associated with cigarette smoking or use of other tobacco products in Iowa". Cancer Epidemiol Biomarkers Prev 10 (4): 413–4. PMID 11319186. 
  5. ↑ Huncharek M, Kupelnick B, Wheeler L (2003). "Dietary cured meat and the risk of adult glioma: a meta-analysis of nine observational studies". J Environ Pathol Toxicol Oncol 22 (2): 129–37. doi:10.1615/JEnvPathToxOncol.v22.i2.60. PMID 14533876. 
  6. ↑ Inskip PD, Tarone RE, Hatch EE, et al. (2001). "Cellular-telephone use and brain tumors". N Engl J Med 344 (2): 79–86. doi:10.1056/NEJM200101113440201. PMID 11150357. 
  7. ↑ Savitz DA, Checkoway H, Loomis DP (1998). "Magnetic field exposure and neurodegenerative disease mortality among electric utility workers". Epidemiology 9 (4): 398–404. doi:10.1097/00001648-199807000-00009. PMID 9647903. 
  8. ↑ Vilchez RA, Kozinetz CA, Arrington AS, et al. (2003). "Simian virus 40 in human cancers". Am J Med 114 (8): 675–84. doi:10.1016/S0002-9343(03)00087-1. PMID 12798456. 
  9. ↑ "Target acquired", The Economist, May 29th, 2008
  10. ↑ Cavenee L (2000). "High-grade gliomas with chromosome 1p loss". J Neurosurg 92 (6): 1080–1. PMID 10839286. 
  11. ↑ http://www.brain-cancer-net.org/pvc-poly-vinyl-chloride.htm
  12. ↑ Wijngaarden, Edwin van, (2006). "Brain cancer mortality and potential occupational exposure to lead: Findings from the National Longitudinal Mortality Study, 1979–1989". International Journal of Cancer 119 (5): 1136–44. doi:10.1002/ijc.21947. PMID 16570286. 
  13. ↑ Lehrer S. Anopheles mosquito transmission of brain tumor. Med Hypotheses. 2010 Jan;74(1):167-8. Epub 2009 Aug 4. [1]
  14. ↑ Glioblastoma multiforme at Mount Sinai
  15. ↑ Erika Check Hayden. Genomics boosts brain-cancer work. Nature. 2010 Jan 21;463(7279):278.
  16. ↑ Bridget M. Kuehn. Genomics illuminates a Deadly Brain Cancer. JAMA, March 10, 2010-Vol 303, No. 10 pp925-927.
  17. ↑ Hiroko Ohgaki and Paul Kleihues (December 2009). "Genetic alterations and signaling pathways in the evolution of gliomas". Cancer Science 100 (12): 2235. doi:10.1111/j.1349-7006.2009.01308.x. PMID 19737147. http://www3.interscience.wiley.com/journal/122539787/abstract?CRETRY=1&SRETRY=0. 
  18. ↑ Murat A, Migliavacca E, Gorlia T, et al. (June 2008). "Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma". J. Clin. Oncol. 26 (18): 3015–24. doi:10.1200/JCO.2007.15.7164. PMID 18565887. http://www.jco.org/cgi/pmidlookup?view=long&pmid=18565887. 
  19. ↑ Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW (2007). "Patterns of contrast enhancement in the brain and meninges". Radiographics 27 (2): 525–51. doi:10.1148/rg.272065155. PMID 17374867. http://radiographics.rsnajnls.org/cgi/pmidlookup?view=long&pmid=17374867. 
  20. ↑ Lawson HC, Sampath P, Bohan E, et al. (2007). "Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience". Journal of Neuro-Oncology 83 (1): 61–70. doi:10.1007/s11060-006-9303-1. PMID 17171441. 
  21. ↑ Stevens GHJ (2006). "Antiepileptic therapy in patients with central nervous system malignancies". Current Neurology and Neuroscience Reports 6 (4): 311–318. doi:10.1007/s11910-006-0024-9. PMID 16822352. 
  22. ↑ Lacroix M, Abi-Said D, Fourney DR, et al. (2001). "A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis and extent of resection". J Neurosurg 95 (2): 190–8. doi:10.3171/jns.2001.95.2.0190. PMID 11780887. 
  23. ↑ Stummer W, Pichimeier U, Meinel T, et al. (2006). "Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial". The Lancet Oncology 7 (5): 392–401. doi:10.1016/S1470-2045(06)70665-9. PMID 16648043. 
  24. ↑ Showalter T, Andrel J, Andrews D, et al. (2007). "Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression". International Journal of Radiation OncologyBiologyPhysics, 69 (3): 820–824. doi:10.1016/j.ijrobp.2007.03.045. PMID 17499453. 
  25. ↑ Fulton DS, Urtasun RC, Scott-Brown, I, et al. (1992). "Increasing radiation dose intensity using hyperfractionation in patients with malignant glioma. Final report of a prospective phase I–II dose response study". Journal of Neuro-Oncolog 14 (1): 63–72. PMID 1335044. 
  26. ↑ Stupp R, Mason WP, van den Bent MJ, et al. (2005). "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma". NEJM 352 (10): 987–996. doi:10.1056/NEJMoa043330. PMID 15758009. 
  27. ↑ Mason WP, Mirimanoff RO, Stupp R, et al. (2006). "Radiotherapy with Concurrent and Adjuvant Temozolomide: A New Standard of Care for Glioblastoma Multiforme". Progress in Neurotherapeutics and Neuropsychopharmacology 1: 37–52. doi:10.1017/S1748232105000054. 
  28. ↑ "Temozolomide Plus Radiation Helps Brain Cancer – National Cancer Institute". http://www.cancer.gov/clinicaltrials/results/glioblastoma0604. Retrieved 2007-09-15. 
  29. ↑ Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE (March 2007). "Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma". J. Neurooncol. 82 (1): 81–3. doi:10.1007/s11060-006-9241-y. PMID 16944309. http://www.springerlink.com/content/9110101173602421/. 
  30. ↑ http://www.springerlink.com/content/c1m089581r66q274/
  31. ↑ FDA Approves Drug for Treatment of Aggressive Brain Cancer [2]
  32. ↑ Ghebah et al. Cancer Stem Cell Immunotherapy: the Right Bullet for the Right Target. Hematol Oncol Stem Cell Ther 2008;1:1-2 "Hematology/Oncology and Stem Cell Therapy"
  33. ↑ Moviglia GA, Carrizo AG, Varela G, et al. Preliminary report on tumor stem cell/B cell hybridoma vaccine for recurrent glioblastoma multiforme. Hematol Oncol Stem Cell Ther 2008;1:3-13. "Hematology/Oncology and Stem Cell Therapy"
  34. ↑ Nieder C, Adama M, Mollsa M and Grosu AL (2006). "Therapeutic options for recurrent high-grade glioma in adult patients: Recent advances". Critical Reviews in Oncology/Hematology 60 (3): 181–193. doi:10.1016/j.critrevonc.2006.06.007. PMID 16875833. 
  35. ↑ Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer T-L, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC Metabolic Modulation of Glioblastoma with Dichloroacetate Sci Transl Med 2010;2;31-34."Metabolic Modulation of Glioblastoma with Dichloroacetate"
  36. ↑ 36.0 36.1 36.2 Krex D, Klink B, Hartmann C, et al. (2007). "Long-term survival with glioblastoma multiforme". Brain 130 (10): 2596–2606. doi:10.1093/brain/awm204. PMID 17785346. 
  37. ↑ Martinez R, Schackert G, Yaya-Tur R, et al. (2007). "Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme". Journal of Neuro-Oncology 83 (1): 91–93. doi:10.1007/s11060-006-9292-0. PMID 17164975. 
  38. ↑ Shawl, EG, Seiferheld, W, Scott, C, et al. (2003). "Re-examining the radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) for glioblastoma multiforme (GBM) patients". International Journal of Radiation Oncology*Biology*Physics 57 (2): S135–6. doi:10.1016/S0360-3016(03)00843-5. 

>

Nervous tissue tumors/NS neoplasm/Neuroectodermal tumor (ICD-O 9350-9589) (C70-C72/D32-D33, 191-192/225)
Endocrine/
sellar (9350-9379)

sellar: Craniopharyngioma · Pituicytoma

other: Pinealoma
CNS
(9380-9539)
Neuroepithelial
(brain tumors,
spinal tumors)
Glioma
Astrocyte
Astrocytoma (Pilocytic astrocytoma, Pleomorphic xanthoastrocytoma, Fibrillary (also diffuse or lowgrade) astrocytomas, Anaplastic astrocytoma, Glioblastoma multiforme)
Oligodendrocyte
Oligodendroglioma
Ependyma
Ependymoma · Subependymoma
Choroid plexus
Choroid plexus tumor (Choroid plexus papilloma, Choroid plexus carcinoma)
Multiple/unknown
Oligoastrocytoma · Gliomatosis cerebri · Gliosarcoma
Mature
neuron
Ganglioneuroma: Ganglioglioma · Retinoblastoma · Neurocytoma · Dysembryoplastic neuroepithelial tumour · Lhermitte-Duclos disease
PNET
Neuroblastoma (Esthesioneuroblastoma, Ganglioneuroblastoma) · Medulloblastoma · Atypical teratoid rhabdoid tumor
Primitive
Medulloepithelioma
Meningiomas
(meninges)
Meningioma
Hematopoietic
Primary central nervous system lymphoma
PNS: NST
(9540-9579)
cranial and paraspinal nerves: Neurofibroma (Neurofibrosarcoma, Neurofibromatosis) · Neurilemmoma/Schwannoma (Acoustic neuroma) · Malignant peripheral nerve sheath tumor
note: not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastases)

: CNS

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: PNS

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