Glioblastoma multiforme

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Glioblastoma multiforme
Classification and external resources
ICD-10 C71.
ICD-9 191
ICD-O: M9440/3
OMIM 137800
DiseasesDB 29448
eMedicine neuro/147  med/2692
MeSH D005909
Image 1a. Coronal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old boy
Image 1b. Sagittal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old boy
Glioblastoma (histology slide)

Glioblastoma multiforme (GBM) is the most common and most aggressive type of primary brain tumor in humans, 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. The standard WHO-2007 name for this brain tumor is “Glioblastoma”[1]. 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.[2]

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.


[edit] Symptoms

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 asymptomatic until it reaches an enormous size.

[edit] Diagnosis

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.[3] Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy or a craniotomy with tumor resection. 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.

[edit] Causes

GBM is more common in males, although the reason for this is not clear.[4] Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking,[5] diet,[6] cellular phones,[7] or electromagnetic fields.[8] Recently, evidence for a viral cause has been discovered, possibly SV40[9] or cytomegalovirus.[10] There also appears to be a small link between ionizing radiation and glioblastoma.[11]

Other risk factors include:[12]

[edit] 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. 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 oligodendrogliomas, 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 lymphocytes. 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 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.

[edit] Treatment

It is very difficult to treat glioblastoma due to several complicating factors:[13]

  • 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.

[edit] Symptomatic therapy

Supportive treatment focuses on relieving symptoms and improving the patient’s neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.

  • Historically, around 90% of patients with glioblastoma underwent anticonvulsant treatment, although it 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[14]. 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.

[edit] 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.

[edit] 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 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.[15] 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.[16]

[edit] Radiotherapy

On average, radiotherapy after surgery can reduce the tumor size to 107 cells. Whole brain radiotherapy does not improve survival when compared to the more precise and targeted three-dimensional conformal radiotherapy.[17] A total radiation dose of 60-65 Gy has been found to be optimal for treatment.[18]

Boron neutron capture therapy has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.

[edit] 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.[19] This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial.[20][21] Temozolomide seems to work by sensitizing the tumor cells to radiation. [22]

[edit] Recurrences

Long-term disease-free survival is unlikely but possible, 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.[23].

[edit] 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 survives for decades[24].

Survival of more than three years has been associated with younger age at diagnosis, a good initial Karnofsky Performance Score (KPS), and MGMT methylation [24]. 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[25]. 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[24]. However, much remains unknown about why some patients survive longer with glioblastoma.

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:[26]

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

[edit] References

  1. ^ 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. PMID 17618441
    (See also WHO Classification > 2007 WHO Classification.)
    In WHO Classification are the previous WHO classifications.
    On is the 2007 WHO Classification (with explicative notes) at it:Classificazione dei tumori del sistema nervoso centrale (Classification of the Tumors of the Central Nervous System).
    The companion article is it:Gradazione dei tumori del sistema nervoso centrale (Grading of the Tumors of the Central Nervous System).
  2. ^ Lipsitz D, Higgins RJ, Kortz GD, Dickinson PJ, Bollen AW, Naydan DK et al (2003). Glioblastoma multiforme: clinical findings, magnetic resonance imaging, and pathology in five dogs. Vet Pathol 40: 659-69.
  3. ^ Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW.Patterns of contrast enhancement in the brain and meninges.Radiographics. 2007 Mar-Apr;27(2):525-51. Review.PMID: 17374867. 
  4. ^ 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: 479–89. PMID 15977639. 
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  8. ^ Savitz DA, Checkoway H, Loomis DP (1998). "Magnetic field exposure and neurodegenerative disease mortality among electric utility workers". Epidemiology 9: 398–404. doi:10.1097/00001648-199807000-00009. PMID 9647903. 
  9. ^ Vilchez RA, Kozinetz CA, Arrington AS, et al (2003). "Simian virus 40 in human cancers". Am J Med 114: 675–84. doi:10.1016/S0002-9343(03)00087-1. PMID 12798456. 
  10. ^ "Target acquired", The Economist, May 29th, 2008
  11. ^ Cavenee L (2000). "High-grade gliomas with chromosome 1p loss". J Neurosurg 92: 1080–1. PMID 10839286. 
  12. ^ Glioblastoma multiforme at Mount Sinai
  13. ^ 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. 
  14. ^ Stevens GHJ (2006). "Antiepileptic therapy in patients with central nervous system malignancies". Current Neurology and Neuroscience Reports 6: 311–318. doi:10.1007/s11910-006-0024-9. PMID 16822352. 
  15. ^ Lacroix M, Abi-Said D, Fourney DR, et al (2001). "A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival". J Neurosurg 95 (2): 190–8. PMID 11780887. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ 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. 
  21. ^ "Temozolomide Plus Radiation Helps Brain Cancer - National Cancer Institute". Retrieved on 2007-09-15. 
  22. ^
  23. ^ 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. 
  24. ^ a b c 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. 
  25. ^ 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. 
  26. ^ 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–S136. doi:10.1016/S0360-3016(03)00843-5. PMID 15758009. 

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