Glioblastoma multiforme

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**Glioblastoma multiforme**
*Classification & external resources*
ICD-10	C 71.
ICD-9	191
ICD-O:	9440/3
OMIM	137800
DiseasesDB	29448
eMedicine	neuro/147

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), also known as grade 4 astrocytoma, is the most common and aggressive type of primary brain tumor, accounting for 52 percent of all primary brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBM's occur at only 2-3 cases per 100,000 people in Europe and North America.

Treatment can involve chemotherapy, radiotherapy and surgery; all of which are acknowledged as palliative measures, meaning that they do not provide a cure. The five year survival rate of the disease has remained unchanged over the past 30 years, and stands at less than three percent. Even with complete surgical resection of the tumor, combined with the best available treatment, the survival rate for GBM remains very low.

1 Causes
2 Pathogenesis
3 Symptoms
4 Diagnosis
5 Treatment
- 5.1 Symptomatic therapy
- 5.2 Palliative therapy
  - 5.2.1 Recurrences
6 Prognosis
7 References
8 Additional reading
9 External links

[edit] Causes

Almost all cases of GBM are sporadic, without a familial predilection, although chromosomal aberrations such as PTEN mutation, MDM2 mutation, and p53 mutation are commonly seen in these tumors. Growth factor aberrant signaling associated with EGFR, and PDGF are also seen.

[edit] Pathogenesis

Glioblastoma multiformes are characterized by the presence of small areas of necrotizing tissue that is surrounded by highly anaplastic cells. This characteristic differentiates the tumor from Grade 3 astrocytomas, which do not have necrotic tissue regions. Although glioblastoma multiforme can be formed from lower grade astrocytomas, post-mortem autopsies have revealed that most glioblastoma multiformes are not caused by previous lesions in the brain.

Unlike oligodendrogliomas, glioblastoma multiformes can form in either the gray matter or 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 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 express a variety of appearance, depending on the amount of hemorrhage or necrosis, or on its age. CT usually shows 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.

[edit] Symptoms

Although common symptoms of the disease can 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. See section of Symptoms in:

Main article: brain tumor

[edit] Diagnosis

Diagnosis of a suspected GBM on CT or MRI should rest on a stereotactic biopsy or by a craniotomy, which can, at the same time, remove as much tumor as possible. Although the entire tumor can never be removed theoretically due to its multicentricity and diffuse character, partial resection ("debulking") can still prolong survival slightly.

[edit] Treatment

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.

Anticonvulsants are administered to the ~25% of patients who have a seizure. Prospective studies have failed to show the efficacy for prophylactic anticonvulsants. 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 done to achieve a longer survival time, albeit only a slight increase [see below]. 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. Total cranial irradiation (4500 cGy) with a boosted dose (1500 to 2000 cGy) at the site of the tumor, can increase survival by 5 months [see below]. The addition of the chemotherapeutic agent carmustine alone increases survival slightly. Most oncologists prefer a combination chemotherapy consisting of procarbazine, lomustine, and vincristine (PCV regimen). Another combination includes carboplatin and cisplatin. Their efficacy is limited, and toxicity, particularly with the PCV regimen, can be considerable. Despite initial studies suggesting the superiority of PCV over BiCNU, there are now clear data demonstrating no benefit of PCV over BiCNU in either glioblastoma or anaplastic astrocytoma patients. Brachytherapy (implantation of radioactive beads or needles) and high-dose focus radiotherapy (stereotactic radiosurgery) have not shown to increase survival times.

In a large phase III trial, implantation of BiCNU-impregnated wafers - trade name Gliadel Wafers- at the time of primary resection, improved median survival to 13.9 months, compared with only 11.6 months for placebo wafers (P = .03), in newly diagnosed patients with malignant glioma. Despite initial treatment, virtually all malignant gliomas recur. At relapse, patients may benefit from re-resection, focal radiotherapy techniques (such as radiosurgery), and different chemotherapeutic agents. Depending upon which chemotherapeutic agent was used at initial treatment, temozolomide, procarbazine, or a nitrosourea would be a reasonable conventional choice at recurrence. Clinical trials employing signal transduction inhibitors, epidermal growth factor receptor inhibitors, or antiangiogenic agents may also be available at tumor relapse.

In a recent article, the antimalarial drug chloroquine has been shown to increase mid-term survival when given in combination with conventional therapy (in this case, surgical ablation and carmustine therapy). Further research in this area needs to be done.

Another possible therapy technique is to use viruses to attack the cancer.

A recent paper titled "Photodynamic therapy of high grade glioma - long term survival" by Stylli et al reported on the treatment of Glioblastoma Multiforme with Photodynamic Therapy at Melbourne Royal Infirmary, Australia since 1986. Five year survival rates were over 30% with some patients surviving over 10 years.

[edit] Recurrences

Tumor recurrence after surgery or radiation is almost inevitable, usually within 2 cm of the original site, and 10% may develop new lesions at distant sites. Reoperation or brachytherapy has been attempted, with uncertain results. The most aggressive therapy, a second surgery and chemotherapy, is generally used in those under 40 years of age whose original operation was many months earlier. If the PCV regimen has not been used, it may be tried; else, the newer agent temozolomide may be used. However, these regimen only increases the symptom-free interval, but does not prolong survival.

[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.

With standard treatment (radiotherapy, chemotherapy (such as temozolomide), and surgery), the median survival is approximately 14 months.^[1] Less than 10% of these patients survive past 5 years.

It is not well known that there are long term survivors of this disease . Notable among them is Dr. Ben Williams who has been cancer free for over ten years and has treated the disease via a cocktail of drugs.

[edit] References

^ Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M, Belanger K, Brandes A, Marosi C, Bogdahn U, Curschmann J, Janzer R, Ludwin S, Gorlia T, Allgeier A, Lacombe D, Cairncross J, Eisenhauer E, Mirimanoff R (2005). "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.". N Engl J Med 352 (10): 987-96. PMID 15758009.