Glioblastoma

Source: Wikipedia, the free encyclopedia.

Glioblastoma
Other namesGlioblastoma multiforme
steroids[1][4]
PrognosisLife expectancy ~12 months with treatment (5 year survival <10%)[2][5]
Frequency3 per 100,000 per year[3]

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival.[6][7][8] Initial signs and symptoms of glioblastoma are nonspecific.[1] They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke.[1] Symptoms often worsen rapidly and may progress to unconsciousness.[2]

The cause of most cases of glioblastoma is not known.

tissue biopsy.[1]

There is no known method of preventing the cancer.[3] Treatment usually involves surgery, after which chemotherapy and radiation therapy are used.[3] The medication temozolomide is frequently used as part of chemotherapy.[3][4][10] High-dose steroids may be used to help reduce swelling and decrease symptoms.[1] Surgical removal (decompression) of the tumor is linked to increased survival, but only by some months.[11]

Despite maximum treatment, the cancer almost always recurs.[3] The typical duration of survival following diagnosis is 10–13 months, with fewer than 5–10% of people surviving longer than five years.[12][13][5] Without treatment, survival is typically three months.[14] It is the most common cancer that begins within the brain and the second-most common brain tumor, after meningioma, which is benign in most cases.[6][15] About 3 in 100,000 people develop the disease per year.[3] The average age at diagnosis is 64, and the disease occurs more commonly in males than females.[2][3]

Tumors of the central nervous system are the 10th leading cause of death worldwide, with up to 90% being brain tumors.[16] Glioblastoma multiforme (GBM) is derived from astrocytes and accounts for 49% of all malignant central nervous system tumors, making it the most common form of central nervous system cancer. Despite countless efforts to develop new therapies for GBM over the years, the median survival rate of GBM patients worldwide is 8 months; radiation and chemotherapy standard-of-care treatment beginning shortly after diagnosis improve the median survival length to around 14 months and a five-year survival rate of 5–10%. The five-year survival rate for individuals with any form of primary malignant brain tumor is 20%.[17] Even when all detectable traces of the tumor are removed through surgery, most patients with GBM experience recurrence of their cancer.

Signs and symptoms

Common symptoms include

asymptomatic condition until it reaches an enormous size.[19]

Risk factors

The cause of most cases is unclear.[2] The best known risk factor is exposure to ionizing radiation, and CT scan radiation is an important cause.[20][21] About 5% develop from certain hereditary syndromes.[18]

Genetics

Uncommon risk factors include genetic disorders such as neurofibromatosis, Li–Fraumeni syndrome, tuberous sclerosis, or Turcot syndrome.[18] Previous radiation therapy is also a risk.[2][3] For unknown reasons, it occurs more commonly in males.[22]

Environmental

Other associations include exposure to smoking, pesticides, and working in petroleum refining or rubber manufacturing.[18]

Glioblastoma has been associated with the viruses SV40,[23] HHV-6,[24][25] and cytomegalovirus (CMV).[26] Infection with an oncogenic CMV may even be necessary for the development of glioblastoma.[27][28]

Other

Research has been done to see if consumption of cured meat is a risk factor. No risk had been confirmed as of 2003.[29] Similarly, exposure to formaldehyde, and residential electromagnetic fields, such as from cell phones and electrical wiring within homes, have been studied as risk factors. As of 2015, they had not been shown to cause GBM.[18][30][31]

Pathogenesis

The cellular origin of glioblastoma is unknown. Because of the similarities in

glial cells and glioblastoma, gliomas such as glioblastoma have long been assumed to originate from glial-type stem cells found in the subventricular zone. More recent studies suggest that astrocytes, oligodendrocyte progenitor cells, and neural stem cells could all serve as the cell of origin.[32][33]

GBMs usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Since the function of glial cells in the brain is to support neurons, they have the ability to divide, to enlarge, and to extend cellular projections along neurons and blood vessels. Once cancerous, these cells are predisposed to spread along existing paths in the brain, typically along white-matter tracts, blood vessels and the

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 GBMs 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 infiltration across the corpus callosum, producing a butterfly (bilateral) glioma.[35]

Glioblastoma classification

Brain tumor classification has been traditionally based on histopathology at macroscopic level, measured in hematoxylin-eosin sections. The World Health Organization published the first standard classification in 1979[36] and has been doing so since. The 2007 WHO Classification of Tumors of the Central Nervous System[37] was the last classification mainly based on microscopy features. The new 2016 WHO Classification of Tumors of the Central Nervous System[38] was a paradigm shift: some of the tumors were defined also by their genetic composition as well as their cell morphology.

In 2021, the fifth edition of the WHO Classification of Tumors of the Central Nervous System was released. This update eliminated the classification of secondary glioblastoma and reclassified those tumors as Astrocytoma, IDH mutant, grade 4. Only tumors that are IDH wild type are now classified as glioblastoma.[39]

Features of glioblastoma, IDH wildtype, WHO 4[40]
Synonyms Glioblastoma, GBM
Cell of origin Astrocyte
Median age at diagnosis ~62 years
Male:Female ratio 1.42:1
Median length of clinical history at diagnosis 4 months
Median overall survival
Surgery + radiotherapy 9.9 months
Surgery + radiotherapy + chemotherapy 15 months
Location Usually supratentorial, rarely cerebellum or spine
Necrosis and microvascular proliferation Extensive
Associated molecular/genetic mutations TERT promoter mutation, combined gain of chromosome 7 and loss of chromosome 10; EGFR amplification

Molecular alterations

There are currently three molecular subtypes of glioblastoma that were identified based on gene expression:[41]

Initial analyses of gene expression had revealed a fourth neural subtype.[44] However, further analyses revealed that this subtype is non-tumor specific and is potential contamination caused by the normal cells.[41]

Many other genetic alterations have been described in glioblastoma, and the majority of them are clustered in two pathways, the RB and the PI3K/AKT.[46] 68–78% and 88% of Glioblastomas have alterations in these pathways, respectively.[6]

Another important alteration is methylation of

MGMT gene promoter greatly affects DNA-repair capacity.[47][48] MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.[49]

Studies using genome-wide profiling have revealed glioblastomas to have a remarkable genetic variety.[50]

At least three distinct paths in the development of Glioblastomas have been identified with the aid of molecular investigations.

Cancer stem cells

Glioblastoma cells with properties similar to progenitor cells (glioblastoma

cancer stem cells) have been found in glioblastomas. Their presence, coupled with the glioblastoma's diffuse nature results in difficulty in removing them completely by surgery, and is therefore believed to be the possible cause behind resistance to conventional treatments, and the high recurrence rate.[52] Glioblastoma cancer stem cells share some resemblance with neural progenitor cells, both expressing the surface receptor CD133.[53] CD44 can also be used as a cancer stem cell marker in a subset of glioblastoma tumour cells.[54] Glioblastoma cancer stem cells appear to exhibit enhanced resistance to radiotherapy and chemotherapy mediated, at least in part, by up-regulation of the DNA damage response.[55]

Metabolism

The IDH1 gene encodes for the enzyme isocitrate dehydrogenase 1 and is not mutated in glioblastoma. As such, these tumors behave more aggressively compared to IDH1-mutated astrocytomas.[48]

Ion channels

Furthermore, GBM exhibits numerous alterations in genes that encode for

ClC-3 chloride channels. By upregulating these ion channels, glioblastoma tumor cells are hypothesized to facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids glioblastoma cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain.[56]

MicroRNA

As of 2012,

LKB1/AMPK signaling in cultured glioma cells[58] and that miRNA clustering controls epigenetic pathways in the disease.[59]

Tumor vasculature

GBM is characterized by abnormal vessels that present disrupted morphology and functionality.[60] The high permeability and poor perfusion of the vasculature result in a disorganized blood flow within the tumor and can lead to increased hypoxia, which in turn facilitates cancer progression by promoting processes such as immunosuppression.[60][61]

Diagnosis

GBM in the frontal right lobe as seen on CT scan
MRI
with contrast of a glioblastoma WHO grade 4 in a 15-year-old boy
Diagnostic algorithm of diffuse glioma.[62]

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.[63] 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 diagnostic value to standard MRI in select cases by showing increased relative cerebral blood volume and increased choline peak, respectively, but pathology remains the gold standard for diagnosis and molecular characterization.[citation needed]

Distinguishing glioblastoma from high-grade astrocytoma is important. These tumors occur spontaneously (de novo) and have not progressed from a lower-grade glioma, as in high-grade astrocytomas.

IDH1 R132H suffices for the classification as IDH-wild-type glioblastoma.[62] In all other instances of diffuse gliomas, a lack of IDH1 R132H immunopositivity should be followed by IDH1 and IDH2 DNA sequencing to detect or exclude the presence of non-canonical mutations.[62] IDH-wild-type diffuse astrocytic gliomas without microvascular proliferation or necrosis should be tested for EGFR amplification, TERT promoter mutation and a +7/–10 cytogenetic signature as molecular characteristics of IDH-wild-type glioblastomas.[62]

  • Histopathology of glioblastoma, showing high grade astrocytoma features of marked nuclear pleomorphism, multiple mitoses (one at white arrow) and multinucleated cells (one at black arrow), with cells having a patternless arrangement in a pink fibrillary background on H&E stain.
    Histopathology of glioblastoma, showing high grade astrocytoma features of marked nuclear pleomorphism, multiple mitoses (one at white arrow) and multinucleated cells (one at black arrow), with cells having a patternless arrangement in a pink fibrillary background on H&E stain.
  • Lower magnification histopathology, showing necrosis surrounded by pseudopalisades of tumor cells, conferring a diagnosis of glioblastoma rather than anaplastic astrocytoma
    Lower magnification histopathology, showing necrosis surrounded by
    pseudopalisades of tumor cells, conferring a diagnosis of glioblastoma rather than anaplastic astrocytoma

Prevention

There are no known methods to prevent glioblastoma.[3] It is the case for most gliomas, unlike for some other forms of cancer, that they happen without previous warning and there are no known ways to prevent them.[66]

Treatment

Management of IDH wild type glioblastoma, WHO grade 4. KPS, Karnofsky performance status.[62]

Treating glioblastoma is difficult due to several complicating factors:[67]

  • The tumor cells are resistant to conventional therapies.
  • The brain is susceptible to damage from conventional therapy.
  • The brain has a limited capacity to repair itself.
  • Many drugs cannot cross the blood–brain barrier to act on the tumor.

Treatment of primary brain tumors consists of palliative (symptomatic) care and therapies intended to improve survival.

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 only an estimated 40% of patients required this treatment. Neurosurgeons have recommended that anticonvulsants not be administered prophylactically, and should wait until a seizure occurs before prescribing this medication.[68] Those receiving phenytoin concurrent with radiation may have serious skin reactions such as erythema multiforme and Stevens–Johnson syndrome.
  • Corticosteroids, usually dexamethasone, 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.

Surgery

Glioblastoma pre (left) and post (right) resection.

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 (a reduction of 99%). Benefits of surgery include resection for a pathological diagnosis, alleviation of symptoms related to mass effect, and potentially removing disease before secondary resistance to radiotherapy and chemotherapy occurs.[69]

The greater the extent of tumor removal, the better. In retrospective analyses, 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.

5-aminolevulinic acid.[71][72] GBM cells are widely infiltrative through the brain at diagnosis, and despite a "total resection" of all obvious tumor, most people with GBM later develop recurrent tumors either near the original site or at more distant locations within the brain. Other modalities, typically radiation and chemotherapy, are used after surgery in an effort to suppress and slow recurrent disease through damaging the DNA of rapidly proliferative GBM cells.[73]

Between 60–85% of glioblastoma patients report cancer-related cognitive impairments following surgery, which refers to problems with executive functioning, verbal fluency, attention, and speed of processing.[74][75][76] These symptoms may be managed with cognitive behavioral therapy,[77][75] physical exercise, yoga and meditation.[77][75][78]

Radiotherapy

Radiation treatment planning for glioblastoma. GTV: gross tumor volume, CTV: clinical target volume, PTV: planning target volume.

Subsequent to surgery, radiotherapy becomes the mainstay of treatment for people with glioblastoma. It is typically performed along with giving temozolomide.[10] A pivotal clinical trial carried out in the early 1970s showed that among 303 GBM patients randomized to radiation or best medical therapy, those who received radiation had a median survival more than double those who did not.[79] Subsequent clinical research has attempted to build on the backbone of surgery followed by radiation. Whole-brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy.[80] A total radiation dose of 60–65 Gy has been found to be optimal for treatment.[81]

GBM tumors are well known to contain zones of tissue exhibiting

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

Chemotherapy

Most studies show no benefit from the addition of chemotherapy. However, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived a median of 14.6 months as opposed to 12.1 months for the group receiving radiation alone.

Antiangiogenic therapy with medications such as bevacizumab control symptoms, but do not appear to affect overall survival in those with glioblastoma. A 2018 systematic review found that the overall benefit of anti-angiogenic therapies was unclear.[89] In elderly people with newly diagnosed glioblastoma who are reasonably fit, concurrent and adjuvant chemoradiotherapy gives the best overall survival but is associated with a greater risk of haematological adverse events than radiotherapy alone.[90]

Immunotherapy

Phase 3 clinical trials of immunotherapy treatments for glioblastoma have largely failed.[91]

Other procedures

Alternating electric field therapy is an FDA-approved therapy for newly diagnosed[92] and recurrent glioblastoma.[93] In 2015, initial results from a phase-III randomized clinical trial of alternating electric field therapy plus temozolomide in newly diagnosed glioblastoma reported a three-month improvement in progression-free survival, and a five-month improvement in overall survival compared to temozolomide therapy alone,[94][95] representing the first large trial in a decade to show a survival improvement in this setting.[95] Despite these results, the efficacy of this approach remains controversial among medical experts.[96] However, increasing understanding of the mechanistic basis through which alternating electric field therapy exerts anti-cancer effects and results from ongoing phase-III clinical trials in extracranial cancers may help facilitate increased clinical acceptance to treat glioblastoma in the future.[97]

Often for those who hear about the diagnosis Glioblastoma they go to a dark place right away as the disease is unfortunately terminal. It is overlooked how despite the terminal outcome there are still treatments to help improve activities of daily living. Despite this, it has been shown that with exercise and physical rehabilitation, this can greatly improve the quality of life for an individual with glioblastoma.[98]

Prognosis

The most common length of survival following diagnosis is 10 to 13 months (although recent research points to a median survival rate of 15 months),[99][100][8] with fewer than 1–3% of people surviving longer than five years.[2][5][101] In the United States between 2012 and 2016 five-year survival was 6.8%.[5] Without treatment, survival is typically three months.[14] Complete cures are extremely rare, but have been reported.[102][103]

Increasing age (> 60 years) carries a worse prognostic risk. Death is usually due to widespread tumor infiltration with cerebral edema and increased intracranial pressure.[104]

A good initial

methylated. Patients with a methylated MGMT promoter have longer survival than those with an unmethylated MGMT promoter, due in part to increased sensitivity to temozolomide.[105]

Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy.[104] However, much remains unknown about why some patients survive longer with glioblastoma. Age under 50 is linked to longer survival in GBM, as is 98%+ resection and use of temozolomide chemotherapy and better KPSs. A recent study confirms that younger age is associated with a much better prognosis, with a small fraction of patients under 40 years of age achieving a population-based cure. Cure is thought to occur when a person's risk of death returns to that of the normal population, and in GBM, this is thought to occur after 10 years.[103]

UCLA Neuro-oncology publishes real-time survival data for patients with this diagnosis.[106]

According to a 2003 study, GBM prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.[107]

Recursive partitioning analysis
(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, no surgical removal 7.5 months 28% 1% 0%
Age ≥ 50, KPS < 70

Epidemiology

About three per 100,000 people develop the disease a year,[3] although regional frequency may be much higher.[108] The frequency in England doubled between 1995 and 2015.[109]

It is the second-most common central nervous system tumor after meningioma.[15] It occurs more commonly in males than females.[2][3] Although the median age at diagnosis is 64,[2][3] in 2014, the broad category of brain cancers was second only to leukemia in people in the United States under 20 years of age.[110]

History

The term glioblastoma multiforme was introduced in 1926 by

glial cells (glioblasts), and the highly variable appearance due to the presence of necrosis, hemorrhage, and cysts (multiform).[111]

Research

Gene therapy

Gene therapy has been explored as a method to treat glioblastoma, and while animal models and early-phase clinical trials have been successful, as of 2017, all gene-therapy drugs that had been tested in phase-III clinical trials for glioblastoma had failed.[112][113][114] Scientists have developed the core–shell nanostructured LPLNP-PPT (long persistent luminescence nanoparticles. PPT refers to polyetherimide, PEG and trans-activator of transcription, and TRAIL is the human tumor necrosis factor-related apoptosis-induced ligand[115]) for effective gene delivery and tracking, with positive results. This is a TRAIL ligand that has been encoded to induce apoptosis of cancer cells, more specifically glioblastomas. Although this study was still in clinical trials in 2017, it has shown diagnostic and therapeutic functionalities, and will open great interest for clinical applications in stem-cell-based therapy.[116]

Other gene therapy approaches have also been explored in the context of glioblastoma, including suicide gene therapy. Suicide gene therapy is a two-step approach that includes the delivery of a foreign enzyme-gene to the cancer cells followed by activation with a pro-drug causing toxicities in the cancer-cells, which induces cell death. This approach has succeeded in animal models and small clinical studies but has not shown survival benefit in larger clinical studies. Using new, more efficient delivery vectors and suicide gene-prodrug systems could improve the clinical benefit from these types of therapies.[117]

Oncolytic virotherapy

Oncolytic virotherapy is an emerging novel treatment that is under investigation both at preclinical and clinical stages. Several viruses including herpes simplex virus, adenovirus, poliovirus, and reovirus are currently being tested in phases I and II of clinical trials for glioblastoma therapy and have shown to improve overall survival.[118]

Intranasal drug delivery

Direct nose-to-brain drug delivery is being explored as a means to achieve higher, and hopefully more effective, drug concentrations in the brain.[119][120] A clinical phase-I/II study with glioblastoma patients in Brazil investigated the natural compound perillyl alcohol for intranasal delivery as an aerosol. The results were encouraging[119][121][122] and, as of 2016, a similar trial has been initiated in the United States.[123]

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