Glioblastoma multiforme

Glioblastoma ( also glioblastoma multiforme) is the most common malignant brain tumor in adults own. Glioblastoma has histological similarities with the cells of the brain and is classified as grade IV due to the very poor prognosis according to the WHO classification of tumors of the central nervous system. Treatment consists of surgical reduction of the tumor mass, radiation and chemotherapy. A definitive cure currently can not be achieved. The mean survival time is on the order of months, some sufferers survive longer, but only a few more years. The glioblastoma cell line U87MG was the first cancer cell line whose genome was completely sequenced.

Historical

The term glioblastoma multiforme was coined in 1926 by Percival Bailey and Harvey Cushing and was based on the idea that developed the tumor originates from primitive precursors of glial cells ( glioblasts ), as well as the observation that the appearance of necrosis, hemorrhage, and cysts highly variable ( multiform may be ). The term Spongioblastoma multiforme in 1914 used by the pathologist Frank Burr Mallory could not prevail.

Dissemination

Glioblastoma is the most common malignant primary brain tumors in adults. Among the neuroepithelial tumors, they account for about half. The tumor occurs most frequently in older adults; the median age at diagnosis is 64 years. Men are much more frequently affected than women (ratio 1.7:1 ). Data from the American Brain Tumor Registry that glioblastomas are at least twice as likely as whites in the black population. Compared to adults, glioblastomas are very rare in children. The incidence was in Europe and North America with 2.9 to 3.5 new cases per year calculated per 100,000 population. As the only secure causal ( etiological ) environmental factor is considered an exposure to ionizing radiation.

In the majority of glioblastomas are sporadic cases with no evidence of heritability. In the Li -Fraumeni syndrome or Turcot syndrome rare inherited disorders, glioblastomas, however, familial incidence.

Pathogenesis

Glioblastomas can completely new ( de novo ) or by progressive de-differentiation of malignant astrocytomas arise less. Hence it is not uncommon that patients treated astrocytomas manifest in the recurrence as glioblastoma. These so-called secondary glioblastomas tend to occur in younger patients and have a different spectrum of genetic changes as a newly emerged (see molecular pathology). In a survey conducted in Switzerland epidemiological study primary glioblastomas in Canton Zurich were about twenty times more common than secondary.

Localization

Glioblastoma proceeds from the white matter. Its by far the most common site is the cerebrum, where it can occur in all lobes of the brain, but the frontal and temporal lobes of the preferred. In the area of the cerebellum, brain stem and spinal cord glioblastomas are rare. Often hemisphärielle glioblastomas over the bar to the other side over. Such tumors are known as so-called " Schmetterlingsgliome ". The growth of glioblastomas is diffuse infiltrative.

Clinical manifestations

Because of rapid growth, the symptoms usually develop rapidly within a few weeks to months. Initial symptoms may be persistent and unusual headache, but also emerging epileptic seizures. Focal neurological deficits such as paralysis, aphasia, and visual disturbances may be added depending on localization. Finally it is often striking personality changes, apathy, or psychomotor retardation, which lead the patient to the doctor. Intracranial pressure such as papilledema, vomiting, somnolence and coma occur late and are prognostically unfavorable.

Methods of investigation

The diagnosis is first through imaging techniques such as computed tomography (CT) or magnetic resonance imaging ( MRI) supported. In the CT imaging with contrast, glioblastoma ( ring enhancement ) appear irregularly shaped with marginal strong contrast enhancement. For smaller tumors this is annular configured with larger, it forms a garland- like formation from. In the vicinity of the tumor typically forms a significant edema. The MRI findings is quite typical: the solid parts of glioblastoma accumulate contrast sharply contrast the recesses lift by cystic and bleeding from. Ultimately, the diagnosis of the tumor tissue, which was obtained in a stereotactic brain biopsy or tumor resection, neuropathologically confirmed. In individual cases Supplementäruntersuchungen as electroencephalography and lumbar puncture should be performed, the purpose of assessing the fit inclination or the differential diagnosis against brain abscess or lymphoma.

Pathology

Glioblastoma is by its inhomogeneous and diverse (hence multiforme) in appearance: the tumor cut surface often has reddish yellow hemorrhaging and Gewebsuntergänge (necrosis ) on.

Histology

Histologically ( histologically ) is cell-density astrozytär differentiated tumors that diffusely infiltrate the surrounding reactive changes in brain tissue. The tumor cells are differentiated fibrillary - astrozytär with multipolar fine appendages or have a fattened -cell differentiation with a bloated cytoplasm. Even giant cells with bizarre nuclei or small-cell areas with little extended cell bodies occur. The nuclei are usually chromatin and diverse ( polymorphic ). Mitotic and proliferative activity are increased.

Crucial for the diagnosis of glioblastoma (and the distinction from anaplastic astrocytoma ) but according to the WHO classification of tumors of the central nervous system, the detection of tumor necrosis ( surface or typically the form of lines with perifocal cell density increase ) or highly pathological blood vessels.

Variants

In Gliosarkomen is glioblastomas, which in addition to the astrocytic tumor areas described above also in connective tissue sections with sarcomatous spindle cell tumor cells. As giant cell glioblastomas glioblastomas are denoted by a pronounced riesenzelligen component. Also delineate are glioblastomas with oligodendroglial component that may have a slightly better prognosis.

Immunohistochemistry

Immunohistochemistry in the tumor cells - as in those of other glial brain tumors - glial fibrillary acidic protein ( glial fibrillary acidic protein, GFAP) demonstrated, which allows in most cases to be distinguished from brain metastases.

Molecular Pathology

The gene losses (deletions ) that make up the glioblastoma to see that in most cases, the tumor suppressor gene TP53 (chromosome 17), the retinoblastoma suppressor gene RB-1 (chromosome 13) and deletions of chromosome 22 as well as the complete loss of the long arm of chromosome 10 These genetic lesions are frequently combined. In the newly created primary glioblastomas that occur predominantly in the elderly, are more frequent loss of PTEN gene or amplification of the EGFR gene. In the predominantly occurring in middle-aged secondary glioblastoma, which, through a gradual evolution ( progression) from less malignant are ( malignant ) astrocytomas incurred, often are mutations of the TP53 gene. In addition, point mutations are more common in coding for isocitrate dehydrogenase IDH1 and IDH2 genes in this group, particularly - R132H Muation in IDH1 gene. The rare childhood glioblastomas differ in the pattern of genetic changes in the tumors occurring in adults: play here especially mutations of the gene H3F3A a role. Based on genetic and epigenetic changes in the classification of glioblastomas into six subgroups was proposed in 2012.

Treatment

A short-term clinical improvement can be achieved by treating the virtually ever-present perifocal brain edema with dexamethasone. The neurosurgical operation with reduction ( tumor reduction ) of the main mass of the tumor may slow the progression of the disease but do not prevent permanent as virtually always single tumor cells have the healthy brain tissue has been walking infiltrative and therefore a complete tumor removal is not possible. A new innovative method for the treatment of malignant brain tumors ( gliomas ) is the fluorescence- guided surgery with 5- aminolevulinic acid ( 5 -ALA). Here, an endogenous substance (5- ALA), the patient receives about four hours before the operation as a drinking solution in the brain tumor accumulates strongly and is converted into a fluorescent dye. During the operation, then this dye by blue-violet light (wavelength 410-440 nm) to light ( fluorescence) are excited, so that the tumor ( pink ) leaves (dark blue ) limitations particularly clear from healthy brain tissue. By this method, a complete removal of the tumors is much safer and more effective possible. This leads to an extension of time to regrowth of these tumors ( recurrence-free interval ), making the prognosis of this disease is significantly improved. The procedure was developed in Dusseldorf and Munich in 2004 and is applied in more and more German hospitals. To prolong the recurrence-free and absolute survival practically agrees with the operation always irradiation and often a chemotherapy, in particular, patients with evidence of epigenetic changes ( hypermethylation ) of the promoter of DNA repair enzyme O6 -methylguanine - DNA methyltransferase ( MGMT ) of chemotherapy with temozolomide benefit. Other chemotherapeutic agents that are used in the case of recurrence, are nitrosoureas, Vinkaalkaloide and cytosine arabinoside, with different treatment regimens in use. Which patients may benefit from local chemotherapy with carmustine implant bound to polymers, is still unclear.

Clinical trials

The development of new forms of treatment for glioblastoma is the subject of intensive research. In February 2013 257 Clinical studies in Clinicaltrials.gov, a register of the United States National Library of Medicine were registered as active or in preparation. In combination with the drug temozolomide Cilengitide is currently being tested in a clinical phase III trial. The results indicate improved efficacy of radiation and chemotherapy in little additional strain on the system. The success of treatment is dependent on the Methylisierungszustand of the MGMT gene promoter. Tyrosine kinase receptors such as the receptors for epidermal growth factor ( EGFR) and platelet derived growth factor (PDGF), represent potential targets for new therapeutic approaches dar.

Treatment with bevacizumab, a the Vascular endothelial growth factor ( VEGF) neutralizing antibody was able to reduce the extent of the tumor with the topoisomerase inhibitor irinotecan in clinical trials in combination with individual groups of patients may respond very favorably to this treatment.

Therapy with APG101, a fully human CD95 -Fc fusion protein that prevents the binding of CD95 ligand to the CD95 receptor, represents a novel treatment approach; they do is based on findings from the German Cancer Research Center, which in glioblastoma cells, the binding the CD95 ligand, the invasive growth and migration of tumor cells stimulates the CD95 receptor. Therefore, a blockage of this bond by APG101 leads to a reduction of the invasive growth and migration of these cells. A randomized, double-blind, placebo -controlled phase I study with 34 healthy volunteers to evaluate the safety and tolerability of APG101 showed good tolerability of the substance. The effectiveness of APG101 was investigated in a randomized, controlled phase II clinical trial with patients suffering from GBM and in which a relapse of the disease occurred. Patient recruitment for the study began in late 2009, and the first results were announced in 2012. A total of 83 patients were treated in the clinical trial. The primary endpoint of the study, a doubling of the number of patients with progression-free survival at six months was significantly exceeded. During treatment with APG101, which lasted up to two years, no serious side effects were observed, which are in connection with the drug.

Also, methods of gene therapy are being tested in clinical trials. Is also in clinical trials Enzastaurinum, a drug based on a Bisindolylmaleimides.

An exemplary experimental approach is treatment with nanoparticles. These consist of an iron oxide core and a shell, which is to facilitate the penetration of the iron oxide particles in the cancer cells. The particles are injected directly into the tumor. Multiple passes of the iron oxide particles with so forming a ferrofluid enriched tumor is heated by the alternating magnetic fields of about 46 ° C. In animal models, significantly improved survival times were. Study results in humans have been available since September 2010, since mid- 2011, the therapy is available.

In another research approach working with parvovirus. This treatment option has recently become available as part of a Phase-I/IIa-Studie.

Forecast

Glioblastoma is extremely difficult to treat. A definitive cure is not yet possible. The treatment with surgery, followed by radiation and chemotherapy, the median survival time is extended by a few months and alleviate the symptoms according to the current study area. A study of 2003 divided the forecast using the Recursive Partitioning Analysis ( RPA) in three groups depending on the patient's age, the type of treatment and the Karnofsky score (KPS ).

Because of the diffuse infiltration of the brain tissue by tumor cells occurs after treatment, often within months to a relapse. Individual patients may live with a glioblastoma, notwithstanding several years in relatively good health. Identifying clinical and molecular factors that are characteristic of such long-term survivors is the subject of intensive research.

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