User Tools

Site Tools


glioblastoma_multiforme

Glioblastoma multiforme (GBM)

J.Sales-Llopis

Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain

Glioblastoma Multiforme (GBM) is a tumor of neuroepithelial cell tissue.

Considered a high grade glioma type WHO grade IV astrocytoma.

High-grade gliomas (HGG), such as glioblastoma, may arise from low grade gliomas (LGG) that have a more indolent course.

They are comprised of a heterogeneous population of tumor cells, immune cells, and extracellular matrix.

Interactions among these different cell types and pro-/anti-inflammatory cytokines may promote tumor development and progression.

History

During the early 19th century, glioblastoma was considered of mesenchymal origin and was defined as a sarcoma. In 1863, Rudolf Virchow demonstrated its glial origin 1) , and in 1914 Mallory proposed the term glioblastoma multiforme. However, it was not until 1925 that Globus and Strass presented a complete description of the neoplasm, at which point the most common term became spongioblastoma multiforme. Finally, in 1926, Bailey and Cushing successfully reintroduced the term originally proposed by Mallory: glioblastoma multiforme.

Epidemiology

It is the most common primary tumor of the CNS in adults and accounts for more than 50% of malignant gliomas, and the most common glial tumor. 2).

Its incidence continues to increase in the elderly because the older segment of the population is growing faster than any other age group. Most clinical studies exclude elderly patients, and “standards of care” do not exist for GBM patients aged >70 years 3).

Predominantly localized in the hemisphere, in 24% in and directly around the motor area 4).

see Glioblastoma multiforme in the motor area.

Prior malignancies in patients harboring glioblastoma

Patients who develop GBM following a prior malignancy constitute ~8% of patients with GBM. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of GBM should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies 5).

Types

With the advance of genomics research, there have been a new breakthrough in the molecular classification of gliomas. Glioblastoma (WHO grade Ⅳ) could be subtyped to proneural, neural, classical, and mesenchymal according to the mRNA expression. Low grade gliomas (WHO grade Ⅱ and Ⅲ) could be divided into 5 types using 1p/19q co-deletion, isocitrate dehydrogenase(IDH) mutation, and TERTp (promotor region) mutation. In 2016, a new classification of tumors of the central nervous system was proposed, and some new markers such as IDH1 mutation were introduced into the diagnosis of gliomas. Genotype and phenotype were integrated to diagnose gliomas. In the meantime, precision treatment for gliomas has also been vigorously developed 6).


Glioblastoma IDH wildtype

Glioblastoma IDH mutant

Glioblastoma NOS


Adult glioblastoma

Cerebellar glioblastoma multiforme

Elderly Glioblastoma

Pediatric glioblastoma.

The giant cell glioblastoma is a histological variant of glioblastoma, presenting a prevalence of bizarre, multinucleated (more than 20 nuclei) giant (up to 400 μm diameter) cells.

see Glioblastoma multiforme in the motor area.

It is of great importance to seek further subclassifications, biomarkers, and new treatment modalities to make a significant change in survival for individuals 7).

Histopathology

Histologically, they are characterized by hypercellularity, nuclear pleomorphism, microvascular proliferation, and pseudopalisading necrosis.

Glioblastomas are among the most vascularized tumors in humans. There is also an abnormal vascular remodeling process that leads to microvascular proliferation that is a histopathological hallmark of glioblastoma.

In these tumors, angiogenesis appears to be triggered by expression of vascular endothelial growth factor, an important regulator of tumor blood vessel permeability 8)

Biomarkers

Pathogenesis

Genomic alterations

Localization

Other types

Metastasis

Clinical Features

It generally presents with epilepsy, cognitive decline, headache, dysphasia, or progressive hemiparesis. 9).

Seizures as the presenting symptom of glioblastoma predicted longer survival in adults younger than 60 years. The IDH1 R132H mutation and p53 overexpression (>40%) were associated with seizures at presentation. Seizures showed no relationship with the tumor size or proliferation parameters 10).

Diagnosis

Diagnostic tools include computed tomography (CT or CAT scan) and magnetic resonance imaging (MRI). Magnetic resonance imaging (MRI) is the most sensitive and best method of detecting brain tumors. Magnetic resonance spectroscopy (MRS) is used to study the tumor’s chemical profile and determine the nature of the lesions seen on the MRI. Positron emission tomography (PET scan) can help detect recurring brain tumors.

see Glioblastoma multiforme magnetic resonance imaging

Treatment

Not good candidates for surgery

Outcome

Diet

Recurrence

Complications

Thromboembolic events, seizures, neurologic symptoms and adverse effects from corticosteroids and chemotherapies are frequent clinical complications seen in Glioblastoma (GB) patients. The exact impact these have on dismal patient outcome has not been fully elucidated.

Complications significantly decrease GB patient survival. Age, poor functional status, other than standard adjuvant therapy and eloquent tumor location proved as significant risk factors for encountering a therapy associated complication. Not extensive surgery or tumor size but surgery at eloquent locations impacts complication occurrence the strongest with a 2 fold increased complication occurrence risk 11).

Case series

2017

A study enrolled 60 glioblastoma patients with more than 5-mm-thick surgical cavity wall enhancement (SCWE)s as detected on contrast-enhanced MR imaging after concurrent chemoradiation therapy. Two independent readers categorized the shape and perfusion state of SCWEs as nodular or non-nodular and as having positive or negative perfusion compared with the contralateral grey matter on arterial spin labeling (ASL). The perfusion fraction on ASL within the contrast-enhancing lesion was calculated. The independent predictability of TTP was analyzed using the Kaplan-Meier method and Cox proportional hazards modelling.

The perfusion fraction was higher in the non-progression group, significantly for reader 2 (P = 0.03) and borderline significantly for reader 1 (P = 0.08). A positive perfusion state and (P = 0.02) a higher perfusion fraction of the SCWE were found to become an independent predictor of longer TTP (P = 0.001 for reader 1 and P < 0.001 for reader 2). The contrast enhancement pattern did not become a TTP predictor.

Assessment of perfusion in early post-treatment MR imaging can stratify TTP in patients with glioblastoma for adjuvant temozolomide therapy. Positive perfusion in SCWEs can become a predictor of a longer TTP 12).

2016

The Medicare database was searched to identify patients 66 years of age and older with glioblastoma, with and without infection, from 1997 to 2010. The primary outcome was survival after diagnosis. The statistical analysis was performed with a graphical representation using Kaplan-Meier curves, univariate analysis with the log-rank test, and multivariate analysis with proportional hazards modeling.

A total of 3784 patients with glioblastoma were identified from the database, and from these, 369 (9.8%) had postoperative infection within 1 month of surgery. In patients with glioblastoma who had an infection within 1 month of surgery, there was no significant difference in survival (median 5 months) compared with patients with no infection (median 6 months; p = 0.17). The study also showed that older age, increased Gagne comorbidity score, and having diabetes may be negatively associated with survival.

Infection after craniotomy within 1 month was not associated with a survival benefit in patients with glioblastoma 13).


Álvarez de Eulate-Beramendi et al. retrospectively included all patients over 70 years of age, who underwent surgery at the Department of Neurosurgery (HUCA and HUMV) and were diagnosed of GBM by pathological criteria from January 2007 to September 2014. Results Eighty-one patients were analysed, whose mean age was 75 (SD 4) and 48 were male. Karnofsky performance status (KPS) was over 70 in 61 patients and 38.3% presented with motor deficit. Sixty-three patients underwent resection, and 18 had only a diagnostic biopsy. The complication rate was 17.28% and mortality rate was 7.4%. Survival was increased in patients who received radiotherapy (n = 41) or additional chemotherapy (n = 26) (p < 0.001). KPS < 70 was an independent factor associated with low-rate survival. Patients with optimal treatment had a median survival of 8 months compared to patients with suboptimal treatment who had a median survival of 4 months (p < 0.001). Conclusions This study suggests that KPS is the most important preoperative prognostic factor. Maximal safe resection followed by radical radiotherapy and temozolomide might be the optimal treatment of choice since glioblastoma-diagnosed patients over 70 years of age showed a statistically significant survival benefit 14)

2015

With the publication of the European Organisation for Research and Treatment of Cancer/National Cancer Information Center EORTC NCIC protocol, concomitant radiochemotherapy followed by intermittent chemotherapy became the new treatment standard for patients with primary glioblastoma.

Eight years after widespread introduction of this protocol, it is of interest to investigate whether this new standard has been established in daily neuro-oncologic practice.

Rapp et al. analyzed primary glioblastoma patients diagnosed between 2005 and 2013 treated at the Heinrich Heine Medical Centre, Düsseldorf, Germany according to the EORTC/NCIC trial. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were retrospectively analyzed and compared with the available data from the EORTC/NCIC trial.

In this single-center retrospective study, they identified 189 patients (116 men, 73 women; median age: 62 years) who were treated according to the EORTC/NCIC trial protocol.

A total of 176 patients received cytoreductive surgery; 13 patients had stereotactic biopsy only (EORTC/NCIC trial: 239 patients and 48 patients, respectively). Radiotherapy had to be interrupted in 9 patients (5%) (EORTC/NCIC trial: 15 patients [5%]) and concomitant chemotherapy in 26 patients (14%) (EORTC/NCIC trial: 37 patients [13%]). In 156 patients (83%), adjuvant TMZ chemotherapy was initiated (6 median temozolomide [TMZ] cycles; range: 1-30). In the EORTC/NCIC trial, 223 patients (47%) received the intermittent chemotherapy protocol (median: 3 cycles; range: 1-7). Overall, 97 patients (62%) completed 6 TMZ cycles (EORTC/NCIC-trial: 105 patients [47%]); dose escalation to 200 mg/qm at the second cycle was performed in 91 patients (58%) (versus 149 patients [67%]). Intermittent TMZ therapy was discontinued in 59 patients (38%) (versus 118 patients [53%]). Median overall survival in our patient cohort was 19 months (versus 14.6 months); median time to progression was 9 months (versus 6.9 months).

Comparison between the feasibility of the treatment protocol established by the EORTC/NCIC trial (performed within the setting of a prospective randomized trial) and the daily routine in a dedicated neurosurgical neuro-oncologic department demonstrates that the protocol is suitable for daily practice within a neurosurgical unit 15).


A total of 126 patients were reviewed. Median progression-free survival was 5 months (95% confidence interval [CI], 4.138 to 5.862 months). Median overall survival (OS) was 8 months (95% CI, 5.950 to 10.050 months). Univariate analysis showed the statistically significant associations between the higher OS and age <70 (P = 0.046), Karnofsky performance status ≥70 (P = 0.001), single lesions (P = 0.007), lesions affecting one lobe (P = 0.007), total resection (P = 0.048), and Charlson Comorbidity Scoring System ≤5. Multivariate analysis identified the completion of 60 Gy radiotherapy and completion of 6 or more cycles of temozolomide chemotherapy as independent prognostic factors positively correlated with increased survival.

Maximal resection and radiochemotherapy treatment completion are associated with longer OS, and age alone should not preclude elderly patients from receiving surgery and adjuvant treatment. However, only a few patients were able to finish the proposed treatments. Poor performance and high comorbidity index status might compromise the benefit of treatment aggressiveness and must be considered in therapeutic decision 16).


2013

Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31).

The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy 17).

Case reports

A 57-year-old man presented with seizures. Until the seizure onset, he had been treated for thyroid cancer and its metastasis to the thoracic vertebral body with the multi-receptor tyrosine kinase inhibitor (RTK) lenvatinib for 4 years. MRI revealed a slightly high intensity lesion in the left frontal base area on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images, and the lesion showed only faint enhancement on T1-weighted images after gadolinium administration. Total resection was performed and the histopathological diagnosis was glioblastoma. However, grade IV histology was observed in only a limited area, and the majority of the specimen showed lower grade histology with moderate vascularization that lacked microvascular proliferation.

Lenvatinib, which is anti-angiogenic, might have affected the radiological characteristics, as well as the pathology of the tumor. Brain tumors arising during treatment with RTKs for other cancers could show atypical imaging findings 18).

1)
Virchow R. Pathologie In Die Krankhaften Geschwülste. Berlin. 1864-1865.
2)
Moore Kraig, Kim Lyndon. Springer Science+Business Media, LLC; 2010. Primary brain tumors: Characteristics, practical diagnostic and treatment approaches; pp. 43–75.
3)
Bauchet L, Zouaoui S, Darlix A, Menjot de Champfleur N, Ferreira E, Fabbro M, Kerr C, Taillandier L. Assessment and treatment relevance in elderly glioblastoma patients. Neuro Oncol. 2014 May 2. [Epub ahead of print] PubMed PMID: 24792440.
4)
Saksena S, Jain R, Narang J, Scarpace L, Schultz LR, Lehman NL, Hearshen D, Patel SC, Mikkelsen T: Predicting survival in glioblastomas using diffusion tensor imaging metrics. Journal of Magnetic Resonance Imaging 32:788-759, 2010
5)
Zacharia BE, DiStefano N, Mader MM, Chohan MO, Ogilvie S, Brennan C, Gutin P, Tabar V. Prior malignancies in patients harboring glioblastoma: an institutional case-study of 2164 patients. J Neurooncol. 2017 May 27. doi: 10.1007/s11060-017-2512-y. [Epub ahead of print] Review. PubMed PMID: 28551847.
6)
Hua W, Mao Y. [Advance of molecular subtyping and precise treatment for gliomas]. Zhonghua Wai Ke Za Zhi. 2017 Jan 1;55(1):63-66. doi: 10.3760/cma.j.issn.0529-5815.2017.01.016. Chinese. PubMed PMID: 28056258.
7)
Fekete B, Werlenius K, Örndal C, Rydenhag B. Prognostic factors for glioblastoma patients - a clinical population-based study. Acta Neurol Scand. 2016 Jun;133(6):434-41. doi: 10.1111/ane.12481. Epub 2015 Sep 11. PubMed PMID: 26358197.
8)
Thomas AA, Omuro A. Current role of antiangiogenic strategies for glioblas- toma. Curr Treat Options Oncol. 2014;15:551–66.
9)
Thomas DGT,Graham DI, McKeran RO,Thomas DGT. The clinical study of gliomas. In: Brain tumours: scientific basis, clinical investigation and current therapy. In: Thomas DGT, Graham DI eds. London: Butterworths, 1980:194–230.
10)
Toledo M, Sarria-Estrada S, Quintana M, Maldonado X, Martinez-Ricarte F, Rodon J, Auger C, Aizpurua M, Salas-Puig J, Santamarina E, Martinez-Saez E. Epileptic features and survival in glioblastomas presenting with seizures. Epilepsy Res. 2016 Dec 26;130:1-6. doi: 10.1016/j.eplepsyres.2016.12.013. [Epub ahead of print] PubMed PMID: 28073027.
11)
Ening G, Osterheld F, Capper D, Schmieder K, Brenke C. Risk factors for glioblastoma therapy associated complications. Clin Neurol Neurosurg. 2015 Jul;134:55-9. doi: 10.1016/j.clineuro.2015.01.006. Epub 2015 Jan 9. PubMed PMID: 25942630.
12)
Park JE, Ryu KH, Kim HS, Kim HW, Shim WH, Jung SC, Choi CG, Kim SJ, Kim JH. Perfusion of surgical cavity wall enhancement in early post-treatment MR imaging may stratify the time-to-progression in glioblastoma. PLoS One. 2017 Jul 21;12(7):e0181933. doi: 10.1371/journal.pone.0181933. eCollection 2017. PubMed PMID: 28732091.
13)
Chen YR, Ugiliweneza B, Burton E, Woo SY, Boakye M, Skirboll S. The effect of postoperative infection on survival in patients with glioblastoma. J Neurosurg. 2016 Dec 9:1-5. [Epub ahead of print] PubMed PMID: 27935360.
14)
Álvarez de Eulate-Beramendi S, Álvarez-Vega MA, Balbin M, Sanchez-Pitiot A, Vallina-Alvarez A, Martino-González J. Prognostic factors and survival study in high-grade glioma in the elderly. Br J Neurosurg. 2016 Feb 1:1-7. [Epub ahead of print] PubMed PMID: 26828095.
15)
Rapp M, Sadat H, Slotty PJ, Steiger HJ, Budach W, Sabel M. Feasibility of the EORTC/NCIC Trial Protocol in a Neurosurgical Outpatient Unit: The Case for Neurosurgical Neuro-Oncology. J Neurol Surg A Cent Eur Neurosurg. 2015 Jul;76(4):298-302. doi: 10.1055/s-0034-1396437. Epub 2015 Apr 27. PubMed PMID: 25915500.
16)
Pereira AF, Carvalho BF, Vaz RM, Linhares PJ. Glioblastoma in the elderly: Therapeutic dilemmas. Surg Neurol Int. 2015 Nov 16;6(Suppl 23):S573-S582. eCollection 2015. PubMed PMID: 26664927.
17)
Kreth FW, Thon N, Simon M, Westphal M, Schackert G, Nikkhah G, Hentschel B, Reifenberger G, Pietsch T, Weller M, Tonn JC; German Glioma Network.. Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol. 2013 Dec;24(12):3117-23. doi: 10.1093/annonc/mdt388. PubMed PMID: 24130262.
18)
Arai N, Sasaki H, Tamura R, Obara K, Yoshida K. Unusual magnetic resonance imaging findings of a glioblastoma arising during treatment with lenvatinib for thyroid cancer. World Neurosurg. 2017 Aug 10. pii: S1878-8750(17)31314-1. doi: 10.1016/j.wneu.2017.08.017. [Epub ahead of print] PubMed PMID: 28804045.
glioblastoma_multiforme.txt · Last modified: 2017/08/15 23:05 by administrador