Open access
1. Introduction
The incidence of the brain tumors is 14.8 per 100,000 people per year. An estimated 43,800 new brain tumors are diagnosed each year in the United States of America. It has been stated that 92.2% of these are observed in adults and over age groups, and 7.8% are observed in children and adolescents. About half of the brain tumors are histologically in benign character, and the most common histologically observed tumor type in this group is Meningioma. The primary brain tumors with the malignant character comprise 2% of all cancers. The primary brain tumors with the malignant character are in the 1st rank among the causes of death due to the solid tumors in children and in the 3rd rank among the causes of death due to the cancer in adolescents aged 15–34 and adults. The most common histologically observed tumor type in this group is glioblastoma [1].
2. Brain tumors
2.1 Clinical features
Depending on the histopathological structure of the brain tumors, they can only make external compression on the adjacent brain parenchyma or cause necrosis with different levels of the parenchymal infiltration. The most common symptom observed for the brain tumors is headache, which develops as a result of increased intracranial pressure. The epileptic seizures are frequently observed in the low-grade tumors. The focal neurological deficits, such as hemiparesis and hemihypoesthesia, are usually related to the localization of the tumor. The mental status changes that range from sleepiness to deep coma are observed in 15–20% of the patients with glioma [2].
2.2 Diagnostic techniques
The contrast-enhanced brain magnetic resonance imaging (MRI) is essential in the diagnosis of the primary brain tumors. Both the annular areas with the live tumor tissue with the contrast enhancement and the central necrotic areas can be displayed in more detail in the high-grade gliomas, especially like the glioblastoma by means of the contrast-enhanced brain MRI. The peritumoral vasogenic edema area is also evaluated on the MRI T2 sequences. The brain MR-spectroscopy, in which the metabolic activity of the relevant tumor is evaluated, is used especially in the diagnosis of the low-grade gliomas. The tumors such as medulloblastoma, which often spread to the leptomeninges
2.3 Treatment protocols
2.3.1 Surgery
In the benign brain tumors such as meningioma, the first treatment option is surgical tumor resection, and in most cases, total removal of the tumor is possible. Due to their infiltrative natural structure, there are difficulties encountered in total surgical removal of the high-grade brain tumors. However, since the level of surgical resection has been shown to have a positive effect on the prognosis of the malignant brain tumors, the radical tumor resection is recommended as much as possible without causing morbidity [3, 4, 5]. By means of the tumor cytoreduction, both the existing neurological conditions of the patients can be improved and the radiotherapy and/or chemotherapy protocols to be applied after the surgery can be applied more effectively. By means of the advances in the microsurgical techniques and surgical approaches, more radical resections of the brain tumors can be performed today. In addition, the development of auxiliary microsurgical techniques such as intraoperative neuronavigation, which allows real-time evaluation of the stereotaxic three-dimensional images during the surgery, greatly increases the success of microsurgical tumor resection. The cortical mapping of the brain and white matter pathways is used to prevent postoperative morbidity in the radical surgical resections of the tumors located near critical functional areas of the brain. In the tumors localized in the critical functional areas of the brain with an unacceptable high risk of the postoperative morbidity, the stereotaxic biopsy performed with the computed tomography is preferred for the histopathological diagnosis [2].
2.3.2 Radiotherapy, chemotherapy, and molecular targeted therapy
The radiotherapy has become the standard adjuvant treatment method, especially in the high-grade gliomas, after it was shown that the radiotherapy applied in the postsurgical period prolongs the median life span by 14–36 weeks [6]. For the brain tumors, the radiotherapy is used as adjuvant therapy in the postoperative period. By means of the calculated therapeutic rate by taking into account the radiosensitivity of the normal parenchymal tissue, currently, the fractionated radiotherapy protocols, in which the multiple small doses of the radiation are applied, have been developed for many infiltrative malignant brain tumors. In the non-infiltrative brain tumors such as brain metastases, meningiomas adjacent to the optic nerve, and residual vestibular schwannomas, the stereotaxic radiosurgery is preferred, in which a single fraction and high-dose radiotherapy can be applied to the tumor area [7]. The temozolomide is the most commonly used chemotherapeutic agent, with the proven usefulness as a postoperative adjuvant therapy for the high-grade gliomas. Currently, in the treatment of the glioblastoma, concomitant therapy protocol is used, which is planned to be continued with temozolomide for six more cycles after the temozolomide treatment used at the same time with radiotherapy. While the median life expectancy is 12.1 months in the patients who received only radiotherapy, this has been 14.6 months with this concomitant treatment with temozolomide [8]. Bevacizumab, which is a monoclonal antibody binding to the vascular endothelial growth factor, with its antiangiogenic effect, has increased progression-free survival rates in the patients with relapsed GBM following the concomitant treatment with temozolomide [9].
Especially in the treatment of high-grade brain tumors, by means of the positive developments observed in recent years, although the life span of the patients is partially prolonged, these treatment results are still not at an acceptable level today. Therefore, there is a need to develop new agents targeting the aberrant signaling pathways of the high-grade brain tumors. In this context, the World Health Organization’s (WHO) Classification of Central Nervous System (CNS) Tumors for 2016, in which histology of the CNS tumors and molecular data were combined, was updated in 2021.
3. Significant updates for brain tumors to the 2021 WHO classification of CNS tumors
In the WHO 2021 classification of the CNS tumors (WHO CNS5), the natural course of the tumors as a result of their molecular and biological behavior was better characterized. In this classification, especially practical approaches obtained as a result of the molecular translation of the tumors occupy a place in the taxonomy of the CNS tumors [10]. The most important change in the WHO CNS5 updated classification is that the subtypes of the gliomas have been also stated by separating them as adult-type and pediatric-type gliomas by considering the deep-rooted molecular genetic differences. The data stated in this classification make important contributions both to the planning of optimal treatment specific to the tumor subtypes and to the development of new treatment protocols in this way. As a result, the prognosis of the homogeneous patient groups with the CNS tumors and subtypes will also be better understood [11].
When the adult-type gliomas were examined, the glioblastoma was divided into IDH-mutant type (10%) and IDH-wildtype (90%) tumors in the previous classifications. To eliminate the problems observed due to the very different biological behavior of these tumors, only IDH-wildtype tumors are included in glioblastoma in the WHO CNS5 classification. In addition, although it does not have the histological features of glioblastoma typical of adults, the IDH-wildtype diffuse astrocytic tumors with one or more of three genetic parameters have been included in the glioblastoma group. In these genetic parameters, there are TERT promoter mutation, EGFR gene amplification, or combined gain of entire chromosome 7 and loss of entire chromosome 10 (+7/−10). In the WHO CNS5 classification, all IDH-mutant diffuse astrocytic tumors have been classified separately and named as IDH-mutant astrocytoma. The IDH-mutant astrocytomas have been graded as grades 2, 3, and 4. The tumors having the CDKN2A/B homozygous deletion have been classified as the WHO grade 4, and all IDH-mutant diffuse astrocytic tumors have been classified separately and named as IDH-mutant astrocytoma [11].
When the pediatric-type gliomas are examined, they have divided into two groups as pediatric-type diffuse low-grade glioma and pediatric-type diffuse high-grade glioma. There are four glioma subtypes that take place within these two tumor groups. The pediatric low-grade gliomas have been classified as tumors with the specific BRAF mutations and fusions, by taking into account the differences in the molecular structures. This situation is very important in terms of the current treatment protocols, especially in the pediatric patient groups having the low-grade glioma [12]. In addition, in the WHO CNS5 classification, as it is in the pilocytic astrocytomas having the complex histological features, in addition to the
The modified ependymoma subtypes have been stated in the WHO CNS5 classification based on the histological and molecular features, as well as the anatomical locations of the ependymomas. In addition, it has been stated that the different predictive values are observed in these tumor subtypes as a result of the detection of the specific molecular changes such as loss of chromosome 6q in the ependymoma subtypes located in the posterior fossa [14]. For the medulloblastomas, the WHO CNS5 classification has been created based on the biological and clinical heterogeneity of the tumors generally used in the WHO 2016 classification [15]. In this classification, the non-WNT/non-SHH tumors appear to be the most common types of medulloblastoma. The SHH-associated tumors have been evaluated in two subgroups as TP53 wild-type and TP53-mutant type, due to the differences in their prognosis. In conclusion, 13 or more subgroups have been defined in the WHO CNS5 classification, by taking into account the molecular information of medulloblastoma tumors. Despite the surgical treatment, the local and craniospinal radiotherapy for the non-medulloblastoma embryonal tumors, except for the atypical teratoid/rhabdoid tumors, the prognosis is still poor in this patient group. For this reason, it is extremely important to develop molecular targeted therapy agents, as well as effective chemotherapeutic agents to be used in the treatment of the patients found in this group [11].
4. Conclusions
In addition to the genetic and molecular structures of the CNS tumors, which are tried to be described in detail in the WHO CNS5 classification, the interactions between the immunological aspects of the tumor and its microenvironment are better understood; various molecular targeted therapy protocols for these tumors will be able to be developed. In this context, the targeted therapies such as immunotherapy protocols currently being studied are promising developments today including vaccines. This book has been designed by many internationally respected authors in their field to understand the natural history and biological behavior of the CNS tumors and to update information on the treatment protocols.
Abbreviations
| CNS | Central nervous system |
| MRI | magnetic resonance imaging |
| WHO | World Health Organization |
| WHO CNS5 | 2021 WHO classification of the CNS tumors |
References
- 1.
Jemal A, Siegal R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA: a Cancer Journal for Clinicians. 2007; 57 :43-66. DOI: 10.3322/canjckin.57.1.43 - 2.
Buckner JC, Brown PD, O’Neill BP, Meyer FB, Wetmore CJ, Uhm JH. Central nervous system tumors. Mayo Clinic Proceedings. 2007; 82 (10):1271-1286. DOI: 10.4065/82.10.1271 - 3.
Simpson JR, Horton J, Scott C, Curran WJ, Rubin P, Fischbach J, et al. Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: Results of three consecutive radiation therapy oncology group (RTOG) clinical trials. International Journal of Radiation Oncology, Biology, Physics. 1993; 26 (2):239-244. DOI: 10.1016/0360-3016(93)90203-8 - 4.
Keles GE, Anderson B, Berger MS. The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surgical Neurology. 1999; 52 (4):371-379. DOI: 10.1016/s0090-3019(99)00103-2 - 5.
Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. Journal of Neurosurgery. 2001; 95 (2):190-198. DOI: 10.3171/jns.2001.95.2.0190 - 6.
Stupp R, Tonn JC, Brada M, Pentheroudakis G. ESMO guidelines working group. High-grade malignant glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncology. 2010; 21 (Suppl. 5):190-193. DOI: 10.1093/annonc/mdq187 - 7.
Souhami L, Seiferheld W, Brachman D, Poggorsak EB, Werner-Wasik M, Lustig R, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine for patients with glioblastoma multiforme: Report of radiation therapy oncology group 39-05 protocol. International Journal of Radiation Oncology, Biology, Physics. 2004; 60 :853-860. DOI: 10.1016/j.ijrobp.2004.04.011 - 8.
Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. European Organisation for Research and Treatment of Cancer brain tumor and radiotherapy groups, National Cancer Institute of Canada clinical trials group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine. 2005; 352 :987-996. DOI: 10.1056/NEJMoa043330 - 9.
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. Journal of Clinical Oncology. 2009; 27 :4733-4740. DOI: 10.1200/JCO.2008.19.8721 - 10.
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro-Oncology. 2021; 23 (8):1231-1251. DOI: 10.1093/neuonc/noab106 - 11.
Wen PY, Packer RJ. The 2021 WHO classification of tumors of the central nervous system: Clinical implications. Neuro-Oncology. 2021; 23 (8):1215-1217. DOI: 10.1093/neuroonc/noab120 - 12.
Jones DTW, Kieran MW, Bouffet E, Alexandrescu S, Bandopadhayay P, Bornhorst M, et al. Pediatric low-grade gliomas: Next biologically driven steps. Neuro-Oncology. 2018; 20 (2):160-173. DOI: 10.1093/neuonc/nox141 - 13.
Reinhardt A, Stichel D, Schrimpf D, Sahm F, Korshunov A, Reuss DE, et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathologica. 2018; 136 (2):273-291. DOI: 10.1007/s00401-018-1837-8 - 14.
Baroni L, Sundaresan L, Heled A, Coltin H, Pajtler KW, Lin T, et al. Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro-Oncology. 2021; 23 (8):1372-1381. DOI: 10.1093/neuonc/noab034 - 15.
Hovestadt V, Ayrault O, Swartling FJ, Robinson GW, Pfister SM, Northcott PA. Medulloblastomics revisited: Biological and clinical insights from thousands of patients. Nature Reviews. Cancer. 2020; 20 (1):42-56. DOI: 10.1038/s41568-019-0223-8