Meningiomas: From Pathogenesis to Therapeutics-Current Perspectives and a Holistic Review

Positive cerebrospinal fluid (CSF) cytology typically indicates leptomeningeal dissemination of metastatic, secondary, or rarely, primary central nervous system (CNS) tumors. To the authors' knowledge, large-scale studies on clinicocytologic features of various primary CNS tumors in CSF are lacking. The authors performed a retrospective cytomorphologic study on 127 positive CSF specimens from 87 patients with a history of primary nonhematologic CNS tumors. Pertinent clinical, radiological, and histologic findings were reviewed. Pediatric tumors accounted for the majority (82.6%) of the primary CNS tumors with positive CSF cytology. The most common radiological finding of neuraxial dissemination was diffuse leptomeningeal enhancement. Greater than 95% of the cases with positive CSF cytology were high-grade or malignant tumors. The most common tumor type was central primitive neuroectodermal tumors (47.2%). Overall, the frequency of initial metastasis was found to be lowest in central primitive neuroectodermal tumors and retinoblastomas (approximately one-third). They also had the longest latency (1.5-2 years) in cases without initial metastasis. The majority of metastatic tumors in CSF demonstrated distinct cytomorphology reminiscent of the histologic features of the primary tumor, such as prominent nucleoli, cell wrapping, and apoptosis in large cell/anaplastic medulloblastomas; rhabdoid morphology and cytoplasmic inclusions in atypical teratoid/rhabdoid tumors; large clusters of cells with scant cytoplasm and nuclear molding in retinoblastomas; nuclear pleomorphism and hyperchromasia in high-grade infiltrating astrocytomas; and small clusters/rosettes of epithelioid cells in ependymomas. The results of the current study provide useful clinicoradiological information and cytomorphologic findings for both common and rare primary CNS tumors that cytopathologists might encounter on CSF examination.

Primary central nervous system (CNS) tumors account for only 2% of all adult cancers and the annual incidence of primary malignant brain cancer was 7.3 per 100,000 person-years. Malignant gliomas are the most common primary CNS tumors in adults accounting for 78% of all primary malignant CNS tumors. Glial neoplasms represent about 40% of all primary CNS tumors, over three quarters being malignant. The median survival of patients with glioblastoma was 14.6 months after tereatment. Although recent basic and clinical research of malignant gliomas has improved, there is limitation of the outcome of the patients with malignant gliomas. Treatment strategy of tumor resection and radiotherapy for this tumor is still important and a recent advance in the use of concurrent chemo-radiation has improved survival in a large fraction of patients. New approaches using these signal transductional and gene researches are developing and may promise for further survival gains in the near future. Keywords: Signal transduction, brain tumors, target therapy, gene therapy

The aim of this report is to provide accurate nationwide epidemiologic data on primary central nervous system (CNS) tumors in Korea. Despite its importance, there are no accurate statistics on primary CNS tumors in Korea. We analyzed primary CNS tumors diagnosed in 2005 from the nationwide registry. Data on primary CNS tumors diagnosed in 2005 were collected from the Korean Central Cancer Registry and the Korean Brain Tumor Society. Crude and age-standardized rates were calculated in terms of gender, age, and histological type. Tumors of uncertain histology were investigated individually at the corresponding hospitals and had their diagnoses confirmed. A total of 5,692 patients diagnosed with primary CNS tumors in 2005 were included in this study. CNS tumors occurred in females more often than in males (female to male, 1.43 : 1). The most common tumor was meningioma (31.2%). Glioblastoma accounted for 30.7% of all gliomas, and 19.3% of all malignant primary CNS tumors. In children under 19 years of age, both germ cell tumor and embryonal/primitive/medulloblastoma were the most common tumors. This article is the first nationwide primary CNS tumor epidemiology report in Korea. Data from this study should provide valuable information regarding the understanding of primary CNS tumors epidemiology in Korea.

Adolescents and young adults (AYA: ages 15-39 years) are a unique population atrisk of both pediatric-type and adult-type central nervous system (CNS) tumors. Targeted therapies are now available for a growing subset of CNS tumors represented within AYA. Gliomas represent 25% of all primary brain tumors in AYA, with up to 30% of these harboring a pediatric-type molecular alteration in the mitogen-activated protein kinase (MAPK) pathway. MAPK-pathway inhibitors are often utilized in AYA patients with a pediatric low-grade glioma (pLGG), however specific clinical trials spanning the entire AYA age range for this molecular alteration are absent. Isocitrate dehydrogenase (IDH) mutations are the most common molecular alteration found in AYA glioma. The IDH-mutant inhibitor vorasidenib has been demonstrated to prolong progression-free survival in grade 2 IDH-mutant glioma; however, there is a lack of evidence in patients younger than 18. Meningioma is the most common primary CNS tumor in adults and represents 15% of primary CNS tumors in the AYA population. Recent molecular characterization of meningioma has led to several targeted therapeutic clinical trials in the relapsed/refractory setting. Medulloblastoma is the most common embryonal CNS tumor in AYA patients and is primarily driven by a mutation in the sonic hedgehog (SHH) pathway. The SHH pathway is targetable with Smoothened (SMO) inhibitors which has been utilized in the relapsed/refractory setting for both pediatric and adult patients, with mixed responses. Clinical trials incorporating SMO inhibition upfront treatment have been hampered by low accrual numbers and lack of sponsor support. Craniopharyngioma is a rare CNS tumor in the AYA population, and BRAFV600E mutations in papillary craniopharyngioma represent a targetable alteration. Solutions to improving the care of AYA should include appropriate representation in clinical trials and specialized care by experienced clinicians.

The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours. A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included. Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated. Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms.

Background. Central Nervous System (CNS) tumor is neoplasm that located in central nervous system, which include brain and medulla spinalis. Despite its significant raise of incidence and morbidities, limited epidemiological data was available. Therefore, this study aimed to describe the epidemiological characteristic of CNS tumor over a 3-year period in a single tertiary hospital in Bali, Indonesia. Methods. This study was a descriptive study with cross sectional design. This study included all patients aged 18 year or over who were histopathologically diagnosed with central nervous tumor at “Prof. Dr. I.G.N.G. Ngoerah General Hospital”, Denpasar, between January 2020 and December 2022. Data about age, gender, tumor location, histopathological type, tumor grading, and source of metastases in secondary CNS tumor were obtained from medical record. Result. A total of 221 cases were recorded during this study period. The prevalence of primary CNS tumor was 81.9% while secondary CNS tumor was 18.1%. The majority of case, both in primary and secondary CNS tumor were female in age group of 50-59. Supratentorial constituted the most common lesion site in primary and secondary CNS tumor. The most frequent histopathological type of primary CNS tumor was meningioma, making up 48.1% of cases, followed by diffuse astrocytic and oligodendroglial tumors (26.5%), and tumor of the cranial and paraspinal nerve (9.9%). Carcinoma is the most common histological type in secondary CNS tumor with lung and breast tumor being the majority source of secondary CNS tumor, found in 40% and 27.5%, respectively. Conclusion. Adult female with age of 50-59 is the most affected group in CNS tumor. Primary CNS tumor were commonly found in supratentorial with meningioma and WHO grade I being the most frequent histopathological type and grade. Secondary CNS tumor were mostly found in supratentorial and originated from primary lung tumor.

Pediatric central nervous system (CNS) tumors are the most common solid cancers and the leading cause of cancer-related morbidity and mortality in children. The global demographic and epidemiological trends indicate a significant increase in childhood and adolescent cancers, including pediatric brain tumors, in low- and middle-income countries, particularly in Sub-Saharan African countries necessitating the dire need of multidisciplinary Pediatric Neuro-Oncology (PNO) teams to improve outcomes. The primary objective of the study was to evaluate the patterns, clinical presentations, time to diagnosis (TD), and treatment provided to pediatric and adolescent patients with central nervous system tumors who were discussed at the pediatric neuro-oncology tumor board and treated by the neuro-oncology team at Tikur Anbessa Specialized Hospital in Ethiopia. This retrospective cross-sectional study was conducted in the Pediatric Hematology and Oncology (PHO) unit at Tikur Anbessa Specialized Hospital in Ethiopia. It included all pediatric patients under 15 years old with primary central nervous system (CNS) tumors from December 2021 to May 2024. The study aimed to provide an overview of the sociodemographic characteristics of the children, clinical presentation, time to diagnosis, histopathology of the tumors, and treatment modalities recommended by the PNO tumor board. A total of two hundred ten patients with pediatric CNS tumors were discussed and reviewed at the Pediatric Neuro-Oncology (PNO) Tumor Board during the study period. More than half of the patients (54.8%, n = 114) were males. The median age at diagnosis was 7 years, and nearly half of the patients (48.6%) were between 5 and 10 years old. The most common clinical presentations were headache (66.2%), vomiting (64.3%), visual symptoms (44.8%), and cerebellar symptoms (43.8%). The median time to diagnosis was 90 days (IQR 60-210), and 60% of the patients presented after three months of symptom onset of the disease. The most common pediatric CNS tumors were medulloblastoma and embryonal CNS tumors, accounting for 32.9% (n = 69), followed by astrocytic tumors; 30.0% (n = 63), craniopharyngiomas (14.0%), and ependymal tumors (11.4%). The main treatments offered by the PNO Tumor Board were a combination of surgery, radiotherapy, and systemic chemotherapy (33.8%), surgery alone (23.8%), and surgery with radiotherapy (21.4%). The PNO Tumor Board was primarily attended by pediatric hematology-oncology fellows, pediatric oncologists (90%), and neurosurgeons (86%). This study focused on analyzing the age distribution, clinical presentation, time to diagnosis, burden, and patterns of pediatric primary CNS tumors at the largest tertiary referral center in Ethiopia. It is imperative to prioritize educating healthcare professionals about the symptoms and signs of CNS tumors in children, promoting early diagnosis, facilitating timely referrals, and enhancing the effectiveness of the PNO tumor board. These measures should be considered essential aspects of care for children with CNS tumors.

Insights into the molecular underpinnings of primary central nervous system tumors have radically changed the approach to tumor diagnosis and classification. Diagnostic emphasis has shifted from the morphology of a tumor under the microscope to an integrated approach based on morphologic and molecular features, including gene mutations, chromosomal copy number alterations, and gene rearrangements. In 2016, the World Health Organization provided guidelines for making an integrated diagnosis that incorporates both morphologic and molecular features in a subset of brain tumors. The integrated diagnosis now applies to infiltrating gliomas, a category that includes diffusely infiltrating astrocytoma grades II, III, and IV, and oligodendroglioma, grades II and III, thereby encompassing the most common primary intra-axial central nervous system tumors. Other neoplasms such as medulloblastoma, embryonal tumor with multilayered rosettes, certain supratentorial ependymomas, and atypical teratoid/rhabdoid tumor are also eligible for integrated diagnosis, which can sometimes be aided by characteristic immunohistochemical markers. Since 2016, advances in molecular neuro-oncology have resulted in periodic updates and clarifications to the integrated diagnostic approach. These advances reflect expanding knowledge on the molecular pathology of brain tumors, but raise a challenge in rapidly incorporating new molecular findings into diagnostic practice. This review provides a background on the molecular characteristics of primary brain tumors, emphasizing the molecular basis for classification of infiltrating gliomas, the most common entities that are eligible for an integrated diagnosis. We then discuss entities within the diffuse gliomas that do not receive an integrated diagnosis by WHO 2016 criteria, but have distinctive molecular features that are important to recognize because their clinical behavior can influence clinical management and prognosis. Particular attention is given to the histone H3 G34R/G34V mutant astrocytomas, an entity to consider when faced with an infiltrating glioma in the cerebral hemisphere of children and young adults, and to the group of histologically lower grade diffuse astrocytic gliomas with molecular features of glioblastoma, an important category of tumors to recognize due to their aggressive clinical behavior.

Tumors of the human central nervous system (CNS) can be divided into two large groups: primary and metastatic. Although primary CNS tumors are less common than metastatic tumors, primary tumors are seen at a rate of about 10,000–15,000 per year or 0.5–2/100,000 population. This is a higher incidence than is seen in Hodgkin’s disease. Primary CNS tumors are also the most common solid tumors of childhood (Jellinger, 1978; Posner et al., 1979). Although a large number of systems for the classification of primary CNS neoplasia has been generated during the last century, primary intracranial tumors are now categorized using one of a small number of systems. The most common primary CNS tumors of adults are of glial origin, including astrocytomas, glioblastomas, oligodendrogliomas, and ependymomas. Other tumors are of questioned origin. Included here are medulloblastoma, a tumor of childhood, and hemangioblastoma, a tumor classically described as being of blood vessel origin; that concept is, however, now under scrutiny. Several types of meningiomas develop from the tissues covering the brain, the leptomeninges. The adenohypophysis is the source of four types of pituitary adenomas; some of these benign tumors secrete pituitary hormones. A discussion of CNS tumor morphology and classification is outside the limits of this review and if the reader wishes a comprehensive treatment if this subject, he is referred to Burger and Vogel (1976) and Russell and Rubinstein (1977).

Metastases represent the most common type of intracranial neoplasm. In women, 30% of such tumors derive from breast carcinoma. In neurosurgical cases with ambiguous cellular morphology and/or limited biopsy material, immunohistochemistry (IHC) is often performed to distinguish metastases from primary central nervous system (CNS) neoplasms. IHC for mammaglobin-A (MGA), a protein expressed in a majority of breast carcinomas, is commonly applied in this setting, but its utility for distinguishing primary CNS neoplasms from metastatic breast carcinoma is unknown; the reactivity of MGA in primary and metastatic CNS neoplasms has never been described. Here, we describe the frequency and patterns of IHC reactivity for MGA in metastatic and primary CNS neoplasms from patients with well-documented histories of breast carcinoma. Following a published protocol previously applied to non-CNS neoplasms, MGA staining of moderate to strong intensity within 5% or more of a neoplasm was considered positive. On the basis of these criteria, 3 of 12 (25.0%) glioblastomas, 1 of 10 (10.0%) meningiomas, and 47 of 95 (49.5%) metastases were positive. Importantly, the cytoarchitectural staining characteristics among all 4 MGA-positive primary CNS neoplasms (cytoplasmic and nuclear) differed from those of the metastases (cytoplasmic and membranous). These findings suggest that MGA IHC staining intensity and distribution can distinguish metastases from primary CNS neoplasms (P=0.0086) in women with a history of breast carcinoma but also indicate that cytologic staining patterns must be interpreted for more accurate tumor classification.

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all primary CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients – medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome.

Central nervous system

Primary central nervous system (CNS) neoplasms are uncommonly diagnosed in cats. The majority of primary feline CNS neoplasms described in the veterinary literature consist of meningioma and glioma occurring mainly in the brain and less often in the spinal cord. Although most neoplasms can be diagnosed based on routine histologic evaluation, less typical tumors need to be further characterized using immunohistochemistry. This review compiles the relevant information about the most common primary CNS neoplasms of cats available in the veterinary literature, aiming to serve as a converging source of information for the topic.

Tumors of the central nervous system (CNS) encompass a wide variety of entities, which span from benign to highly malignant.The classification of these tumors is typically based on their histopathological features or their location within the CNS.Despite these apparently simple criteria, there are a great number of independent CNS tumor types as defined by the most recent World Health Organization (WHO) classification of CNS tumors (Louis et al., 2007), which is the standard for the definition of CNS tumors worldwide.The WHO listing of CNS tumors is impressively vast and has, in fact, been surrounded by some controversy concerning the nosology of some tumor entities (e.g., the nosologic place of highly anaplastic oligoastrocytic tumors, glioblastoma with oligodendroglioma components).The agestandardized incidence rate of all primary non-malignant and malignant CNS tumors in the US is 16.5 per 100,000 person-years (9.2 per 100,000 person-years for non-malignant tumors and 7.3 per 100,000 person-years for malignant tumors) (CBTRUS, 2010).This rate is higher in females (17.2 per 100,000 person-years) than males (15.8 per 100,000 person-years).Worldwide data is available only for malignant primary CNS tumors; in this setting, the incidence rates are higher in males (approximately 3.7 per 100,000 person-years) than females (2.6 per 100,000 person-years) (Ferlay et al., 2008).In Western Europe, the male and female incidence rates of malignant CNS tumors are 6.7 per 100,000 person-years and 4.5 per 100,000 person-years, respectively.Very similar figures are observed in Northern America (6.0 and 4.5 per 100,000 person-years for males and females, respectively).Interestingly, the incidence rates are higher in more developed countries than in less developed ones, but these differences may be a consequence of differences in diagnostic practices, completeness of reporting and access to adequate health care, rather than attributable to geographic and genetic variation.CNS tumors are considered to be primary when the tumor originally initiates in the CNS, as opposed to the far more common brain metastases derived from malignant tumors located in other organs, which are considered secondary brain tumors.Primary brain and CNS tumors account for only approximately 2% of all primary tumors (Louis et al., 2007), but they rank first among tumor types for the average years of life lost (~20 years, compared, for example, with ~6 years for prostate cancer and ~12 years for lung cancer) (Burnet et al., 2005).These tumors are the most frequent solid malignancy in children, being the leading cause of cancer-related death in children under the age of 19 (Rickert & Paulus, 2001).The impact and nature of primary brain tumors in adults is somewhat different, but they still rank second as cause of cancer death in males aged 20 to 39 years, and fifth in females of www.intechopen.com

Simple SummaryGlioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. Liquid biopsy, particularly targeting cell-free DNA (cfDNA) in cerebrospinal fluid (CSF), is a minimally invasive method, and emerges as a promising alternative, overcoming spatial and temporal heterogeneity in CNS tumors. Unlike extracranial cancers, cfDNA in the blood is scarce in CNS tumors, including glioma, emphasizing the relevance of CSF. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review provides an overview of the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It delineates distinctions from liquid biopsies for extracranial cancers, addresses prevailing challenges, and explores future prospects in this field.Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. In such cases, a minimally invasive approach to liquid biopsy is beneficial. Cell-free DNA (cfDNA), which directly reflects tumor-specific genetic changes, has attracted attention as a target for liquid biopsy, and blood-based cfDNA monitoring has been demonstrated for other extra-cranial cancers. However, it is still challenging to fully detect CNS tumors derived from cfDNA in the blood, including gliomas, because of the unique structure of the blood–brain barrier. Alternatively, cerebrospinal fluid (CSF) is an ideal source of cfDNA and is expected to contribute significantly to the liquid biopsy of gliomas. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review summarizes the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It highlights how the approaches differ from liquid biopsies of other extra-cranial cancers and discusses the current issues and prospects.