Preface

Tumors of the central nervous system (CNS), as described in the World Health Organization's 2021 *Classification of CNS Tumors*, may be of more than 100 types, originating from the brain, cerebellum, brain stem, spinal cord, and meninges. Thanks to advances in microsurgery and intraoperative assistive imaging technologies, total or gross-total resections of many CNS tumors can now be achieved. However, treatment of high-grade CNS tumors such as glioblastoma multiforme remains difficult. With adjuvant radiotherapy, chemotherapy (such as Temozolomide) and anti-angiogenic agents (such as Bevacizumab), partial increases in the life span of patients with these tumors have been observed. At the same time, due to advances in clinical and experimental studies, the genetic, molecular and immunological structures of many high-grade CNS tumors, as well as their interactions with the tumor microenvironment, are now better understood. Today, targeted therapies and vaccines developed with immunotherapy protocols are promising developments. This book is designed to increase understanding of the natural history of CNS tumors and to update knowledge on relevant treatment protocols.

Chapter 1 is the Introductory Chapter.

Chapter 2 focuses on histopathology, epidemiology, and multidisciplinary treatment protocols for intracranial meningiomas. Selective surgical approaches, depending on the location of these tumors, are explained in detail. The advantages of stereotactic radiosurgery (SRC), used in tumors that cannot be completely removed and whose residues are detected in the postoperative period, are discussed, and clinical studies are described in which therapeutically effective anti-angiogenic agents are used to target intracranial meningiomas. In Chapter 3 the role of radiotherapy and stereotactic radiosurgery in the treatment of residual or recurrent high-grade tumors is discussed. These techniques can be especially useful, with the MR-perfusion technique, or differentiating meningioma subtypes. A significant relationship has been established between MR elastography measurements and the intraoperative qualitative assessment of tumor consistency. The use of this technique is very useful in the gross-total removal of these tumors during surgery. Radiomics and artificial intelligence are described as potential methods for preoperative evaluation of high-grade meningiomas, prediction of recurrence and outcomes, and radiation therapy planning. Studies on smart drug molecules that can be developed in accordance with the molecular characteristics of high-grade meningiomas are also included.

Chapter 4 describes surgical and radiosurgical treatment (gamma-knife, etc.) options for pituitary neuroendocrine tumors. Surgical (transcranial and transsphenoidal) options for these tumors, and tumoral and hormonal control rates are also covered. It is reported that more than 90% of tumor control in non-functional adenomas is achieved with SRC, and the morbidity associated with radiosurgery is less than 1% in lesions invading the cavernous sinus. Chapter 5 discusses diagnostic methods, clinical

findings and multidisciplinary treatment approaches to craniopharyngioma. Surgical and/or endoscopic approaches preferred for total or gross-total tumor resection, depending on craniopharyngioma classifications (including endoscopic ones), are explained.

Chapter 6 explores general metastatic pathways and pathobiological processes, with particular reference to tumors that metastasize to the brain. This study underlines the importance of radiotherapy (especially whole-brain radiotherapy) and SRC (gammaknife, cyber-knife, etc.). Chapter 7 considers the incidence of pediatric CNS tumors in the world and specifically in India, with the different treatment protocols (such as surgery, WBRT, SRC, and proton therapy) and their contribution to patients' life expectancy. Attention is drawn to the lack of radiotherapy and oncology centers in India and other developing countries, and the consequent inadequacy of pediatric CNS tumor data reporting. It is especially important that guidelines containing treatment algorithms for pediatric CNS tumors should be established in developing countries.

Chapter 8 discusses brain tumor detection techniques based on MR images and using unconventional soft computing approaches. An extensive literature survey reveals that brain tumor detection and classification using artificial neural networks (ANN), self-organizing maps (SOM) and back propagation networks (BPN) is a promising research field. An automated tumor detection system using ANN is proposed to classify the images as metastasis, glioma, astrocytoma and meningioma. Analysis of a simulation using modified SOM and modified BPN techniques showed superior results for tumors of different sizes and shapes, compared to conventional MR imaging methods, with 96% accuracy in tumor classification and an average efficiency of 93% (improvements of 10% and 8%, respectively).

For optimal resection of brain tumors, intraoperative real-time 2D USG should be preferred by neurosurgeons to intraoperative neuro-navigation techniques because it is both cheaper and more accessible. Ultrasound is used during tumor resection for different purposes: tumor location and characterization, surgical planning, and evaluation of the extent of resection. Chapter 9 compares ultrasonography techniques for gross-total or total tumor resections.

The possible oncolytic effect of the Zika virus, especially in high-grade brain tumors, is explored in Chapter 10. Zika virus originates from non-structural protein 5 (NS5). In the future, there is the potential for Zika virus vaccines to be used as an adjuvant treatment in patients with glioblastoma multiforme tumors, whose life expectancy is quite short compared to other organ tumors. Tumor remission has been reported in mice inoculated with Zika virus-infected cells and in mice with diagnosed glioblastoma multiforme with intracranial injections of live attenuated Zika virus. These findings still need to be investigated in vivo, and there are currently no human studies to support the safety of CNS studies of the Zika virus.

Epidemiological, histopathological and genetic features of intradural intramedullary spinal tumors are described in Chapter 11. The relevant diagnostic imaging techniques are also indicated. Surgical and adjuvant radiotherapy protocols for these tumors are discussed. The pathogenesis, predisposing factors and clinical

symptomatology of spinal meningiomas are reported in Chapter 12, together with appropriate surgical approaches, depending on the location and topography of the tumor, and factors affecting the prognosis of these patients.

## **Feyzi Birol Sarica**

Associate Professor, Department of Neurosurgery, Giresun University Faculty of Medicine, Giresun, Turkey

**1**

Section 1

Introduction

Section 1 Introduction

## **Chapter 1**

Introductory Chapter: Significant Updates for Brain Tumors to the 2021 WHO Classification of the CNS Tumors (WHO CNS5) and Clinical Overview – Molecular Translation of the Brain Tumors

*Feyzi Birol Sarica*

## **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 *via* the subarachnoid space, are required to be scanned with the MRI in the spinal area along with the brain [2]. The definitive diagnosis of the brain tumors is made either by the surgical biopsy or by the histopathological examination of the tumoral tissue taken by the stereotaxic biopsy in the tumor localizations having a high risk of the surgical morbidity [3–5].

## **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 [3–5]. 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 threedimensional 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

## *Introductory Chapter: Significant Updates for Brain Tumors to the 2021 WHO Classification… DOI: http://dx.doi.org/10.5772/intechopen.108991*

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 *BRAF* mutations and/or fusions having the prognostic significance for the high-grade astrocytomas with the piloid features, other accompanying mutations, such as CDKN2A/B and ATRX, have been stated [13]. In addition, the infant-type hemispheric gliomas associated with the NTRK family or other genetic abnormalities have been described in this classification. This situation is very important in the preparation of the current treatment plans for the patients having this group of tumors [11].

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.

*Introductory Chapter: Significant Updates for Brain Tumors to the 2021 WHO Classification… DOI: http://dx.doi.org/10.5772/intechopen.108991*

## **Conflict of interest**

The authors declare no conflict of interest.

## **Abbreviations**


## **Author details**

Feyzi Birol Sarica Giresun University Faculty of Medicine, Department of Neurosurgery, Giresun Education and Research Hospital, Giresun, Turkey

\*Address all correspondence to: saricafb@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

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[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

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*Introductory Chapter: Significant Updates for Brain Tumors to the 2021 WHO Classification… DOI: http://dx.doi.org/10.5772/intechopen.108991*

[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

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## Section 2

## Intracranial Central Nervous System Tumors

## **Chapter 2** Meningiomas

*İsmail Kaya and Hüseyin Yakar*

## **Abstract**

Meningiomas are among the most common central nervous system (CNS) tumors worldwide. These extra-axial lesions, which usually originate from neoplastic arachnoidal (meningothelial) cells, often appear in mid-late adulthood and are more common in women. Due to their heterogeneous morphology, the World Health Organization (WHO) divided meningiomas into three main groups, and these three main groups are divided into nine subgroups with histopathological differences according to their biological behavior. Clinical signs and symptoms, as in other central nervous system tumors, vary considerably depending on the compression or invasion of the neurovascular structures in the compartment where the meningioma is located. Meningiomas that are presented as benign lesions often have the potential to grow slowly, but could be associated with morbidity, such as poor quality of life, depending on the histopathological grade and localization of the lesion. Although fractionated radiotherapy or stereotactic radiosurgery is an alternative treatment option for meningiomas that cannot be completely removed (surgically inaccessible, or recurrent (atypical or anaplastic)) the primary treatment for these lesions is surgery. In this context, we have detailed meningiomas in this section.

**Keywords:** central nervous system tumors, intracranial meningioma, clinic, diagnosis, treatment

## **1. Introduction**

Meningiomas, i.e., nonglial and extra-axial tumors of the central nervous system (CNS), are benign primary brain tumors that arise from neoplastic arachnoid (meningothelial) cells [1]. These epithelial cells, usually located in the arachnoid villi of the brain and spinal cord (rarely in the ventricles and extracranial area), are a component of the meninges that protect the brain [1]. Meningothelial cells, which form the interface between the parenchymal neurons and the cerebrospinal fluid (CSF), have an important barrier function for the CNS [1]. Thus, these cells are involved in removing waste products from the CSF with the protection of the optic nerve microenvironment and play a role in immunological processes through the secretion of proinflammatory cytokines in response to pathological stress conditions [2].

Felix Plater first defined meningioma in autopsy reports in 1614 as a roundish, fleshy, hard tumor with holes and the size of a medium-sized apple, covered with its membrane, and interspersed with venous lesions [3]. In the following years, different names were used for these pathological extra-axial structures, such as fungus durae matrix (Antoine Louis, 1774) and psammoma (Virchow, 1847), epithelioma

(Bouchard, 1864), endothelioma (Golgi1869) [4–7]. In 1922, Harvey Cushing's current definition of "meningiomas" prevailed in the literature to eliminate the diversity and confusion of this definition and to group many different pathologic tumor types arising from the meninges [6].

Meningiomas are common tumors, accounting for approximately 36% of all CNS tumors and 53% of non-malignant CNS tumors [8].

While meningiomas present as benign lesions they are often associated with treatable focal neurologic deficits and epileptic seizures, they may rarely be associated with morbidity, such as poor quality of life, depending on the histopathologic grade and location of the lesion [8].

Although the treatment principles are almost the same, spinal meningiomas and meningiomas of childhood are not discussed in this section to maintain the integrity of the topic. In this section, we aimed to give basic information about meningiomas, the importance of which we briefly mentioned.

## **2. Epidemiology, incidence, and prevalence**

The incidence of meningiomas is based on hospital- or population-based information [8]. In parallel with developments in neuroradiology and increasing accuracy of disease reporting, the incidence has gradually increased over the years [9]. Hospitalbased brain tumor series reported approximately 20% of all intracranial tumors, whereas autopsy studies found an overall incidence of almost 30% [10]. Meningiomas have the highest incidence rate among CNS tumors [10, 11]. They account for 38% of all intracranial tumors in women and 20% in men [10, 11]. Population-based studies have found an overall annual incidence of 6/100,000 [10, 11]. The incidence increases significantly with age. It is considered an age-related incidence, being 0.3/at 100,000 in childhood and 8.4/100,000 in the elderly [12, 13]. Intracranial meningiomas are most common in adults between the fourth and sixth decade [13]. While the incidence increases in patients with breast tumors and after head trauma, it reaches the highest rates after 50 years [9, 14, 15]. Although intracranial tumors have an overall higher prevalence in men than in women, the situation is reversed for meningiomas (women/men: 2/1) [9]. It is suggested that this increase is due to steroid receptors activating tumor growth [9]. However, female dominance of meningiomas, which is reported to be more common in Black people, has not been demonstrated in Black people [9]. Prevalence rates vary from 50.4/100,000 to 70.7/100,000 [16, 17]. Asymptomatic meningiomas are estimated to be discovered incidentally in 2–3% of the population and more than one in 8% of these cases [17]. Interestingly, nonmalignant meningiomas are predominantly female, whereas atypical and anaplastic meningiomas are more common in men [18].

## **3. Neuropathological features and classification**

Meningiomas are neoplastic changes of meningothelial cells tasked with barrierlike functions [2]. They originate from any region where the dura mater is located, often from the skull base and rarely from the extensions of the dura mater such as falx cerebri, tentorium cerebelli, and rarely from the optic nerve sheath and internal choroid plexuses in the ventricles [1]. Meningiomas, an extra-axial lesion, have a slow growth character, and macroscopically, a CSF cleft may be present adjacent to the


## **Table 1.**

*WHO classification of meningiomas.*

tumor, facilitating dissection between neuronal tissues at surgery [19]. These masses often present as a single, lobulated, and solitary extra-axial lesion [19]. Multiple lesions defined as "meningiomatosis" in syndromic patients, such as neurofibromatosis type 2 (NF2), can be seen [19].

Meningiomas can be classified according to their dural site of origin, involvement of adjacent tissues (e.g., bone, venous sinus, nerves, and brain), and histologic grading [20]. According to the World Health Organization (WHO), meningiomas are classified into three main groups based on their heterogeneous morphology: WHO Grade 1 (80% most common), WHO Grade 2 (10–18%), WHO Grade 3 (2–4% most aggressive) [20]. These three main groups were also subdivided into subgroups with histopathological differences [20]. This classification is based on pathologic criteria and is used to estimate the tumor progress (**Table 1**) [19, 20]. WHO Grading depends on brain invasion, specific histological features, or mitotic rate [21]. Although grade 1 meningiomas are designated as benign histopathologically, and they have a low recurrence rate of 5 years after surgery, the lifetime recurrence rate is approximately 30% [22]. In contrast, the 5-year recurrence rate for atypical (WHO 2) and anaplastic (WHO 3) meningiomas can be as high as 50% and 80% [21, 22]. The increase in recurrence rate after surgery is related to factors such as high-grade meningioma, brain or bone involvement, and a high proliferation index [23, 24]. However, it is impossible to determine which tumors will recur, based on the histologic criteria alone [20]. In addition, grade I and grade II meningiomas can progress to grade III by malignant transformation, but it is still unclear in which cases such progression occurs [20]. To this end, molecular characterization of meningiomas has defined several genetic biomarkers that can hopefully predict tumor behavior, and clinical trials are underway to address genetic subtypes [20]. These include BAP1 (rhabdoid and papillary subtype), SMARCE1 (clear cell subtype), TERT promoter mutation, and/or homozygous deletion of CDKN2A/B (CNS WHO grade 3), H3K27me3 loss of nuclear expression (potentially worse prognosis), KLF4/TRAF7 (secretory subtype) mutations, and methylome profiling (prognostic subtyping) [20].

## **3.1 WHO classification**

## *3.1.1 WHO grade 1 (benign)*

The most common meningiomas are classified into nine subgroups (**Table 1**). WHO grade 1 meningiomas generally have a good clinical course and a low risk of recurrence [20]. They rarely present with a histopathologic feature characterized by the presence of mitotic figures with pleomorphic nuclei [20, 25, 26].

## *3.1.2 WHO grade 2 (atypical)*

WHO grade II meningiomas, referred to as the atypical group, have increased mitotic activity and a recurrence rate of up to 40% in 5 years [20, 25, 26].

## *3.1.3 WHO grade 3 (anaplastic)*

This group represents malignant tumors with a very high recurrence rate as well as high mortality and morbidity. The 5-year progression-free survival for anaplastic variants is only 10% [20, 25, 26].

As mentioned before, CNS meningiomas are also named after the regions from which they arise. There are several classifications on this subject, but one of the most important is the one established by Yaşargil in 1966 [27]. According to Yaşargil, they are divided into six main groups (**Table 2**) [27].

## **3.2 Meningiomas, according to their localization**

## *3.2.1 Olfactory groove meningiomas*

This meningioma develops from arachnoid cap cells around the cribriform plate and crista galli [28, 29]. They may occur unilaterally or bilaterally [29]. Olfactory


## **Table 2.**

*Yaşargil meningioma classification.*

## *Meningiomas DOI: http://dx.doi.org/10.5772/intechopen.106665*

groove meningiomas generally cause compression of the olfactory nerve and grow into the hemispheres [29]. Larger ones grow in the epidural plane and invade the ethmoid and sphenoid sinuses [29]. The most common findings in these cases are headache, personality changes, epilepsy, memory visual, and olfactory disturbances [28–30]. The arterial supply is usually through the ethmoid, meningeal, and ophthalmic arteries [29]. For this reason, central enucleation of the tumor should be performed after occluding the dural arterial supplies during surgery [27]. When removing the tumor, attention should be paid to the optic nerve and the anterior communicating arterial complex [27]. The operation is performed in two ways. One is the unilateral pterional transsylvian approach, and the other is bifrontal craniotomy [29, 31]. In the bifrontal craniotomy approach, less frontal lobe retraction and direct tumor intervention are easily possible, but more scar tissue is formed [29, 31]. With the pterional approach, although it provides relatively minor surgery, frontal lobe resection may sometimes be required [27, 30, 32]. To prevent CSF leakage from the cribriform plate after surgery, it should be covered with a pericranial flap, and fibrin glue should be used if necessary [27]. Postoperative CSF fistula may still occur [31]. It is recommended that lumbar drainage be attempted first, and if this attempt fails, radical dural repair is recommended [31].

## *3.2.2 Tuberculum sella meningiomas*

These meningiomas arise from the tuberculum sellae, limbus sphenoidale, chiasmatic sulcus, and planum sphenoidale [33]. They account for 3% of all intracranial meningiomas [33]. Tuberculum sellae meningiomas most commonly originate from the optic nerves and chiasm [33]. Tuberculum sella meningiomas push the optic nerves upward and sideways [33]. The tumor grows posteriorly and superiorly, compressing the anterior cerebral artery and the anterior communicating artery complex [33]. Again, because of its growth, the tumor may invade the optic canal and frontobasal interhemispheric fissure [33]. When they reach a larger volume, they can compress the hypothalamus and cause an upward displacement of the third ventricle [33]. Very rarely, they can cause carotid artery dislocation [33]. In their clinic, they most commonly cause asymmetric vision loss [27]. In such cases, unilateral optic atrophy is noted [27]. This situation is in itself an indication of surgery [27]. Depending on the size and direction of the tumor, subfrontal, unilateral, supraorbital, or pterional transsylvian surgery may be performed [27, 33–36]. In the postoperative period, a 42–64% improvement in vision is observed [27, 30, 37, 38]. Vision impairment is observed in 10–20% of cases [27, 30, 37, 38]. The duration of visual impairment before surgery, tumor size, extent of visual loss, and advanced optic atrophy are key factors in postoperative recovery [9, 30, 37, 38]. In recent series, recurrence rates are less than 3% [39–44].

## *3.2.3 Sphenoid wing meningiomas*

According to Al-Mefty, meningiomas of the sphenoid and parasellar regions are classified into five regions, including:


All of these have been mentioned in the classification of Yaşargil later on.

## *3.2.4 Clinoidal meningiomas*

They are also meningiomas of the internal or medial sphenoid wing and arise from the anterior sphenoid process and the periphery of the lesser sphenoid wing [45]. As tumors grow, they compress the optic nerve, internal carotid artery, and branches, causing displacement [45]. Sometimes they can encircle these entities. Al-Mefty divided this group of meningiomas into three groups [45].

Group 1: These tumors originate on the underside of the anterior clinoid process and mainly involve the adventitia of the carotid artery [45]. For this reason, it may not be possible to distinguish this group of tumors from the branches of the carotid and middle cerebral arteries [45].

Group 2: These tumors originate at the superior or lateral projection of the anterior clinoid process [45]. The arachnoid of the carotid cistern separates it from the tumor adventitia [45]. Therefore, it is easy to separate the tumor from the carotid artery [45].

Group 3: The origin of these tumors is the optic foramen, so it grows toward the tip of the optic canal and anterior clinoid process [45]. These are relatively small tumors [46]. They are more easily scraped from the carotid arteries [45]. Clinically, unilateral optic atrophy is the most important finding [46–48]. In some cases, papilledema (Foster-Kennedy syndrome) may be observed on the opposite side of the eye [28, 49]. Depending on the size and orientation of the tumor, mental changes, hemiparesis, anosmia, and epileptic seizures may be observed [46–48]. It is more common in women and may enlarge during pregnancy [49]. The headache often manifests as orbital pain [49].

Pterional craniotomy is often preferred in treating this tumor group [50]. With advancing surgical techniques, vascular structures can be scraped microsurgically, and cranial nerves can be preserved safely, as with cavernous intrasinusal spread [50–52]. Despite all these options, the surgical cure of meningiomas of the middle sphenoid wing is still problematic [53, 54]. Radical resection is difficult despite all the developments [27, 31, 36, 45, 53, 54]. In Al-Mefty's series, it was reported that complete resection was not possible in group 1 cases, while group 2 and 3 cases could be treated without problems [45].

## *3.2.5 Lateral and middle sphenoid wing meningiomas*

Rosal et al. divided this group of meningiomas into seven groups by extending the classification of Brotchi and Bonnal (**Figure 1**) [53].

Brotchi and Bonnal classification modified by Rosal et al.: Group 1: Medial sphenoid wing no cavernous sinus infiltration; Group 2: Medial sphenoid wing with cavernous sinus infiltration; Group 3: Middle sphenoid wing; Group 4: Lateral sphenoid wing; Group 5: En-plaque no cavernous sinus infiltration (first third and fourth areas combined); Group 6: En-plaque with cavernous sinus infiltration (first second third and fourth areas combined); Group 7: Pure intraosseous tumor infiltration.

They form clinics according to their location. While the second group tends to cause exophthalmos, the third and fourth groups cause hemiparesis and epilepsy [53]. In the

**Figure 1.** *Lateral and middle sphenoid wing meningiomas classification.*

fifth group, there is localized and prolonged pain due to the spread of the plaques [53]. This sometimes occurs with the orbit and sphenoid bone invasion without mass effect [53]. In the case of invasion of the cavernous sinus, paralysis of the third, fourth, and sixth nerves may be observed [53]. When meningiomas in either group grow into the Sylvian fissure, they may encircle the middle cerebral artery [53]. In this case, differentiation from important structures is difficult. It is necessary to leave some tumor tissue [27]. Bone resection may be required to achieve a complete cure, especially because of bone invasion in groups 5, 6, and 7 [27]. The most appropriate surgical approach is the pterional approach [27]. The lateral sphenoid wing should be straightened to obtain an optimal field of view of this area [27].

## *3.2.6 Cavernous sinus meningiomas*

While cavernous meningiomas can arise outside the cavernous sinus and invade it, they can also arise primarily from the cavernous sinus and invade externally [54]. The cavernous sinus is frequently invaded by meningiomas located in the orbital apex, internal sphenoid wing, middle fossa, tentorium, and superior clival region [54]. The reverse is also true [54]. Cavernous meningiomas were classified into five groups by Sekhar [55]. This classification was based on the location of the tumor in the sinus and the condition of the cavernous portion of the internal carotid artery [55]. Clinical findings refer to 3, 4, first and second branches of 5, and 6 nerves [55]. Therefore, diplopia and ophthalmoplegia can be seen [55]. The disease generally progresses slowly and worsens over time [55]. Angiography should be performed in all cases [55]. Patients should undergo a balloon occlusion test to determine collateral circulation [55]. After this test, cases are classified into low, intermediate, and high risk [55]. Because of the high likelihood of potential morbidities, adequate information and appropriate patient selection are important [55]. The main indication of surgery is a progressive deterioration of neurologic findings and evidence of radiographic growth [55]. While the indication for surgery is straightforward in large tumors and young

patients, the decision to operate should be cautioned in elderly and high-risk patients with balloon occlusion tests [55]. Parkinson first performed surgery in 1965 [55]. Many authors have reported new surgical approaches and techniques [51, 52, 55–57]. Frontotemporal craniotomy and orbitozygomatic osteotomy are mostly used in surgery [51, 52, 55–57]. If the tumor infiltrates Meckel's cavity, tumor dissection should be performed [50, 56, 57].

## *3.2.7 Foramen magnum meningiomas*

They are studied in two groups. The craniospinal ones arise from the basal groove in the lower part of the ⅓-clivus and extend from anteriorly and anterolaterally of the medulla to the foramen magnum [58]. The spinocranial, on the other hand, begins in the upper cervical region and extends upward from the posterior and postero-lateral aspect of the medulla to the cerebellomedullary cistern [58]. The most common finding is neck pain that is unilateral and occurs primarily with coughing, Lhermitte's phenomenon, cold dysesthesia due to the eleventh nerve compression, progressive sensorineural and motor deficits that begin in one arm and spread to the other extremities, and atrophy of intrinsic limb muscles [58–60]. Lower cranial nerve palsies, Horner syndrome, respiratory problems, sphincter disturbances, nystagmus, and papilledema are observed less frequently [58–60]. To reach foramen magnum meningiomas, there are four main entry sites [44, 61–67]. These are posterior, postero-lateral, anterior, and transcervical approaches [44, 61–67]. The most commonly used approaches are posterior ones and among them, transcondylar and inferior suboccipital approaches are widespread [44, 61–67]. Most lesions can be resected simply with the inferior suboccipital approach [44, 61–67]. The most important factor to complicate the approach is the venous plexus [44, 61–67]. For those originating from the anterior aspect of foramen magnum, the postero-lateral (far lateral) approach is beneficial, especially when the tumor is large, opening a corridor to the anterior aspect of the brain stem and upper spinal cord [44, 61–67]. The transcondylar approach is associated with a higher morbidity rate than the far lateral approach [44, 61–67]. But it gives a wider viewing angle and accesses hard-to-reach areas [44, 61–67]. It should be applied if the benefit of the transcondylar approach is greater when weighed against the risks associated with CN XI dissection, VA transposition, and condyle drilling [44, 61–67].

## *3.2.8 Cerebellopontine angle meningiomas*

Cerebellopontine angle meningiomas, which arise from the dorsal part of the petrous bone, are divided into two parts according to their location [67, 68]. These are antero-medial angle meningiomas and postero-lateral angle meningiomas [67, 68]. While the first group originates from the anteromedial side of the internal meatus acousticus, the tumors of the second group originate from the postero-lateral side [68]. These tumors spread toward the jugular foramen and hypoglossal foramen [68]. These can cause compression of the cerebellar hemispheres and pons, which results in their displacement [68]. Cerebellopontine angle meningiomas may cause erosions in the petrous bone [68]. About half of all meningiomas of the posterior fossa consist of cerebellopontine angle meningiomas [67]. While their incidence peaks in the fifth decade cerebellopontine angle meningiomas are 2–4 times more common in women than men [68]. Symptoms it causes include hearing loss, tinnitus, vertigo, headache, trigeminal neuralgia, long-track findings, and increased cerebral pressure (ICP) [68].

## *Meningiomas DOI: http://dx.doi.org/10.5772/intechopen.106665*

Meningiomas of this region invade the fifth and seventh nerves more frequently than acoustic neuromas [68]. Lower cranial nerve findings are also seen in large lesions [68]. It is difficult to differentiate meningiomas in this region from acoustic neuromas [42, 68]. In the differential diagnosis, subarachnoid hemorrhage, which Yaşargil noted at a rate of 6%, may be a clue to angle meningiomas [67–70]. Another distinguishing feature for meningiomas could be the dural tail [68–70]. Angiographic staining is common in meningiomas but not in acoustic neuromas [68–70]. While intracanalicular tumors are rare in meningiomas, they are always found in acoustic neuromas [68–70]. As well as there is no hyperostosis in acoustic neuromas, it is found in meningiomas [68–70]. Additionally, the internal auditory canal is enlarged in acoustic neuromas, it is normal in meningiomas [68–70]. Despite these differences, diagnosing is not always easy [68–70]. While the facial nerve is anterior or anterosuperior to the tumor in acoustic neuromas, it can be located anywhere in the tumor in meningiomas [68–70]. For this reason, it is relatively easy to preserve hearing in meningiomas, but this is often impossible in acoustic neuromas [69, 70]. To reach these tumors, petrosal procedures in the anteromedial location of the tumor and retrosigmoid suboccipital procedures in the cerebellopontine angle location are used [70]. The surgeon's choice of surgical approach mainly depends on the characteristics of the tumor and the surgeon's personal preferences and the patient's clinic [70]. Most neurosurgeons prefer a single approach, while others use combinations. However, there are some points that need to be mentioned [70]. Petrosal procedures should be performed in patients with hearing loss because hearing preservation is not possible with this technique [70]. Retrosigmoid suboccipital procedures can be used in lesions that have serviceable hearing and can be resected posteriorly [70]. However, in the retrosigmoid approach, it is relatively more difficult to protect the adjacent cranial nerves [70].

## *3.2.9 Petroclival meningiomas*

Petroclival meningiomas arise from the upper part of the ⅔ clivus and petrous region medial to the fifth nerve [71]. The brainstem and basilar artery complex are typically pushed to the opposite side [71]. Clival meningiomas originate in the superior part of the clivus ⅔ and midline [71]. They cause backward displacement of the brainstem and basilar artery complex [72–74]. Another group is the sphenopetroclival meningiomas defined by Yaşargil [71]. This type occurs when Meckel's cave is invaded by petroclival meningiomas [71]. In addition to the features of petroclival meningiomas, they invade the lateral wall of the cavernous sinus [71–75]. In the typical clinic of these tumors, headache and ataxia are observed with a frequency of 70%, while spastic paraparesis and somatosensory deficits are less common [71–75]. In these tumors, the fifth and eighth nerves are involved in ⅔ of the cases, the seventh nerve in half of the cases, and inferior cranial nerves in ⅓ of the cases [67, 72, 76]. Commonly used approaches for resection of these tumors are petrosal procedures, mid-fossa base procedures, or extended petrosal procedures that combine these two procedures [72, 76, 77].

## *3.2.10 Falx meningiomas*

They can originate from any part of the falx [78]. Depending on their location, they are examined in three sections called anterior, middle, and posterior [78].

Anterior falx meningiomas are found in the part of the falx between the crista galli and the coronal suture [78]. Meningiomas of this region show an insidious

course clinically and become noticeable only when they have reached a large size [78]. Common findings include headaches, visual disturbances, personality changes, and dementia [78]. Seizures are observed less frequently than in other regions [78].

Meningiomas of the middle falx arise in the falx region between the coronal suture and the lambdoid suture [78]. This region's most common clinical finding is focal motor or Jacksonian spasms [78]. Similarly, motor deficits may be seen [78].

Posterior falx meningiomas are meningiomas consisting of the falx portion between the lambdoid suture and the torcula [78]. They most commonly present with headaches [78]. Visual hallucinations and homonymous hemianopsia may occur in these patients [78].

For the resection of these tumors, various approaches can be used depending on the site of onset [27, 78].

## *3.2.11 Parasagittal meningiomas*

These tumors are meningiomas that infiltrate the sagittal sinus, surrounding convex dura, and falx [79]. Bone involvement may also occur. According to the classification system of Sindou and Alvernia, sinus invasion is studied in six types (**Figure 2**)[79].

Type I: Lesion attachment to the outer surface of the sinus wall.

Type II: Tumor fragment inside the lateral recess.

Type III: Invasion of the ipsilateral wall.

Type IV: Invasion of the lateral wall and roof.

Types V and VI: Complete sinus occlusion with or without one wall free, respectively [79].

As with falx meningiomas, they are studied as anterior, middle, and posterior. Again, the symptoms and findings are the same as in Falx tumors [78, 79].

The most important question in surgical treatment is the condition of the sinuses [27, 78, 79]. Anterior meningiomas can be resected even if the sinus is open, but excision cannot be performed in intermediate and posterior tumors without complete closure of the sinus [27, 78, 79]. In such cases, subtotal resection (STR) is performed [27, 78, 79].

Surgical intervention for these lesions can be performed in various ways, depending on the location of the tumor [27, 78, 79]. All surgical methods used in other meningioma lesions can be used singly or in combination [27, 78, 79].

**Figure 2.** *Sindou and Alvernia classification.*

## *3.2.12 Convexity meningiomas*

Convexity meningiomas are meningiomas that are not associated with the dura of the skull base and do not invade the dural venous sinuses [80, 81]. They account for 15% of all meningiomas [80, 81]. They have been classified into precoronal, coronal, postcoronal, paracentral, parietal, occipital, and temporal subgroups by Cushing and Eisenhardt [28]. Clinically, the main findings are headache, mental symptoms, visual disturbances, and epilepsy [80, 81]. The surgical approach differs depending on the origin of the lesion [35, 82, 83]. Complete excision is simple compared with other groups, and mortality is negligible [35, 82, 83].

## *3.2.13 Tentorial meningiomas*

Tentorial meningiomas are divided into three groups as medial, lateral, and falcotentorial meningiomas [84]. Tentorial meningiomas grow below or above the tentorium [84]. In most cases, the tumor grows infratentorial and typically causes headaches and ataxia [84].

The subtemporal approach is recommended for medial and lateral tentorial meningiomas [84]. An interhemispheric or supratentorial approach is recommended for posterior tentorial and falcotentorial meningiomas, and a combined supratentorial approach is recommended for the infratentorial portion of lateral tentorial meningiomas [27, 84].

## *3.2.14 Intraventricular meningiomas*

Intraventricular meningiomas account for 5% of all meningiomas [85]. They originate from the tela choroidea or the choroid plexus, and 80% are in the lateral ventricle, 15% in the third ventricle, and 5% in the fourth ventricle [85]. Most of the meningiomas in the lateral ventricle are located in the trigone region [85]. Headache, vomiting, speech disorders, homonymous hemianopsia, and sensorimotor hemiparesis are observed in meningiomas at the trigonal region [85]. Papilledema, vomiting, and hypothalamic disturbances are common in third ventricular meningiomas [85]. Obstructive hydrocephalus findings occur in the fourth ventricle meningiomas [85]. Intraventricular meningiomas are supplied by the choroidal arteries and their venous drainage is through the ependymal veins [85]. They are often of the fibroblastic type [85]. Since 90% of intraventricular meningiomas are WHO grade I, the prognosis is favorable [85]. Surgery is considered curative if gross total resection is possible [85]. However, 10% of patients have intraventricular meningiomas WHO grades II and III and may require additional radiosurgery [85]. According to the WHO grading for all types of meningiomas, survival rates are valid for intraventricular meningiomas, but the recurrence and mortality rates are lower due to their generally lower grade and a better rate of complete surgical resection [85].

Transcortical interventions (middle frontal gyrus, posterior-middle temporal gyrus, superior parieto-occipital fissure) and interhemispheric transcallosal approaches are used in the surgery of meningiomas located in the lateral ventricle [44]. While the interforniceal approach is preferred for meningiomas in the third ventricle, the suboccipital route is preferred for meningiomas in the fourth ventricle [44].

## *3.2.15 Orbital meningiomas*

Meningiomas in orbit are divided into primary and secondary meningiomas [49]. Whereas primary orbital meningiomas arise from the optic nerve sheath and are located throughout the orbit, secondary tumors arise from the dura around the orbit and grow into the orbit [49]. Orbital meningiomas account for 9% of all orbital tumors [49]. They commonly occur in childhood [49]. Loss of vision is the most important symptom [49]. In addition, optic disk changes, visual field loss, proptosis, and pain may also occur [49]. The recurrence rate ranges from about 17–42% [86]. The recurrence rate is lower in patients receiving postoperative radiation therapy, depending on the WHO grade [86]. Surgical interventions include transorbital and transcranial procedures [86].

## *3.2.16 Calvarial meningiomas*

This group is a rare tumor that arises from the calvarium [27]. They do not have intradural components [27]. Cases have been reported in the scalp, temporal bone, jugular foramen, orbit, paranasal sinuses, infratemporal fossa, and parotid gland [27]. They are more common in childhood and among the elderly [27].

## **4. Etiology**

Compared with malignant glial tumors, there are fewer studies on the etiologic risk factors for meningiomas. Although the exact etiology of meningiomas is still unknown, some recognized risk factors are present.

## **4.1 Molecular etiology (genetic)**

Although meningiomas have benign pathophysiology, they are thought to arise from clonal growth from a single cell, which is a characteristic of carcinomas [87, 88]. Sporadic meningiomas are generally associated with one or more focal chromosomal deletion(s) [87, 88]. In contrast, atypical and malignant meningiomas usually have more than one chromosomal replica number change [89]. It is now known that the complexity of genetic abnormalities also leads to an increase in tumor grade in meningiomas [90]. The most common genetic disorder associated with an increased risk of meningiomas is NF2 [91]. These patients are more likely to develop second- and third-grade meningiomas or multiple meningiomas [91]. Gorlin, von Hippel-Lindau, Li-Fraumeni, multiple endocrine neoplasia (MEN), and Cowden disease are also syndromes that predispose to the development of meningiomas [92].

## **4.2 Ionizing radiation**

Exposure to ionizing radiation is the most important risk factor for developing meningiomas [92, 93]. It has been found that there is an increased risk for the development of meningiomas when ionizing radiation is used in the context of indications for the treatment of various diseases (e.g., cranial irradiation for tinea capitis, dental radiography) [93]. This risk is increased not only in patients who have been exposed to ionizing radiation for treatment but also in people who have been exposed to the effects of the atomic bomb [93]. Ionizing radiation is a risk factor for the

## *Meningiomas DOI: http://dx.doi.org/10.5772/intechopen.106665*

predisposition of meningiomas, with a six- to tenfold relative risk after a delay and without a dose relationship [93]. Based on this risk, ionizing radiation of radiographic examinations was recalculated and reduced [93].

## **4.3 Hormone**

Because of the high incidence of meningiomas in women of reproductive age and women with breast cancer as well as the changes in meningioma size found in studies during pregnancy, the menstrual cycle, and menopause, it has been suggested that the increased risk for meningiomas may be related to hormones [94]. However, no association has been found between the use of oral contraceptives and the development of meningiomas [95, 96]. In addition, some other studies find no association between meningioma development and hormonal factors [95, 96].

Among the etiologically explained risk factors, head trauma, the presence of breast cancer, smoking, and cell phone use are mentioned. However, the causal relationship between these factors and meningioma development has not been established. For this reason, future studies will clarify these issues and uncover new developmental/acquired etiologic factors.

## **5. Diagnosis**

These dural-based tumors are routinely discovered incidentally by neurologists, neurosurgeons, and other clinicians because of the wider use of computed tomography (CT) and magnetic resonance imaging (MRI) [97]. Nowadays, radiologic imaging with contrast-enhanced cranial CT or MRI provides very useful information not only in the diagnosis of meningiomas but also in monitoring asymptomatic cases, deciding on surgical/systemic treatment, and distinguishing between tumor recurrence and radiologic changes [97]. Histopathologic analysis by biopsy or resection is required for definitive diagnosis. However, thanks to evolving neuroradiology, MRI results have become the standard method for radiologic diagnosis and follow-up of meningiomas [97]. Contrast-enhanced CT can be performed in patients whose MRI is contraindicated for patient-related reasons (e.g., pacemakers, in-body metallic implants, claustrophobia) [97]. In addition, CT is superior to MRI in radiologic diagnosis by revealing the chronic effects of the tumor such as intra-tumoral calcification (25% of cases seen) and changes in the bone structure such as hyperostosis and interosseous bone growth [97]. However, the simultaneous use of both diagnostic tools provides more detailed information before and after surgery in most cases [97]. When imaging findings suggest meningioma, a biopsy is not required in these patients [97].

Benign meningiomas are usually isointense or mildly hypointense on T1-weighted brain imaging and hyperintense on T2-weighted/FLAIR sequences of MRI [97]. They have a characteristic thickened, contrast-enhancing dural tail (60%), and contain a CSF cleft [97]. Additionally, they have clearly defined margins and homogeneous enhancement (95%) [97]. Meningiomas displace the brain away from the overlying dura [97]. The dural tail is a useful radiologic finding at diagnosis to distinguish meningiomas from other lesions such as schwannomas [97]. However, the dural tail is not pathognomonic for meningiomas and may also be seen in metastases or hemangiopericytomas [97]. Again, it should be remembered that approximately 10–15% of meningiomas may have an atypical appearance on MRI images that mimics metastases or malignant gliomas [98]. Central necrosis, which is specific for

malignant gliomas (hypointense, non-enhancing central necrotic area in the lesion at the T1-weighted images), can interestingly be found in both benign and malignant variants of meningiomas [98]. A cystic appearance is a rare radiologic finding for this tumor [98]. Although uncertain, peritumoral edema can be seen on T2-weighted and FLAIR images [98]. Peritumoral edema is attributed to more aggressive meningiomas invading the brain [98]. In particular, significant peritumoral edema may be present in secretory meningiomas [98].

MRI spectroscopy (MRIs) can be used for differential diagnosis of meningiomas [99]. This modality can be particularly beneficial in patients who cannot undergo surgery [99]. Compared with normal brain tissue, MRIs usually reveal decreased N-acetyl-aspartate and creatinine peaks and increased choline and alanine peaks. In contrast, atypical meningiomas may have an increased lactate peak caused by necrotic tumor tissue [99, 100]. Buhl et al. reported a characteristic lactate peak in more than 63% of patients with atypical meningiomas on preoperative MRIs [100].

Depending on radiology, WHO grading degrees may be suspected [101]. However, there are currently no imaging criteria for preoperative differentiation of the various WHO grades of intracranial meningiomas [101]. Therefore, there is still uncertainty about which patients should be followed up or operated on early [102]. Although it is not possible today to determine the variants of meningiomas radiologically, invasion of the adjacent brain parenchyma and bone tissue in its location, heterogeneous contrast enhancement, intense peritumoral edema, seen in T2-weighted and FLAIR sequences, and central necrosis seen as hypointense in the T1-weighted sequence (non-enhancing tumor area) are also considered indicative of high-grade meningiomas [102, 103]. In addition, meningiomas with calcifications on cranial CT (hyperdense) and T2-weighted MRI imaging (hypointense) have been associated with a slower growth rate [104, 105].

Recently, the role of radiomics has been investigated in meningiomas. Radiomics consists of the correlation of quantitative radiological features with pathological and molecular features of the tumor [106]. This novel method has the potential to increase knowledge of the tumor, which is beneficial given the tumor's hard-to-access location [106]. Several studies showed a potential role of radiomics in predicting the pathological grade and subtypes of meningiomas [106–109]. However, it is not currently in standard clinical use.

Because meningiomas easily invade the cerebral veins and cerebral venous sinuses, the MRI venogram is useful to visualize the relationship of the tumor to the lateral or superior sagittal sinus (direct invasion or compression) to determine the degree of tumor invasion and to reveal collateral venous outflow [107].

Conventional angiography no longer has a place in diagnosing meningiomas [110]. However, this technique can be used for intravascular embolization or to clarify the diagnosis when the appearance on CT or MRI remains unclear [110]. Angiographic findings suggest that meningioma includes dural arteries supplying the central tumor and pial arteries supplying the tumor periphery and bilateral vasculature [110].

Although positron emission tomography (PET) is not routinely used in clinical practice, it can be useful for meningiomas at the skull base, which are often difficult to detect with standard imaging modalities CT and MRI [111, 112]. Furthermore, PET(68-Ga-DOTATATE) can aid in the diagnosis during follow-up of recurrent meningiomas in cases where biopsy specimens cannot be obtained easily or undecided ones [111, 112].

## **6. Clinic**

We have briefly mentioned above the clinical appearance caused by meningioma subgroups specifically. In general, clinical findings in meningiomas result from the tumor tissue compressing adjacent neural, vascular structures or occluding CSF flow pathways, cortical veins, and venous sinuses, depending on the compartment in which meningioma originated [113, 114]. Symptoms and signs of ICP such as papilledema, headache, nausea, and vomiting can occur not only in anterior skull base meningiomas that reach giant sizes (6 cm in diameter) but also in small tumors that cause severe reactive vasogenic edema [113, 114]. Although not common, they may present with clinical signs of transient ischemic attack or intracranial hemorrhage [113, 114]. Usually, meningiomas commonly cause peritumoral edema and epileptic seizures episodes (27–67%), which are thought to be site-dependent and may be partial (37%), complex partial (8%), generalized (60%), or a combination thereof [115, 116].

## **7. Treatment**

The treatment of meningiomas varies widely and depends on patient-related factors such as age, performance status, concomitant medical conditions, and the targeted treatment modality (observation, symptomatic treatment, surgical treatment). Currently, the main treatment modality is observation with intermittent radiologic imaging for asymptomatic meningiomas, whereas complete surgical resection is sought for meningiomas that progress or cause symptoms (**Table 3**) [117].

## **7.1 Observation**

Because the tumor growth rate for asymptomatic intracranial meningiomas is 2–4 mm/year, they can be treated conservatively. However, close surveillance is required clinically and radiologically, especially in young patients, because they can grow rapidly [117]. When a patient with a meningioma is planned for follow-up, the gold standard for it is intermittent MRI [117]. Contrast-enhanced T1-weighted sequences provide images suitable for evaluating volume increases in tumor mass [117]. In a study to determine tumor growth behavior in 64 patients with asymptomatic meningiomas, no patient had tumor-related symptoms in a 5-year follow-up [117]. During this 5-year follow-up period, 48 (75%) of the 64 patients experienced an increase in tumor size of 15% or more [117]. Therefore, serial imaging can follow asymptomatic meningiomas until permanent tumor growth is detected radiologically or symptoms develop [117]. However, even if an increase in tumor size is detected on serial volume measurements in the follow-up, the decision to proceed


with surgery still depends on the patient's age, symptomatology, and comorbidities [118, 119]. This is because the morbidity rate in surgically treated asymptomatic meningiomas is not negligible, especially in patients older than 70 [118, 119]. Therefore, the natural history of incidentally discovered tumors remains a concern for physicians and patients.

## **7.2 Surgery**

Surgery is the primary treatment for meningiomas with volume increase on symptomatic or neuroradiologic follow-up [117–120]. The main goal of surgery is:


The basic principles of surgical treatment are central debulking and peripheral dissection, which facilitates resection in hard and calcified tumors, with good control of bleeding during surgery [27, 119]. Often, an arachnoid plane allowing reliable differentiation of the tumor from normal structures is discovered during surgery [27]. If this arachnoid plane is preserved, bleeding and injury to neurovascular structures are largely avoided [27].

As with other CNS tumors, the primary goal of surgical treatment for meningiomas is complete resection of the pathologic tissue [120]. However, several patient-related factors, such as tumor location, invasion of adjacent brain parenchyma, venous sinuses, encasement of arteries and cranial nerves by tumor tissue, or age and cardiovascular disease, may prevent complete resection from achieving good outcomes [27, 119, 120]. Therefore, complete resection is impossible without compromising functional outcomes for meningiomas in near-critical neurologic structures or surrounding neurovascular structures in some patients [27, 119, 120]. While resection for convexity meningiomas is relatively simple, resection for parasagittal tumors is more complicated because they often invade the sagittal sinus [120]. In cases where the tumor invades the sinus and venous flow persists, the portion of the tumor within the sinus should not be resected because of the risk of air embolism, hemorrhage, and acute sinus thrombosis [120]. Skull base meningiomas in the tuberculum sella, sphenoid wing, cerebellopontine angle, olfactory groove, or petroclival region require advanced surgical techniques [120]. Endoscopic endonasal procedures have been described that allow safe access without retraction of the parenchyma, especially for tumors located in the anterior midline region of the skull base [120]. Where necessary, an attempt should be made to achieve gross total resection (GTR) using all available modalities.

As with other intracranial tumors, it is possible to assess the success of the surgical resection with contrast-enhanced CT or MRI in the first 72 h after surgery [121]. In addition, neuro-radiologic imaging forms the basis for the Simpson grading system, which can predict recurrence after surgery [121]. According to Simpson's criteria, the extent of resection is considered a factor for progression-free and disease-free survival [121]. As the grade increases from Simpson grade 1 to grade 5, recurrence rates also increase (**Table 4**) [121]. Another factor affecting recurrence rates is the

## *Meningiomas DOI: http://dx.doi.org/10.5772/intechopen.106665*

histopathologic grading of meningiomas [122, 123]. The 5-year recurrence rate after total gross resection of WHO grade I meningiomas was 7–23%, whereas WHO grade 2 meningiomas were 50–55%, and WHO grade 3 was 72–78% [122, 123]. However, the 15-year recurrence rate in patients who underwent GTR for all types of meningiomas was 24–60%, whereas this rate was over 70% in patients who underwent STR [124]. Other factors affecting survival include patient age and tumor location.

Preoperative embolization may be performed before surgery in very large or difficult-to-remove tumors with complex vascular feeding [125, 126]. However, because of cardiovascular complications, preoperative embolization is not a routine procedure and is not recommended in every case [125, 126]. In addition to shortening the operative

**Table 4.** *Overall evidence-based treatment algorithm.*

time, preoperative embolization may be beneficial in cases where it is difficult to reach the feeding arteries, such as petroclival meningiomas [125, 126]. Therefore, the surgical team should evaluate the decision individually in each case [125, 126].

## **7.3 Endovascular treatment**

The increase in interventional neuroradiologic applications and developments in microvascular catheters have also raised hopes for endovascular treatment of meningioma, which is a vascular tumor [127]. Some studies on this topic have found that the benefits of endovascular therapy are uncertain [128]. Therefore, significant obstacles remain to accepting endovascular intervention as a treatment modality. Selective microcatheter embolization of the meningeal arterial supply with various agents can be remarkably effective in the devascularization of the tumor, and preoperative embolization reduces perioperative bleeding [129]. However, there is still uncertainty about when preoperative embolization before resection is appropriate [129]. Furthermore, because atypical histopathologic features are more common in patients undergoing endovascular embolization, embolization could induce atypical histologic changes associated with benign (WHO 1) meningiomas [130, 131]. For the above reasons, endovascular embolization may be considered an alternative treatment option for managing meningiomas, but only for patients in whom surgical intervention is not feasible. It is not a stand-alone treatment modality.

## **7.4 Radiotherapy**

Although radiation therapy has been used to treat tumors for many years, there are not as much clinical studies on treating meningiomas with radiation therapy as other pathologies. While radiotherapy (RT) is usually a secondary treatment modality to surgical resection to prevent higher-grade progression of meningiomas and reduce the recurrence rate, it may be considered a primary treatment option in a well-defined, inoperable small group of patients [132]. For this purpose, both fractionated external beam radiation therapy (EBRT) and stereotactic single-fraction radiation therapy (SRS) are used as adjuvant treatment tools [132]. SRS is increasingly used for lesions and may better protect the surrounding brain parenchyma from potential radiation toxicity [132]. Single-fraction SRS is usually limited to tumors <30 mm diameter and for meningiomas not directly adjacent to (or compressing) sensitive structures such as the hypothalamus [132]. Multifractional SRS can be used for bigger tumors [132]. Local control of meningiomas of a diameter of 3 cm or less after SRS was the effect of Simpson Grade I resection [133]. Two retrospective series found that a reduction of tumor size after SRS or EBRT provided tumor control after 5 and 10 years [134, 135]. The 10-year recurrence-free follow-up is 93.4% and 95.7%, respectively [135]. WHO grade II and III meningiomas are aggressive tumors [135]. The 1- and 4-year progression-free survival of these lesions after the first SRS is 92% and 31%, respectively [135]. Radiosurgery may be an important adjuvant and salvage therapy for lesions that will likely require more than one treatment [135]. Although discussions continue, combined treatment approaches that include surgery and fractionated RT are increasingly preferred.

## **7.5 Systemic treatments**

There is no effective medical treatment for meningiomas because the beneficial effects of systemic agents have not been fully demonstrated in clinical trials.

## *Meningiomas DOI: http://dx.doi.org/10.5772/intechopen.106665*

Currently, conventional cytotoxic agents are not thought to have a beneficial effect on the tumor. Data about that subject are generally based on observational or retrospective data from a small group of patients rather than prospective studies.

Systemic therapy is currently an alternative treatment option for a small group of patients with recurrent/progressive diseases who cannot be treated with RT or for whom further surgical resection is not possible. Thus, systemic treatment is not the initial treatment for meningiomas but the final treatment step. These can be studied as follows.

## *7.5.1 Hormone therapy*

Knowing that 70% of meningiomas have progesterone receptors, 60% have prolactin receptors, 30% have estrogen receptors, and female predominance suggests the growth of such tumors may be hormone-dependent [136–139]. Knowledge of the presence of hormone receptors has led to the idea that hormone antagonists can also be used in treating meningiomas. To this end, Koide et al. used mifepristone (progesterone antagonist) at 200 or 400 mg daily doses [140]. Although they reported improvement in 25% of the patients included in the study, they noted a decrease in tumor size in 35% of fourteen patients using the same hormone antagonist at similar doses [140]. Grunberg et al. used similar doses of mifepristone and had five out of 14 patients show a meaningful decrease in tumor size [141]. However, continuing studies with larger patient groups failed to achieve the cure mentioned above rates [140–142]. The trial with tamoxifen, an estrogen receptor modulator, conducted with 19 patients also failed to provide positive results [142].

## *7.5.2 Chemotherapy*

Hydroxyurea, a drug commonly used in cancers, inhibits proliferation by inhibiting the S phase of replication [143, 144]. Swinnen et al. reported a decrease in tumor size in three of four patients in their study with hydroxyurea [143]. However, these responses could not be replicated in phase II clinical trials, and Chamberlain's study also failed to demonstrate efficacy [143, 144]. Currently, there is no routine clinical use.

## *7.5.3 Somatostatin analogs*

Somatostatin receptors were found to be expressed in approximately 90% of meningiomas using single-photon emission computed tomography (SPECT) scanning [145]. Although 44% of 16 patients treated with a somatostatin agonist with a high affinity for somatostatin receptors (Sandostatin LAR) had positive results in terms of progression-free survival at 6 months, this agonist was found to have no effect in recurrent high-grade meningiomas [146]. In a study conducted with pasireotide, another agonist with higher receptor affinity than Sandostatin, no improvement in progression-free survival (PFS) at 6 months was observed [147]. The studies remain controversial, with no consensus. Currently, there is no routine clinical use.

## *7.5.4 Targeted agents*

In recent studies, bevacizumab, an antibody against vascular endothelial growth factor (VEGF), has been shown to inhibit growth in meningiomas [148, 149]. Bevacizumab shows this effect possibly by blocking angiogenesis [148, 149]. Overall, bevacizumab appears to be an effective therapeutic approach for patients with atypical and anaplastic meningiomas who have exhausted surgical and radiation therapy options [148, 149]. Also because of the programmed death receptor (PDL1) in solid organ tumors outside the CNS, immunotherapeutics such as nivolumab and ipilimumab are quite effective [150]. After Du et al. presented evidence of PDL1 receptors in meningiomas, the use of nivolumab in recurrent meningiomas and pembrolizumab in atypical and anaplastic meningiomas paved the way for promising clinical trials [151]. There is currently an intense debate on the subject [151]. There is still no opinion due to the studies concluded in both directions [151]. Currently, there is no routine clinical use.

## **8. Conclusion**

Within the framework of the rules of the book, we have tried to write this section without going into unnecessary detail. We hope it is useful for the reader.

## **Acknowledgements**

We would like to thank our devoted families, whom we would not be able to reach without their support and sacrifice, and Operator Doctor Engin ELMACI for his support in our clinic.

## **Conflict of interest**

The authors declare that they have no known competing financial interests or personal relationships between any person/persons or institution/institutions and the authors that could have appeared to influence the work reported in this paper.

## **Other declarations**

Finally, we dedicate it to the great Türk nation, which sheds light on our future with its thousands of years of history.

## **Appendices and nomenclature**


*Meningiomas DOI: http://dx.doi.org/10.5772/intechopen.106665*


## **Author details**

İsmail Kaya\* and Hüseyin Yakar Faculty of Medicine, Department of Neurosurgery, Niğde Ömer Halisdemir University, Niğde, Turkey

\*Address all correspondence to: hekimikaya@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 3**

## Management of High-Grade Meningioma: Present, Past and Promising Future

*Nazmin Ahmed*

## **Abstract**

High-grade meningiomas have a persistent therapeutic challenge, which the World Health Organization (WHO) categorizes as grade II and III lesions, represent 10–20% and 5% of individuals with meningiomas, respectively. Although grade I meningiomas can be completely surgically removed and have long-term progressionfree survival, higher grade meningiomas are more likely to return aggressively and to be resistant to conventional treatments. Recently, stereotactic radiosurgery (SRS) has offered promise for the treatment of localized tumors. The era of molecular targeted treatment is now upon us. Patients are being enrolled in clinical trials with a variety of innovative medications that target driver mutations, and these trials might result in more effective treatment plans. Alpha-interferon, vascular endothelial growth factor inhibitors, and somatostatin receptor agonists are among the medications that are advised for the medical treatment of meningiomas in addition to radiation and surgical excision. For the treatment of meningioma, efforts to find novel informative mutations and protein biomarkers have advanced. Several patient populations have shown promise for improved outcomes with EZH2 inhibition. Overall, it is hoped that targeted research and the application of those strategies, such as PRRT and TTF devices, would lead to better results in future. This chapter aims to discuss the neuroimaging features of high grade meningiomas, diagnostic and therapeutic implications of recently discovered genetic alterations and outcome. There will be a brief review focusing on ongoing clinical trials of novel therapeutic agents and future research scope in this arena.

**Keywords:** meningioma, molecular targeted therapy, surgery

## **1. Introduction**

The majority of primary central nervous system (CNS) tumors (37% of cases) are meningiomas. The prognosis for low grade (I) meningiomas is generally good, with a 20-year recurrence rate of 20%. Grade II meningiomas is difficult to cure and have a high chance of coming back after treatment. However, the prognosis for anaplastic meningiomas is dismal, with a median overall survival of only 1.5 years [1–3]. Additionally, clinical professionals frequently have to make tough treatment choices in instances with complicated morphology or localization, close to important brain

structures like the optic nerve, or when incidental cancers are present. Here, we have discussed the epidemiology, natural history and cytogenetics of high grade meningioma. Moreover, we have discussed current theories of diagnosis, therapy, molecular biology. Additionally, improvements in imaging, particularly positron emission tomography (PET) and molecular profiling, are likely to soon have an influence on current clinical practice and be included into existing guidelines [4–6].

## **2. Epidemiology**

Around 70% of cases are classified as WHO grade I meningiomas, 28% as WHO grade II meningiomas, and just around 3% as WHO grade III meningiomas. Meningiomas of grades II and III are more prevalent in males than in girls, according to various studies, however some also found different findings [7]. Research among participants in USA found that the age-adjusted incidence rate for WHO grade II meningiomas is 0.26/100,000 in the male population and 0.30/100,000 in the female population. On the other hand, age-adjusted incidence rates for meningiomas of WHO grade III are 0.08 per 100,000 for men and 0.09 per 100,000 for women [8]. Black individuals are more likely than white people, Asian-Pacific Islanders, and then white people to have high grade meningiomas. With aging comes an increased chance of developing these meningiomas, which often affect adults around the age of 60 [9].

Around 90% of WHO grade II meningiomas survive after five years. The number of tissue and cell abnormalities is increased in atypical meningiomas (WHO grade II). These tumors have a larger chance of recurrence than benign meningiomas, develop more quickly than benign meningiomas, and frequently invade the brain (WHO grade I). In comparison to benign and atypical meningiomas, malignant meningiomas (WHO grade III) have more cellular abnormalities and progress more quickly. The two kinds of malignant meningiomas return more frequently than the other two and are more likely to penetrate the brain. 1.7% of meningiomas with tissue confirmation



*Management of High-Grade Meningioma: Present, Past and Promising Future DOI: http://dx.doi.org/10.5772/intechopen.108414*

## **Table 1.**

*Cytogenetic variation of Grade-I, Grade-II and Grade-III meningioma.*

are malignant, making up the bulk of meningiomas (WHO grade III) [8, 10]. After age 65, the chance of high grade meningiomas dramatically increases with age. The least at risk age group is 0 to 14 year olds. In comparison to other ethnic groups in the United States, African Americans have been found to have greater incidence of high grade meningioma [8]. High levels of ionizing radiation exposure have been linked to an increased risk of high grade meningiomas. Additionally, there is evidence between low radiation exposures to meningiomas. The most frequent source of ionizing radiation exposure in the US is dental X-rays. Numerous studies have connected a higher risk of meningioma to the frequency of full mouth dental radiographs. It is thought that individuals with the genetic condition Neurofibromatosis type 2 (NF2) have an increased chance of developing meningioma. Additionally, meningiomas that are malignant or numerous may be more common in NF2 patients [10]. While postmenopausal women without these traits are more likely to have Grade I meningiomas, meningioma patients with past CVA and those with grade 4/4 vascularity are more likely to develop WHO Grade II-III tumors [11] (**Table 1**).

## **3. Natural history of high-grade meningioma**

The natural history of high-grade meningioma remains largely unknown. Based on the natural history of patients younger than 60 to 70 years of age and those with meningiomas characterized by surrounding brain hyperintensity on T2-weighted MRI, absence of calcification, and tumor diameter > 25–30 mm exhibit a higher risk for early recurrence [20–23]. For patients with NF2 linked malignancies, which typically exhibit a saltatory growth pattern, it is extremely important to be aware of and take

## **Figure 1.**

*Schematic picture demonstrated the natural history of an untreated high grade parasagittal meningioma. With the course of time, progressive invasion of SSS and overlying hyperostosis and/or, osteolysis occur. Later on, pial invasion and aquisition of pial feeders give to peritumoral edema, compression/effacement of ventricles and midline shifting. (1) parasagittal meningioma, (2) invasion of superior sagittal sinus, (3) hyperostosis of overlying bone, (4) peritumoral edema, (5) midline shifting, (6) effacement of lateral ventricle, (7&8) acquisition of pial feeders.*

appropriate action in response to genetic abnormalities [24]. Because new tumors can develop in NF2 patients over their lifetime and because radiographic and symptomatic progression are unpredictable, resection may be best reserved for symptom-producing tumors, de novo, and brain edema-associated meningiomas in NF2 patients [24, 25]. Numerous investigations revealed that a number of chromosomal changes were linked to the development of cancer, and these changes may also be indicators of cancerous potential that affect tumor recurrence and a bad prognosis. Young age, lack of calcification, peritumoral edema, and high-intensity signal on T2WI were associated with clinical progression, according to Kim et al. [26] (**Figure 1**).

## **4. Diagnostic neuroimaging**

## **4.1 X-ray**

A general x-ray uses a modest quantity of radiation to provide an image of the inside organs and structures of the body. An x-ray of the head can occasionally help doctors locate a tumor, but it is insufficient to identify meningioma. By using X-Ray radiograph imaging, osteolysis and hyperostosis results may also be observed [27].

## **4.2 Computed tomography (CT or CAT)**

A CT scan uses head x-rays to acquire photographs of the brain. A computer then combines these data to create a comprehensive, three-dimensional image

*Management of High-Grade Meningioma: Present, Past and Promising Future DOI: http://dx.doi.org/10.5772/intechopen.108414*

## **Figure 2.**

*Post contrast coronal (A) and sagittal (B) CT scan of a 45 year-old lady with histopathologically proven anaplastic meningioma (WHO grade-III) demonstrated an extra-axial heterogeneously contrast enhancing right parasagittal mass, invading the superior sagittal sinus with compression and displacement of falx cerebri towards the left side. The mass had irregular margin with evidence of surrounding vasogenic edema. Beside this, no features of hyperostosis was seen.*

that displays any anomalies or tumours, including the size of the tumours. Before a scan, a patient may get an injection of a specific dye called a contrast medium to improve the image's clarity. The most effective method for identifying changes in the skull that a meningioma may produce is a CT scan. When individuals are not appropriate for MRI, particularly when the meningioma is completely ossified or calcified, CT is helpful. The first modality used to assess neurological indications or symptoms is frequently computed tomography (CT), which is also frequently the modality that finds an accidental injury [27]. For the presentation of tumourinduced osseous alterations such remodelling with localized hyperostosis and bone thickening or bone invasion with concomitant osteoblastic response (more rarely osteolysis) in malignant patients, CT continues to be the gold standard alongside MRI [28–30] (**Figure 2**).

## **4.3 Magnetic resonance imaging (MRI)**

The preferred examination for identifying and classifying meningiomas is MRI. Instead than using x-rays, an MRI creates precise pictures of the body using magnetic fields. MRIs often reveal changes in the brain brought on by tumors, such as swelling or places where the tumor has grown, and can produce more comprehensive images than CT scans. The diagnosis may be determined with an extremely high degree of accuracy when both the look and location are usual. However, in other cases, the appearances are uncommon, necessitating careful interpretation in order to determine the proper preoperative diagnosis. Meningiomas' T2-weighted imaging signal intensity corresponds with their histological subtypes. MRI offers excellent contrast definition, soft tissue characterization, and multiplanar reconstructions, making it the gold standard method for meningioma diagnosis and assessment [11] (**Figure 3**). The correlation between DWI and tumor grade is still debatable because no clear-cut statistical relationship between ADC values and tumoral behavior has yet been established. DWI has also been used to depict

## **Figure 3.**

*A lady of 35 year-old with no history of prior radiation, presented with intermittent dull aching localized headache for years. MRI of brain, T1-weighted axial (A) section demonstrated a predominantly hypointense extra-axial dural based mass measuring about 6×5 cm located along the lesser wing of the sphenoid bone. The mass became hyperintense in T2-weighted image with numerous intrinsic flow voids (B). After administration of contrast, there was intense homogenous contrast enhancement (C). Mass effect was evidenced by flattening of the underlying sulci and gyri, compression of the lateral ventricle and midline shifting. However, histopathology demonstrated Chordoid meningioma (WHO grade-II).*

higher-grade meningiomas with increased cellularity, which show reduced values on corresponding apparent diffusion coefficient (ADC) maps [31–33]. Unenhanced and contrast-enhanced MR angiography are superior at identifying intra-tumoral dysplastic vasculature. While unenhanced phase-contrast MR venogram (and also black-blood MR imaging) has been shown to be a valid tool in detecting sinus invasion, MR venogram is often employed to evaluate venous sinuses invasion thrombosis or occlusion. For both diagnosis and follow-up, MRI of the spine is the preferred modality; the features are comparable to intracranial meningiomas [28–30].

## **4.4 Cerebral angiogram**

Cerebral angiography reveals the arteries and veins in the brain with specific relationships with the tumor. After a specific dye known as a contrast medium is injected into the major arteries of the brain, CT scans are obtained. An angiography may be necessary to plan surgery because meningioma can obstruct or invade the venous sinuses or vital veins that drain blood from the brain. Additionally, the angiography might show any aberrant arteries that may be feeding the tumor (**Figure 4**). Sometimes, Digital subtraction angiography plays a pivotal role for pre-operative documentation of feeding arteries, involvement of veins, and to assess the extent of cross circulation. Beside this, intraoperative bleeding can be minimized by injecting sclerosing agents into feeding arteries in the same sitting [19].

## **4.5 Advanced techniques: Possible applications**

Conventional MRI often performs well for diagnostic reasons, although it can be exceedingly difficult to differentiate between extra-axial dural-based masses or between various meningioma subtypes. The application of sophisticated imaging techniques can improve tissue characterisation, the identification of key characteristics for surgical planning, and the discovery of prognostic biomarkers.

*Management of High-Grade Meningioma: Present, Past and Promising Future DOI: http://dx.doi.org/10.5772/intechopen.108414*

## **Figure 4.**

*CT angiogram of cerebral vessels (A) with 3D reconstruction arteriogram (B) demonstrated compression and displacement of M2 and M3 segments of left middle cerebral artery(MCA). This highly vascularized grade-II meningioma was feeded by the branches from M3 and M4 segments of MCA.*

## *4.5.1 Spectroscopy*

Spectroscopy is an MRI method used to determine the concentration of metabolites in an area of interest. Conversely, increased alanine has been shown to be unique for meningioma but can be challenging to detect. Meningiomas have high choline and reduced N-acetylaspartate as well as decreased creatinine, a metabolic profile common to other neoplastic processes. Meningiomas have been shown to have an enhanced metabolite peak at 3.8 parts per million, which helps to distinguish them from high-grade gliomas and intracranial metastases. It has been shown that MR spectroscopy cannot distinguish between atypical and normal meningiomas [34–37].

## *4.5.2 Perfusion imaging*

The dynamic susceptibility contrast (DSC) technique and the dynamic contrast enhancement (DCE) approach, both of which call for the injection of intravenous gadolinium, as well as arterial spin labeling, are methods used in MR perfusion to measure blood flow in tissues. When making a differential diagnosis, MR perfusion can be particularly helpful in separating meningiomas from dural-based metastases and from high-grade gliomas that have invaded the dura mater. However, hypervascular metastases, such as those from melanoma, renal carcinoma, or Merkel cell carcinoma, cannot be distinguished by MR perfusion. Meningioma and dural metastases from diverse sources (breast, colon, and prostate) may be distinguished by MR perfusion (increased cerebral blood volume) [38, 39].

A primary glial neoplastic process may be distinguished from intracranial metastases and meningiomas via the analysis of the time-intensity curve. Meningioma vascularity appears to be significantly correlated with cerebral blood flow (CBF) values, and more recently, a significant correlation between CBV and VEGF expression has also been shown, raising the possibility of using perfusion MR to predict

resistance to conventional treatment and potential responsiveness to anti-angiogenic therapies [40, 41].

Although peritumoral rCBV often exhibits lower values in meningiomas, probably because of peritumoral vasogenic edema, its values are greater in the case of anaplastic meningiomas (WHO Grade III) compared to the other forms. Similarly, reduced peritumoral CBF can be detected by CT perfusion, which may indicate ischemic tissue that can be salvaged following meningioma excision [42, 43].

By measuring perfusion without the confusing impact of permeability, arterial spine labeling offers the benefit of perhaps enabling the distinction between WHO Grade I and WHO Grades II and III cerebral meningiomas. Vascular permeability was directly measured using the DCE technique and had a role in the grading of meningiomas; atypical meningiomas had greater Ktrans values than benign meningiomas. Additionally, several meningioma subtypes can be distinguished with the use of MR perfusion. In comparison to meningothelial, fibrous, or anaplastic subtypes, angiomatous meningioma has shown increased tumor rCBV [43, 44].

## *4.5.3 Diffusion tensor imaging*

Diffusion tensor imaging (DTI) has been used to distinguish between various meningioma grades due to the ability to measure the amount and directionality of water diffusion. Despite the fact that high-grade meningiomas often have lower ADC values than low-grade ones, there have been some disputed findings, particularly for the other DTI metrics. In terms of predicting preoperative consistency, DTI has demonstrated considerable possibilities. The majority of research have found that hard meningiomas had greater fractional anisotropy (FA) values than soft ones, with a few exceptions. Meningioma consistency has also been found to be predicted by signal intensity on FA and mean diffusivity maps [45–47]. Tractography, derived from DTI data, may give additional information for treatment planning of skull base meningiomas [48].

## *4.5.4 MR elastography*

A promising new method called MR elastography (MRe) may be able to determine the consistency of a tumor and how it interacts with nearby structures. By analyzing the share wave passage through that specific tissue, it offers a measurement of the stiffness of the tissue. A substantial association between the MRe measures and the intraoperative qualitative evaluation of tumor consistency has been shown in recent investigations [36].

## *4.5.5 Molecular imaging*

Due to strong physiological FDG uptake in the cerebral cortex and FDG buildup in inflammatory processes, the most common molecular imaging method in the area of oncology is (18F-FDG)-PET, which employs a glucose analog to identify metabolically active cells. There is no link between FDG uptake and WHO grading, MIB-1 labeling index, or tumor doubling time, despite certain studies showing its capacity to identify benign meningioma from atypical/malignant ones and to separate recurrent/growing meningiomas from static ones [48].

On the other hand, due to the enhanced expression of SSTR II in meningiomas compared to the relatively low expression in bone and brain tissue, a strong meningioma-to-background contrast can be achieved utilizing radiolabeled somatostatin

## *Management of High-Grade Meningioma: Present, Past and Promising Future DOI: http://dx.doi.org/10.5772/intechopen.108414*

receptors II (SSTR II) ligands. When compared to contrast-enhanced MRI, PET using gallium-68-labeled SSTR-ligands, such as 68Ga-DOTATOC (DOTA-(Tyr3)-octreotid) and 68Ga DOTATATE (DOTA-DPhe1-Tyr3-octreotate), has shown a better sensitivity in identifying meningiomas. When researching optic sheath meningioma, for example, SSTR-PET is helpful for differential diagnosis. Additionally, this method enables the precise delineation of meningioma extent, which is crucial for treatment planning but difficult in cases of complex localization (skull base, orbit, falx cerebri, sagittal, and cavernous sinuses), trans-osseous growth, or in cases of meningiomas that have already received treatment, when MR contrast results are constrained [36, 49–52].

Additionally, SSTR-PET may distinguish between live tumor and scar tissue using a semi-quantitative data analysis since SSTR II expression as determined by immunostaining and semi-quantitative uptake values (SUV) have a strong correlation. Additionally, SSTR-PET may be used if MRI results are unclear since it has been shown to be more accurate at locating residual meningioma. The RANO-PET workgroup has put out an evidence-based recommendation for the use of molecular imaging in meningiomas, even if SSTR II imaging's usefulness still needs to be further validated [53–55].

## *4.5.6 Future directions*

Radiomics is a young branch of study that analyzes medical pictures and extracts several aspects from them. Following lesion segmentation, two types of features semantic and agnostic—can be retrieved from the region of interest. Semantic characteristics, such as form, position, etc., are frequently employed in radiology to characterize a lesion in detail, but in the discipline of radiomics, they are quantified with computer aid. Because artificial intelligence is better at handling this volume of data than traditional statistics, it may be used with radiology. Artificial intelligence uses algorithms to let computers learn directly from the data and make predictions on unknown datasets [56, 57].

Radiomics and artificial intelligence have showed potential in the study of meningiomas for preoperative assessment, recurrence and outcome prediction, and radiation therapy planning. Planning and monitoring of therapy also greatly benefit from volumetric evaluation of meningiomas. The ability to predict local failure and overall survival in these patients using preoperative radiologic and radiomic characteristics such apparent diffusion coefficient and sphericity has shown to be successful. With promising findings (accuracy 90%), MR radiomics has also been used to predict early progression or recurrence, which define a subgroup of skull base meningiomas. In order to enhance the texture-based distinction of tumor from edema and to distinguish vasogenic from tumor infiltration edema, radiomics has shown effective in the determination of radiation target volume, which constitutes a crucial step in treatment planning [58, 59].

## **5. Management**

Surgery with the aim of full excision is the traditional first-line therapy for all MNs. The recurrence rate for high grade meningiomas is considerable; up to 60% of tumors may return after 15 years following total excision. Due to a lack of available data, there are currently no recognized standard effective therapies [60, 61]. Depending on the tumor grade and the degree of tumor excision as determined

by Simpson, current recommendations call for progressive treatment regimens. Treatment and follow-up based on the most recent EANO is recommended widely. For grade I tumors (Simpson grades I–III) that can be completely removed, surveillance is advised. Stereotactic radiosurgery is the adjuvant of choice when complete resection is not possible [62, 63].

The ongoing ROAM/EORTC 1308 experiment is testing whether Simpson grade I resected atypical tumors should be treated with radiation or observation. The recommended follow-up schedule is six months apart for the first five years, then yearly. Given their severe clinical history, Grade III cancers necessitate major surgery and adjuvant radiation. No matter how extensive the surgery, fractionated radiation is recommended (recommendation level B). Anaplastic meningiomas should be followed up with every three to six months. Meningioma metastasis is uncommon, even in WHO grade III malignancies (**Figure 5**) [64, 65].

## **5.1 Surgical management**

The development of endoscopic transsphenoidal methods for skull base meningiomas has led to a recent progression in surgical procedures during the past few decades.

## **Figure 5.**

*A 45 year-old lady presented with progressive left sided hemiparesis for 2 years and convulsion for several episodes for the same duration. Pre-operative MRI of brain demonstrated a fairly large (6×5×4.5 cm) lobulated T1 weighted isointense (A), T2 weighted heterogeneously hypointense mass in the right parietal parasagittal location with moderate perilesional edema. The mass showed avid contrast enhancement after administration of the gadolinium (C). Mass effect was evidenced by compression of underlying sulci, lateral ventricle and gross midline shifting (8 mm). Magnetic resonance Venogram demonstrated filling defect at middle part of SSS with development of multiple collaterals (D). Follow up CT scan of brain after 5 years demonstrated no evidence of recurrence with encephalomalachic changes (E, F).*

## *Management of High-Grade Meningioma: Present, Past and Promising Future DOI: http://dx.doi.org/10.5772/intechopen.108414*

Although it was quite popular, its usage is now in decline because cerebrospinal fluid leaking could result in serious local and neurological consequences [66, 67].

Total removal is not usually feasible due to the tumor's location, infiltration of nearby tissues, and brain parenchyma. Regardless of the histological grade, postoperative Simpson grading based on the surgeon's assessment grades removal from grade 1 (complete) to 5 (simple biopsy) and enables prediction of symptomatic recurrence at 10 years from 10% to 100%. Since it was first reported in 1957, this conclusion has drawn criticism from a number of scientists, particularly given the lack of a systematic postoperative MRI. It has been established that, for grade II meningiomas, patients who undergo Simpson 1 resection had a longer overall and progression-free survival (**Figure 6**) [60, 68].

For grade III meningiomas selectively, the progression-free survival at 5 years is 28% after gross total resection alone, versus 0% after subtotal removal alone. Although the results all tend to favor gross total resection, this goal should not affect the patients' immediate neurological status, and combined strategies could be used to maximize progression-free survival while reducing the neurological risks [69, 70].

## **Figure 6.**

*A 46year-old lady, known case of papillary carcinoma of thyroid, presented with progressive enlargement of palpable hard mass in the frontal region for 2 years and convulsion for several episodes for the same duration. Pre-operative MRI of brain demonstrated a fairly large (7×6×5.5 cm) irregular T1WI iso to hypointense (A) and mixed intensity (B) mass present in both frontal region, having extra and intradural extension and invasion of the brain parenchyma. Mass effect was evident by moderate perilesional edema, compression of ventricles and gross midline shifting. After administration of contrast, there was heterogenous contrast enhancement with central non enhancing necrosed area (C). Magnetic resonance Venogram demonstrated obliteration of the anterior 1/3rd of SSS with development of multiple collaterals (D). Intraoperative photograph showed evidence of bone infiltration as well as osteolysis (E). Follow up CT scan of brain after 6 months demonstrated no evidence of recurrence (F).*

Surgical resection is typically the first-line treatment for high-grade meningiomas when the tumor is in an accessible location, and the extent of surgical resection is an important prognostic factor for progression-free and overall survival (OS), with gross tumor resection (GTR) defined as Simpson grade 1–3 and subtotal tumor resection (STR) classified as Simpson grade 4 and 5. However, rates of recurrence are high, especially with STR, and radiotherapy may significantly decrease this risk. For the purposes of this review, we will exclusively focus on the role of RT for high-grade meningiomas. Interstitial brachytherapy can be an effective adjunct to surgical resection and external beam radiotherapy, especially for aggressive, recurrent, and/or large meningiomas, but is associated with high complication rates [71–73].

## **5.2 Radiation therapy**

Radiation therapy has emerged as the first-line treatment for some meningiomas, particularly skull base lesions surrounding the vascular and nerve structures like the optic nerve sheath or the cavernous sinus. Surgery still holds a significant position because it can alleviate the tumor mass effect and establish a histological diagnosis. If imaging results are usual and surgery is not an option, radiation therapy alone may be suggested. These findings, combined with radiation-induced damage, highlight the importance of these therapies for untreatable cancers less than 3 cm. Stereotactic radiotherapy for tiny tumors has few side effects, however there have been occurrences of radionecrosis, and pituitary function must be monitored following skull base irradiation [74–78].

## **5.3 Targeted therapy**

Meningiomas exhibit a modest mutation rate, and there are not many known possible molecular targets. In high-grade MN (80% of cases), NF2 is commonly changed compared to low-grade MN (40%). The majority of the genomic and regulatory changes that have been identified in high grade MN take place in the wake of NF2 protein disruption. Furthermore, the mTOR signaling cascade is one of the primary routes connected to NF2. Natural NF2 functions as a repressor of mTORC1 and mTORC2, and when it is altered, this pathway is uncontrollably activated. This has led to the identification of mTOR and several of its downstream and upstream effectors as potential targets. Research is also being done on other pathways controlled by receptor tyrosine kinases as EGFR, PDGFR, and VEGFR (angiogenesis) [79, 80].

## **5.4 Adjuvant treatment: Radiotherapy indications**

Meningiomas of grades II and III are aggressive tumors that have greater recurrence rates. Adjuvant radiation treatment of the tumor zone could be useful for these cancers even after gross complete resection [68, 81–83]. Based on the grade, size, and location of the tumor, the best form of radiation therapy must be chosen. In the event of a small tumor, stereotactic radiation in a single or series of doses is advised. External beam irradiation is the go-to treatment option for recurring, many, or large lesions, with doses up to 70 Gy for grade II-III meningiomas, whether using 3D conformal radiotherapy or intensity-modulated radiation therapy with or without tomotherapy. Additionally helpful, proton radiation can be utilized in conjunction with photon radiotherapy [84, 85]. Tumor recurrence less likely (2%) with Stereotactic Radiotherapy compared to 12% for surgical treatment [86].

## *Management of High-Grade Meningioma: Present, Past and Promising Future DOI: http://dx.doi.org/10.5772/intechopen.108414*

For grade III tumors, it is established that adjuvant radiation improves long-term control and overall survival, even after total gross removal. In contrast, there is conflicting evidence for its role in grade II meningiomas. It has been shown that radiation therapy improves overall and progression-free survival when the tumor has been sub-totally removed, but not after total gross resection. Indeed, reported side-effects of radiotherapy and radiosurgery are usually mild but there is also evidence that radiation increases the risk of malignant transformation [70, 87–89].

After stereotactic radiosurgery for brain malignancies, radiation necrosis is a known consequence that affects 15% of patients. No matter the type of tumor in patients having radiosurgery, large diameter and high doses were reliable independent risk factors that led to more often occurring radiation necroses. Due to the increased risk of developing radiation necrosis, other therapeutic approaches may be taken into account in lesions with a large volume and an anticipated high radiation dosage [90]. Grade III anaplastic meningiomas are malignant (cancerous) and associated with cranial radiation exposure. People with neurofibromatosis type 2 are also at increased risk for developing meningiomas [91]. Radiation exposure during childhood significantly increases the risk of second malignancy as compared to older population. Malignant transformation can occur after radiation treatment in around 2% people due to insufficient killing of cells and some of the surviving cells acquire mutations in genes, such as TP53, that can transform a benign tumour into a malignant one [92, 93].

## **5.5 Chemotherapy and ongoing clinical trials**

In the context of meningioma, chemotherapy is regarded as experimental since there is insufficient data on most drugs or just conflicting findings. As a result, their usage is only advised in anaplastic situations and is preferred within clinical studies. With SMO- and NF2-mutant meningiomas, respectively, targeted therapy studies for SMO and FAK inhibitors are currently being conducted. Only this trial stratifies individuals according to tumor genotype and considers potential driver mutations. Regardless of molecular background, the mTOR inhibitor vistusertib is being examined in phase II research; nonetheless, there may be a benefit to mTOR inhibition in cancers that have PI3K or AKT mutations. Bevacizumab, a number of immune checkpoint inhibitors, and tumor-treating technologies are also being studied [94, 95].

The European Organization for Research and Treatment of Cancer (EORTC) oversaw a phase II research that compared adjuvant postoperative radiation treatment with observation in patients with newly diagnosed grade II or grade III meningiomas between 2008 and 2013. (NCT00626730, Switzerland). Due to significant protocol violations and inclusion issues, this experiment had to be stopped. The second study, the American RTOG 0539 (NCT00895622) trial, involved 244 patients and is still underway. It focuses on observation for low-risk meningiomas and radiation for intermediate and high-risk meningiomas. After three years, preliminary results indicate that patients with totally resected grade II and recurring grade I who received postoperative radiation had a 96% survival rate without progression [68, 96]. A phase II randomized controlled study (ROAM/EORTC-1308) comparing radiation (60 Gy in 30 fractions) with observation after surgical excision of an atypical meningioma was launched in the UK in 2015. Distinct facilities have different treatment decisions in clinical practice. In the United Kingdom, Germany, and France, radiation is administered to patients after subtotal grade II removal by 59%, 74%, and 80% of neurosurgeons, respectively, whereas following grade II gross complete resection by 45-60% of neurosurgeons, immediate adjuvant radiotherapy is recommended [64, 97, 98].

## **6. Challenges in meningioma management**

## **6.1 Surgical challenges**

Due to poor localization of otherwise benign tumors, such as skull base meningiomas, or invasion of healthy brain, which indicates malignancy in the first place, surgery might be challenging. While the first group's neurosurgical procedure improves, anaplastic tumors require adjuvant treatment. It is suggested to employ advanced preoperative and postoperative imaging methods for tumor definition, determining residual tumor mass, and identifying bone or brain invasion [53, 99].

## **6.2 Radiotherapeutic challenges**

Patients with poor clinical outcomes, tumors with complicated morphologies, or cancers in challenging sites are frequently evaluated for primary or adjuvant radiation. Planning for radiation is likewise impacted by all of these variables. It is essential to precisely assess tumor size in order to treat the tumor mass as a whole while sparing normal brain tissue and important systems like the optic nerve. PET imaging employing SSTR ligands (current data indicate 68Ga-DOTATOC) has shown to be helpful in planning the target volume in skull base cancers for stereotactic or intensity-modulated radiotherapy, and may help with both volume definition and dose sparing [100–102].

## **6.3 Peritumoral edema**

Peritumoral edema is a symptom of meningiomas in 40–66% of cases. Particularly for the histological subtype of secretory meningiomas, which are non-NF2 tumors distinguished by the co-occurrence of KLF4 and TRAF7 mutations, life-threatening episodes of peritumoral edema have been observed. Steroids, particularly dexamethasone, are the mainstay of treatment for peritumoral edema, however antiangiogenic therapy may be used in rare circumstances where (long-term) adverse effects or inadequate effectiveness are present. Critical cases, particularly those with secretory meningioma, may necessitate treatment in an intensive care unit with sedation, mechanical breathing, and intracranial pressure monitoring [103–105].

## **6.4 Meningioma en plaque**

En plaque meningiomas are tumors that develop along the dura in a pattern resembling a sheet. They frequently include the orbit, but mostly occur at the sphenoid wing. They often have a noticeable hyperostosis at presentation. With extensive complete resection occurring in 56–83% of cases, their surgical removal is difficult. Therefore, a combination primary strategy with adjuvant radiosurgery may be preferable over extensive resection [106, 107].

## **6.5 Optic nerve sheath meningioma**

1-2% of meningiomas are optic nerve sheath meningiomas (ONSM). When MRI results are ambiguous, 68Ga-DOTATATE-PET molecular imaging should be considered to rule out other possible diagnoses (e.g. lymphoma, optic neuritis, metastasis). OnSM, in particular intracanalicular ONSM, might resemble ocular neuritis. Most of the time, surgery is not an option, particularly when the tumor and the optic nerve

share the same blood supply. The suggested treatment of preference is stereotactic fractionated radiation [50, 108, 109].

## **6.6 Multiple meningiomas**

The majority of multiple meningiomas are associated with neurofibromatosis type 2, which is identified by heterozygous NF2 germline inactivation. In NF2, intracranial meningiomas frequently involve numerous tumors, with a median of three tumors. Even though the majority of the evidence predates the difference between sporadic NF2-mutated meningiomas and non-NF2 sporadic cases, meningiomas with neurofibromatosis type 2 are more likely to be atypical or anaplastic than sporadic instances. Young age ( 30 years) at the time of the initial meningioma presentation should raise the possibility of a germline mutation and may call for molecular testing. Patients with suspected or confirmed neurofibromatosis should be provided genetic counseling due to the disease's high penetrance and potential impact on family planning. Other genetic predispositions to meningioma have been identified in addition to neurofibromatosis type 2. Clear cell meningioma of the spinal cord and intracranially are predisposed by SMARCE1 mutations [25, 110–112].

## **7. Future research**

In bigger trials that stratify between grade-2 and grade-3 meningioma, combination regimens such as ICI with targeted treatments or new therapeutics targeting immunosuppressive myeloid cells will be evaluated. Future investigations that stratify patients based on previous systemic therapies are necessary given the evidence that chemotherapy sensitizes solid tumors to ICI by increasing dendritic-cell activation and decreasing regulatory T-cell and myeloid-derived suppressor-cell responses [113, 114].

The most often used and researched adjuvant treatment for meningiomas is radiotherapy, however there are still a lot of unanswered problems. The majority of experts think that RT has no place in treating WHO grade I cancers, unless they are symptomatic primary or recurring tumors that cannot be surgically removed. Numerous phase II and randomized controlled trials are attempting to shed light on the function of radiation in WHO grade II GTR tumors, despite the fact that this involvement has not yet been completely understood. In a phase II trial (RTOG 0539), it was found that the intermediate risk group's 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 98.3% and 96%, respectively, for newly diagnosed WHO grade II GTR (69.2%) and recurrent WHO grade I with any resection extent (30.8%), respectively (OS). Using adjuvant RT at a high dosage of 60 Gy, WHO grade II GTR meningiomas were shown to have an 88.7% 3-year PFS and a 98.2% 3-year OS in another phase II study. Currently, grade II GTR meningiomas receiving adjuvant RT are the subject of the randomized controlled trials ns20191111, NRG-BN003, and the ROAM/EORTC-1308 study, which compares at least 5-year OS and PFS [115–117].

There are clinical trials investigating pathway-directed therapies such as MEK pathway inhibitor, selumetinib (SEL-TH-1601, NCT03095248), CDK-p16-Rb pathway inhibitor, ribociclib (LEE-011, NCT02933736), and mTOR-pathway inhibitor, everolimus (NCT01880749 and NCT01419639), and vistusertib (AZD2014, NCT03071874). The ALTREM clinical trial is investigating the co-administration of phosphoinositide 3-kinase α (PI3Kα) specific inhibitor, alpelisib, and the MEK inhibitor, trametinib (NCT03631953). The phase II CEVOREM trial demonstrated that

the coadministration of everolimus and octreotide (SSTR2A agonist) had a 6-month PFS of 55%, and 6- and 12-month OS of 90% and 75%, respectively. The CEVOREM trial showed more than a 50% decrease in the growth rate at 3 months in 78% of tumors and the median tumor growth rate over 3 months decreased from 16.6% before treatment to 0.02% at 3 months and 0.48% at 6 months after treatment. The NCT02831257 trial demonstrated that patients treated with AZD2014 had a 6-month PFS of 88.9 and 5.6% (1/18) of patients experienced a decrease in tumor volume of at least 20% compared to baseline [118].

There are also clinical trials investigating immunotherapy agents such as checkpoint inhibitors PD-1 antagonist, nivolumab (NCT02648997, NCT03173950, and NCT03604978 in combination with ipilimumab), another PD-1 antagonist, pembrolizumab (NCT03279692, NCT03016091, and NCT04659811 in combination with stereotactic radiosurgery), and PD-L1 antagonist, avelumab (NCT03267836 in combination with proton radiotherapy).

The discovery of innovative treatments to combat meningioma is being driven by growing biological understanding of this disease. Additionally, prognostication and trial stratification may benefit from genomic and epigenetic characteristics. Meningioma quantitative radiomic characterizations that are still under development may offer more tumor stratification tools and early tumor behavior prediction at the time of initial diagnosis. Finally, taking into account the multidrug-resistant meningioma's cellular heterogeneity, which cancer stem cells bestow, opens a parallel pathway for therapeutic discoveries.

## **8. Conclusion**

Meningioma development has been linked to particular molecular changes and ionizing radiation. In many cases of high-grade meningioma, current treatment protocols using surgery and/or radiation are sufficient for tumor management. Prospective research is required to confirm potential molecular prognostic indicators and detect negative clinical trends early on. An integrated diagnostic approach can increase the precision of recurrence and outcome forecasting and assist in the development of customized treatment programs for particular patients. Despite the discovery of important mutations and signaling pathways, targeted systemic treatments are still lacking, despite the fact that several clinical studies are now being conducted.

## **Conflict of interest**

The author of the chapter declares that, there was no conflict of interest.

*Management of High-Grade Meningioma: Present, Past and Promising Future DOI: http://dx.doi.org/10.5772/intechopen.108414*

## **Author details**

Nazmin Ahmed

Department of Neurosurgery, Ibrahim Cardiac Hospital and Research Institute (A Centre for Cardiovascular, Neuroscience and Organ Transplant Units), Shahbag, Dhaka, Bangladesh

\*Address all correspondence to: nazmin.bsmmu@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[111] Smith MJ, Wallace AJ, Bennett C, Hasselblatt M, Elert-Dobkowska E, Evans LT, et al. Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. The Journal of Pathology. 2014;**234**:436-440. DOI: 10.1002/path.4427

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## **Chapter 4**

## Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors

*Mustafa Caglar Sahin and Gokhan Kurt*

## **Abstract**

Pituitary neuroendocrine tumors (PitNETs) arising from adenohypophyseal cells are generally accepted as benign. It is a very heterogeneous group of tumors according to their origin, biological behavior, and growth patterns. It is the third most common intracranial tumor type after meningiomas and gliomas. Transsphenoidal surgery (TSS) is the primary treatment of choice in all PitNETs except for lactotroph tumors, which are primarily treated with dopamine agonists. In this book section, surgical approaches in the treatment of PitNETs will be explained. In addition, PitNET radiosurgery will be explained in detail by using current literature information.

**Keywords:** PitNETs, pituitary adenoma, endoscopic surgery, transsphenoidal surgery, radiosurgery

## **1. Introduction**

The new classification clearly distinguishes anterior lobe (adenohypophyseal) from posterior lobe (neurohypophyseal) and hypothalamic tumors. Anterior lobe tumors include (i) well-differentiated adenohypophyseal tumors that are now classified as pituitary neuroendocrine tumors (PitNETs; formerly known as pituitary adenoma), (ii) pituitary blastoma, and (iii) the two types of craniopharyngioma.

Pituitary adenomas usually present with three types of clinical signs. The first type of clinical manifestations includes amenorrhea-galactorrhea syndrome, acromegaly or gigantism, Cushing's disease, and secondary hyperthyroidism because of hypersecretion of prolactin, growth hormone, adrenocorticotropic hormone, and thyroid stimulating hormone (very rare). About 70% of pituitary adenomas are endocrinely active, the presence of hypersecretory endocrine status is the most common presentation.

The second type of clinical manifestations includes pituitary insufficiency and is typically associated with large tumors compressing the nontumoral pituitary gland or stalk. In general, the pituitary gland exhibits outstanding functional resistance, even in chronic compression and distortion. The tolerance of each pituitary axis to chronic compression is different. Gonadotropes are the most susceptible and the first to be affected. After that, thyrotropic, somatotropic, and corticotropic functions are affected respectively. Regardless of the size of the tumor or the degree of compression of the gland or stalk, pituitary adenomas rarely present with posterior pituitary insufficiency; the preoperative presence of this condition almost excludes the diagnosis of pituitary adenoma. The hypopituitarism associated with pituitary adenomas is usually a chronic process, but when pituitary apoplexy is present, it can be acute, unexpected, and immediately life-threatening.

The third type of clinical manifestations includes mass effect symptoms with or without endocrinopathy. Headache is usually the first finding and is attributed to stretching of the diaphragm sella innervated by the trigeminal nerve. The most common objective finding of these tumors is loss of vision, the result of the suprasellar growing tumor pressing on the anterior visual pathways. Although many patterns of visual dysfunctions are seen, asymmetrical bitemporal hemianopsia is the pathognomonic deficit. Visual field disorders decreased visual acuity, afferent pupillary defects, papilledema, optic atrophy, and total blindness can be observed.

Although the suprasellar and lateral areas are difficult to see with the microscope, the transsphenoidal microsurgical approach has yielded results as a surgical treatment for pituitary adenomas. The first transsphenoidal approach for resection of a pituitary lesion was documented by Schloffer in 1906. In 1914, Dr. Harvey Cushing developed the sublabial transseptal technique, which reduces the degree of nasal trauma associated with previous external rhinotomy incisions. The integration of the operative microscope into pituitary surgery by Hardy in the 1960s provided magnification and illumination, enabling more precise tumor resection via the transsphenoidal route, especially for pituitary microadenomas [1].

In 1987, Griffith and Veerapen reviewed the endonasal approach for microscopic pituitary surgery with the placement of a transsphenoidal retractor through the natural nasal airway into the sphenoid rostrum [2]. The first reported use of the endoscope specifically for transsphenoidal surgery was in the sublabial approach by Guiot and colleagues in 1963 [3]. Jankowski et al. performed the first full endoscopic pituitary surgery in 1992 [4]. In 1996, Jho and Carrau described their technique of a pure endoscopic approach in detail, and in 1997, they published their report of endoscopic removal of pituitary adenomas in 44 patients [5, 6]. The continuous development and improvement of endoscopic equipment and surgical instruments have greatly contributed to the advancement of endoscopic surgery as a viable procedure for transsphenoidal approaches to the sella.

## **2. Pituitary neuroendocrine tumors surgery**

## **2.1 Surgical management and indications**

A comprehensive preoperative evaluation is performed after the decision for surgery for resection of the pituitary tumor is made. First, the patient's medical condition should be optimized. Hypertension, heart disease, diabetes, thyroid status, hematological problems, the presence of sleep apnea, and pituitary endocrine function should be carefully evaluated, especially in patients with Cushing's disease or acromegaly. Common comorbid conditions in patients with pituitary tumors require special considerations regarding anesthesia [6, 7]. Prognathism and soft tissue hypertrophy (including macroglossia) in patients with acromegaly and cervico-cranial stoutness in patients with Cushing disease challenge intubation and airway management.

Hypopituitarism is among the important endocrine conditions that require preoperative treatment, especially for hypocortisolism and hypothyroidism. For patients *Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.106883*

### **Figure 1.**

*A: Sagittal and coronal preoperative MRI image in pituitary-focused contrast-enhanced brain MRI of the patient who was operated with the diagnosis of Pitnet B: Sagittal and coronal postoperative MRI image in pituitaryfocused contrast-enhanced brain MRI of the patient who was operated with the diagnosis.*

with preoperative vision problems or tumors affecting the optic apparatus on MRI, formal neuro-ophthalmologic evaluations are performed with preoperative follow-up eye exams. Brain MRI with pituitary focus, with and without contrast, is the best diagnostic imaging modality of choice for most pituitary adenomas (**Figure 1**). CT imaging with pituitary focus and dynamic contrast protocol may be an alternative for patients who cannot undergo MRI for various reasons. The basic anatomy of the paranasal sinuses and any variation of the patient can be adequately evaluated on MRI for transsphenoidal surgical planning. However, in patients with prior paranasal sinus or transsphenoidal surgery, bone window CT scans with thin-slice axial and coronal views can reveal the bony anatomy of the paranasal sinuses in detail (**Figure 2**).

In the treatment of pituitary adenomas, it is aimed to normalize the excess of hormone secretion, if any, to preserve and even restore normal pituitary function, to eliminate the mass effect, to preserve or restore visual acuity and/or visual field, and to obtain a complete pathological diagnosis. Clinically silent pituitary tumors are primarily treated surgically because the surgical treatment modality is currently the only method that can achieve all the previously mentioned goals. Pituitary apoplexy and visual impairment due to mass effect or cranial nerve palsy can be shown as a general surgical indication for such lesions. Large invasive pituitary tumors and tumors with

**Figure 2.** *Detailed view of the paranasal sinuses in thin section axial and coronal sections. Permission has been obtained for the figures used in the book section.*

open cavernous sinus invasion are considered difficult to treat independently of the surgical approach, because gross complete removal of the tumor is often not achieved. Patients with hormonally inactive or dysfunctional pituitary adenomas are operated when they have symptomatic findings such as optic chiasm compression, hypopituitarism, pituitary apoplexy, or severe persistent headaches.

Prolactinoma patients are operated on only when they do not respond appropriately to dopaminergic drugs and develop intolerable side effects to drugs. In other hormonesecreting pituitary adenomas, the primary treatment is surgical, not medical.

Clear identification of anatomical landmarks is especially important for a transsphenoidal approach to the sella. The surgeon should be aware of nasal septal deviations, sphenoid septations and their relationship to the carotids, bony defects in the carotid canal, the degree of sphenoid bone pneumatization, and the extent of bone expansion or erosion from an aggressive lesion. The surgeon should try to determine the position of the normal pituitary gland and any deviations in the infundibulum prior to surgery.

## **2.2 Surgical approaches**

## *2.2.1 Transcranial approaches*

There are conditions that limit and sometimes contraindicate the choice of the transsphenoidal approach over the transcranial approach, regarding the anatomy of the surgical route, morphology, or consistency of the lesion. The size of the sella, the size and pneumatization of the sphenoid sinus, and the position and tortuosity of the carotid arteries can significantly increase the difficulty of the transsphenoidal procedure. When such selected indications warrant a transcranial approach, there are several options. These are pterional, subfrontal unilateral, subfrontal bilateral interhemispheric approaches.

## *2.2.2 Transsphenoidal approaches*

Transsphenoidal resection of pituitary masses involves the operating microscope, endoscope, or a combination of both. The microsurgical transsphenoidal technique provides bimanual dexterity during dissection of the tumor from the surrounding

neurovascular structures, but the viewing angle may be limited. Endoscopic techniques offer a wider field of view and flexibility to change the viewpoint all the way from the cribriform plate to the cervical junction. Transsphenoidal approaches can be divided into three main stages as nasal, sphenoidal, and sellar.

## *2.2.2.1 Microsurgical transsphenoidal approaches*

Although many different transsphenoidal procedures and variations have been described, there are currently three mains microsurgical transsphenoidal approaches to pituitary tumors. These are the transnasal transseptal transsphenoidal approach, the sublabial transseptal transsphenoidal approach, and the endonasal trans-sphenoidal approach.

The procedure is performed with an operating microscope to visualize, illuminate, and magnify the surgical field. The three mains microscopic transsphenoidal methods differ slightly, mainly in the initial stage up to the exposure of the sphenoid sinus; they then follow the same surgical sphenoidal and sellar steps.

## *2.2.2.2 Endoscopic endonasal transsphenoidal approach*

The main advantages of the endoscopic procedure over microsurgical procedures are the features of the endoscope itself and the absence of a nasal speculum [8, 9]. The nasal speculum forms a fixed tunnel. The endoscope allows a wider view of the surgical field with a close view inside the anatomy. Angle lens endoscopes allow the surgeon to study tumors located in the suprasellar and parasellar regions under direct visual control. The endoscopic endonasal procedure has a lower complication rate than the traditional microsurgical approach [10]. With the endoscopic procedure, microsurgery makes the procedure faster and easier compared to microsurgery, as the submucosal nasal phase of the operation is avoided.

Disadvantages of the endoscopic approach include the unusual anatomy of the nasal cavities and the learning curve to rely on specific endoscopic dexterity. However, after sufficient experience, especially in the case of relapse, the operative time becomes the same or shorter than the time required for transsphenoidal microsurgery. The endoscope offers only two-dimensional vision on the video monitor. The sense of depth can be gained by the surgeon's experience, allowing the endoscope to move in and out. To achieve surgical targets, especially those that angled endoscopes can show special microsurgical endoscopic instruments with secure grip, flat and non-bayonet-shaped, equipped with different and variableangle tips are required.

In general, endoscopic instruments are long, rotating instruments with a single straight shaft equipped with angled tips. Angled tips on the working ends of many surgical instruments allow for a greater range of motion than standard instruments. The use of straight shaft instruments is preferred in endoscopy compared with the microsurgical technique, which typically uses bayonet instruments to avoid interference with the light source. The endoscope can be inserted into the nostrils with a sheath attached to an irrigation system that allows cleaning the lens without repeatedly removing and reentering the telescope. An endoscope holder can be used during the sellar phase of the procedure to stabilize the view of the surgical field, but its use limits dynamic movement that helps compensate for the loss of depth perception. The use of neuronavigational systems, although not essential, may be helpful in patients with recurrent lesions or abnormal sellar or paranasal sinus anatomy.

Key components of the endoscopic setup include a rigid lens endoscope, a high-resolution camera, a fiberoptic cable and light source, a large high-definition video monitor, and a video recording system. The most used endoscope is 4 mm in diameter and 18 or 30 cm in length. Differences in lens angle exist for certain steps of the operation, including 0-degree binoculars, 30-degree binoculars, and 45-degree binoculars. Wider-angle binoculars, ranging from 70 to 120 degrees, are available, but are rarely required for most endoscopic skull base operations.

## *2.2.2.2.1 Operational setup in surgery*

The video monitor is placed behind the patient's head and, in most cases, in the direct line of sight of the surgeon standing on the right side of the patient. The anesthesiologist is on the left side of the patient. The head of the bed is turned approximately 120 degrees away from the anesthesiologist, and the patient is placed in a semirecumbent position with the thorax elevated to 15 degrees to optimize venous flow. The head is positioned with a slight degree of rotation toward the surgeon, approximately 10 degrees, with the midline of the patient's head parallel to the side walls of the operating room and the patient's nose bridge parallel to the floor. The degree of flexion/extension of the patient's head depends on the location of the lesion. Lesions located primarily in the clivus, or sphenoid sinus, often require slight flexion of the head to allow working space for the endoscope. More anteriorly located lesions, such as the planum sphenoidale, require the head to be neutral or slightly hyperextended.

## *2.2.2.2.2 Patient preparation*

Nasal decongestion facilitates pituitary procedures in most patients, except for patients with a history of hypertension and coronary artery disease. Before and immediately after induction of anesthesia, patients are given a 0.05% spray solution of oxymetazoline (Afrin) intranasally. During positioning, bayonet forceps are used to insert cotton pads soaked in oxymetazoline, followed by pads soaked in 1:200,000 epinephrine and 1% lidocaine between the middle turbinates and septum. The pads are allowed to remain in contact with the nasal mucosa for 5–10 minutes. The nostrils are then wiped with an aqueous solution of antibiotics such as chlorhexidine. A broad-spectrum antibiotic is given perioperatively with a nasal packing attached. If the results of the preoperative adrenal axis test suggest adrenal insufficiency, intravenous hydrocortisone is given before induction of anesthesia. Steroids are avoided in patients with Cushing's disease to allow postoperative evaluation of successful resection. Leg fascia lata area or lower quadrant abdominal area is prepared in all patients to allow potential fat grafting in case of encountering cerebrospinal fluid (CSF).

## *2.2.2.2.3 Nasal stage*

The aim of the nasal phase is to reach the sphenoid sinus through the sphenoid ostium and posterior nasal septectomy, which can be achieved with different strategies for manipulation of the mucosa and nasal septum. The endoscopic endonasal transsphenoidal technique begins with the insertion of a 0-degree endoscope into one nostril to identify the nasal cavity floor for orientation, the inferior turbinate laterally, the nasal septum medially, and the choana posteroinferiorly. The inferior and middle turbinates, which are the main barriers to the sphenoid ostium, should be carefully lateralized with blunt pressure to avoid excessive mucosal damage. Some surgeons

## *Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.106883*

choose to remove part of the middle or upper turbinate, but this is not usually necessary for resection of most pituitary tumors. After creating an appropriately wide working corridor, the sphenoid ostium is defined 1.5 cm above the choana.

The sphenoid ostium is sometimes hidden by mucous membranes or a thin layer of bone, in which case it may be helpful to first try to identify the ostium on the opposite side. Use of neuronavigational can also be helpful in confirming the pathway to the sphenoid sinus, then a small dissector instrument can be used to gently probe for the ostium and enter the sinus. If a pedicled nasoseptal flap is being prepared, it should be done at this stage. Once the ostium has been identified, its mucosal edges are coagulated using light monopolar cautery, which can be extended toward the medial and inferior surfaces of the sphenoid cusp. Avoiding inferolateral cauterization and dissection helps prevent arterial bleeding from septal branches of the sphenopalatine artery. Local anesthesia (epinephrine 1:100,000 to 1% lidocaine) is then injected medially into the posterior nasal septum using a spinal needle with a 20-degree bend.

Placement of the mucosal incision is dependent on expected closure needs and whether a nasoseptal flap is required to close the skull base. An incision can be made at the junction of the bony and cartilage septum and moved inferiorly and posteriorly in a standard transsphenoidal approach for an intrasellar lesion. Extended transsphenoidal approaches for complex sellar, parasellar, and suprasellar lesions often result in high-flow CSF leaks. In this situation, a vascularized nasoseptal flap closure is important to take advantage of natural wound healing mechanisms. While preparing the nasoseptal flap, parallel incisions can be made along the maxillary crest, inferiorly and superiorly caudal to the olfactory epithelium, with an anteriorly connected vertical incision [11]. The size of the flap can be adjusted according to the size of the expected defect. The flap remaining at the base of the sphenopalatine artery is compressed into the nasopharynx or, in some extended approaches, into the maxillary sinus for protection during the operation.

A posterior bite instrument can be used to extend the posterior septectomy further forward as needed to improve communication between both sides of the nasal cavity, improve visualization and instrument mobility, and minimize the possibility of instrument collision. The lateral and superior soft tissue and bony prominence of the sphenoid rostrum and sinus may be resected to provide sufficient space to position the endoscope superolateral at the 10 o'clock position. The bony rostrum is raised to the level of the floor of the sphenoid sinus to create a working area for the endoscope and two instruments.

## *2.2.2.2.4 Sphenoid stage*

The sphenoid surface of the pneumatized sinus can be entered after dilation of the ostium or resection of the vertical plate. In a presellar or conchal sphenoid sinus, the bone is removed with a chisel or drill. Care must be taken to avoid injury to the sphenopalatine artery as it arises near the inferolateral vomer. This is particularly important when a pedicled nasoseptal flap is envisioned for reconstruction at the end of the procedure, called the salvage flap. The mucosa within the sphenoid sinus is often removed to reduce the risk of postoperative mucocele. Septations within the sphenoid sinus are also removed. The surgical view at this point should encompass the sellar floor at the center, the rostral clivus inferiorly, the planum sphenoidale superiorly, the bulge of the internal carotid siphon immediately juxtaposed to the sella, the wings of the optic nerves coursing superolaterally with respect to the sella, and the opticocarotid recess in between the optic nerve canal and the carotid protuberance.

## *2.2.2.2.5 Sellar stage*

To safely perform bimanual microdissection for the sellar phase of the operation, two surgeons switch to the "four-handed" technique. Alternatively, the endoscope can be secured with the endoscope holder so that a single surgeon can operate with both hands. When the base of the sella is enlarged and thinned by an intrasellar lesion, it can usually be fractured using a pituitary rongeur or blunt microdissector. In some cases, a thicker sellar floor prevents this maneuver and requires the use of an osteotome, drill, or ultrasonic bony curette. A sellar bone defect is then performed, typically extending from one cavernous sinus to the other. In addition to defining the cavernous sinuses laterally, the anterior intercavernous sinus is often defined in the rostral aspect of exposure. A micro-Doppler probe and neuro-navigation can be routinely used to check the location of the internal carotid arteries and to confirm the location of the planned dural opening. The carotid artery may be ectatic within the sella, especially in acromegalic patients. Macroadenomas often compress the venous plexus between the two leaves of the dura, allowing a relatively bloodless opening. In contrast, intact venous channels between the dura and intercavernous sinuses may surround smaller tumors and should be thoroughly investigated prior to tumor resection.

Dural clearance differs according to surgeon preference; A rectangular opening allows dural pathology to be obtained for pathological examination when dural invasion is suspected. If the gland needs to be separated from an underlying lesion, the first vertical incision preserves blood flow. Care should be taken to remove as many tumors as possible for pathology and/or tissue banking. After sufficient specimen has been collected, curettes and aspiration can be used to remove the remainder of the tumor. The arachnoid may descend into the field of view at this point and should be carefully manipulated and protected with a cotton swab to avoid direct aspiration. Venous cavernous sinus bleeding may be encountered following tumor removal and temporary gelatin foam filling and/or injection may be given. A 30- or 45-degree endoscope may be inserted to look laterally and superiorly into the cavernous sinuses to assess the remaining tumor. In cases of macroadenoma with large suprasellar extension, the tumor will often subside spontaneously with mild curettage given sufficient time. Intrasellar and cavernous sinus hemostasis can be achieved, typically by temporary packing with a gelatin sponge followed by coating the tumor cavity with oxidized cellulose (Surgicel).

## *2.2.2.2.6 Closure*

After tumor resection is complete and hemostasis is achieved, the closure phase begins with the goal of reconstructing the skull base defect and repairing any possible CSF leak. Many methods are available to perform reconstruction, including conventional repairs with autologous or artificial grafts, vascularized pedicled nasoseptal flap formation and rotation, and multilayer closure techniques using dural and bone substitutes.

CSF leaks may result from tumor removal from a thinned or inadequate diaphragm, from traction applied during dissection, or from deliberate opening of the diaphragm to access suprasellar lesions. High-flow CSF leakage is expected, especially in tumors that extend into the suprasellar compartment or the third ventricle. In the absence of significant CSF leakage, the Valsalva maneuver can be performed to detect minimal CSF leakage. A drip of dark liquid against the background of venous bleeding indicates a hidden leak.

*Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.106883*

For smaller defects, the sellar base can be reconstructed with allograft bone, cartilage, or ideally a biosynthetic substitute placed in the sellar extradural space. Alternative reconstruction techniques include the gasket-seal method and the use of synthetic grafts reinforced with fascia lata or fibrin sealant [12, 13]. For large CSF leaks, in addition to the maneuvers mentioned above, a vascularized flap provides the most effective closure.

## *2.2.2.3 Extended endoscopic endonasal transsphenoidal approach*

Medial cavernous sinus tumor surgery can be performed with an extended transsphenoidal transsellar approach. This approach involves puncturing the bone over the carotid siphon and removing the medial opticocarotid recess. However, this only provides limited access to the medial cavernous sinus wall. The ethmoids need to be opened using the transethmoidal corridor to gain better access to the cavernous sinus. Additional lateral access can be achieved using the transmaxillary corridor. This approach can be used for cavernous sinus tumors or lateral sphenoid pathology.

The extended endoscopic endonasal approach does not require brain and optic nerve manipulation compared with transcranial approaches. It provides a direct view of the suprasellar region. Because of this advantage, the risk of worsening postoperative vision is much less than with transcranial approaches. However, the extended endoscopic endonasal approach is technically much more difficult and can be performed by experienced surgeons.

## **2.3 Complications**

Despite the minimally invasive nature of transsphenoidal approaches to sella turcica, complications can occur. Complications encountered in the nasal cavity during the approach include anosmia, nasal septal perforation, crusting, saddle nose deformity, orbital fracture, cribriform plate injury with CSF leakage, and epistaxis. Complications occurring within the sphenoid sinus include sinusitis, mucocele formation, and optic nerve or carotid artery injury resulting from sphenoid body fracture. Potential complications associated with tumor resection and the sellar phase include CSF leakage, hypopituitarism, diabetes mellitus, meningitis, postoperative hematoma, carotid artery or other vascular injury, optic nerve injury, ophthalmoplegia, subarachnoid hemorrhage, vasospasm, and tension pneumocephalus. The most common non-endocrine complications for both microscopic and endoscopic transsphenoidal surgery are CSF leakage, meningitis, and sinusitis [14, 15].

## **2.4 Postoperative care and follow-up**

Patients should be observed very closely following endoscopic transsphenoidal pituitary surgery. Most patients are discharged home on the second or third day after surgery. In most patients, serum sodium levels and urine output are monitored every 6–8 hours for the first 48 hours. Patients with any new evidence of hypocortisolemia should receive adequate replacement therapy. Patients with functional pituitary adenomas typically undergo basic non-stimulation hormonal testing (e.g., serum prolactin, cortisol, or growth hormone) on the first and second postoperative days. If nasal packing is used, it is usually removed on the first postoperative day. The patient is usually discharged from the hospital on the second or third postoperative day and is expected to see an endocrinologist for hormonal follow-up. The patient will be evaluated in the outpatient clinic 3 months later with sellar contrast MRI postoperatively.

## **3. Pituitary neuroendocrine tumors radiosurgery**

Especially in macroadenomas and tumors invading the cavernous sinus, total resection is not always possible. Total resection rate in pituitary adenomas remains below 70% [15]. Tumor control rates with microsurgery between 50 and 80% vary [16]. Another factor limiting the effectiveness of surgical treatment in pituitary adenomas is recurrence in 11.5% of radiologically resected pituitary adenomas [17].

Pituitary adenomas are very suitable lesions for radiosurgery if suprasellar and parasellar neural tissues can be preserved because they are in a well-circumscribed environment. For this reason, radiosurgery has been applied as an adjuvant treatment method for many years to provide hormonal normalization and control of tumor growth. It has been proven that a single dose of stereotactic radiosurgery can effectively provide tumor control and hormonal normalization as adjuvant therapy [18]. It can even be applied as a primary treatment method in cases where surgical and medical treatment cannot be applied.

The aim of radiosurgery of pituitary adenomas is to normalize abnormal levels of hormone, reduce the size of the tumor, or at least control its growth, without damaging neural tissues, especially the optic apparatus, and without causing pituitary insufficiency.

The marginal dose should be at least 12 Gray (gy) to achieve tumor control. Otherwise, even if growth control is achieved, hormonal recovery may not be possible. It has been reported that small lesions at some distance from optic nerves marginal doses about up to 30–35 Gy. Although it is recommended to avoid doses of more than 8–10 Gy to protect the optic nerve, there are series in which the median maximum dose of the optic apparatus is increased up to 12 Gy [19, 20].

Hormone-suppressing drugs should be quitted 1–2 months ago because of the possibility of affecting tumor cell cycle and metabolism and reducing sensitivity to radiation. There is no consensus on the time of initiation after radiosurgery [21].

The effectiveness of conventional radiotherapy in pituitary adenomas is well known. Although different results have been reported between series, it generally provides approximately 90% tumor control and 40–70% hormonal control [22]. However, in addition to this efficacy, it has disadvantages such as toxicity in temporomesial and hypothalamic structures, high pituitary insufficiency rate, optic neuropathy, long treatment time, and long time required for the effect to occur [16].

## **3.1 Tumor growth and hormonal control**

Pituitary adenomas are already very slow growing tumors. For this reason, longterm follow-ups should be made after radiosurgery to decide that the growth is under control. This rate has been reported as 83–100% in series with a follow-up period of 4 years or more. This rate includes not only patients with reduced tumor volume, but also patients with growth arrest. For growth control of hormone-active tumors compared with nonfunctional adenomas, higher doses are needed.

Volumetric shrinkage may vary depending on the pathology of the tumor. Growth hormone-secreting adenomas tend to shrink more than prolactinomas and nonfunctional adenomas [23].

In the series published by Park et al. in 2011, in which they applied radiosurgery to 125 cases of nonfunctional adenoma, the 1-year control rates were 99%, while this rate decreased to 94% in 5 follow-ups and to 76% at the end of 10-year follow-up [24].

## *Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.106883*

The onset of hormonal recovery after radiosurgery takes an average of 2 years (3 months–8 years). Hormone remission rate varies according to which hormone the adenoma secretes, how much maximum and marginal dose is applied, and whether antisecretory drugs are used during radiosurgery. If infundibulum damage develops during surgery and/or radiosurgery due to the compression of the tumor, it should be kept in mind that a decrease in prolactin level can be observed regardless of the adenoma [25].

The hormone remission rate after radiosurgery is the lowest in prolactinomas (25–30%). The most important factor here is thought to be the long-term dopaminergic treatment of the patients. Therefore, it is recommended to quitting antisecretory therapy at least 1–2 months before radiosurgery.

In tumors that secrete growth hormone, the hormonal response is obtained after an average of 2 years. The aim of radiosurgery is to reduce the GH level below 1 ng/ ml. In big series with long follow-up, it has been reported that the hormonal cure rate between 20 and 96% varies. Also, it is thought that using somatostatin analogue reduces the response radiosurgery by changing the cell cycle. For this reason, it is recommended to stop or reduce the treatment at least 1 month before the radiosurgery.

Although hormone remission starts a little earlier in Cushing's disease (14– 18 months), they reported remission rates varying between 17 and 83% in big series.

## **3.2 Non-functional adenomas and stereotactic radiosurgery**

Since non-functional adenomas are usually asymptomatic until signs of compression appear, they are found to be larger than functional adenomas at the time of diagnosis, and surgical resection is the first choice. However, the development of residual or recurrent tumors after surgery is substantial. For these cases, radiosurgery has become a comfortable and very effective treatment option, protecting patients from the risks of revision surgery. In non-functional microadenomas or macroadenomas that do not create optic pressure, follow-up is the strategy that should be considered first, and treatment should be planned in case of tumor growth.

There are many studies in the literature showing the efficacy of radiosurgery in nonfunctional adenomas. When the data of 512 patients with non-functional adenomas from nine Gamma Knife centers were analyzed, 94% had a history of previous surgical treatment, 6% had a history of prior radiotherapy. In the series, where the mean dose was 16 Gy and the mean follow-up was 36 months, the tumor control rate was 98, 95, 91, and 85% at the 3rd, 5th, 8th, and 10th years, respectively. The rate of pituitary insufficiency after radiosurgery was 21%, new or progressive cranial nerve deficit was 9%, and new or progressive optic nerve dysfunction was 6.6%. When the factors associated with cranial nerve deficit were examined, it was revealed that young age, increased volume, and the presence of previous radiation therapy increased the risk [26].

In the review of Kim et al., tumor marginal dose ranges between 13 and 24 Gy and 83–100% tumor control are reported in Gamma Knife series. The authors, who did not detect a significant relationship between tumor control and dose, reported a decrease in these rates as the follow-up period increased. Tumor shrinkage ranged from 42–89% [27].

In a large series evaluating Gamma Knife radiosurgery results in non-functional adenomas, visual side effects were found to be 0.8%, and cranial nerve deficit rate was 1.6%. This series shows that tumor control rates decrease as the tumor volume grows, the follow-up period increases, and the treatment dose decreases. In addition, there was no difference in outcome between operated and unoperated cases [24].

In the long-term follow-up (80.5 months mean) series of Gopalan et al. 48 cases, the tumor control rate was 83% and the new hormone deficit was 39%. Hormone deficits were found to be 8% for corticotropin deficiency, and as 4.2% for thyroid hormone deficiency with 20.8% gonadotropin deficiency, respectively. A decrease in tumor control rate and an increase in complications were found to be associated with the size of the irradiated tumor volume [28].

It has been shown that Gamma Knife radiosurgery at doses ranging from 10 to 25 Gy provides tumor control at a rate of 94–95% in 5–7 years of follow-up, and these rates decrease to 76% at the end of 10-year follow-ups [20, 29].

Effective tumoral control can be achieved with 12–15 Gy in non-functional adenomas. Therefore, in non-functional adenomas, radiosurgery can be applied even in some cases where the tumor meets the optic apparatus. Another option for large tumors is hypo-fractionated radiosurgery, and it is possible to better protect the optic structures by dividing the total dose 3–4 times.

As can be seen, radiosurgery provides more than 90% tumor control in nonfunctional adenomas. Since hormonal remission is not targeted, the fact that lower doses are frequently administered ensures that the rates of pituitary insufficiency and visual complications are lower than in the functional adenomas. In cases where it is thought that complete removal cannot be achieved due to cavernous sinus invasion or other reasons, surgical strategies that will reduce the tumor below 3 cm and remove it from the optic structures can make patients suitable for radiosurgery and provide an effective and safe treatment.

## **3.3 Functional adenomas and radiosurgery**

Despite advances in surgical techniques and medical agents, endocrine remission, or recurrences are observed in a significant proportion of pituitary adenomas. In such difficult cases, the option of radiosurgery is often on the agenda. The literature clearly reveals hormonal remission rates with radiosurgery, endocrine cure is between 20 and 30% in prolactinomas, 50% in growth hormone adenomas, and 40–65% in ACTHsecreting adenomas.

The ideal dose for functional adenomas has not been determined, yet. However, the chance of achieving hormonal normalization at doses below 16 Gy is low. The chance of success increases with doses up to 30 Gy. Doses between 20 and 25 Gy are frequently preferred [16]. The possibility of pituitary insufficiency increases, especially at doses above 24 Gy [30].

The major disadvantage in radiation therapy of pituitary adenomas is the length of time required for biochemical remission. Sheehan et al.'s study of 418 cases found the mean time required for remission to be 48.9 months. They reported that this time was inversely proportional to the dose received by the tumor and directly proportional to the tumor volume [21].

## *3.3.1 Cushing's disease*

The first and most effective treatment for Cushing's disease is surgery. However, there is a significant group of patients who cannot be cured by surgery, and radiosurgery has become an effective option for these patients. Recurrence develops in 30% of patients after successful surgery in Cushing's disease [31]. In these patients, radiosurgery is one of the treatment options.

## *Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.106883*

Jaganathan et al. evaluated the results of 49 Cushing's patients who applied Gamma Knife and followed up for an average of 45 months and reported that the tumor shrank 80%. The average dose in this series is 23 Gy. In this study, in which the criterion of successful endocrinological response was determined as the normal level of free cortisol in 24-hour urine, successful endocrinological results were obtained in 54% of the patients in 13 months average. In 27 months, average, 20% of the patients relapsed and new hormonal deficits occurred in 22% of the patients. In this study, no relationship was found between tumor volume and endocrine response to radiosurgery. Hormonal normalization after radiosurgery varies between 7.5 and 58 months [13, 20]. In series where the marginal dose ranged from 15 to 30 Gy, it was reported that an average of 20 Gy accelerated the clinical and endocrine cure response. Cushing's disease's radiosurgery response develops more rapidly than other functional tumors. Although hormonal normalization has been reported between 10 and 87%, the success rate in most series is between 40 and 65%. Tumor control is reported in 80–100%, and shrinkage is reported in 10–70% of cases [16]. As with other adenomas, the response to radiosurgery is higher in ACTH-secreting microadenomas [32].

## *3.3.2 Prolactinomas*

Surgery and radiosurgery options should be considered in a group of patients who are resistant or intolerant to medical treatment.

In the study of Jezkova et al. examining the role of radiosurgery in prolactinomas with 35 cases with an average follow-up of 75 months, normoprolactinemia was achieved in 37%, and dopamine agonist use was discontinued in 43% of cases. The time required for hormone normalization has been reported as 96 months. The tumor control rate was found to be 97% [33].

In the series of 38 cases with 22 years of follow-up, published by Sheehan et al. in 2015, it was reported that 55% of the patients used dopamine agonists before radiosurgery. In this series with an average follow-up of 43 months, endocrine remission was reported as 50% without using dopamine agonists. Pituitary insufficiency secondary to radiosurgery was found to be 30%. In this study, it is reported that medical treatment before radiosurgery worsens hormone normalization results [34].

Although a higher dose (mean marginal dose of 25Gy) is applied in the radiosurgical treatment of prolactinomas compared with other functional adenomas, the endocrine remission rate is lower. In addition, 80% of the patients have a decrease in prolactin level [16].

## *3.3.3 Growth-hormone-secreting adenomas*

In the study by Franzin et al., in which they examined the Gamma Knife radiosurgery results in 103 patients with acromegaly, 58.3% of the 63 patients who were followed up for an average of 71 months achieved remission in 58.3%, while 14.6% of the patients achieved remission with somatostatin analogues. The rate of hormonal deficit was found 7.8% [6]. It has been determined that the most important factor affecting the success of radiosurgery is low GH and/or IGF-I levels during treatment. IGF-1 lower than 2.25 times normal is a positive prognostic factor [16].

In the series of Jagannathan et al.'s 95 cases, which were followed up 57 months average and underwent radiosurgery after unsuccessful surgery, a successful result was accepted as IGF-I normalization, and a successful result was obtained in 53%

of the patients after an average of 30 months after radiosurgery. In this study, where the mean treatment dose was 22Gy, reduction in tumor volume was found in 92% of patients, and new endocrinological deficits occurred in 34% of patients. This study also shows that the duration of hormonal remission is faster in radiosurgery than radiotherapy. Researchers recommended that hormone-suppressing therapy should be discontinued 2 months before radiosurgery and not used for 6 weeks afterwards [35].

## **3.4 Radiosurgery in cavernous sinus invasive adenomas**

Cavernous sinus invasion is observed in 7–42% of the cases in pituitary adenomas. Post-surgical residual tumor in pituitary adenomas is most frequently observed in tumors that have spread to the cavernous sinus. Neurovascular complex and venous hemorrhage in this region reduce the chance of surgeons to intervene in this area, and morbidity may be 27–50% because of intervention in this area. For this reason, radiosurgery is frequently the option for residual tumors in this region.

In 89 patients with recurrent or residual pituitary adenomas located in the cavernous sinus, who underwent radiosurgery by Hayashi et al., 97% tumor control was achieved at a mean 36-month follow-ups. Tumor shrinkage was detected in 64% of them. 18.2 Gy average was applied in non-functional adenomas, and 25.2 Gy average was applied in functional adenomas, and transient cranial nerve dysfunction was observed in 2% of cases. In this series, hormonal normalization was found in 39% of cases. Radiosurgeryrelated morbidity is less than 1% in lesions invading the cavernous sinus [36].

## **3.5 Complications**

The main problems that may arise in radiosurgery of pituitary adenomas are pituitary insufficiency, optic neuropathy, and other cranial nerve paralysis.

The most important risk factors in the development of optic neuropathy are the contact of the tumor with the optic nerve, the size of the tumor, and the inability to clearly evaluate the relationship between the tumor and the optic apparatus in operated cases. After radiosurgery, a decrease in visual acuity and/or narrowing of the visual field may occur due to the proximity of the residual mass to the optic nerve. This rate is 1–6% and decreases further with advanced MRI. It is known that the cranial nerves in the cavernous sinus are more radioresistant than the optic nerve. In big series, damage to other cranial nerves (CN III, IV, V, VI, VII) is 2–3%.

Diabetes insipidus development due to neurohypophysis or infundibulum damage is approximately 1–2% in big series [19, 28]. Very rarely, narrowing of the carotid artery has been observed after radiosurgery, but it is even rarer to cause symptoms [26].

Stereotactic radiosurgery is an effective and safe alternative or supportive treatment to conventional treatments in the treatment of pituitary adenomas. Due to the risks of radiation, it should be applied in the right indications, considering the appropriate dose-volume relationship, and protecting critical structures. While the short duration of the treatment is advantageous, the most important risks that may develop after the procedure are pituitary insufficiency and vision problems due to optic nerve damage. Neurosurgeons, endocrinologists, and ophthalmologists should take a multidisciplinary approach together both in the evaluation of the efficacy of the treatment and in the management of its complications.

After radiosurgery, patient follow-up should continue for a long time, both to evaluate the effectiveness of the treatment and to develop complications after a long time.

*Surgical and Radiosurgical Treatment of the Pituitary Neuroendocrine Tumors DOI: http://dx.doi.org/10.5772/intechopen.106883*

## **Conflict of interest**

The authors declare no conflict of interest.

## **Acronyms and abbreviations**


## **Author details**

Mustafa Caglar Sahin\* and Gokhan Kurt Gazi University Faculty of Medicine Department of Neurosurgery, Ankara, Turkey

\*Address all correspondence to: dr.mcaglarsahin@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 5** Craniopharyngioma

*Gökhan Kurt and Ayfer Aslan*

## **Abstract**

Craniopharyngioma (CP) is a rare, benign, slow-growing, but clinically aggressive tumor located mainly in the sellar and suprasellar regions. While it occurs equally in children and adults, there are two peaks in the age distribution: first in 5–14 years of age and second in 45–74 years of age. The clinical presentation varies according to the age of patients, while the predominant symptoms are visual disturbances, headache, and endocrine dysfunctions. CPs are topographically classified in several subgroups based on the relationship of the tumor to the sella, diaphragma sellae, optic chiasm, stalk, and third ventricle; whereas the pathological classification includes two types: adamantinomatous (aCP) and papillary (pCP). Distinctive features of aCP are cysts with content of "motor-oil" fluid, calcification, wet keratin, peripheral palisading of basal cells, stellate reticulum, and mutations in CTNNB1/β-catenin gene; and those of Pcp are regular stratified squamous epithelium, devoid of cilia, papillary projections, no calcification, rare cyst with a clear fluid, and mutations in BRAF V600E. The surgical approaches include transcranial (subfrontal, pterional, transcallosal, and transcortical-transventricular) and transsfenoidal approaches, having different selection criteria, advantages, and disadvantages. Despite complete resection and radiotherapy, CPs are inclined to recur causing high morbidity and mortality.

**Keywords:** adamantinomatous, craniopharyngioma, papillary, sellar tumor, suprasellar tumor, surgery

## **1. Introduction**

New information about tumor types and subtypes based on molecular studies were introduced first by 2016 update, and then lately by 2021 update of the World Health Organisation (WHO) Classification of Tumors of the Central Nervous System (CNS) [1]. One of the updated tumors is Craniopharyngoma (CP), particularly in the aspects of molecular pathology. We aim to review CPs with the new updates by 2016 and 2021 WHO classification systems highlighting important implications for clinical practice including diagnosis and management. We also intend to include a brief consideration of epidemiology and demographics, clinical manifestations, morphologic and molecular features, behavior, and prognosis of craniopharyngioma along with the current treatment modalities – surgery, radiosurgery, radiation therapy – with a thorough review of the literature.

## **2. Terminology and staging**

Craniopharyngioma (CP) is a benign primary brain tumor originating from epithelial remnants of craniopharyngeal duct (Rathke's pouch, a diverticulum arising from the embryonic buccal cavity and rising to form the anterior pituitary gland) [2].

CP is a WHO grade I neoplasm often with a low proliferation index (MIB-1 < 10%) [1]. Although it is classified as a benign tumor, it has a tendency to recur due to its invasive nature, and inability to complete excision, particularly when MIB-1 is higher than 7% [3].

Despite its current WHO grade I classification with no malignant subtype, more and more case reports of a malignant form of CP occurring de novo or transforming from a benign variant have been published in recent years [4–10]. The exact pathogenesis and biological behavior of malignant change in CP are not yet clear; however, some reports have suggested that radiation may be a contributing factor to carcinogenesis [4, 6, 7, 9] though such a link has not been proven yet by any studies with high level of evidence [8, 11, 12]. Although malignant CP is still a rare clinical entity with less than 40 reported cases in the current literature, it may induce a new update in the WHO classification system in the future.

## **3. Epidemiology**

CP is overall rare accounting for 1.2–4.6% of all brain tumors; [2, 13] yet, its incidence is higher in children, accounting for 5–13% of all pediatric brain tumors [14–16]. The overall incidence of CP was reported as 0.13 per 100,000 person-years in the USA with no difference between genders or races [17]. CPs occur almost equally in children and adults, and there is a bimodal age distribution with the first peak in children at the age of 5–14 years, and the second peak in older adults aged 45–74 years [14, 17, 18]. Between two types of CPs (adamantinomatous and papillary), the adamantinomatous CP (aCP) occurs predominantly in children, while papillary (pCP) is seen almost exclusively in adults [19, 20]. About 90% of CPs are aCP, and 10% are pCPs [14, 19].

## **4. Anatomy**

## **4.1 Location**

CPs may originate from anywhere along the pituitary stalk, extending from the tuber cinereum to the pituitary gland, where the remnants of an incompletely involuted hypophyseal-pharyngeal duct may locate [21, 22]. Most frequently, CPs originate in the suprasellar location; while some cases can be exclusively intrasellar or extend in any direction to encompass crucial structures, such as pituitary stalk, optic chiasm, optic tracts, third ventricle, hypothalamus, and thalamus [14, 15].

## **4.2 Topographical classification**

CP has been anatomically classified based on the relationship of the tumor to the sella, diaphragma sellae, optic chiasm, stalk (infundibulum), and third ventricle

mainly to assist in planning optimal surgical approach [21, 23]. The first classification was introduced by Gazi Yaşargil based on his microsurgical experience with CPs [23]. According to his scheme, type A is confined within the sella (intrasellar infra diaphragmatic); type B is both intra- and suprasellar, infra- and supradiaphragmatic; type C is supradiaphragmatic, parachiasmatic, and extraventricular; type D is intraand extraventricular; type E is paraventricular with respect to the third ventricle; type F is purely intraventricular [24].

Upon the development of endoscope and advances in transsphenoidal endoscopic surgeries, Kassam et al [25] have suggested a different classification system based on the relationship of the lesion to the infundibulum, which is the key anatomical consideration determining the amount of additional exposure needed in expanded endonasal approach (EEA). Accordingly, type I is preinfundibular, type II is transinfundibular, type III is post- or retroinfundibular, and type IV is isolated third ventricular. However, CPs are rarely restricted to only one location but spread widely engulfing the entire suprasellar and prepontine cisterns. In the latter case, the authors of this classification suggest surgeons consider the predominant site in which the greater part of the solid component is located to be the primary target when determining the specific EEA module [25]. Later, Jamshidi et al. [26] added an additional subtype to this scale, called type 0, which describes fully subdiaphragmatic tumors located within the sella.

Recently, Fan et al [27] also suggest a new classification system, called QST, based on tumor origin. They classified CPs into three types as follows: infrasellar/ subdiaphragmatic CPs (Q-CPs), subarachnoidal CPs (S-CPs), and pars tuberalis CPs (T-CPs). Q-CPs arise from the subdiaphragmatic infrasellar space with an enlarged pituitary fossa, and the gland is scarcely recognizable; S-CPs arise from the middle or inferior segment of the stalk and tend to extend among cisterns, and the entire stalk can be recognized on MRI; and T-CPs arise in the top of the pars tuberalis, mainly extend upward, and occupy the space of the third ventricle [27]. This new scheme has been proposed to guide the surgeons in choosing the best surgical approach between endoscopic endonasal and transcranial surgery and to predict the outcomes.

Despite the several topographical classifications of CPs, there has not been a consensus on a standard reference classification system [28].

## **5. Diagnosis**

## **5.1 Clinical presentation**

The origin and size of CPs and the patient's age significantly affect the symptoms and signs. Clinical presentations are generally related to the mass effect, high intracranial pressure, and hypothalamic and endocrinologic dysfunctions. Overall, the most frequent symptoms are headache and visual problems due to pressurized optic structures and obstructive hydrocephalus. Patients with CP frequently exhibit the manifestations of hypothalamic-pituitary axis dysfunction, including growth hormone deficiency, adrenocortical insufficiency, central hypothyroidism, hypogonadism, precocious puberty, hyperprolactinemia, central diabetes insipidus, and hypothalamic obesity [14, 19, 20, 29, 30]. Fatigue, nausea/vomiting, somnolence, and memory impairment are the other signs of the clinical presentation related to CPs [2].

## **5.2 Microscopic histopathology**

CP is known to be arising from rest of pharyngeal epithelium remaining from embryogenesis. Histopathologically, two types of CPs are recognized: adamantinomatous and papillary. The distinction between the two types is made by the encapsulating epithelial lining [15].

Adamantinomatous CP (aCP) has internal layers of stratified squamous epithelium anastomosing with the basal layer of columnar cells and forming stellate reticulum. The surface of aCP is usually irregular and infiltrative, with long epithelial extensions penetrating the adjacent neuroglial tissue. Dysmorphic calcification, lamellar keratin formation ("wet keratin"), and fibrosis can be often noted [14, 15, 31]. It generally has multi-cysts with contents of cholesterol crystals giving the fluid a dark, "motor-oil" appearance [19].

Papillary CP (pCP) has a more regularly stratified mature squamous epithelium, with papillary projections of epithelial cords into the surrounding tissues, but without significant infiltration [15, 31]. They are more commonly solid, with rare cyst formation and no calcification, and if cystic, the contents are clear without significant cholesterol crystals [19, 20].

## **5.3 Molecular pathology**

Owing to advances in technology, the genetic mutations of CPs have been identified. Wnt/β-catenin signaling pathway in particular is important in the development of pituitary [32]. aCP and pCP also differ genetically, as BRAF V600E mutations are detected in pCP and CTNNB1 mutations in aCP [1, 2, 19, 33–35]. CTNNB1 gene encodes β-catenin, mutations of which have been found in 70–90% of aCPs and seem to play important role in the tumorigenesis of aCP [34, 36, 37]. BRAF V600E is reported to be the most common mutation in pCPs (65–100%) [34, 35]. These findings have important implications for the diagnosis and treatment of these neoplasms.

## **5.4 Macroscopic features**

The typical macroscopic appearance of aCP is a small solid portion and large single or multiple cysts containing dark, viscous, "motor-oil" colored fluid rich in cholesterol crystals. aCP has calcification and irregular surfaces adhered to the surrounding normal structures [14]. On the other hand, pCP is usually solid, has a smooth surface and a cauliflower-like appearance, is rarely cystic, and if so filled with clear fluid [14].

## **5.5 Imaging features**

Radiological appearances of aCPs and pCPs also differ due to their distinct histopathological features. aCPs present with 90% calcifications, 90% enhancement, and 90% cysts containing cholesterol-rich fluid; whereas, pCPs appear mostly solid, rarely cystic, with more homogeneous enhancement and without calcifications [2, 13, 38].

## *5.5.1 Computed tomography (CT)*

A large conglomerate suprasellar mass with an area of calcification is a common computed tomography (CT) finding in CPs [13]. CT is superior to magnetic

## *Craniopharyngioma DOI: http://dx.doi.org/10.5772/intechopen.106635*

resonance imaging (MRI) in detecting the presence of calcification, and therefore, seems more specific in establishing the diagnosis of CP (**Figure 1**) [39]. It may present as a suprasellar ring lesion with a peripheral rim of increased enhancement after contrast administration. CPs are generally mixed solid and cystic tumors, the former having well defined hyperdense appearance, while the latter presenting an area of low density on CT [13]. The sella turcica is usually intact or only minimally enlarged, suprasellar cistern is distorted, and hydrocephalus is common [13].

## *5.5.2 Magnetic resonance imaging (MRI)*

MRI is the preferred method in the evaluation of tumor extent and recurrence. MRI is valuable in preoperative and radiation therapy planning due to its multiplanar capabilities [39]. Signal intensity on MRI varies with cyst contents [14]. CPs mostly demonstrate high signal intensity on both T2- and T1-weighted images (**Figures 2** and **3**) [38, 39]. High intensity on T1-weighted images corresponded to high cholesterol content or presence of methemoglobin in cystic lesions. Tumors lacking significant cholesterol or blood show moderate intensity (hypo- or iso intensity) on T1-weighted images [39]. While the CP cysts are variably hyperintense on FLAIR scan, the solid portion of the lesion does not suppress (**Figure 2**) [14]. CPs generally appear as mixed solid and cystic, lobulated lesions extending superiorly with the third ventricle compression, and reticular enhancement of the solid portion (**Figures 2** and **3**) [40].

## **5.6 Differential diagnosis**

Most common lesions involving intrasellar and suprasellar regions include pituitary adenoma, CP, and Rathke cleft cyst. Pituitary adenoma has often a snowman shape, solid characteristics with less cystic changes, and more homogenous contrast enhancement; while CPs frequently present with superiorly lobulated shape, cystic changes, calcification, and heterogeneity of enhancement with enhancing solid

## **Figure 1.**

*Axial (A) and coronal (B) non-enhanced CT shows suprasellar dispersed calcifications (black arrow) in a patient with adamantinomatous craniopharyngioma.*

## **Figure 2.**

*The MRI of a 33-year-old man shows a lobulated sellar and suprasellar mass that is hyperintense on axial (A, B), coronal (C) and sagittal (D) T2-weighted scans; and nearly isotense or slightly hyperintense on axial (E, F) and sagittal (G) T1-weighted, and FLAIR scans (black arrow) with some small cystic areas (white arrow), radiologically suggesting craniopharyngioma.*

## **Figure 3.**

*The sellar and suprallar masses appear hyperintense on axial (A, F) and coronal (B) T2-weighted images; isointense and slightly hiperintense on sagittal (C, H) and coronal (G) T1-weighted images (black arrow). Coronal (D, I) and sagittal (E, J) contrast enhanced T1-weightes scans show thin rim enhancement around the mass with a small tumor nodule at the base of the mass (white arrow).*

portion and unenhanced areas on contrast-enhanced T1WI [38, 40]. On the other hand, Rathke cleft cysts are in ovoid shape, with cystic lesions with no or thin cyst wall enhancement without calcification [14, 40].

## **6. Management**

Because of the high variability in the manifestations of CPs, the management strategy should be tailored to the patient. The important parameters for treatment planning are the volumes of the solid and cystic parts of the tumor, its proximity and adhesion to the hypothalamus and optical structures, and the neurological and endocrinological state of the patient [41]. Moreover, the management of CP should be carried out by multidisciplinary teams including neurosurgeons, endocrinologists, ophthalmologists, and oncologists.

## **6.1 Observation alone**

Although the mere observation of the tumor without treatment is currently not recommended, it gives the opportunity to observe natural course of the disease. Nevertheless, the natural growth of the CP seems unpredictable. In the literature, there have been a few case reports of CPs presented with long-term survival (up to 60 years), in spite of receiving no treatment and having some degree of morbidity [42, 43]. In these cases, tumors were mostly calcified, had low proliferative activity, and with partly cessation growth.

## **6.2 Surgical treatment**

Microsurgical resection should be preferred when the solid part of the tumor is large and if the resection is feasible with a low risk of morbidity and mortality. The position of optic chiasm in relation to the sella is an important criterion for the selection of an approach. The chiasm may be above the tuberculum (prefixed), above the diaphragm or the middle of the sellae (normal), or above the dorsum sellae (postfixed) [44].

Postoperative care is vital in CP management. Endocrine dysfunctions often ensue from the surgery. Therefore, following the removal of a CP, patients must be carefully monitored, including for their urination as total removal of a CP frequently leads to diabetes insipidus. To overcome the risk of hypocortisolism, preoperative doses of dexamethasone should be continued for a period of time and tapered off without causing insufficiency. Thyroid function, sexual function, and growth should be carefully observed, as a replacement therapy may be needed [22].

The ideal surgical approach is still controversial. However, some criteria can guide surgeons to choose the best approach to surgery.

## *6.2.1 Transcranial Approaches*

## *6.2.1.1 Subfrontal approach*

CPs that are considered prechiasmatic can be more easily resected via subfrontal approach. A right-sided unilateral frontal craniotomy usually suffices and a unilateral approach along the falx provides approximately equal visualization of both sides of the optic chiasm [45]. Osmotic diuretics and lumbar drainage of cerebrospinal fluid can be used to minimize the retraction of the frontal lobe. If there is a need for approaching the tumor through lamina terminalis behind the optic chiasm, the necessity of removing a small strip of the undersurface of the frontal lobe from the frontal pole to the chiasm along the falx might arise, which is the main limitation

of subfrontal approach [45]. Moreover, inevitable dissection of the olfactory nerves brings about the risk of olfaction impairment [46].

## *6.2.1.2 Pterional approach*

The pterional approach has been traditionally used most frequently because it allows early identification of the stalk, anterior circulation, and protection of the chiasm while giving access to virtually all parts of even very large tumors [24, 46]. The exposure through pterional craniotomy can be widened by adding the resection of the orbital rim and zygoma, which gives access to the skull base and minimize brain retraction [46]. Dissection can be performed through several corridors in the parachiasmal spaces: prechiasmatic, opticocarotid (between carotid artery and optic nerve), and carotidotentorial triangles (superior to the carotid artery bifurcation) or through the opening of the lamina terminalis [24, 46]. The main limitation of the pterional approach is the tumor extending into the upper part of the third ventricle and retrosellar region [46]. When tumors extend superiorly in the third ventricle, the pterional approach can be combined with the transcallosal approach because the pure pterional approach may be insufficient for proper dissection of the superior and posterior portions of the tumor within the third ventricle [23, 24]. CPs are usually subarachnoid tumors; therefore, they may be easily dissected from the surrounding structures covered with their own arachnoid layers. Nevertheless, great care should be paid to differentiating the tumor from hypothalamus and pituitary stalk. To avoid dreadful hypothalamic and infundibular injuries, tumor removal should be done stepwise, starting with the most easily accessible tumor portions, through internal decompression and dissection of the capsular-arachnoid plane [24, 46].

## *6.2.1.3 Transcallosal approach*

Transcallosal approach is used for tumors primarily involving the third ventricle. Following a unilateral paramedian frontal craniotomy, the brain is retracted away from the falx and the corpus callosum will be exposed. A small callosal incision is made and intraventricular parts of the tumor can be removed through foramen of Monro [24]. With the pure transcallosal approach, optic chiasm and pituitary stalk cannot be identified early, and the anterosuperior portions of the tumor under chiasm and lamina terminalis may not be visible, in case of which a combined pterionaltranscallosal approach is recommended [24, 46].

## *6.2.1.4 Transcortical-transventricular approach*

Transcortical-transventricular approach via a frontal craniotomy was first introduced by Busch in 1944 mainly for tumors of the third ventricle [47]. It was used for CPs with giant cysts extended to the dorsal surface of the frontal lobe; nevertheless, it is unfavorable for the risk of producing porencephalic cyst or postoperative epilepsy [24].

## *6.2.2 Transsphenoidal Approach*

If predominant portion of the tumor is intrasellar, the approach should be transsphenoidal (TS). TS approaches were traditionally reserved only for intrasellar

## *Craniopharyngioma DOI: http://dx.doi.org/10.5772/intechopen.106635*

infradiaphragmatic tumors; [24] yet, with technological developments, new transsphenoidal approaches, such as expanded endonasal approach (EEA), the exclusive or additional use of the endoscope, have been introduced also for the resection of suprasellar craniopharyngiomas [25, 48]. Nevertheless, TS approach can be combined with the pterional approach in cases of CPs with supradiaphragmatic extensions to achieve a total resection (**Figure 4**) [24]. Reconstruction of the sellar floor is one of the most crucial steps of TS as it was associated with a high incidence of cerebrospinal fluid (CSF) leak [49]. To prevent this complication, autologous grafts, such as fascia, muscle, or adipose tissue can be fixed with fibrin glue and patched to the base of the sella. On the other hand, shorter hospital stays, and a higher rate of preservation of pituitary function are its main advantages [50, 51].

## *6.2.2.1 Expanded endonasal approach (EEA)*

Exposure of suprasellar tumor components is improved with the development of EEA [46]. Currently, EEA is considered the first-line therapy when the distance between the optic chiasm and the surface of the pituitary gland is large, the lateral extension does not go beyond the internal carotid artery, and there is no extension beyond the posterior clinoid process; whereas, poorly developed sphenoid sinus, the pituitary stalk traveling anterior to the tumor, and CPs predominantly in the third ventricle are limitations of EEA [48].

In EEA, the bone of the sellar floor, tuberculum sellae, and planum sphenoidale are removed; while the optic canals mark the lateral limits, and the posterior ethmoidal arteries mark the anterior limit of the bony resection. The medial opticocarotid recess is a very important landmark marking the medial aspect of carotid and

## **Figure 4.**

*The postoperative MRI of the patient on the Figure 2 following the surgery by combined transsphenoidal and pterional approach reveals total resection without residue or recurrence after 5 years. Papillary craniopharyngioma was diagnosed at histopathology. (A) axial T2-, (B) coronal T2-, (C) axial T1-, (D) sagittal T1-, (E) coronal T1, (F) axial contrast enhanced T1-, (G) sagittal contrast enhanced T1-, (H) coronal contrast enhanced T1-weighted images.*

optic canals [52]. In CPs confined to the sella, removal of the anterior sella wall only would suffice, while preinfundibular tumors require larger bone resection over tuberculum sella and planum sphenoidale, rather than the anterior sellar wall. Whereas, in transinfundibular CPs, additional bone removal from the anterior sella; and in retroinfundibular CPs, extensive bone removal from the sellar floor, posterior clinoid processes, and dorsum sella may be needed [52].

## **6.3 Radiation therapy**

Due to the proximity and adhesiveness of CP to critical structures, including the optic chiasm, pituitary stalk, and hypothalamus, a complete removal is not always feasible, which increases the risk of recurrence. Postoperative radiation therapy (RT) is beneficial in patients with subtotal resection and recurrence, increasing the 10-year progression-free survival rates from 30 to 50% (of incomplete excision alone) to 75–90% (of incomplete excision followed by conventional RT) [20, 53]. Moreover, the tumor control rates were reported over 90% with newer higher precision techniques such as fractionated stereotactic conformal radiotherapy [53–56]. Radiation-related toxicities include impairment of endocrinological functions and vision, necrosis, radiation-induced tumors, and cognitive decline.

## *6.3.1 Conventional radiation therapy*

The standard conventional radiotherapy technique is fractionated 3-dimensional (3D) conformal external beam radiotherapy (3DCRT) using computerized 3D treatment planning coupled with imaging for conforming to the shape of the tumor and delivering photons through a linear accelerator under precise immobilisation [53]. A more complex computerized treatment planning, called intensity-modulated radiotherapy (IMRT), using the modulation of the intensity of radiation can be preferred for more individualized beam shaping, particularly for the avoidance of some critical normal structures [53].

## *6.3.2 Stereotactic radiosurgery*

Stereotactic radiosurgery (SRS) is an efficient option of radiotherapy for recurrent CPs following the surgical removal, ensuring tumor shrinkage and clinical improvement, without significant complications [57, 58]. Radiation can be delivered using gamma rays from multiple cobalt sources arranged in a hemisphere focused through a static collimator system onto the tumor (defined as Gamma Knife Radiosurgery) [53]. In this treatment modality, the use of a fixed frame entails completing the treatment in one day with a single fraction. Hypofractionated SRS may be useful for protecting the visual nerve and neuroendocrine function [58].

## *6.3.3 Fractionated stereotactic radiotherapy*

Fractionated stereotactic conformal radiotherapy was developed to provide more localized irradiation administered in fractions over weeks with a steeper dose gradient between the tumor and surrounding normal structures compared to conventional radiotherapy [54]. This method has been found as effective and safe adjuvant therapy in the treatment of cystic CPs [55, 56].

## *6.3.4 Intracavitary irradiation*

Stereotactic intracavitary brachytherapy with injection of colloidal phosphorus-32 (P-32) is a minimally invasive treatment modality for patients with cystic CP, resulting in improvement of symptoms and cyst regression [59, 60]. Some reports suggested that stereotactic intracavitary irradiation should be considered as the initial surgery for cystic CPs since it seems a safe and effective treatment [59, 60].

## **6.4 Chemotherapy**

Chemotherapy is an option of adjuvant therapy in cases of multiple recurrences of CP despite surgical and radiotherapeutic treatments. Systemic chemotherapy includes vincristine, procarbazine, cisplatin, etoposide, anthracyclines (Adriamycin/doxorubicin), and nitrourea-derivates (BCNU, CCNU/lomustine) can be administered at six weeks intervals and found to be effective in preventing recurrence [61–63].

In cases of subtotal resection, injection of some chemotherapeutical agents such as bleomycin, and interferon alpha into the remaining tumor has been also introduced as a postoperative adjuvant therapy [64–68]. The intratumoral chemotherapy was found to reduce the volume of cystic CPs, and was considered a new therapeutic alternative, proposed to be more advantageous than total excision for cystic-type CPs; [64–69] still, it is not without serious risks of side effects due to its probable toxicity on deep brain structures [70].

## **7. Outcomes and prognosis**

CPs may behave aggressively despite their benign histological nature. Tumor recurrence is very common because of their location and tendency to invasion into surrounding structures, such as the hypothalamus, pituitary gland, and optic apparatus, which makes total resection difficult [18]. Even after complete resection and radiotherapy, CPs have a propensity to recur. Most recurrences appear during the first five years following the first surgery, and during the first three years following repeated surgery [29]. Recurrence rates were reported between 5% and 59% in some series [24, 71].

The recurrence rate and outcomes are mainly dependent on the extent of surgical resection. Katz [72] reported the surgical outcomes of a case series of 34 surgically treated for the first time and 24 reoperated patients with CP. In their series, they noted 74% of cure rate without recurrence after radical primary excision and 16% of cure after reoperation. In the follow-up of 31 living patients of this series, the quality of survival was reported as 39% excellent, 29% good, 29% fair, and 3% poor [72]. In another study among patients with limited surgery (biopsy or removal of less than 25% of the tumor) followed by conventional radiotherapy, the outcomes were good in 50%, poor in 43%, and death in 7% [73]. Yaşargil [24] reported 90% complete resection, with 16% mortality and 7% recurrence rates in their case series of 144 CPs, suggesting that primary total removal of CPs yields the best long-term outcome for the patients.

Perioperative mortality rates were reported between 0% and 25% with higher rates in repeated surgeries [24, 29, 72]. Overall, one- and three-year survival rates are 91% and 86%, respectively [18].

Some studies suggested some potential predictor factors for poor prognosis including histopathological subtype of adamantinous pattern, higher proliferative index (MIB-1/Ki67 > 7%), nuclear atypia, hyperchromatic nuclei of basaloid cells, vascular invasion, coagulative necrosis, and p53 expression pattern [3, 71, 74]. Younger age, smaller tumor size, subtotal resection, and radiation therapy were associated with prolonged survival [17, 18].

The quality of life during follow-up after surgery is closely associated with the extent of removal during surgery. Total and near total resections have more risks of complications, such as hypothalamic syndrome (intellectual impairment, increased appetite, and weight gain) and hypopituitarism (hypogonadism, growth hormone deficiency, hypothyroidism, and hypocortisolemia) [51, 75, 76]. Furthermore, the incidence of CSF leak is much higher after EEA, reaching up to 58% [49].

## **8. Conclusions**

CPs are histopathologically benign, but clinically aggressive suprasellar masses arising from Rathke's pouch. Despite its rarity overall, it is the most common non-glial brain tumor in childhood. It may present with visual and endocrine disturbances, growth retardation, secondary sexual dysfunction, weight gain, polyuria, headache, nausea, and vomiting. aCPs are lobulated, calcified, cystic with cholesterol-rich fluid, and infiltrative lesions; while pCPs are mostly solid, without significant infiltration to the surrounding tissue. Although the management of CPs is controversial, the current consensus is that surgical resection is the first-line therapy for primary and recurrent tumors, while radiation therapy and chemotherapy should be considered adjuvant treatments for subtotal or limited resected and recurrent tumors. Based on individual characteristics and selection criteria; pterional, transsfenoidal, transcallosal, or transcortical-transventricular approaches may be preferred for surgery. Radiation therapy includes the options of conventional radiotherapy, stereotactic radiosurgery, or intracavitary irradiation. Finally, if needed, chemotherapy can be administered intravenously or intralesionally. Owing to the advances in diagnostic and treatment modalities, the outcomes and survival rates have increased despite their inclination to recur.

## **Acknowledgements**

No financial support or benefits have been received by any of the authors from any commercial source which is related directly or indirectly to the scientific work presented.

## **Conflict of interest**

The authors declare no conflict of interest between any person/persons or institution/institutions and the authors in this study. The materials used in the study are extracted from the archives of the authors and have not been published before. The authors declare no conflict of interest for the materials used in the study.

## **Author details**

Gökhan Kurt1 and Ayfer Aslan<sup>2</sup> \*

1 Gazi University Faculty of Medicine, Ankara, Turkey

2 Hitit University Faculty of Medicine, Erol Olçok Training and Research Hospital, Çorum, Turkey

\*Address all correspondence to: ayferaslan86@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 6**

## Overview of Brain Metastasis and Treatment Modalities

*Edwina Ayaaba Ayabilah, Andrew Yaw Nyantakyi and Joseph Daniels*

## **Abstract**

Brain metastasis (BM) is the commonest form of intracranial malignancy, historically considered a single disease entity with a gloomy outcome, often resulting in a palliative approach to clinical management. Primary cancers that most frequently spread to the brain are lung, breast, and renal carcinomas as well as malignant melanomas. Global incidence of brain metastasis is on the rise but may still be underestimated. About 67% of patients with BM present with either generalized or focal symptoms and sometimes both. A thorough clinical workup and application of verified prognostic scores lead to optimal stratification and strongly influences therapeutic decisions and patients' outcomes. Management is multidisciplinary and involves symptomatic treatment, use of best supportive care, radiotherapy, surgery as well as targeted therapy.

**Keywords:** brain metastasis, cancer, brain tumors, neurological symptoms, whole brain radiotherapy, stereotactic radiosurgery

## **1. Introduction**

Brain metastasis (BM) is the commonest group of intracranial tumors and is considered a direct neurological complication of cancer. It is 10 times more frequent than primary brain neoplasms [1], occurring at a median time of 8.5–12 months from primary diagnosis. About 20–40% of adult cancer patients develop brain metastases, with 40% of these presenting with a limited number of lesions (i.e., 1–4 lesions whereas 60% present with multiple lesions. Brain metastasis is the direct cause of death in 30–50% of cases [2]. Improved cancer survival is one of the key reasons for the rise in prevalence of brain metastasis (Reference). Brain metastasis generally has poor prognosis, causes significant morbidity and is fatal if left untreated. Median survival time ranges from 4.9 to 16.4 months [3]. Localization of brain metastases is influenced by the arterial blood flow distribution with about 80% localized in the cerebral hemispheres, 15% in the cerebellum and 5% in the brainstem [4]. Research has shown a strong correlation between the localization of brain metastases and clinical outcomes, as such infratentorial metastases though not frequent have the worst prognosis [5].

### **Figure 1.**

*Distribution of incidence of brain metastasis by cancer site [8].*

## **2. Epidemiology**

Population-based studies show global incidence ranging from 8.3 to 14.3 per 100,000 population per year. This is likely underestimated owing to significant inaccuracies associated with these population and pathologic studies [6]. Any type of cancer can metastasize to the brain, however the three commonest primary tumors associated with brain metastases are lung (20–56%), breast (5–20%) and malignant melanomas (7–16%) [2, 6, 7]. Data from the Surveillance, Epidemiology, and End Results (SEER) Program indicate that patients with either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) have the highest rates of brain metastases at diagnosis, whilst patients with malignant melanomas have the highest risk of presenting with metastatic brain disease. By contrast cancers of the prostate, head and neck, skin (non-melanoma skin cancer), and esophagus rarely metastasize to the brain (**Figure 1**) [6].

## **3. Risk factors**

Tumor site and molecular subtype of primary tumors are important factors that influence the risk of distant brain metastases among cancer patients. Some tumors have very high propensity to metastasize to the brain whereas other tumors rarely spread to the brain. For instance, ALK-rearranged NSCLC specifically metastasizes to the brain. Patients with human epidermal growth factor receptor 2 (ERBB2 or HER2) amplification or triple-negative breast cancers (TNBC) have a higher risk of developing brain metastases than those with other molecular subtypes of breast cancer [9]. Other risk factors include advanced age, sex, ethnicity, and geographic location.

## **4. Pathobiology**

The blood-brain barrier (BBB) protects the brain from the effect of chemicals in the blood circulatory system. The BBB maintains normal brain function by tight

## *Overview of Brain Metastasis and Treatment Modalities DOI: http://dx.doi.org/10.5772/intechopen.106789*

regulation of transfer of molecules and ions between blood and the brain. The BBB is made up of endothelial cells. Its basement membrane is adjoined by tight cell-to-cell junction proteins with specific transport mechanisms and pinocytic vesicles. The endothelium is further surrounded by cellular elements including pericytes and astroglia foot processes (end foot processes), forming an additional continuous stratum that reinforces the barrier [10]. This barrier permits only small uncharged compounds to diffuse from blood into the brain without a specific transporter.

Metastasis of cancer cells is a multifaceted process that has been simplified in several critical steps. It involves epithelial to mesenchymal transition (EMT) of cancer cells at their primary site, extracellular matrix modulation, intravasation, circulation, extravasation, homing, formation of the premetastatic niche for organotypic colonization and mesenchymal-epithelial transition (MET) at the secondary site. This stepwise process takes into account the interaction between the tumor and the tumor micro-environment, host immunity and secondary site micro-environment.

Multiple hypotheses have been proposed to explain metastatic patterns observed among different primary cancers. Two longstanding theories on the metastatic spread of cancer are the "seed and soil" hypothesis and mechanical theory [11, 12].

The "seed and soil hypothesis" seems to best explain the pathophysiology of brain metastases with the following steps.


BM requires synergy between cancer cells and the parenchymal tissue of the central nervous system (CNS). Different primary tumors are characterized by distinct patterns of brain metastasis. Clonal cells of primary tumors undergo a series of genetic changes as they accumulate more and more mutations in their DNA with subsequent divisions and damage of repair mechanisms. This contributes to genomic instability which is associated with the activation of genes that promote abnormal cellular growth and the silencing of genes that regulate the cell cycle. Ultimately, this culminates in the immortalization of cancer cells. This is classically seen in the inactivation of the Retinoblastoma (Rb) protein and destruction of the p53 protein which plays a key role in the pathogenesis of Human Papilloma Virus 16 (HPV 16)-associated head and neck

cancers as well as HPV-positive cervical cancers [13]. Mutations downstream from the parent stem cell with subsequent mutations result in a heterogeneous tumor with some cells having the propensity to metastasize. As tumors continue to proliferate and increase in size, increased demand for nutrition and oxygenation to maintain growth triggers angiogenesis. Switch for angiogenesis requires a tip of the balance between pro and anti-angiogenic factors towards the former. This occurs as hypoxia sets in at tumor regions far from blood supply. Under hypoxic conditions, Hypoxia Inducible Factor (HIF) is activated. HIF-1a is stabilized because of the lack of oxygen and dimerizes with HIF-1beta to bind to the hypoxia response element (HRE; 50 -G/ACGTG30). HIF-1 activates the transcription of target genes by interacting with co-activator CBP/ p300. These genes regulate and promote glucose transporters and glycolysis, angiogenesis, proliferation, invasion and metastasis [14]. HIF controls the activity of VEGF over-expression promoting angiogenesis; however, blood vessels are poorly formed and defective. Newly formed blood vessels are tortuous and dilated with endothelial cells forming a monolayer and resting on a basement membrane of variable thickness and pericytes forming loose associations of endothelial cells [14, 15]. This results in leakiness of the vessel formed and gives rise to chronic hypoxia in the tumor. This leakiness in the newly formed vasculature also serves as an easy portal for cancer cells to circulate in the bloodstream. HIF-dependent upregulation of transcription repressors of E-cadherin, such as zinc finger protein SNAI1 (SNAIL), twist related protein 1 (TWIST1), transcription factor 3 (TCF3), zinc finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2) results in loss of receptors [14, 16]. E-cadherin among others is a major component of adherent junctions that maintain the integrity of the epithelium. This loss is a functional requirement for EMT [14].

EMT is a natural phenomenon that is employed during embryogenesis. Cancer cells employ this principle to aid distant spread. It is a biochemically stimulated process during which epithelial cells acquire a mesenchymal phenotype through EMT transcription factors (these repress epithelial genes and promote mesenchymal genes) [15]. It encompasses changes in multiple phenotypic characteristics including but not limited to apicobasal polarity, cell-cell adhesion, cytoskeleton remodeling and cellmatrix adhesion as well as the gain of mesenchymal markers such as vimentin and alpha smooth muscle actin (αSMA) [16]. All these changes promote the detachment of cancer cells from the parent tumor into the extracellular matrix. Using proteolytic enzymes such as metalloproteinase degrades the extracellular matrix and travels through the extracellular matrix to reach blood and lymphatic vessels [17].

Neo-vascularization by tumor is ineffective as described earlier hence cancer cells easily enter the lumen of blood vessels. In areas where blood vessels do not have the defect of leakiness, intravasation is achieved by use the of enzymes such as heparinase which degrades the basement membrane of vessels and allows cancer cells to enter circulation. Circulation is not a friendly environment for the cell because of host immune system that attacks and lyses these cancer cells. Cancer cells have developed strategies for evasion of host immune defense mechanisms through immune mimicry [15]. This is achieved by upregulating specific receptors such as integrins and protein death ligand 1 (PD-L1) that bind to platelets and host leukocytes to form a complex structure which facilitates immune evasion and also protects cancer cells from mechanical damage [17].

Metastatic tumor cells travel along blood vessels and can get trapped in smaller vessels (end arteries of the brain). Here they adhere to the endothelial lining and have to break through the BBB described earlier. There are various hypotheses that have been generated over the years to explain how this occurs. Three of these hypotheses

## *Overview of Brain Metastasis and Treatment Modalities DOI: http://dx.doi.org/10.5772/intechopen.106789*

are; First, tumor adhere to proteins expressed by endothelial cells allowing them to cross the BBB into the perivascular space; Second, tumor cells adhere to systemic immune cells via receptor-ligand interactions and cross through the BBB with the "hijacked" cells; Third, tumor cells modify the endothelial cell wall by stimulating expression of matrix metalloproteases (MMPs), allowing extravasation into the perivascular space [10]. Hereafter there is local extracellular matrix (ECM) remodeling to suit the tumor cells and this is achieved through paracrine interactions between the brain stromal, endothelial wall and invading tumor cells [18]. Proteolytic degradation of the ECM by enzymes such as heparinase concentrated mainly around the region of the advancing cancer cell membrane promotes the breakdown of the endothelial wall into the brain parenchyma. Astedt et al noted urokinase-type plasminogen activator (uPA) is produced and released from cancer cells. Also, tumor associated serine protease plasmin, its activator uPA, the receptor uPA-R (CD87), and plasminogen activator inhibitor type 1 and 2 (PAI-1/2) are linked to cancer invasion and metastasis [19]. At the BBB Urokinase converts the zymogen plasminogen to plasmin, a trypsinlike enzyme with broad substrate specificities. uPA binds to the surface of the cell membrane and causes localized cell surface proteolytic activity, which is required for the destruction of the ECM. PA1-1 modulates the activity of uPa. Plasmin on the other hand activates the other proteolytic enzymes (such as metalloproteases) and degrades components of the ECM as well [18]. In the brain perivascular or parenchymal space, tumor cells adhere for survival through the E-cadherin-catenin complex. This process is a reversal of the epithelial to mesenchymal transition that was seen at the initial stages of metastasis [10]. Through interaction between the tumor cells, ECM and stroma, multiple cytokines, growth factors and enzymes are secreted by microglia and macrophages to promote inflammation, growth and survival of the tumor cells. For instance, vascular endothelial factor (VEGF) promotes angiogenesis, epidermal growth factor (EGF) promotes tumor proliferation and matrix metalloproteases promotes further invasion of tumor cells in the brain. Vessels are poorly formed in this process as described earlier and this results in leakage of water, proteins, and inflammatory mediators at the site of metastasis resulting in edema (perilesional edema as seen on imaging studies).

Specifically in malignant melanoma, expression of programmed death ligand 1 (PD-L1) by microglia promotes invasion of tumor cells and inhibits cytotoxic T cell activity [20]. Furthermore, there is production of proinflammatory chemokine CXCL10 and release of Interleukin 23 (IL-23) as a result of interaction between tumor cells and astrocytes. CXCL10 chemokine attracts T lymphocyte cells as well as tumor cells via CXC3R. Thus, malignant melanoma is the seed and astrocytes make the brain a suitable soil for metastasis. Both malignant melanoma and neural cells originate from neural crest cells hence express neurotrophin receptors (such as P75NRT and TrkC) [21]. This is regulated by neural growth factor (NGF) and neurotrophin 3 secreted by astrocytes and resulting in promoting invasion [20].

Brain tissue uniquely appears to downregulate the expression of the tumor suppressor "phosphatase and tensin homolog" (PTEN) culminating in the growth of tumor in the brain microenvironment in lung cancer. MicroRNA (specifically miR-19) released from astrocytes plays a role in downregulating PTEN expression in invading tumor cells [22]. Over-expression of a disintegrin and metalloprotease 9 (ADAM9) protein promotes migration and expression of integrin 1 on lung cancer cells. This results in adhesion to endothelial cells. It may also increase the activity of tissue plasminogen activator (tPA) culminating in angiogenesis, tumor invasion and proliferation [23]. The chemokine CXCL12 binds the G-protein-coupled receptor

CXCR4 and stimulates the pathways leading to chemotaxis, enhanced intracellular calcium, tumor growth, invasion, homing, angiogenesis and metastasis [24].

In breast cancer, activation of the AKT/MAPK signaling pathway stimulates upregulation of interleukin 6 and 8 (IL-6 and IL-8), B-cell lymphoma 2L1 (BCL2L1), TWIST1, and glutathione S-transferase A5 (GSTA5) anti-apoptotic genes that are responsible for breast cancer metastases to the brain [25]. Phospholipid-binding proteins such as annexin A1 (ANXA1 or lipocortin) ignite CXCR4- mediated migration of breast cancer cells in response to stromal cell derived factor 1α (SDF-1α) which incorporates with CXCR4 [26]. This promotes penetration of breast cancer cells into human brain microvascular endothelial cells [27].

Wyler et al. studied the chemokine and chemoreceptors in 246 autopsy specimens that could explain the frequency and patterns of brain metastasis in renal cell carcinoma (RCC) at autopsy [28]. In all, 15% of the sample had brain metastasis. CXCR4 expression levels were 85.7% and 91.7% in primary RCC and brain metastases respectively. CCR2 and CCL7 expression were 52.1% and 75% respectively metastatic brain cells as compared with primary tumors (15.5% and 16.7%, respectively; P<0.0001 each). CD68+ tumor-associated macrophages (TAMs) were similar in primary RCC and brain metastases. However, TAMs were more frequently CCR2-positive in brain metastases than in primary RCC (P < 0.001) [28]. This further confirms the changes seen in chemokine and chemoreceptor expression seen in metastatic brain tumor cells.

There is uneven distribution of metastatic lesions in the brain. This distribution is partly explained by the tissue volume in these areas. The lesions are distributed along the grey-white matter junctions and tumor emboli lodges in capillary beds with smaller diameter (thus the watershed distribution). However, it should be noted that the within the cerebral hemisphere, distribution in the frontal and parietal region is higher than the temporal and occipital region as related to the mass of these regions. In the cerebrum, some literature have suggested that the Batson venous plexus via a retrograde pathway through the basilar plexus of veins plays a role in the preferential metastasis of abdominal and pelvic primary lesions [29]. The incidence of vertebral bone metastasis also via this pathway is well documented in literature for prostate, renal, breast, lung and colon cancers [30].

Stephen Paget first proposed that metastatic development was a consequence of particular tumor cells ('seeds') finding a suitable environment ('soil') in order to develop and grow. James Ewing on the other hand proposed that circulatory patterns between the primary tumor and specific secondary organs are sufficient to explain the majority of organ-specific metastatic spread thus the mechanical hypothesis. Interplay between tumor molecular, epigenetic, genetic factors and that of secondary site all contribute to the metastasis of specific tumors to the brain. Presented here is a brief overview of this in-depth picture.

## **5. Clinical presentation**

The clinical manifestation of distant metastatic brain lesions is associated with a wide array of signs and symptoms that are influenced by the region of the brain involved as well as the extent of peritumoral edema. There is a need for high index of suspicion among cancer patients because some of these symptoms can be as vague as mild headaches or mood changes and may be easily taken for granted. Some lesions may be asymptomatic and discovered as incidental findings on brain imaging studies done for other unrelated reasons. Progression of intraparenchymal metastasis may lead to

leptomeningeal spread [31]. Leptomeningeal spread occurs in both adults and children especially those with acute leukemia and lymphomas. Intracranial metastasis can present as hemorrhagic or cystic lesions on imaging. The former is likely to occur in cancer types such as renal cell carcinoma, choriocarcinoma, thyroid carcinoma as well as malignant melanoma whereas the latter is predominantly associated with gastro-intestinal malignancies. Common signs and symptoms presented by patients include the following.

## **5.1 Headache**

Headache is a common presenting complaint among 32% - 54% of cancer patients who are diagnosed with brain metastasis [31, 32]. As many as 71% of brain neoplasms are associated with tension headache. Under normal physiologic conditions, the brain is largely insensate demonstrated in neurosurgical procedures in which stimulation of the brain parenchyma in awake patients caused no pain. Projections from the trigeminal [33] and upper cervical dorsal root ganglia innervate the pial, dural, and extracranial blood vessels. Therefore, metastatic brain lesions with their associated peritumoral edema cause pressure and stretching of the pia and dura matter resulting in stimulation of the unmyelinated C fibers (afferent neurons). These fibers transmit the nociceptive information mediated by glutamate through the trigeminal ganglia to synapses on second-order neurons within the trigeminal nucleus. Headache associated with increased ICP typically worsens in the morning and is aggravated with coughing, carotid massage, or Valsalva maneuver. Multiple brain lesions and localization in the posterior cranial fossa are associated with more frequent headaches.

## **5.2 Increased intracranial pressure (ICP)**

The skull bone provides a fixed space that accommodates a person's brain tissue and associated meninges, CSF and vasculature. The presence of a lesion that is increasing size increases the ICP in this fixed space. As a result, there are symptoms that occur due to increased ICP such as altered level of consciousness (confusion), headache, nausea, vomiting and visual disturbance in the form of blurred vision or diplopia. Vomiting is more common with children than adults.

## **5.3 Seizure**

Seizures are potential life-threatening complications of brain metastases; and are a presenting symptom in up to 40% of patients [34]. The risk of developing a seizure is influenced by the tumor type, the location and its proximity to the cortical graymatter. Prophylactic anticonvulsants are not recommended for routine use by the ASCO guidelines in patients with brain metastases who have not undergone surgical resection and who are otherwise seizure free. It's routine use in the post craniotomy setting for seizure-free patients with brain metastases is not recommended either (Level 3 evidence).

## **5.4 Cerebrovascular accident (CVA)**

Hemorrhagic strokes can occur from metastatic brain lesions with intralesional bleeding, vascular invasion, or embolization of tumor cells. Cancers such as malignant melanoma, choriocarcinoma, thyroid and renal carcinoma are associated with this kind of presentation.

## **5.5 Altered level of consciousness**

The reticular activating system (RAS) is a component of the reticular formation, found in the brainstem. The reticular formation receives afferent neurons from the spinal cord, sensory pathways, thalamus, and cortex and has efferent connections throughout the nervous system. The RAS is composed of four groupings of nuclei namely locus coeruleus, raphe nuclei, posterior tuberomammillary hypothalamus and pedunculopontine tegmentum. The locus coeruleus is located within the upper dorsolateral pons [35] whiles raphe nuclei are located midline throughout the brainstem within the pons, midbrain, and medulla [36]. The tuberomammillary nucleus is located within the posterior aspect of the hypothalamus [37]. The lateral and dorsal pedunculopontine tegmentum lies within the midbrain and pons [38]. Each is unique in the neuropeptides they release, however these centers are largely activated by the lateral hypothalamus (LH), via the release of the neuropeptide orexin in response to the light hitting the eyes, which then stimulates arousal and the transition from sleep to waking [39]. Disruption and inactivation of the intricate network of the RAS decreases the release of neurotransmitters (serotonin, histamine, norepinephrine and nitric oxide) needed for arousal and wakefulness. This results in altered level of consciousness manifested by inattentiveness, drowsiness, decreased cognition, memory impairment, confusion and even hallucinations.

## **5.6 Focal neurological symptoms**

Focal neurological symptoms may manifest on the side of the body opposite to the location of the lesion in the brain. Metastatic brain lesions are usually located in cerebral cortex (80%), cerebellum (15%) and brainstem (5%) [40, 41]. Focal symptoms may manifest as unilateral limb weakness known as Todd's paralysis. Some neurological symptoms are directly dependent on the exact localization of metastatic lesions in the lobes of the brain.

## *5.6.1 Frontal lobe lesions*

Tumor metastasis in the frontal lobe can affect motor function, speech, attention, planning, change in personality and ability to solve problems. Focal weakness is common.

## *5.6.2 Parietal lobe*

Parietal lobe lesions can affect one or several of the core functions of the parietal lobe namely, vision, perception, sensation and spatial-visual coordination. This results in symptoms such as apraxia, right-left confusion, inability to read, write or complete simple calculations.

## *5.6.3 Temporal lobe*

Important cerebral structures in the temporal lobe include the hippocampus, auditory cortex as well as Wernicke's area. Lesions in the temporal lobe may affect the function of these structures leading to receptive aphasia, impaired speech recognition and inability to store new memories.

## *5.6.4 Occipital lobe*

The occipital lobes house's the visual cortex. Metastatic lesions affecting this lobe can result in hemianopsia or cortical blindness.

## **6. Clinical workup**

The initial workup of patients with metastatic brain lesions must include a complete history and physical examination. Immediate relatives and close friends are also a good source of information concerning changes in mental state which the patient may not appreciate as important. During this exercise, the clinician probes into the onset and clinical course of symptoms as well as any history of a previous diagnosis of cancer, previous surgeries and their indication and biopsy taken. A high index of suspicion is present if patient has a known history of cancer and presents with a change in mentation. Physical examination is performed to document firstly the patient's current neurologic deficit and this serves as a baseline for assessment to treatment responds later.

Imaging studies help to confirm a lesion in the brain. Magnetic resonance imaging (MRI) with a gadolinium (Gd)-containing contrast agent is the imaging modality of choice for brain metastasis. Gd-based contrast leaks into parenchyma in areas with BBB breakdown, and the paramagnetic properties of Gd generate hyperintense signal on T1 weighted images. These images are better at demonstrating the anatomy and areas of contrast enhancement just like a contrast enhanced CT scan (which in place of MRI is helpful in a low resource setting) however a better tumor delineation is seen on MRI. T2 weighted and FLAIR images are more sensitive for detecting edema and tumor infiltration.

Computed tomography (CT) scan can be used in situations in which MRI is contraindicated, such as implanted pacemaker, metal fragment or metallic implants. In low-resource countries, a Ct scan done in a planning position saves cost as this can be used to confirm diagnosis radiologically and for radiation treatment. A biopsy of the primary lesion and further immunohistochemistry is essential in the management of brain metastasis as this helps determine the choice of treatment and may predict the responds to treatment.

Examination of blood and serum should include full blood count, renal and liver function tests, and, if any risk factors are present such as HIV antibody status.

## **7. Prognostic classification**

Prognostic classification of brain metastatic disease patients has important implications for patient education and choice of treatment approach. A recursive partitioning analysis of 1200 patients enrolled in one of three consecutive Radiation Therapy Oncology Group (RTOG) trials established three classes (I -III) of patients with different survival estimates based on four key prognostic factors: age, Karnofsky performance status (KPS), evidence of control of the primary tumor and the status of extracranial metastases.

Additional prognostic classification systems have provided an initial framework for estimating a patient's overall survival. These systems include firstly, the Score

Index for Radiosurgery (SIR), which was developed for the classification of patients undergoing Stereotactic radiosurgery (SRS) and hence placed importance on the number and the volume of brain metastases [42]. Secondly, the Basic Score for Brain Metastases in which Karnofsky Performance Score, control of the primary tumor and presence of extracranial disease are used to estimate survival [43].

## **8. Management**

The management of metastatic brain disease requires a multimodality approach involving radiation oncologists, neurosurgeons, neurologists and clinical psychologists amongst others. Treatment options for brain metastases include whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), conventional surgery, and systemic therapies (chemotherapy, immunotherapy).

## **8.1 General management**

The general management of patients with metastatic brain lesions includes control of increased intracranial pressure (ICP) and seizures. ICP is due the lesion growing in a fixed space with associated perilesional edema. This manifests as headaches, blurred vision or diplopia, nausea, vomiting and seizures as seen in primary brain lesions. If left unresolved increased ICP can eventually result in coning. Steroids are employed to control the neurologic signs and symptoms associated with cerebral edema caused by metastatic brain lesions.

Kofman first used prednisone for the management of perilesional edema due to brain metastasis in 1957 [44]. Years afterwards, dexamethasone revolutionized care of brain lesions by alleviating cerebral edema. Dexamethasone like other glucocorticoids interacts with the glucocorticoid receptor (GR) which is encoded by a gene located on chromosome 5 [45]. Ligand binding of GR can result in a direct induction or repression of target gene expression and this in turn gives rise to a multitude of steroid exerted effects. The result is a reduction of perilesional edema and a decrease in the permeability of the blood brain barrier [46]. Though there are other medications in this group, dexamethasone is the most commonly used. It has a biological half-life of more than 30 hours with minimal mineralocorticoid effect as compared to hydrocortisone, prednisone, cortisone and methylprednisolone [45]. Steroids are metabolized in the liver in a cytochrome P450-dependent manner therefore a p450 inducer affects the bioavailability of the medication as seen in combined use with anti-seizure medication such as phenytoin carbamazepine and phenobarbital [47]. Non-enzymeinducing anticonvulsants, such as levetiracetam, lacosamide, lamotrigine, and pregabalin, are preferred in the management of seizures associated with brain metastasis.

Veicht et al in a randomized trial compared 8 mg dexamethasone versus 16 mg dexamethasone or 4 mg versus 16 mg in patients with brain metastases [48]. A similar improvement of the Karnofsky performance status was observed in all groups. However, side effects were significantly more frequent in patients treated with 16 mg dexamethasone per day. Steroids can be stopped without tapering down for a short period of time however prolonged administration lasting for weeks or months requires tapering over a longer period of time to avoid hypocortisolism due to suppression of adrenal function [49]. Effects of long-term use of steroids include osteoporosis, steroid-induced diabetes, myopathy, thromboembolic event, psychiatric disorders and immunosuppression. Furthermore, Patients on glucocorticoids may

experience symptoms of gastric irritation which may not translate into an increased risk of peptic ulcer disease (PUD) with only 0.4% of this group developing it [50]. However, the combination of glucocorticoids with nonsteroidal anti-inflammatory medication increases the risk for PUD [51]. Proton pump inhibitors are started to counter this effect.

## **8.2 Radiotherapy**

Different types of cancers have different sensitivities to radiation. Small cell lung cancer and germ cell tumors are very sensitive to radiation whereas lung and breast cancers are only moderately sensitive to radiation. Malignant melanoma and renal cell carcinoma are less sensitive to radiation.

## *8.2.1 WBRT*

WBRT involves irradiating the entire brain and is considered to be a standard of care in select patients with diffuse brain metastasis (≥5 brain metastases). It is also considered for patients in whom surgery or stereotactic radiosurgery (SRS) is not recommended, for example, those with leptomeningeal disease, innumerable metastases, low RTOG DS-GPA scores or medical contraindications. It has the advantage of simplicity of delivery and the ability to treat both local and distant intracranial disease. There is no consensus on the optimal dose and fractionation schedule for WBRT, despite multiple studies to determine the optimal delivery.

An updated Cochrane review from 2018 support the use of a biologically effective WBRT doses, with respect to consequences for survival and improvement in neurological function. WBRT dose of 30 Gy in 10 fractions, as opposed to a lower total of 30 Gy in 10 fractions or 37.5 Gy in 15 fractions continue to remain the standard for a vast majority of patients receiving WBRT. Nieder et al. reported the radiographic overall response rate with this fractionation scheme to be 59%. For patients with poor performance status, and/or uncontrolled extracranial disease, a shorter fractionation scheme (e.g., 20 Gy in 5 fractions) or best supportive care can be considered.

A phase III randomized, noninferiority study, the QUARTZ (Quality of Life after Treatment of Brain Metastases) trial, compared the Quality Adjusted Life Years (QALY) between optimal supportive care (OSC) alone and OSC + WBRT (20 Gy in 5 daily fractions) for NSCLC patients with brain metastases unsuitable for resection or stereotactic radiotherapy. OSC consisted of dexamethasone titrated based on patient's symptoms as well as patient access to palliative care clinicians and nurses. Results revealed a difference in mean QALY of 4.7 days (46.4 QALY days for OSC + WBRT vs. 41.7 QALY days for OSC), which was within the prespecified noninferiority margin of 7 days. Overall survival was not significantly different between randomization arms (OSC + WBRT: 9.2 weeks vs. OSC alone: 8.5 weeks). Subgroup analysis suggested a survival benefit in favor of OSC + WBRT for patients younger than 60, KPS ≥ 70, and controlled extracranial primary disease.

The role of surgery and WBRT in patients with a single metastatic lesion in the brain has been demonstrated to improve both OS and local control (LC) in several trials. In a study by Patchell et al, the efficacy of biopsy sampling plus WBRT was compared with that of WBRT and complete resection in 48 patients with a single metastatic lesion in the brain. Both OS (median 40 weeks versus 15 weeks; P < 0.01) and local control (median 38 weeks versus 8 weeks; P<0.005) were improved with surgical resection [52]. In another study by Noordijk et al. similar outcomes were

reported in a trial involving 63 patients randomized to either surgical resection plus WBRT or to WBRT alone (median OS 10 months versus 6 months; P = 0.04), with those with controlled extracranial disease having the best outcomes [53].

Acute adverse effects of WBRT include skin erythema, alopecia, fatigue, serous otitis and an altered sense of smell and taste. Late-onset adverse effects, such as memory loss, confusion and leukoencephalopathy. The late effects are of most concern to patients, caregivers and health care providers. Effects of WBRT on neurocognitive function (NCF) are best assessed using objective psychometric tests such as Hopkins Verbal Learning Tests (HVLT), Controlled Oral Word Association, Grooved Pegboard test, and Trail Making Tests Parts A and B.

Strategies to mitigate neurocognitive decline from WBRT include the use of Memantine (a non-competitive NMDA receptor antagonist that retains activated NMDA receptors in an open-channel state, thus preserving long-term potentiation) and hippocampal avoidance (HA-WBRT).

In the RTOG 0614 trial, Memantine was started once daily with WBRT and increased to 10 mg twice daily over a few weeks, for a total of 24 weeks. The primary end point was preservation of cognitive function particularly memory function, which was assessed using the revised HVLT (HVLT-R) to measure changes in delayed recall at 24 weeks. Patients in the memantine arm had less decline in performance on HVLT-R delayed recall at 24 weeks: median decline was 0 in the memantine arm versus –0.9 in the placebo arm at 24 weeks, although this difference was not statistically significant (P = 0.059) [54].

## *8.2.2 Stereotactic radiosurgery*

Stereotactic radiosurgery (SRS) is a minimally invasive treatment option in the management of brain metastases with efficacy demonstrated in several randomized trials and multi-institutional studies. It is associated with similarly high efficacy for both radiosensitive and radioresistant tumors. SRS is a preferred option mainly because of the limited area irradiated. It is however limited by its small therapeutic ratio in lesions ≥ 4cm and/or tumor localization in the brainstem. This limitation has recently been solved with the use of fractionated SRS given in 3–7 fractions which typically results in a good therapeutic ratio with high local control rates (75–85%) and lower toxicity rates for large lesions.

SRS can be used alone or as a combined modality with WBRT or surgery. SRS has demonstrated superior local tumor control and functional autonomy for patients with brain metastases when combined with WBRT compared with WBRT alone. Patients with single metastatic brain lesions also experience longer survival with the use of SRS combined with WBRT. The reported survival for patients with RPA prognostic class I is 18–24 months, RPA class II from 9 to 11 months and RPA class III only 3 months.

Postoperative SRS is an alternative to WBRT for patients who undergo resection of brain metastases, with a reduced risk of neurocognitive decline; however, preoperative SRS might be favored given the lower risks of radiation necrosis and leptomeningeal disease. SRS is highly recommended in the American Society of Radiation Oncology (ASTRO) and International Stereotactic Radiosurgery Society (ISRS) consensus guidelines owing to the absence of compromise in survival outcomes with no increase in neurocognitive toxicities, unlike with WBRT. SRS is now the primary treatment for patients with either limited or multiple brain metastases, with potential synergistic effects when combined with certain immunotherapeutic agents or targeted therapies.

## **8.3 Principles of surgical management**

Cancer patients with single metastatic lesions have been shown to benefit more from treatment with surgical resection plus radiotherapy compared to radiotherapy alone. This benefit includes incidence of fewer recurrences, better quality of life and longer overall survival time [52]. Surgery offers rapid and effective symptom control for patients with large tumors or those associated with significant peritumoral edema or mass effect. For patients with active extracranial disease or older age > 60years, surgery has not been shown to provide benefit. Even though age has been identified as a risk factor for high surgery related mortality, it has not been demonstrated to be a strict basis for withholding surgical treatment [53, 55]. Surgical complications encountered include infection, post-op CVA and intracranial bleeding.

Prior to the early nineties, surgery only had a controversial role in the management of brain metastasis. The benefit of surgery as a modality for treatment of brain metastasis was established by two randomized prospective trials published by Patchell et al and Vecht et al. in 1990 and 1994 respectively [48, 51]. Clinical studies show that about 30–50% of all patients with brain metastasis present with multiple lesions [16, 56]. Multiple lesions are known to have poorer prognosis as compared to singular or solitary metastatic brain lesions. Surgery is indicated for patients with single lesions ≤3 cm whereas SRS is preferred for larger lesions [51]. Tumors must be located outside the speech and motor cortices with controlled extracranial disease to be deemed resectable. Surgery is contraindicated for multiple brain lesions and patients who have serious comorbidities as there is no class I evidence in support of surgery among patients with multiple metastatic brain lesions [57].

Microsurgical resection of metastatic brain lesions is effective in relieving brainstem compression and reducing peritumoral edema as well as decreasing ICP caused by "mass effect" of the gross tumor in the brain parenchyma. This translates into improved functional state and overall survival of patients [3, 58, 59]. Microsurgical resection followed by whole brain radiation therapy (WBRT) has been shown to result in prolonged median overall survival compared with WBRT alone in patients with brain metastasis [48, 51]. Furthermore, microsurgical resection results in improvement of neurological function. It enhances quality of life of patients with brain metastasis and may lead to improvement of performance status as evaluated with the Karnofsky score as well as improvement in Recursion Partition Analysis (RPA) score [60]. This benefit is more in elderly patients with symptomatic metastatic brain tumors. Eradication of the gross macroscopic lesion also contributes to the normalization of brain microenvironment further reducing patient's symptoms. Microsurgical brain tumor resection also serves the purpose of tissue sampling for histological, molecular and mutational analysis.

Surgical resection of metastatic brain lesions is associated with a morbidity rate of 2–10%. In the past, this rate was as high as 24.8% [48, 51, 55, 57, 61–65]. The observed reduction in morbidity associated with brain surgery is due to improved surgical techniques, prophylactic anticoagulation, appropriate seizure prophylaxis as well as availability of contemporary imaging modalities [66, 67]. The commonest complications are postoperative hemorrhage (2.7%), pulmonary embolism (2.2%), CSF leakage (0.8%) and cardiovascular accident (0.6%) [61]. Permanent neurological complications range from 6% to 11% [59, 61, 65]. These events are associated more with tumors in eloquent areas of the brain. Contrary to what was previously thought, advanced age > 65 years has not been found to be associated with significantly higher morbidity rate for patients who undergo brain microsurgery [55]. Surgical mortality rates used to

be as high as 8–11% but have been shown in recent studies to have improved to about 2–4% [48, 62, 63].

## **9. Conclusions**

BM is a heterogeneous group of diseases with increasing prevalence. The three most common cancers associated with brain metastasis are lung cancer, breast cancer and malignant melanoma. Use of prognostic functional scales such as KPS, RPA and GPA are necessary for the comprehensive evaluation of patients with brain metastasis. Control of extracranial malignant disease is an important survival factor in the management of these patients. The therapeutic decision for each patient must be individualized and a multi-disciplinary approach applied.

## **Acknowledgements**

We wish to express our sincere gratitude to all our friends and loved ones who provided the motivation and encouragement to see this work through to the end.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Edwina Ayaaba Ayabilah\*, Andrew Yaw Nyantakyi and Joseph Daniels National Centre for Radiotherapy, Oncology and Nuclear Medicine, Korle Bu Teaching Hospital, Accra, Ghana

\*Address all correspondence to: edwina.ayaaba@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Overview of Brain Metastasis and Treatment Modalities DOI: http://dx.doi.org/10.5772/intechopen.106789*

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## Section 3
