Review of Intracranial Meningiomas: An Update on ...

Internal Medicine Review

Review of Intracranial Meningiomas: An Update on Management from Diagnosis to Treatment

April 2018

Review of Intracranial Meningiomas: An Update on Management from Diagnosis to Treatment Karine A. Al Feghali, MD, MSc1 , Lara Hilal, MD 2 , Caroline Chung, MD 1* Author detail: 1 Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 2

Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon

Abstract Intracranial meningiomas represent the most common type of brain tumors. Meningiomas differ widely based on their presenting symptoms, their grade and biological behavior, location, and proximity to critical structures. We review briefly the epidemiology and clinical presentation of meningiomas, and present an overview of diagnostic approaches, as well as the evidence behind the different management strategies in meningioma, with emphasis on shifting paradigms in the surgical approach, and on the different radiation therapy modalities. We also shed light on the diagnostic challenges, and literature gaps in the treatment of meningiomas. Future studies will provide clinicians with more guidance regarding the optimal timing of intervention and the need for adjuvant treatment in completely resected atypical meningiomas.

*Corresponding author: Caroline Chung, MD Department of Radiation Oncology University of Texas MD Anderson Cancer Center, Houston, TX, USA Email: [email protected].

Copyright 2017, Internal Medicine Review. All Rights Reserved. Vol. 4, Issue 4 1



I. Introduction & Epidemiology Meningiomas are extra-axial tumors that originate from non-neuroepithelial progenitor cells, the arachnoidal cap cells 1 . Intracranial meningiomas represent a heterogeneous group of tumors, presenting and behaving in a variety of ways. Treatment approaches vary depending on clinical presentation, the grade and biological behavior, location, and proximity to critical structures. According to a recent epidemiological report by the Central Brain Tumor Registry of the United States (CBTRUS), meningiomas represent the most common type (36.8%) of central nervous system (CNS) tumors 2 , most of which (98.7%) are non- malignant. There are 29,320 new cases projected in 2018 2 . The incidence rates of meningioma increase with age, with a median age at diagnosis of 65 2,3 . Most meningiomas are sporadic, but some of the established risk factors for the development of meningiomas are advancing age 2 , female gender 3 , type 2 neurofibromatosis 4,5 , and prior ionizing radiation exposure 6,7 . Some studies have also suggested an association between meningioma and a history of breast cancer 8 , and this may reflect their common hormonal risk factors 9 . Mobile phone use has not been determined as an associated risk factor for the development of meningiomas 10 . II. Meningioma classification Meningiomas are classified according to the World Health Organization (WHO) schema 11 (Table 1). The updated 2016 WHO meningioma classification did not differ from the 2007 WHO classification, except for the addition of brain invasion as a criterion for the diagnosis of atypical meningiomas (WHO grade II) 11,12 . Generally, the majority (81.3%) of meningiomas diagnosed are WHO grade I, 16.9% WHO grade II, and 1.7% are WHO grade III 2 . However, a proportion of patients

April 2018

are diagnosed without pathological confirmation, based on clinical and radiological presentation and features. III. Clinical presentation With the increasing availability and wider use of CT and MRI, many meningiomas are diagnosed incidentally while they are still asymptomatic 13–15 . Symptoms can vary widely depending on the location of the meningioma, its rate of growth, and on whether it compresses adjacent structures, invades brain tissue, or obstructs cerebrospinal fluid (CSF) flow causing hydrocephalus 16 . One of the most common symptoms seen in about 30% of patients with meningioma is seizure activity 17–20 . The risk of seizure is higher in patients with peritumoral edema and non-skull base location 20 . Symptoms and signs of increased intracranial pressure, such as early morning headaches, nausea and vomiting, and papilledema, are also common 16 . Focal neurological deficits also constitute possible presenting symptoms. For example, language dysfunction can result from a meningioma in the dominant hemisphere 21 . Other focal localizing neurological symptoms include visual disturbances with meningiomas involving the optic pathways, hearing loss from a cerebellopontine angle meningioma, other cranial neuropathies, motor and sensory deficits, personality changes and ataxia 22 . IV. Diagnostic approach to me ningiomas and diagnostic challenges Contrast-enhanced magnetic resonance imaging (MRI) is considered the standard of care imaging modality of choice for meningiomas. Typically, meningiomas are extra-axial masses, isointense to slightly hypointense on T1-weighted MRI, hyperintense on T2-weighted MRI, and display avid homogeneous enhancement post-contrast administration 23,24 . A variety




of brain lesions may radiologically mimic meningiomas. These include hemangiopericytoma and meningeal metastasis 25 , as well as lymphoma 26,27 , 28 inflammatory pseudotumor , and 29 ependymoma . On T1-weighted MRI, the “dural tail sign”, a linear thickening and prominent enhancement of the dura mater adjacent to a peripherally located tumor, is a characteristic finding of meningioma that can help differentiate meningiomas from these other tumors30–33 . This sign is reported to have a sensitivity of 58-68% and a specificity of 88%-94% in the diagnosis of meningioma 34,35 . Many patients who present with neurological symptoms or headache will have an initial CT scan of the brain. Another characteristic finding of meningioma is hyperostosis of the adjacent skull bone, as seen on plain radiographs or on CT scan 23,36 . Calcifications can also be seen on CT scan, and their presence is usually associated with a more indolent behavior 37,38 . Technical refinements of conventional MRI along with the introduction of diffusion-weighting (DW), perfusion, and spectroscopy, have shown promise to improve the ability to diagnose and structurally define meningiomas and also potentially determine the biological behavior of the tumor 24,39–44 . These techniques have the potential to provide clinicians and patients with important information on tumor grade/clinical aggressiveness, resectability, prognosis, and risk of recurrence, and allow for earlier assessment of response to treatment. Beyond MRI and CT, there is increasing interest in the use of nuclear imaging to assist with diagnosis and delineation of meningiomas, particularly for tumors in complex locations that pose greater risk for biopsy or surgical resection. Meningioma cells strongly express somatostatin receptor subtype 2 (SSR2) 45 ,

April 2018

which offers an avenue for positron emission tomography (PET)-based imaging using somatostatin ligands. Both Gallium-68 (68 Ga)-labeled dodecanetetraacetic acidtyrosine-3-octreotate (DOTATATE) and 68 Ga-DOTA (0)-D-Phe (1)-Tyr (3)46,47 Octreotide (DOTATOC) PET/CT have been shown to be useful in discriminating meningiomas from other tumors, and in delineating the tumor as they have a high meningioma to background ratio or discrimination potential 48–50 . V. Timing of intervention Benign meningiomas are indolent tumors that typically exhibit very slow growth rates with possibly no growth observed over years, although typical growth rates are 1-3 mm per year 51–53 In contrast, atypical meningiomas typically grow faster and malignant meninigomas tend to grow exponentially over time 51 . The optimal timing to initiate treatment remains unclear. In the asymptomatic patient, decision to treat should be cautiously weighed against potential complications from treatment versus potential symptoms that may arise from tumor growth. A systematic review published in 2010 demonstrated that most meningiomas measuring 2.5 cm or less will not produce symptoms in the 5-year period following diagnosis 54 . Among factors associated with higher growth rate, are younger patient’s age, presence of symptoms, tumor diameter of >25mm, hyperintensity on T2-weighted MRI, the absence of calcifications, and the presence of peritumoral edema 38,54–56 . VI. Treatment options Management of meningiomas can range from continued observation to multimodality therapy depending on a variety of patientrelated and tumor-related factors 57 . A multidisciplinary team should be involved in management decisions, considering the




WHO grade of the tumor (if pathology is available), the clinical presentation including the presence of absence of symptoms, patient’s age and overall performance status, as well as the proximity to critical structures. Management approaches include observation/active surveillance, definitive radiation therapy (RT) and surgery. There is a paucity of randomized controlled trials comparing these different treatment strategies for meningiomas. 1. Observation Conservative management, consisting of thorough physical examination and imaging at regular follow-up intervals, can be recommended for asymptomatic patients who are considered poor operative candidates due to advanced age or medical comorbidities, or for patients with tumors that have high surgical risk (eg. skull base meningiomas located in the cavernous sinus) 58 . Studies have found that in these conservatively managed meningiomas, 63 to 88% of patients had stable disease that did not require intervention 52,55,58–60 . These studies were heterogeneous in terms of patient and tumor characteristics, as well as number of patients included. Average follow-up times were different across studies, ranging from 2.4-6.2 years 52,55,58–60 . The largest of these series is that of Yano et al., a study that included 603 patients with asymptomatic meningiomas (59.5% aged 95% ST R

57.6 (range 25-58)

WHO grade I: 10-yr LC 91% WHO grades II-III: 10-yr LC 53%

10-yr: 90%

Hardesty et al., 2013 86

228 (39 of them received adjuvant IMRT)

No histology: 47%, Grade I: 46% Grade II: 4% Grade III: 3% Grade II

Adjuvant: 82% At recurrence: 18%

GT R: 58% ST R: 42%

54 (range 5459)

LC: 82% for those receiving IMRT (median F/U 52 months)

NR

Henzel et al., 2006 126

224 (cavernous sinus meningiomas)

Grade I: 87.5% Grade II: 7.7% Grade III: 4.6%

Definitive: 42.4% Adjuvant: 57.6 %

ST R

55.8 (range 50.4–67.5)

5-yr PFS: 96.9%

5-yr: 92.9 %

Paulsen et al., 2012 84

5-yr (WHO grade 0 and I: 85.8% and 71%)

*Grade 0: diagnosis was based in 37 cases (51.4 %) on diagnostic imaging with MRI and CT scans Abbreviations: WHO: World Health Organization; RT: radiation therapy ; DFS: disease-free survival; PFS: progression-free survival; LC: local control; OS: overall survival; ST R: subtotal resection; GT R: gross tumor resection; FRT : fractionated radiation therapy; IMRT : intensitymodulated radiation therapy; NR: not reported




April 2018

Table 3: Studies on the treatment of meningioma with stereotactic radiosurgery Author, year

Sample siz e

WHO Grade

Mean tumor volume

Extent of surgical resection

Indications for RT

SRS

LR/ progressive disease

PFS

Late adve rse e ve nts

Kano et al., 2007 74

30

4.40 cc

NA

Definitive: 100%

LINACbased SRS

Marginal dose: 18 (12-20)

Santacroce et al., 2012

5,300

Grade II: 83% Grade III: 17% Grade I

5-yr: 29.4% (