Somatostatin analogs in meningioma

Somatostatin analogs in meningioma

Meningiomas are associated with several sex hormones-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive.

Miyagishima et al. performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, they reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMedScopus, and the NIH clinical trials database.

They identified that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria.

Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, they clarified the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies 1)


Jensen et al. performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. They applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. They included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked “very low.” Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistency in study designs is warranted to assess somatostatin analog therapy for well-defined meningioma subgroups 2).

Between January 1996 and December 2010, 13 patients harboring a progressive residual meningioma (as indicated by MR imaging criteria) following operative therapy were treated with a monthly injection of the SST analog octreotide (Sandostatin LAR [long-acting repeatable] 30 mg, Novartis). Eight of 13 patients had a meningioma of the skull base and were analyzed in the present study. Postoperative tumor enlargement was documented in all patients on MR images obtained before the initiation of SST therapy. All tumors were benign. No patient received radiation or chemotherapy before treatment with SST. The growth of residual tumor was monitored by MR imaging every 12 months.

Results: Three of the 8 patients had undergone surgical treatment once; 3, 2 times; and 2, 3 times. The mean time after the last meningioma operation (before starting SST treatment) and tumor enlargement as indicated by MR imaging criteria was 24 months. A total of 643 monthly cycles of Sandostatin LAR were administered. Five of the 8 patients were on SST continuously and stabilized disease was documented on MR images obtained in these patients during treatment (median 115 months, range 48-180 months). Three of the 8 patients interrupted treatment: after 60 months in 1 case because of tumor progression, after 36 months in 1 case because of side effects, and after 36 months in 1 case because the health insurance company denied cost absorption.

Conclusions: Although no case of tumor regression was detected on MR imaging, the study results indicated that SST analogs can arrest the progression of unresectable or recurrent benign meningiomas of the skull base in some patients. It remains to be determined whether a controlled prospective clinical trial would be useful 3).


1)

Miyagishima DF, Moliterno J, Claus E, Günel M. Hormone therapies in meningioma-where are we? J Neurooncol. 2022 Nov 23. doi: 10.1007/s11060-022-04187-1. Epub ahead of print. PMID: 36418843.
2)

Jensen LR, Maier AD, Lomstein A, Graillon T, Hrachova M, Bota D, Ruiz-Patiño A, Arrieta O, Cardona AF, Rudà R, Furtner J, Roeckle U, Clement P, Preusser M, Scheie D, Broholm H, Kristensen BW, Skjøth-Rasmussen J, Ziebell M, Munch TN, Fugleholm K, Walter MA, Mathiesen T, Mirian C. Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data. Neurosurg Rev. 2022 Oct;45(5):3067-3081. doi: 10.1007/s10143-022-01849-6. Epub 2022 Aug 19. PMID: 35984552.
3)

Schulz C, Mathieu R, Kunz U, Mauer UM. Treatment of unresectable skull base meningiomas with somatostatin analogs. Neurosurg Focus. 2011 May;30(5):E11. doi: 10.3171/2011.1.FOCUS111. PMID: 21529167.

Foramen magnum meningioma

Foramen magnum meningioma

Foramen magnum meningiomas (FMMs) are slow growing, posterior fossa meningiomas most often intradural and extramedullar. They are those arising anteriorly from the inferior third of the clivus to the superior edge of the C2 body, laterally from the jugular tubercle to the C2 laminae, and posteriorly from the anterior border of the occipital squama to the spinous process of C2 1) 2) 3).

They represent 2% of all meningioma4).

The mean age of the patients with these lesions at the time of diagnosis is approximately 55 years old, but these tumors have been reported in patients of almost every age 5) 6) 7) 8) 9).

They have traditionally been said to involve the lower third of the clivus and the C1 C2 area. However, the last categorizations are arbitrary.

There are some tumors that involve the entire clivus, and others that involve the mid and lower third of the clivus. (The upper clivus is the area above the trigeminal root, the mid-clivus extends to the level of the glossopharyngeal nerve, and the lower clivus is the region below the glossopharyngeal nerve).

The indolent clinical course of FMMs and their insidious onset of symptoms are important factors that contribute to delayed diagnosis and relative large size at the time of presentation. Symptoms are often produced by compression of surrounding structures (such as the medulla oblongata, upper cervical spinal cord, lower cranial nerves, and vertebral artery) within a critically confined space

Matsoukas S, Oemke H, Lopez LS, Gilligan J, Tabani H, Bederson JB. Suboccipital Craniectomy for an Anterior Foramen Magnum Meningioma-Optimization of Resection Using Intraoperative Augmented Reality: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2022 Nov 1;23(5):e321. doi: 10.1227/ons.0000000000000373. Epub 2022 Aug 8. PMID: 36103323.


Emerson SN, Toczylowski M, Al-Mefty O. Dejerine Syndrome Variant Due to Medullary Perforating Artery Ischemia During Foramen Magnum Meningioma Resection: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2022 Jul 1;23(1):e52-e53. doi: 10.1227/ons.0000000000000211. Epub 2022 Apr 20. PMID: 35726936. Danish B, Costello MC, Patel NV, Higgins DMO, Komotar RJ, Ivan ME. Commentary: Dejerine Syndrome Variant Due to Medullary Perforating Artery Ischemia During Foramen Magnum Meningioma Resection: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2022 Sep 1;23(3):e205-e206. doi: 10.1227/ons.0000000000000336. Epub 2022 Jul 11. PMID: 35972118.


Danish B, Costello MC, Patel NV, Higgins DMO, Komotar RJ, Ivan ME. Commentary: Dejerine Syndrome Variant Due to Medullary Perforating Artery Ischemia During Foramen Magnum Meningioma Resection: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2022 Sep 1;23(3):e205-e206. doi: 10.1227/ons.0000000000000336. Epub 2022 Jul 11. PMID: 35972118.


Medina EJ, Revuelta Barbero JM, Porto E, Garzon-Muvdi T, Henriquez O, Solares CA, Pradilla G. Exoscopic and Microscopic Combined Far Lateral Retrocondylar Approach for Resection of a Ventral Foramen Magnum Lesion: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2022 Aug 1;23(2):e126. doi: 10.1227/ons.0000000000000250. Epub 2022 May 9. PMID: 35838470.


Jeelani Y, Ibn Essayed W, Al-Mefty O. Extended Transcondylar Approach With C-1 Lateral Mass Resection for the Removal of a Calcified Ventral “Spinocranial” Meningioma: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2022 Aug 1;23(2):e117-e118. doi: 10.1227/ons.0000000000000278. Epub 2022 May 9. PMID: 35838463.


Essayed W, Aboud E, Al-Mefty O. Foramen Magnum Meningioma-The Attainment of the Intra-Arachnoidal Dissection: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2021 Nov 15;21(6):E518-E519. doi: 10.1093/ons/opab317. PMID: 34498699.


Campero A, Baldoncini M, Villalonga JF, Paíz M, Giotta Lucifero A, Luzzi S. Transcondylar Fossa Approach for Resection of Anterolateral Foramen Magnum Meningioma: 2-Dimensional Operative Video. World Neurosurg. 2021 Oct;154:91-92. doi: 10.1016/j.wneu.2021.07.058. Epub 2021 Jul 21. PMID: 34303002.


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George B, Lot G, Boissonnet H. Meningioma of the foramen magnum: a series of 40 cases. Surg Neurol. 1997;47(4):371–9.
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Bruneau M, George B. Foramen magnum meningiomas: detailed surgical approaches and technical aspects at Lariboisière Hospital and review of the literature. Neurosurg Rev. 2008 Jan;31(1):19-32; discussion 32-3. doi: 10.1007/s10143-007-0097-1. Epub 2007 Sep 20. PMID: 17882459; PMCID: PMC2077911.
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Colli BO, Carlotti-Junior CG, Assirati-Junior JA, Borba LA, Coelho-Junior Vde P, Neder L. Foramen magnum meningiomas: surgical treatment in a single public institution in a developing country. Arq Neuropsiquiatr. 2014;72(7):528–37.
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Pirotte BJ, Brotchi J, DeWitte O. Management of anterolateral foramen magnum meningiomas: surgical vs conservative decision making. Neurosurgery. 2010;67(3):58–70.
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Flores BC, Boudreaux BP, Klinger DR, Mickey BE, Barnett SL. The far-lateral approach for foramen magnum meningiomas. Neurosurg Focus. 2013;35(6):E12. doi:10.3171/2013.10.FOCUS13332.
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Borba LA, de Oliveira JG, Giudicissi-Filho M, Colli BO. Surgical management of foramen magnum meningiomas. Neurosurg Rev. 2009;32(1):49–60.
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Goel A, Desai K, Muzumdar D. Surgery on anterior foramen magnum meningiomas using a conventional posterior suboccipital approach: a report on an experience with 17 cases. Neurosurgery. 2001;49(1):102–7.
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Suisa H, Soustiel JF, Grober Y. IgG4-related pachymeningitis masquerading as foramen magnum meningioma: illustrative case. J Neurosurg Case Lessons. 2021 Dec 6;2(23):CASE21398. doi: 10.3171/CASE21398. PMID: 36061082; PMCID: PMC9435580.
11)

Uramaru K, Sakata K, Shimohigoshi W, Kawasaki T, Manaka H. Primary Meningeal Melanocytoma Located in the Craniovertebral Junction: A Case Report and Literature Review. NMC Case Rep J. 2021 Jun 25;8(1):349-354. doi: 10.2176/nmccrj.cr.2020-0191. PMID: 35079487; PMCID: PMC8769411.

Anaplastic meningioma

Anaplastic meningioma

Anaplastic meningioma (also known as malignant meningiomas) is defined by several criteria including:

1) Invasion of adjacent brain parenchyma or skull. (see invasive meningioma)

2) Numerous mitosis (> 5/high-powered field)

3) Elevated proliferative index (>3%) as assessed by either 5-bromodeoxyuridine or KI-67 staining

4) Necrosis

5) Increased cellularity

6) Nuclear pleomorphism

7) metastases

Anaplastic meningiomas are uncommon, accounting for only ~1% of all meningiomas 1).

Generally, it is not possible to confidently distinguish benign (WHO grade I) and atypical (WHO grade II) from anaplastic (WHO grade III) meningiomas on general morphology. The most reliable feature in suggesting a non-grade I tumour is the presence of lower ADC values (reflecting higher cellularity) 2) 3).

Importantly presence of vasogenic oedema in adjacent brain parenchyma is not a predictor of atypical or anaplastic histology 4).

Brain invasion, although by definition denoting at least a grade II tumour, is also surprisingly difficult to predict on MRI.

There are, some CT or MRI trends that point in favor of malignant meningioma:

1) the absence of visible calcium aggregates 5).

2) “mushrooming” or the presence of a prominent pannus of tumor extending well away from the globoid mass 6) 7) 8).

Ki-67 index >10% was associated with a trend toward worse PFS. Given the long-term survival, high recurrence rates, and efficacy of salvage therapy, patients with atypical and malignant meningiomas should be monitored systematically long after initial treatment 9).

Older age, male gender, distant metastasis, and radiotherapy were significantly related to poor prognosis; and the extent of resection did not affect survival 10).


Malignant progression with the accumulation of mutations in a benign meningioma can result in an atypical meningioma and/or anaplastic meningioma. Both tumors are difficult to manage and have a high recurrence and poor survival rates. The extent of tumor resection and histological grade are the key determinants for recurrence.

Anaplastic meningiomas are aggressive tumors, with a median overall survival time of 15 months 11).

They have a higher rate of recurrence and metastases accompanied by a significantly shorter survival rate compared to benign variants. Meningioma cancer stem cells (CSCs) have been previously shown to be associated with resistance and aggressiveness. However, the role they play in meningioma progression is still being investigated 12).

Maier AD. Malignant meningioma. APMIS. 2022 Nov;130 Suppl 145:1-58. doi: 10.1111/apm.13276. PMID: 36424331.

Baeesa et al. from the Division of Neurosurgery, Department of Surgery, King Abdulaziz University Hospital, Faculty of Medicine, JeddahSaudi Arabia, report a 29-year-old man who underwent a resection of a grade I meningioma in 2011. The patient had multiple local recurrences of the tumor that exhibited an aggressive change in behavior and transformation to grade III meningioma and developed extracranial metastases to the cervical spine. He underwent multiple operations and received radiotherapy. Analysis of the meningioma indicated the presence of CSCs markers before metastases and showed elevated expressions of associated markers in the metastasized tissue. Also, and similar to the patient’s profile, the pharmacological testing of a primary cell line retrieved from the metastasized tissues showed a high level of drug tolerance and a loss of ability to initiate apoptosis.

Malignant progression of grade I meningioma can occur, and its eventuality may be anticipated by detecting CSCs. We included a comprehensive literature review of relevant cases and discussed the clinical, diagnostic and management characteristics of the reported cases 13).


A patient had an intracranial malignant meningioma and developed a symptomatic osteolytic contrast-enhancing lesion in the left C-1 lateral mass suspicious for metastases. The authors performed a minimally invasive posterior resection of the lesion with vertebroplasty of C-1. Histopathology verified metastases of the malignant meningioma. The surgical procedure resulted in prompt and permanent pain reduction until the patient died 18 months later. Given the very limited life expectancy in this case, the authors did not consider occipitocervical fusion because of their desire to preserve the range of motion of the head. Therefore, they suggest minimally invasive tumor resection and vertebroplasty in selected palliative tumor patients 14).


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Backer-Grøndahl T, Moen BH, Torp SH. The histopathological spectrum of human meningiomas. Int J Clin Exp Pathol. 2012;5 (3): 231-42.
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Toh CH, Castillo M, Wong AM et-al. Differentiation between classic and atypical meningiomas with use of diffusion tensor imaging. AJNR Am J Neuroradiol. 2008;29 (9): 1630-5. doi:10.3174/ajnr.A1170
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Younis GA, Sawaya R, DeMonte F, Hess KR, Albrecht S, Bruner JM. Aggressive meningeal tumors: review of a series. J Neurosurg 1995; 82:17-27.
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Mahmood A, Caccamo DV, Tomecek FJ, Malik GM. Atypical and malignant meningiomas: a clinicopathological review. Neurosurgery 1993;33:955-963.
7)

Jaaskelainen J, Haltia M, Servo A. Atypical and anaplastic meningiomas: radiology, surgery, radiotherapy, and outcome. Surg Neurol 1986; 25:233-242.
9)

Kent CL, Mowery YM, Babatunde O, Wright AO, Barak I, McSherry F, Herndon JE 2nd, Friedman AH, Zomorodi A, Peters K, Desjardins A, Friedman H, Sperduto W, Kirkpatrick JP. Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With or Without Radiation Therapy: A 25-Year Retrospective Analysis of a Single-Institution Experience. Adv Radiat Oncol. 2021 Dec 24;7(3):100878. doi: 10.1016/j.adro.2021.100878. PMID: 35647401; PMCID: PMC9133398.
10)

Zhang GJ, Liu XY, Wang W, You C. Clinical factors and outcomes of malignant meningioma: a population-based study. Neurol Res. 2022 Mar 30:1-9. doi: 10.1080/01616412.2022.2056343. Epub ahead of print. PMID: 35353024.
11)

Modha A, Gutin PH. Diagnosis and treatment of atypical and anaplastic meningiomas: a review. Neurosurgery. 2005 Sep;57(3):538-50; discussion 538-50. Review. PubMed PMID: 16145534.
12) , 13)

Baeesa SS, Hussein D, Altalhy A, Bakhaidar MG, Alghamdi FA, Bangash M, Abuzenadah A. Malignant Transformation and Spine metastases of an Intracranial Grade I Meningioma: In Situ Immunofluorescence analysis of Cancer Stem Cells. World Neurosurg. 2018 Sep 8. pii: S1878-8750(18)32024-2. doi: 10.1016/j.wneu.2018.09.004. [Epub ahead of print] PubMed PMID: 30205223.
14)

Klingler JH, Krüger MT, Kogias E, Brendecke SM, Hubbe U, Scheiwe C. Minimally invasive resection and vertebroplasty for an osteolytic C-1 metastases of malignant meningioma: case report. J Neurosurg Spine. 2015 Jul 17:1-5. [Epub ahead of print] PubMed PMID: 26185898.
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