Exogenous Factors Affecting Meningiomas

Keywords: exogenous factors, ionizing radiation, female sexual hormones, radiofrequency electromagnetic fields

Moujahed Labidi, Anne Laure Bernat, Sebastien Froelich

Abstract

On rare occasions, intracranial meningiomas are associated with genetic syndromes or occur in familial clusters. However, the vast majority of meningiomas are sporadic. A few environmental (or exogenous) factors have been associated with the occurrence of these tumors. In this review, we will see that the most clearly established risk factor for the development of intracranial meningiomas is ionizing radiation. In fact, there is strong evidence in support of this causal relationship from studies involving survivors of exposure to irradiation from atomic bombs, childhood cancer survivors, and patients previously irradiated for tinea capitis. Similarly, there are now data in support of a direct effect of female sex hormones on meningioma growth. As a matter of fact, exogenous hormone intake, especially progestational agents, has to be specifically inquired about when assessing a patient with a newly diagnosed meningioma. In such cases, hormonal therapy cessation may be the only required intervention in the management of these tumors.

Other probable or suspected risk factors for the development of meningioma discussed in this chapter are radiofrequency electromagnetic fields, such as those emitted by mobile phones, obesity, and exposure to iron. We will also review evidence indicating that there may be a protective association between smoking and diabetes, and meningioma.

4.1 Introduction

Meningiomas account for approximately 35% of all primary intracranial tumors. ¹ In some rare situations, meningiomas occur in association with genetic syndromes. Among these, the most frequently encountered is neurofibromatosis type II, but there are few others, namely ataxia telangiectasia syndrome, Gorlin syndrome, Rubinstein-Taybi syndrome, etc. There have also been reports of familial clustering of intracranial meningiomas, in the absence of a genetic syndrome. ²^, ³

However, most meningiomas are sporadic and their etiology remains largely unknown. In this chapter, we will review the most recent evidence on exogenous factors that may act as risk factors for the development of intracranial meningiomas. Understanding this data is key in the hypothesis-generation of pathophysiological mechanisms of meningioma induction and growth. Among the suspected risk factors, we will focus this review on (1) ionizing radiation, (2) exogenous hormones, (3) radiofrequency magnetic fields (emitted by cellular phones), (4) metabolic syndrome, (5) occupational exposures, (6) smoking, (7) immunity, and (8) trauma.

4.2 Ionizing Radiation

Moderate to high dose ionizing radiation is the most clearly established risk factor for the development of intracranial meningiomas. In fact, there is strong evidence in support of this causal relationship from studies involving survivors of exposure to irradiation from atomic bombs, childhood cancer survivors, and patients previously irradiated for tinea capitis.

The two largest studies on the subject of childhood cancer survivors, the USA Childhood Cancer Survivor Study (CCSS) and the British Childhood Cancer Survivor Study (BCCSS) both reported a significant increase in the rate of secondary malignancies, including intracranial meningiomas. In the American study, the cumulative incidence of secondary malignancy at 30 years after primary diagnosis was 20.5%, including a 3.1% increase in meningioma incidence alone. ⁴ Moreover, in the British study, the risk of having a meningioma after radiation was linearly related to the radiation dose received. The adjusted relative risk (RR) of meningioma among those irradiated with doses of at least 40 Grays (Gy) was 479 times that of unexposed control cases. ⁵

In the Japanese Life Span Study of Atomic Bomb Survivors, the mean dose to the brain during this one-time exposure to radiation was 0.078 to 10 Gy. In this report, although it was not statistically significant, there was an elevated risk of meningioma with an excess relative risk (ERR)/Sievert (Sv) of 0.64 (95% confidence interval; –0.01 to 1.8). In other data from both Nagasaki and Hiroshima bombs survivors, there was a correlation between the incidence of meningioma and the distance from the hypocenter of the atomic blast. ⁶ In Hiroshima, during the period between 1990 and 1992, the incidences of meningioma among the population within 1.0 km compared to the nonexposed group were 36.3 versus 5.6. The RR of radiation effect for meningioma was thus calculated as 6.48. ⁶

Another seminal study that established association between ionizing radiation and meningiomas was the Israel Tinea Capitis Cohort. In its investigation, 10,834 individuals who were treated with cranial irradiation in the 1950s for a skin condition of the scalp were compared to nonexposed matched cohorts. The mean estimated radiation dose to the brain was 1.5 Gy. After 40 years, the ERR/Gy was found to be 4.63 (95% confidence interval; 2.43 to 9.12) for the development of benign meningiomas (data acquired through a national registry). This risk was positively associated with the radiation dose. ⁷

In more recent evidence, even the low doses administered during dental X-rays, especially with older X-ray technology, were found to be associated with an increased risk of intracranial meningioma. ⁸

Meningiomas associated with previous exposure to radiation differ from spontaneous meningiomas on many aspects, including age at presentation, multiplicity, clinical aggressiveness, and recurrence rate. In fact, multiplicity ranges from 4.6 to 18.7% in this particular subgroup of meningiomas (compared to 2.4% in spontaneous meningiomas in the Israel Tinea Capitis Cohort). In a series of 43 radiation-induced meningiomas, a 25.6% recurrence rate and an 11.6% rate of multiple recurrences were noted. ⁹ In our experience in treating these lesions, each patient often requires multiple operations and, during each surgical sitting, we do not hesitate to perform wide resection of the surrounding dura mater in the hope of reducing the recurrence rate.

4.3 Exogenous Hormones

The incidence of meningiomas is more than twofold higher in women than in men, an observation that has suggested very early on a role for sex hormones in the development and growth of meningiomas. The acceleration of meningioma growth during pregnancy, the subsequent shrinkage in size after delivery ¹⁰ and the association between breast cancer and meningiomas also supports this hypothesis. ¹¹^, ¹²^, ¹³

As a matter of fact, progesterone and estrogen receptors are very frequently expressed in meningiomas (progesterone in 61–95% of meningiomas and estrogens in 0–8.6% of cases). ¹⁴^, ¹⁵^, ¹⁶ Progesterone receptors have been shown to be associated with a more favorable prognosis, while the estrogen receptors are associated with an increased risk of tumor recurrence and progression. The meningioma’s growth rate peaks during the reproductive life period. ¹⁰^, ¹⁷ In fact, molecular studies have shown that progesterone and estrogens together can stimulate cellular proliferation in meningiomas. ¹⁸ The precise mechanism involved in the hormonal induction and growth of meningiomas is not well understood but female hormones may modulate proliferation and cell cycle progression through transcriptional mechanisms involving the receptors. ¹⁸^, ¹⁹ In addition, estrogens have been postulated to affect genomic stability. ²⁰^, ²¹ Lastly, estrogens interact with insulin-like growth factor, which stimulates tumor growth and prohibits cellular apoptosis. ²²

Consequently, several progesterone antagonist (mifepristone or onapristone) and antiestrogens (tamoxifen) have been proposed as potential therapeutic agents for unresectable meningiomas by blocking angiogenesis, although strong data is still lacking in this regard. ²³^, ²⁴^, ²⁵

4.3.1 Link between Cyproterone Acetate and Meningiomas

An important practical issue when managing intracranial meningiomas is the potential role of hormonal treatments. Epidemiologic studies have shown either an absence or a weak relationship between meningiomas and hormone replacement therapy or oral contraception. ²⁶ However, a definitive association between the prolonged use of high-dose progestational agents and meningiomas has been shown. More specifically, numerous patients treated with cyproterone acetate (CPA) for many years have been diagnosed with one or multiple meningiomas, mainly located on the anterior skull base and stabilizing or shrinking significantly after CPA withdrawal (cf. ▶ Fig. 4.1 and ▶ Fig. 4.2). ²⁷^, ²⁸^, ²⁹^, ³⁰

Fig. 4.1 Two (A and B) typical cases of multiple small meningiomas seen in association with cyproterone acetate. The preoperative T1-weighted axial images are seen in i and iii for the first case (A) and in v and vii for the second case (B). The same postoperative axial images are seen in ii and iv for the first case (A) and in vi and vii for the second case (B). The tumor’s volume reduction was faster in both convexity meningiomas (*) than for the ones located in the anterior skull base (arrowhead).

Fig. 4.2 Three cases of large solitary meningiomas on cyproterone acetate located in the olfactory groove (a and b, c and d) and convexity (e and f).

CPA is prescribed mainly in Europe, predominantly in Spain and France, in Latin America and much less in some Asian countries. It is not available in the United States due to the risk of liver side effects. CPA’s most common indications are signs of hyperandrogenism, such as those seen in polycystic ovary syndrome (PCOS), hirsutism, acne, and alopecia. It has also been used less commonly as an alternate contraceptive agent. In author’s previously published series, ²⁷ a link was reported between the duration of the exposure to CPA and the development of meningioma and an association between CPA and multiple meningiomas. It was also observed that the location of the meningiomas was more often found in the anterior skull base. Several authors subsequently reported similar findings. ³⁰^, ³¹^, ³²^, ³³^, ³⁴

Pathophysiological mechanisms underlying this association between CPA and meningiomas, but also the significant tumor volume reductions seen after medication discontinuation are still unknown. Megestrol acetate and luteinizing hormone releasing hormone, both progesterone agonists have been reported to induce meningioma growth ³⁵^, ³⁶ but cases of spontaneous shrinkage after medication discontinuation are rare and have been reported with dramatic results only for CPA et chlormadinone acetate. ³⁷ We also observed that peritumoral edema decreases after CPA withdrawal, which may be explained by the affinity of progesterone for glucocorticoid receptors of meningiomas. ³⁸

Meningiomas associated with CPA are located mainly in the anterior skull base. Genetic features related to meningiomas location have been studied previously and might also explain the behavior of these meningiomas induced on progestational agents. Clark et al reported that tumors with NF2 mutations and/or chromosome 22 loss (NF2/chr22loss) were predominantly found in the hemispheres with nearly all posterior cerebral (parieto-occipital), cerebellar, or spinal meningiomas being NF2/chr22loss tumors. ³⁹ They observed a difference between those originating from medial (non-NF2) versus lateral and posterior regions (NF2/chr22loss) of the skull base. Yuzawa et al also reviewed genetic patterns of 553 meningiomas and found a significant percentage of NF2 mutation (55%). ⁴⁰ They found several genes involved such as TRAF7, AKT1, KLF4, PIK3CA, and SMO and that 80% of cases harbored at least one of the genetic alterations in these genes. Tumors with the TRAF7/AKT1 and SMO mutations shared specific features; they were located in the anterior fossa, median middle fossa, or anterior calvaria. Most of them were meningothelial or transitional meningiomas. Meningiomas associated with CPA might have similar genetic features, but this hypothesis warrants further investigation.

Additionally, in meningiomas associated with CPA, the duration of exposure to the medication has been shown to be a risk factor for the development of a meningioma and is proportional with the tumor’s growth rate and volume. ²⁷^, ³⁰ We also observed that patients with multiple meningiomas had used CPA for a longer period of time (mean of 20.4 years) than patients with only one tumor (10 years) suggesting that longer exposure to CPA may induce the development of multiple tumors. ²⁷ Another noteworthy observation made in our experience dealing with these cases is that the volume reduction rate in CPA-associated meningiomas may be slower in overweight patients (▶ Fig. 4.3). CPA is a lipophilic drug and it is possible that it is eliminated more slowly in overweight and obese patients.

Fig. 4.3 A case of olfactory groove meningioma associated with cyproterone acetate [a, axial cuts in T1-weighted post-gadolinium and fluid attenuation inversion recovery (FLAIR) sequences] shrinking after hormone discontinuation (b, same sequences, 2 years after discontinuation). The signal changes seen on FLAIR suggest a modification of the tumor’s vascularity. In c, the initial visual symptoms resolved over 2 months, neurobehavioral troubles over 8 months and there was a dramatic reduction in the tumor’s volume over 26 months. Note that the rate of the tumor’s volume reduction accelerated after December 2015, when the patient started losing weight following initiation of a strict diet.

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