According to medical literature, there are two well stablished risk factors for meningiomas, one genetic and one environmental. The genetic risk factor is the mutation of the type 2 Neurofibromatosis gene (NF2). The environmental risk factor is the exposure to ionizing radiation, especially to higher doses of radiation (such as whole brain radiotherapy); but also being described in patients exposed to moderate or low levels of radiation. It is estimated that patients submitted to moderate or high levels radiation have up to 10 times higher risk to develop meningiomas, when compared to regular population10,11.
The relation between female hormone receptors and meningiomas
The higher incidence of meningiomas among women with previous breast cancer seems to be a fact, since recent papers identified a 26% higher meningioma incidence in this population7. Due to the reported link between BC and female hormones and also between meningioma and these hormones, it has been hypothesized that meningiomas and BCs may be linked12.
The influence of female sex steroids on meningiomas has been suggested based on the following characteristics: a higher incidence in females (two times more frequent than in males), especially during their reproductive period when the ratio increases 3.15 times; the acceleration of tumor growth during the luteal phase of the menstrual cycle and also during pregnancy (two periods when the level of progesterone is elevated), tumor decrease when progesterone levels go back to normal and also the decreasing of meningiomas in size when hormone agonists therapy is suspended 13–15.
Despite these characteristics described, there is no robust evidence supporting the influence of estrogen and progesterone in meningioma oncogenesis, development or its growth. The evidence that patients who use hormonal contraceptive have a higher meningioma risk is weak16. Also, there is poor evidence in the literature supporting the association of hormone therapy after menopause and meningioma development or growth.
Meningiomas’ expression of hormone receptors
The expression of progesterone receptors in regular arachnoid cells was described in 1994, but normal meningeal tissue does not express ER 1,17. The presence of sex hormones receptors in meningiomas have been described since 198018,19; being PRs present in 48 to 88% and ER in 5 to 33% of the meningiomas18,20−22.
Meningiomas may express both hormonal receptors, one hormonal receptor, or do not express hormonal receptors. Among these possibilities, most meningiomas present solely PR (68%), followed by the expression of PR and ER (8%) and ER alone in less than 1% of the cases. Approximately 25% of meningiomas do not express PRs nor ERs23.
There is no difference in the presence of progesterone receptors when primary meningiomas are compared to recurrent tumors, when meningiomas in males are compared to meningiomas in females, neither when supratentorial meningiomas are compared to skull base meningiomas 5,24.
Relation between meningiomas’ hormone receptor profile and tumor aggressiveness
There is an association between the meningioma`s hormone receptor profile and it`s histological degree, biological behavior, genetic profile and prognosis22,25.
It is believed that PR and ER present different meanings in the meningioma`s aggressiveness. There is an inverse correlation between the presence and the proportion of PR and the meningioma`s histological degree 25–27. Grade 1 meningiomas have a higher rate of PR when compared to Grade 2 and Grade 3 meningiomas 24. The rate of receptor-negative or solely ER-positive meningiomas is significantly higher among WHO Grade 2 and 3 meningiomas, when compared to Grade 1 meningiomas. Therefore, meningiomas lose the expression of PR and increase the expression of ER while they evolve to a more aggressive subtype23,2822. On the sample analyzed by the authors, all three cases of grade 2 meningiomas expressed progesterone receptors. The only case that had no expression of hormonal receptors was histologically classified as WHO Grade 1 meningioma, which is not expected compared to the literature.
As previously described, grade 1 meningiomas can be classified in nine different histologic subtypes. Among these subtypes, the well differentiated meningothelial subtype has histological characteristics close to normal arachnoid cells. This similarity is believed to be the reason why the expression of progesterone receptors is higher in the meningothelial subtype when compared to the other eight WHO Grade 1 subtypes 24. In the four cases of meningothelial meningiomas in this sample, one case did not express either hormonal receptors, one case expressed both hormonal receptors and two cases expressed only PR. Among the three cases of meningothelial meningiomas who expressed PR, the range of expression was 60–70% of the tumor.
Relation between meningiomas’ hormone receptor profile and tumor prognosis
The presence of PR is a favorable prognostic factor for the clinical and biological behavior in meningiomas23, associated with lower proliferative index29 and lower recurrence rate21,30. Besides, it is believed that the presence of PR alone has a more favorable prognosis than tumors that express both receptors23.
According to a multivariate analysis conducted by Hsu et al 22, the absence of progesterone receptors is associated with shorter progression free survival and is associated with a worse prognosis. Moreover, meningiomas with aggressive histopathological and genetic characteristics (accumulations of abnormal karyotypes mainly in chromosomes 14 and 22) usually do not express either PRs and ERs, or express solely ER 23,31.
The World Health Organization histopathological classification and the extent of surgical resection (Simpson grade) are associated with the meningioma recurrence rate; however, they often fail to accurately predict the clinical behavior of all meningiomas1,32. Therefore, it has been suggested that other variables should be added in the evaluation of meningiomas, guiding the treatment and follow-up. Among these variables, the classification by molecular groups was independently associated with recurrence-free survival, even after accounting for known prognostic clinical factors—including WHO grade, extent of surgical resection and adjuvant radiotherapy32. Moreover, some authors state that the receptor status should be included in any grading classification for meningiomas, especially for women23. Possibly, the findings described in this study, reinforced by previous studies, state that the receptor profile also has an important impact on the outcome and follow-up.
Relation between BC and meningioma
The association between BC and meningiomas has been studied by some authors in the past decades, and some believe that there is a non-random association between these pathologies33. The occurrence of both tumors in a single patient has a higher incidence among women older than 65 years old6, and the estimated risk to develop a meningioma in a patient with history of BC (regardless its histologic subtype) is 1.40 6.
In a series that analyzed 24 patients who presented both tumors between 1992 and 1998, 10 patients were primarily diagnosed with BC, 11 were diagnosed primarily with meningioma and 3 patients presented synchronous diagnosis6. In another series that analyzed metachronous cases of BC and meningiomas, 80.2% of patients were diagnosed first with BC, with mean interval between diagnoses of 4.5 years 33. The sample analyzed in this study reinforced that metachronous cases are more frequent than synchronous cases, and that usually the diagnosis of BC is made before the diagnosis of meningioma.
Even though there is a higher rate of meningioma in patients with previous BC, this higher risk is not related to the hormone receptor profile of the BC. Three recent papers analyzed a large sample of women who developed metachronous BC and meningiomas demonstrating that a positive ER/PR status of the BC tumor did not confer additional risk of subsequent meningioma when compared to negative ER/PR BC patients7,12,34.
The relation of the hormone receptor profile between BC and meningioma
The same series that analyzed metachronous BC and meningiomas cases, also analyzed the presence of hormone receptors in both tumors. In that sample, 32% of meningiomas expressed PR and 7% ER; while the expression of PR and ER in the BC were, respectively, 43% and 53%33. These findings are in agreement with the results of this sample, once PR was more frequent than ER in meningiomas, while ER was more frequent than PR in BC. The proportion of estrogen and progesterone receptors in the BC samples of this study was similar to the proportion described by Lieu et al33. However, the presence of PR in meningiomas of this sample was higher when compared to the results described by the same author.
Strength and limitations
This study has several limitations that must be recognized. The descriptive characteristic of the study prohibits an analytic comparison between meningiomas of patients with synchronous BC and tumors in patients solely with meningiomas. Therefore, the findings of this paper can only suggest that patients with history of breast cancer do not have a higher risk to develop a more aggressive meningioma and that the hormonal profile is similar to other patients with meningioma. Besides, the retrospective design is also a limitation, since, despite all the variables analyzed were successfully retrieved from the hospital digital system, some cases may had been lost during the research, limiting the sample size. Finally, the results came from the experience of a single center, which may represent a selection bias and restricted the sample size for only 12 patients