Spontaneous Regression of Meningiomas: Literature Review and Case Report

Abstract

Meningiomas are one of the most common primary tumors of the central nervous system, and surgical excision is the gold standard treatment for symptomatic patients. But there is no common algorithm for treatment in asymptomatic patients. Many studies have investigated the natural course of incidental meningiomas. Spontaneous regression refers to the shrinkage of a tumor without any intervention or treatment. Current data on spontaneous regression of meningiomas consists only of case reports. In this article, we present the case of a patient with an incidental meningioma that spontaneously regressed during follow-up and include a review of the literature.

Introduction

Meningiomas constitute approximately 14 to 18% of intracranial tumors. ¹ In autopsy studies, the incidence of incidental meningiomas has been reported as approximately 2.3% in all ages and 3% in those over 60 years of age. ² Today, the number of patients diagnosed with an incidental meningioma is increasing as imaging technologies become more accessible. ¹

The gold standard in the treatment of symptomatic meningiomas is surgical removal of the tumor together with its dural base and the bone. But there is no common algorithm for the treatment of incidental meningiomas. In addition to articles advocating prophylactic stereotactic radiosurgery, ³ some publications do not recommend surgical intervention and advocate for a conservative approach. ⁴ A recent article mentions these differences in the management of incidental meningiomas and emphasizes the need for prospective studies. ⁵ However, there are many studies ^{4 6 7 8 9 10 11} in the literature that recommend close radiological follow-up as the first option in asymptomatic incidental meningiomas. In our clinical practice, we recommend radiological follow-up as the first choice for incidentally diagnosed, asymptomatic, small or medium size meningiomas in the elderly population.

Spontaneous regression refers to the spontaneous shrinkage of a tumor without any intervention or treatment. ¹² Infections, apoptosis, and the immune system are believed to be involved in the pathophysiology, but the exact mechanism is unknown. ¹³ Although rare, the spontaneous regression of meningiomas has been reported. ^{14 15 16 17 18 19 20 21 22 23 24 25 26 27} In this article, we present the case of a patient whose falx meningioma regressed spontaneously over 9 years without treatment and review the literature.

Materials and Methods

Studies of the spontaneous regression of meningiomas were reviewed. PubMed, MEDLINE, Scopus, and Google Scholar databases were searched from their inception until December 10, 2023, with the keywords “spontaneous regression,” “spontaneous shrinkage,” and “meningioma.” Articles written in all languages were included.

Results

Our search of the literature disclosed 21 cases. All patients were diagnosed radiologically and had no histological diagnosis. Tumors that regressed because of hormonal changes and those that regressed due to drug use or drug discontinuation accounted for the majority, 13/21 (62%). These included discontinuation of progesterone agonists in 9/13 (69%) patients, ^{14 16 20 22 23 28} decreased sex hormone levels after pregnancy in 1 patient ¹⁹ and after menopause in 1 patient, ²⁷ interferon β-1a usage for multiple sclerosis in 1 patient, ²¹ and the use of an α-1 adrenergic receptor antagonist in 1 patient. ¹⁷ In addition to these, the tumor regressed after intratumoral hemorrhage in one patient ¹⁵ who was included in this study. As a result, 7/21 (33%) patients experienced spontaneous regression of their tumor without a definable variable. While atherosclerosis was thought to be the etiology in five patients, ^{24 25 29} the etiology of the other two ^{18 26} was not associated with atherosclerosis or an additional cause. All patients in whom atherosclerosis was believed to cause tumor shrinkage were of advanced age. A summary of the analyzed literature is presented in Table 1 .

Table 1. Literature review of spontaneous regression of meningiomas (chronologically listed).

Author	Age/Sex	Signs and symptoms and medical history	Localization	Possible pathogenesis of regression	Volume reduction	Follow-up time
Pozzati et al, 2007 28	59 y/F	Deafness, medroxyprogesterone acetate treatment due to lymphangioleiomyomatosis, operated for right temporal meningioma	Right temporal meningioma, left temporopolar meningioma, left frontal meningioma, right tentorial edge meningioma, right internal acoustic meatus meningioma	Cessation of medroxyprogesterone acetate treatment	Complete regression of the frontal meningioma and partial regression of the others	2 years
Shimizu et al, 2008 22	80 y/M	İncidental diagnosis after a traffic accident, history of BPH	Left sphenoid wing meningioma	Cessation of progesterone agonist treatment for BPH	58%	4 years
de Almeida et al, 2009 15	66 y/F	Dizziness, operated for right sphenoid wing meningioma	Left parietal convexity meningioma	Tumor necrosis due to intratumoral hemorrhage, dural blood supply changes due to right side tumor surgery, activation of immunological response after right side tumor surgery	90%	1 year
Gonçalves et al, 2010 14	46 y/F	İncidental diagnosis, stroke, cyproterone acetate treatment for ten years for androgenic alopecia	Right frontal falx meningioma	Cessation of cyproterone acetate treatment	90%	6 months
Watanabe et al, 2012 25	75 y/M	İncidental diagnosis, history of HT and DM	Left parietal parasagittal meningioma	Atherosclerosis and microangiopathy	82%	4,5 years
	72 y/M	İncidental diagnosis, history of HT and DM	Middle fossa meningioma	Atherosclerosis and microangiopathy	53%	6 years
	79 y/M	Incidental diagnosis after left cerebellar infarct, history of HT and DM	Olfactory groove meningioma	Atherosclerosis and microangiopathy	75%	6,5 years
Kerschbaumer et al, 2016 19	32 y/F	Severe headache, vomiting, 39-week gestation	Left sphenoid wing meningioma	Decreased serum level of sex hormones due to delivery	50%	2 months
Hirota et al, 2014 24	66 y/F	İncidental diagnosis, history of DM, hepatitis C carrier	Right falx meningioma	Atherosclerosis, calcification	60%	7 years
Galloway et al, 2017 21	56 y/F	İncidental diagnosis, history of multiple sclerosis	Right frontal parasagittal meningioma	Multiple sclerosis and interferon β-1a	50%	10 years
Hoegestoel and Berg-Johnsen 17	59 y/M	İncidental diagnosis, α1-adrenoceptor antagonist treatment due to BPH	Right sphenoid wing	Decreased receptor activation due to α1-adrenoceptor antagonist	78%	3 years
Yilmaz et al, 2016 18	17 y/M	İncidental diagnosis	C2-C3 spinal meningioma	Unknown	Disappeared	6 months
Kalamarides and Peyre, 2017 20	26 y/F	Seizure, history of intramedullary glial tumor surgery and chemotherapy, under cyproterone acetate treatment for acne over 10 years	Left parietal, right parasagittal	Cessation of cyproterone acetate treatment	80% on both tumors	1 year
	43 y/F	Seizure, under cyproterone acetate treatment over then 20 years for acne	Left temporal, left posterior petrous bone meningioma, right anterior clinoid meningioma and three small olfactory groove meningiomas	Cessation of cyproterone acetate treatment	83%, 17%, and 56%, respectively
Kumaria et al, 2020 27	51 y/F	Tinnitus, history of DM	Left sphenoid wing meningioma	Decreased sex hormones due to menopause and microangiopathy due to DM	70%	7 years
Passeri et al, 2019 23	37 y/F	Focal seizure	Bilateral sphenoid wing meningioma	Cessation of nomegestrol acetate	76%	1 year
	68 y/F	Loss of vision	Clivus	Cessation of nomegestrol acetate	17%	4 months
	54 y/F	İncidental diagnosis after a minor head trauma	Right frontal, left clinoidal and left temporal meningeal thickening	Cessation of nomegestrol acetate	15% left clinoidal, 9% right frontal	7 months
Shahin et al, 2021 16	40 y/F	Decreased visual acuity, progesterone therapy due to endometriosis, cervical cancer	Multiple meningiomas (operated for planum sphenoidale meningioma)	Cessation of progesterone treatment after surgery	Regression of all meningiomas	4 months
Kim et al, 2022 29	73 y/F	İncidental diagnosis, history of DM	Right sphenoid wing	Atherosclerosis and microangiopathy	37%	10 years
Takada et al, 2022 26	55 y/F	İncidental diagnosis	Left tentorium meningioma	Unknown	80%	3 years
Present case	74 y/F	İncidental diagnosis	Left frontal falx meningioma	Unknown	62%	9 years

Abbreviations: BPH, benign prostatic hyperplasia; DM, diabetes mellitus; HT, hypertension.

Case Report

A 74-year-old female was referred to our center after an incidental mass was detected on magnetic resonance imaging (MRI) done for control purposes only. The patient had no symptoms, and the results of her neurologic examination were normal. The patient's medical history did not include any known disease, previous surgery, or regularly used medication. MRI revealed a left frontal falcine mass measuring 3.76 × 2.62 × 2.88 cm, hyperintense on T2 images compared with surrounding neural structures, and radiologic compatibility with a meningioma. After the initial diagnosis, the patient did not want a contrast-enhanced MRI, so a contrast-enhanced MRI could not be performed. However, the patient also underwent a contrast-enhanced MRI during follow-up ( Fig. 1 ). As the patient was asymptomatic, annual radiologic follow-up was recommended; neither surgical treatment nor stereotactic radiosurgery were considered. The patient had no additional symptoms during follow-up and annual MRI scans showed gradual shrinkage of the mass. MRI scans done 9 years after diagnosis showed the lesion had decreased to 3.06 × 1.8 × 1.98 cm. The tumor volume (length × depth × width × 0.5) ²⁹ decreased from 14.18 cm ³ to 5.45 cm ³ (14.18 cm ³  > 10.78 cm ³  > 9.50 cm ³  > 8.95 cm ³  > 8.43 cm ³  > 7.81 cm ³  > 7.30 cm ³  > 6.97 cm ³  > 6.32 cm ³  > 5.45 cm ³ ), a 62% reduction in tumor volume ( Fig. 1 ). The patient's clinical course was stable throughout the follow-up period and no tumor-related symptoms were observed. No additional examination and/or screening was performed during the patient's clinical follow-up.

Fig. 1.

Patient's first and control magnetic resonance images (MRI). First line: The patient's MRI that was taken at the time of diagnosis (2014) revealed a mass originating from the left frontal falx cerebri on T2 images. It appears hyperintense compared with surrounding neural structures and is radiologically consistent with a meningioma. Second line: First-year follow-up cranial MRI (2015), shows spontaneous regression of the mass. Third and fourth lines: Subsequent follow-up cranial MRIs (2018–2023), show spontaneous regression on T2 images and contrast-enhanced T1 images. Contrast-enhanced T1 images also demonstrate radiological consistency with meningioma.

Discussion

Today, the incidental detection of meningiomas after nonspecific symptoms or trauma is common with the increased accessibility of neuroimaging. ^{30 31} But few studies describe the growth pattern and natural history of meningiomas. ^{1 7 8 30} While surgical treatment is the gold standard for symptomatic patients, there is no consensus on the follow-up and treatment of those with incidental meningiomas. Consequently, understanding the natural history of meningiomas is of great importance in planning the treatment of incidental meningiomas. Surgical treatment should be done for symptomatic patients to prevent growth seen on repeated radiologic imaging and in patients with compression of surrounding neurovascular structures. ¹ However, an algorithm that can help the surgeon in planning, especially for asymptomatic patients of advanced age with a high treatment risk, has not yet been established. There is no study in the literature that investigates the etiological factors related to spontaneous regression of meningiomas, specifies its mechanism, or includes statistical analysis. Studies on the natural history of incidental meningiomas have not reported any data on spontaneous regression ^{6 7 8 31} except for one. ³⁰ Therefore, spontaneous regression is not expected in the follow-up of incidental meningiomas. In our clinical series, for the first time, we observed that an incidental meningioma shrank spontaneously during follow-up and we wanted to review the literature on this subject.

Meningiomas have various growth patterns. ³¹ Some studies indicate that meningiomas have different growth rates according to diameter ³² or different growth patterns according to location. ³³ Other studies show a direct correlation between age, tumor size, and tumor growth and suggest close observation in patients with advanced age and large tumors. ^{6 7 30} Our case does not conform to these studies. In contrast, Nakamura et al ¹ stated that age is the only predictive factor in the growth of incidental meningiomas and that a younger age is associated with faster growth. In addition, they stated that growth slows and stops after the tumor reaches a certain size but this relation could not be confirmed. In contrast to our case, Behbahani et al ³⁰ reported higher growth rates in meningiomas that involve the falx or venous sinuses compared with other locations. Unlike the literature, spontaneous regression was mentioned in only one of the studies of the natural history of incidental meningiomas. In that study ³⁰ in which 64 patients with incidental meningiomas were followed, tumor sizes increased in 55 (85.9%), remained stable in 6 (9.4%), and decreased in 3 (4.7%). However, no information was shared regarding the age, location, or etiology of the patients with regression, and no predictive factor for regression was mentioned.

In several large surgical series, no data on the spontaneous shrinkage of meningiomas have been reported. ^{34 35 36 37 38 39 40 41} Apart from these series, many studies of the natural history of asymptomatic meningiomas have reported stable or increasing size, but no data on spontaneous regression were reported. ^{1 7 8 42 43} In a recent review of the natural history of intracranial meningiomas, Glenn et al did not include any data on spontaneous regression. ⁴⁴

Although age-related analyses of meningiomas reveal an increased incidence in elderly patients, the tumor growth rate in these patients is low, which supports a conservative approach. ^{45 46} In another study, investigators noted a slower overall growth rate in patients older than 60 years compared with those younger than 60. ¹ However, no data on spontaneous tumor shrinkage in the advanced age group have been reported. Niiro et al studied the natural history of asymptomatic meningiomas in late-life patients with an incidental diagnosis and observed tumor growth in 35% of 40 patients. The other 65% had stable tumors. However, the authors did not mention tumor shrinkage in any patient. ⁴⁷

The causal factors of spontaneous tumor shrinkage are unclear. Hypothetical causes include the aging process, vascular anomalies, and immunologically mediated tumor cell apoptosis. ^{48 49} Spontaneous shrinking of meningiomas is limited to case reports, which are rare. Elucidating the etiological factors of spontaneous tumor shrinkage may open new options for the treatment of incidental meningiomas.

Our literature search disclosed 21 patients who experienced spontaneous regression of their meningioma. Including our case, 16 were female and 6 were male. The mean age of the patients was 55 (17–80) years. Nine patients had a history of exogenic sex hormone therapy and the meningiomas were reported to shrink upon diagnosis and discontinuation of this therapy. ^{14 16 20 22 23 28} Two other case reports described spontaneous regression in tumor dimensions with decreasing sex hormone levels after menopause in one patient ²⁷ and after delivery in the other. ¹⁹ Another case report noted that no causal factor could be found, but the most probable factor was the decrease in sex hormone levels due to the patient's hysterectomy and early menopause. ²⁶ Clinical ⁵⁰ and in vivo ⁵¹ studies of meningioma growth have shown that meningiomas grow with sex hormones (especially progesterone and sex hormone-containing medications). Therefore, it is not surprising and expected that meningiomas shrink when sex hormones are physiologically reduced or medications are discontinued in these patients.

In the five patients in whom atherosclerosis and microangiopathy were considered in the pathogenesis, the mean age was 73 (66–79) years. ^{24 25 29} All five had diabetes mellitus, two had hypertension, and one had hepatitis C. Although not pathologically proven, atherosclerosis and microangiopathy, which increase with age and diabetes mellitus, were believed to be factors in the shrinking of tumors in these patients. The single case of a spontaneously regressing spinal meningioma in the literature appeared in a 17-year-old patient with a cervical meningioma. ¹⁸ No causative factor could be suggested in the pathogenesis. The complete disappearance of the lesion in a short time (6 months) and the absence of a pathological diagnosis in this patient indicate that the radiological diagnosis could have been wrong.

In one patient, in whom intratumoral hemorrhage was detected in a left parietal convexity meningioma after surgery for a right sphenoid-wing meningioma and spontaneous regression was observed during follow-up, the authors proposed different hypotheses for the pathogenesis. ¹⁵ They suggested that the tumor may have necrosed after the hemorrhage, surgery may have decreased the vascularity of the tumor by disrupting dural vascularization, or the tumor may have regressed spontaneously after changes in the immunological response in the body after surgery. In one case, the spontaneous regression of a meningioma was observed in a patient who was taking an α-1-adrenergic receptor antagonist for benign prostatic hyperplasia, and it was suggested that the growth of the tumor at the receptor level may have been prevented by this medication. ¹⁷ The spontaneous shrinkage of a meningioma was also observed in a patient with multiple sclerosis, and it was suggested that this shrinkage resulted from changes in the immune system after interferon β-1a treatment. ²¹

As can be understood from the literature, the spontaneous regression of a meningioma, except from a reduction or discontinuation of sex hormones, is rare and the etiology is still unknown. In fact, it is necessary to discuss whether spontaneous meningioma regression after the discontinuation of sex hormone therapy should be considered as spontaneous meningioma regression. In these patients, the medication believed to have caused the growth of the meningioma was discontinued after diagnosis and the meningioma subsequently showed shrinkage. Excluding these nine patients should define more clearly how rare spontaneous meningioma regression really is. Further research on the etiology of these tumors may shed light on this issue. In our case, the patient was 74 years old at the time of diagnosis and spontaneous regression of the mass was observed over 9 years. The patient had no known history of endocrinological or vascular disease or medical treatment. No additional tests were performed. Regarding etiology, although not present in the patient's history and not proven, the progression of cerebral atrophy on follow-up imaging suggested atherosclerosis. Ultimately, the etiology remained unknown.

Although our study has limitations as it is a case report and lacks pathologic proof, the small number of similar cases reported in the literature and our study suggest that additional studies should be conducted on the growth pattern of meningiomas, especially in patients of advanced age. In elderly patients with an incidental meningioma, a wait-and-see strategy can be used in place of surgery or stereotactic radiosurgery. Although similar patients have been described in large meningioma series, they do not appear to have been considered as a separate group in the literature.

Conclusion

Although the spontaneous regression of an incidental meningioma is rare, elucidating its pathophysiology enables both the regulation of treatment algorithms and the development of new treatment methods. Our literature review disclosed that the etiology of spontaneous meningioma regression is not yet understood. There are many factors suggested in the literature. Surgeons must keep this phenomenon in mind when deciding treatment for asymptomatic patients on sex hormone therapy or for those who are diagnosed at an advanced age. Prospective studies on the natural history of asymptomatic meningiomas, especially in patients of advanced age, should be conducted.