Keywords
asymptomatic meningioma - incidental meningioma - regression - shrinkage - spontaneous
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, 200728
|
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, 200822
|
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, 200915
|
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, 201014
|
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, 201225
|
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, 201619
|
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, 201424
|
66 y/F
|
İncidental diagnosis, history of DM, hepatitis C carrier
|
Right falx meningioma
|
Atherosclerosis, calcification
|
60%
|
7 years
|
|
Galloway et al, 201721
|
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-Johnsen17
|
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, 201618
|
17 y/M
|
İncidental diagnosis
|
C2-C3 spinal meningioma
|
Unknown
|
Disappeared
|
6 months
|
|
Kalamarides and Peyre, 201720
|
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, 202027
|
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, 201923
|
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, 202116
|
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, 202229
|
73 y/F
|
İncidental diagnosis, history of DM
|
Right sphenoid wing
|
Atherosclerosis and microangiopathy
|
37%
|
10 years
|
|
Takada et al, 202226
|
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 cm3 to 5.45 cm3 (14.18 cm3 > 10.78 cm3 > 9.50 cm3 > 8.95 cm3 > 8.43 cm3 > 7.81 cm3 > 7.30 cm3 > 6.97 cm3 > 6.32 cm3 > 5.45 cm3), 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.
