Moss J, DeCastro R, Patronas NJ, Taveira-DaSilva A. Meningiomas in Lymphangioleiomyomatosis. JAMA. 2001;286(15):1879-1881. doi:10.1001/jama.286.15.1879
Author Affiliations: Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute (Drs Moss and Taveira-DaSilva and Ms DeCastro), and Department of Diagnostic Radiology, Clinical Center (Dr Patronas), National Institutes of Health, Bethesda, Md.
Context Lymphangioleiomyomatosis (LAM), a cystic lung disease associated with
progressive respiratory failure, is found predominantly in women of childbearing
age and therefore has been treated with progesterone and other hormonal agents.
However, meningiomas have progesterone receptors, and progesterone is believed
to be a mitogen for meningioma cells in culture. Since 30% to 40% of patients
with tuberous sclerosis complex (TSC) have LAM, we routinely screen patients
with LAM for brain lesions found in TSC.
Objective To determine the prevalence of meningiomas in women with LAM.
Design and Setting Analysis of results from ongoing routine screening protocols initiated
in December 1995 at the National Heart, Lung, and Blood Institute.
Patients Two hundred fifty women with sporadic LAM who were referred for screening
by magnetic resonance imaging (MRI) and/or computed tomography (CT) of the
Main Outcome Measures Presence of meningiomas on MRI and/or CT scans.
Results Eight women with LAM (3 with and 5 without a diagnosis of TSC) had lesions
on MRI scans compatible with meningiomas. Five of the patients had been treated
with progesterone. Multiple meningiomas were observed in 2 patients.
Conclusions Women with LAM appear to have a high prevalence of meningiomas. We recommend
that patients with LAM be screened for meningiomas regardless of diagnosis
of TSC. In view of the lack of a documented effect of progesterone on progression
of lung disease in LAM and the reported mitogenic response of meningiomas
to progesterone, we recommend that the drug not be given to LAM patients with
an MRI result consistent with diagnosis of meningioma.
Lymphangioleiomyomatosis (LAM), a multisystem disorder occurring predominantly
in women of childbearing age, is characterized by cystic lung disease, abdominal
tumors (eg, angiomyolipomas), and other mass lesions in the chest, thorax,
and brain.1- 4
It is estimated that the prevalence of LAM is no greater than 3 cases per
100 000 in the US population.1 In some
affected individuals, progressive lung destruction leads to respiratory failure.1- 6
In view of the overwhelming predominance of women among those with LAM,1 it has been postulated that disease progression is
influenced by hormonal factors, leading to the use of oophorectomy, tamoxifen,
and progesterone as potential therapeutic modalities.7,8
Although none of these treatments has been subjected to a controlled trial
to determine efficacy, progesterone is commonly used in the treatment of LAM.
Both sporadic and inherited forms of LAM have been described.9 A suggested genetic influence on LAM is based on its
association with tuberous sclerosis complex (TSC), an autosomal dominant disorder
with variable penetrance that is associated with neurologic (eg, tubers, astrocytomas),
renal (eg, angiomyolipomas), and dermatologic (eg, facial angiofibromata)
manifestations.10 The estimated prevalence
of TSC is 1 in 10 000 to 15 000 in the US population.11
Because lesions common in TSC are found in LAM (eg, angiomyolipomas), the
latter has been thought to represent a forme fruste of TSC.12,13
Mutations in 2 genes, TSC1 and TSC2, are associated with TSC,14- 16
although the molecular basis for the clinical manifestations has not been
determined. In sporadic LAM, mutations as well as loss of heterozygosity affecting
the TSC genes have been found in the abnormal smooth muscle cells ("LAM cells")
that proliferate in the disease, consistent with a common genetic basis for
disease in both sporadic and inherited LAM.17- 19
In a retrospective study as well as in a prospective screening study,
LAM was found in 30% of patients with TSC and no overt clinical disease.20,21 In view of the relatively high frequency
of LAM in patients with TSC, we began routine screening of the brain with
magnetic resonance imaging (MRI) and computed tomography (CT) for evidence
of TSC (eg, tubers) in patients with LAM. In patients with documented TSC,
MRI and/or CT are used also to detect and follow other cerebral lesions, such
as astrocytomas.22 This study was undertaken
to document the prevalence of meningiomas in patients with LAM. A high prevalence
of meningiomas in patients with LAM whose lung disease is often treated with
progesterone would be of concern because meningiomas are progesterone-sensitive
Two hundred fifty women with the diagnosis of LAM, of whom 52 were known
to also have TSC, were referred to the National Institutes of Health for participation
in LAM protocols (Protocols 82-H-0032 and 95-H-0186) approved by the institutional
review board of the National Heart, Lung, and Blood Institute, beginning in
December 1995. In addition to self-referral or referral through individual
physicians, subjects were informed of the study by the LAM Foundation and
the Tuberous Sclerosis Alliance/National Tuberous Sclerosis Association. All
subjects gave informed consent before enrollment. All persons with LAM were
eligible for the study and were screened for TSC.
The diagnosis of LAM was made by tissue biopsy in 220 subjects and by
CT of the chest in the remaining women. Subjects with LAM exhibited characteristic
thin-walled cystic lesions in the lung parenchyma on high-resolution CT.27 Patients diagnosed as having TSC met established
criteria.22 Patients with a diagnosis of LAM
underwent MRI and/or CT of the brain as part of the clinical evaluation for
TSC. Those individuals found to have mass lesions were subject to repeated
scans, as medically indicated. MRI scans were performed using a 1.5-T magnet.
T1-weighted (repetition time in milliseconds/echo time in milliseconds, 400-600/8-22)
and T2-weighted (2000-4384/94-104) spin-echo images were obtained, with a
5-mm section thickness. The T1-weighted scans were repeated after the administration
of 0.1 mmol of gadopentetate dimeglumine per kilogram of body weight (Magnevist;
Berlex Laboratories, Wayne, NJ). All MRI studies were evaluated by a neuroradiologist.
Lesions within the cranial cavity and brain parenchyma were identified. Their
morphological characteristics and enhancing features were recorded and their
probable histology classified using established imaging criteria. Conventional
precontrast CT scans at 5-mm thickness were also performed in most subjects
and postcontrast CT was performed only when deemed necessary.
Of the 250 women with LAM, extra-axial tumor masses with morphological
characteristics of meningiomas were found in 8 (Table 1), 2 of whom had multiple lesions and 3 of whom exhibited
manifestations of TSC. Three women, 1 of whom had a diagnosis of TSC, had
never received progesterone. Other neurologic findings, including astrocytomas
and tubers, as expected in patients with TSC, are summarized in Table 2.
The frequency of meningiomas in LAM far exceeds that expected in the
general population (1:20 000), with women more commonly affected than
men (2:1),28,29 consistent with
the possibility that meningiomas may be associated with the underlying LAM
or with treatments for it. With regard to the latter, progesterone has been
reported to have a mitogenic effect on meningiomas,23- 25
and progesterone receptors are found in meningiomas.24
Indeed, antiprogestins have been used as a treatment for meningiomas.30 The abnormal smooth muscle cells found in LAM have
been implicated in the production of growth factors, including insulin-like
growth factor 1 and platelet-derived growth factor.31,32
Growth factors are believed to be mitogenic for meningiomas,33
consistent with the possibility that secretory products of LAM cells might
enhance proliferation of meningiomas.
One of the concerns engendered by our study is the possible involvement
of progesterone in the formation or progression of meningiomas. Although some
of the women had never been exposed to progesterone, low doses in contraceptive
agents or hormone replacement therapy could have played a part in initiation
or progression of meningiomas. We cannot exclude the possibility that the
high prevalence of meningiomas may be a result of both LAM and progesterone
Progesterone has been used as a potential therapeutic agent in LAM,7 although its efficacy has not been tested in a randomized,
double-blind clinical trial. Preliminary data from the natural history study
at the National Institutes of Health are not consistent with a beneficial
effect of progesterone analogues in LAM. In view of the potential mitogenic
effect of progesterone on meningiomas, it appears prudent for patients with
LAM and meningiomas to avoid this agent.
At present, our standard procedures for screening and monitoring patients
with sporadic LAM include evaluation of the chest for pulmonary disease and
abdomen for angiomyolipomas and lymphangioleiomyomas, but do not include routine
MRI of the head. Screening by abdominal CT has shown that 54% of the patients
with LAM had angiomyolipomas.27 Based on our
findings, we recommend using MRI to screen patients with LAM for meningiomas
and no progesterone administration to patients with meningiomas. Follow-up
for LAM patients with meningiomas should include, in addition to the standard
chest and abdominal CT scans, a yearly MRI of the brain to evaluate tumor
growth or development of new tumors.