0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Investigation |

Meningiomas in Lymphangioleiomyomatosis FREE

Joel Moss, MD, PhD; Rosamma DeCastro, MSN, CRNP; Nicolas J. Patronas, MD; Angelo Taveira-DaSilva, MD, PhD
[+] Author Affiliations

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.


JAMA. 2001;286(15):1879-1881. doi:10.1001/jama.286.15.1879.
Text Size: A A A
Published online

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 brain.

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.14 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.16 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,1416 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.1719

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 tumors.2326

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.

Table Graphic Jump LocationTable 1. Description of Patients With LAM and Meningiomas*
Table Graphic Jump LocationTable 2. Neurologic and Neuroimaging Findings in 250 Women With LAM*

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,2325 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 therapy.

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.

Kalassian GK, Berry GJ, Raffin TA. Lymphangioleiomyomatosis: clinical aspects. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:45-64.
Cordier JF, Lazor R.and the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires.  Perspectives on lymphangioleiomyomatosis in France. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:9-31.
Chu SC, Horiba K, Usuki J.  et al.  Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis.  Chest.1999;115:1041-1052.
Izumi T, Kitaichi M, Nagai S. Perspectives on lymphangioleiomyomatosis in Japan. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:1-31.
Trulock EP. Lung transplantation: special considerations and outcome in LAM. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:65-78.
Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis.  N Engl J Med.1996;335:1275-1280.
Taylor JR, Ryu J, Colby TV, Raffin TA. Lymphangioleiomyomatosis: clinical course in 32 patients.  N Engl J Med.1990;323:1254-1260.
Kalassian KG, Doyle R, Kao P, Ruoss S, Raffin TA. Lymphangioleiomyomatosis: new insights.  Am J Respir Crit Care Med.1997;155:1183-1186.
Strizheva GD, Carsillo T, Kruger WD, Sullivan EJ, Ryu JH, Henske EP. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis.  Am J Respir Crit Care Med.2001;163:253-258.
Gomez MR. Criteria for diagnosis. In: Gomez MR, ed. Tuberous Sclerosis. 2nd ed. New York, NY: Raven Press; 1988:9-19.
Short MP, Kwiatkowski DJ. Lymphangioleiomyomatosis: clinical aspects. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:387-406.
Bonetti F, Chiodera PL, Pea M.  et al.  Transbronchial biopsy in lymphangiomyomatosis of the lung.  Am J Surg Pathol.1993;17:1092-1102.
Lie JT. Pulmonary tuberous sclerosis. In: Gomez MR, Sampson JR, Whittemore VH, eds. Tuberous Sclerosis Complex. 3rd ed. New York, NY: Oxford University Press; 1999:207-217.
Weiner DM, Ewalt DH, Roach ES, Hensle TW. The tuberous sclerosis complex: a comprehensive review.  J Am Coll Surg.1998;187:548-561.
Van Slegtenhorst M, de Hoogt R, Hermans C.  et al.  Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.  Science.1997;277:805-808.
The European Chromosome 16 Tuberous Sclerosis Consortium.  Identification and characterization of the tuberous sclerosis gene on chromosome 16.  Cell.1993;75:1305-1315.
Zhang H, Nanba E, Yamamoto T.  et al.  Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex.  J Hum Genet.1999;44:391-396.
Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EP. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis.  Am J Hum Genet.1998;62:810-815.
Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis.  Proc Natl Acad Sci U S A.2000;97:6085-6090.
Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex.  Mayo Clin Proc.2000;75:591-594.
Moss J, Avila NA, Barnes PM.  et al.  Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex.  Am J Respir Crit Care Med.2001;164:669-671.
Roach ES, DiMario FJ, Kandt RS, Northrup H. Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation.  J Child Neurol.1999;14:401-407.
Jay JR, MacLaughlin DT, Riley KR, Martuza RL. Modulation of meningioma cell growth by sex steroid hormones in vitro.  J Neurosurg.1985;62:757-762.
Carroll RS, Glowacka D, Dashner K, Black PM. Progesterone receptor expression in meningiomas.  Cancer Res.1993;53:1312-1316.
Tonn JC, Ott MM, Meixensberger J, Paulus W, Roosen K. Progesterone receptors are detectable in tumor fragment spheroids of meningiomas in vitro.  Anticancer Res.1994;14:2453-2456.
Blankenstein MA, Verheijen FM, Jacobs JM, Donker TH, van Duijnhoven MWF, Thijssen JHH. Occurrence, regulation, and significance of progesterone receptors in human meningioma.  Steroids.2000;65:795-800.
Avila NA, Chen CC, Chu SC.  et al.  Pulmonary lymphangioleiomyomatosis: correlation of ventilation-perfusion scintigraphy, chest radiography, and CT with pulmonary function tests.  Radiology.2000;214:441-446.
Bondy M, Ligon BL. Epidemiology and etiology of intracranial meningiomas: a review.  J Neurooncol.1996;29:197-205.
Sutherland GR, Florell R, Louw D, Choi NW, Sima AAF. Epidemiology of primary intracranial neoplasms in Manitoba, Canada.  Can J Neurol Sci.1987;14:586-592.
Grunberg SM. Role of antiprogestational therapy for meningiomas.  Hum Reprod.1994;9(suppl 1):202-207.
Valencia JC, Matsui K, Tatsuguchi A.  et al.  Expression of insulin-like growth factors (IGFs) in the smooth muscle cells in pulmonary lymphangioleiomyomatosis (LAM).  Am J Respir Crit Care Med.2000;161(suppl):A15.
Styblo JL, Flaherty D, Li FB, Grassberg MK. Platelet-derived growth factor in LAM.  Am J Respir Crit Care Med.1999;159(suppl):A531.
Maxwell M, Galanopoulos T, Hedley-Whyte ET, Black PM, Antoniades HN. Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their protein products.  Int J Cancer.1990;46:16-21.

Figures

Tables

Table Graphic Jump LocationTable 1. Description of Patients With LAM and Meningiomas*
Table Graphic Jump LocationTable 2. Neurologic and Neuroimaging Findings in 250 Women With LAM*

References

Kalassian GK, Berry GJ, Raffin TA. Lymphangioleiomyomatosis: clinical aspects. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:45-64.
Cordier JF, Lazor R.and the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires.  Perspectives on lymphangioleiomyomatosis in France. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:9-31.
Chu SC, Horiba K, Usuki J.  et al.  Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis.  Chest.1999;115:1041-1052.
Izumi T, Kitaichi M, Nagai S. Perspectives on lymphangioleiomyomatosis in Japan. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:1-31.
Trulock EP. Lung transplantation: special considerations and outcome in LAM. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:65-78.
Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis.  N Engl J Med.1996;335:1275-1280.
Taylor JR, Ryu J, Colby TV, Raffin TA. Lymphangioleiomyomatosis: clinical course in 32 patients.  N Engl J Med.1990;323:1254-1260.
Kalassian KG, Doyle R, Kao P, Ruoss S, Raffin TA. Lymphangioleiomyomatosis: new insights.  Am J Respir Crit Care Med.1997;155:1183-1186.
Strizheva GD, Carsillo T, Kruger WD, Sullivan EJ, Ryu JH, Henske EP. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis.  Am J Respir Crit Care Med.2001;163:253-258.
Gomez MR. Criteria for diagnosis. In: Gomez MR, ed. Tuberous Sclerosis. 2nd ed. New York, NY: Raven Press; 1988:9-19.
Short MP, Kwiatkowski DJ. Lymphangioleiomyomatosis: clinical aspects. In: Moss J, ed. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York, NY: Marcel Dekker Inc; 1999:387-406.
Bonetti F, Chiodera PL, Pea M.  et al.  Transbronchial biopsy in lymphangiomyomatosis of the lung.  Am J Surg Pathol.1993;17:1092-1102.
Lie JT. Pulmonary tuberous sclerosis. In: Gomez MR, Sampson JR, Whittemore VH, eds. Tuberous Sclerosis Complex. 3rd ed. New York, NY: Oxford University Press; 1999:207-217.
Weiner DM, Ewalt DH, Roach ES, Hensle TW. The tuberous sclerosis complex: a comprehensive review.  J Am Coll Surg.1998;187:548-561.
Van Slegtenhorst M, de Hoogt R, Hermans C.  et al.  Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.  Science.1997;277:805-808.
The European Chromosome 16 Tuberous Sclerosis Consortium.  Identification and characterization of the tuberous sclerosis gene on chromosome 16.  Cell.1993;75:1305-1315.
Zhang H, Nanba E, Yamamoto T.  et al.  Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex.  J Hum Genet.1999;44:391-396.
Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EP. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis.  Am J Hum Genet.1998;62:810-815.
Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis.  Proc Natl Acad Sci U S A.2000;97:6085-6090.
Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex.  Mayo Clin Proc.2000;75:591-594.
Moss J, Avila NA, Barnes PM.  et al.  Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex.  Am J Respir Crit Care Med.2001;164:669-671.
Roach ES, DiMario FJ, Kandt RS, Northrup H. Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation.  J Child Neurol.1999;14:401-407.
Jay JR, MacLaughlin DT, Riley KR, Martuza RL. Modulation of meningioma cell growth by sex steroid hormones in vitro.  J Neurosurg.1985;62:757-762.
Carroll RS, Glowacka D, Dashner K, Black PM. Progesterone receptor expression in meningiomas.  Cancer Res.1993;53:1312-1316.
Tonn JC, Ott MM, Meixensberger J, Paulus W, Roosen K. Progesterone receptors are detectable in tumor fragment spheroids of meningiomas in vitro.  Anticancer Res.1994;14:2453-2456.
Blankenstein MA, Verheijen FM, Jacobs JM, Donker TH, van Duijnhoven MWF, Thijssen JHH. Occurrence, regulation, and significance of progesterone receptors in human meningioma.  Steroids.2000;65:795-800.
Avila NA, Chen CC, Chu SC.  et al.  Pulmonary lymphangioleiomyomatosis: correlation of ventilation-perfusion scintigraphy, chest radiography, and CT with pulmonary function tests.  Radiology.2000;214:441-446.
Bondy M, Ligon BL. Epidemiology and etiology of intracranial meningiomas: a review.  J Neurooncol.1996;29:197-205.
Sutherland GR, Florell R, Louw D, Choi NW, Sima AAF. Epidemiology of primary intracranial neoplasms in Manitoba, Canada.  Can J Neurol Sci.1987;14:586-592.
Grunberg SM. Role of antiprogestational therapy for meningiomas.  Hum Reprod.1994;9(suppl 1):202-207.
Valencia JC, Matsui K, Tatsuguchi A.  et al.  Expression of insulin-like growth factors (IGFs) in the smooth muscle cells in pulmonary lymphangioleiomyomatosis (LAM).  Am J Respir Crit Care Med.2000;161(suppl):A15.
Styblo JL, Flaherty D, Li FB, Grassberg MK. Platelet-derived growth factor in LAM.  Am J Respir Crit Care Med.1999;159(suppl):A531.
Maxwell M, Galanopoulos T, Hedley-Whyte ET, Black PM, Antoniades HN. Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their protein products.  Int J Cancer.1990;46:16-21.
CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 28

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles