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Eur Respir J 2004; 24:888-889
Copyright ©ERS Journals Ltd 2004

Should patients with lymphangioleiomyomatosis undergo screening for meningioma?

V. Cottin1, S. Vukusic2, E. Jouanneau3, R. Lazor4 and J-F. Cordier1

1 Service de Pneumologie, Centre des Maladies Orphelines Pulmonaires, Hôpital Cardiovasculaire et Pneumologique Louis Pradel, Université Claude Bernard, Unité Mixte de Recherche 754, 2 Service de Neurologie A, and 3 Service de Neurochirurgie A, Hôpital Pierre Wertheimer, Lyon, France. 4 Service de Pneumologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland.

Received: July 1, 2004
Accepted July 7, 2004

To the Editors:

Pulmonary lymphangioleiomyomatosis (LAM) may be sporadic or associated with tuberous sclerosis complex (TSC). Recently, routine screening for brain abnormalities associated with TSC demonstrated the presence of meningioma in 3.2% of patients with LAM (with or without TSC), a prevalence exceeding that expected in the general population 1, thus suggesting that meningiomas may be associated with LAM or its treatment. Indeed, most patients diagnosed with meningioma (seven out of eight) had received hormone replacement therapy and/or progesterone. Hitherto reported cases of meningiomas associated with LAM were mostly asymptomatic 1, with ensuing controversy about the usefulness of systematic brain imaging in patients with LAM 2. We report the occurrence of symptomatic meningiomas requiring surgery in a patient who had received progesterone therapy for 17 yrs for pulmonary LAM.

A female born in 1946 was diagnosed in 1985 with pulmonary LAM, with dyspnoea on exertion, occasional chyloptysis, and characteristic diffuse cystic lesions on chest computed tomography (CT). Spirometry was normal, carbon dioxide diffusing capacity of the lung was 54% predicted, and resting arterial oxygen tension was 9.3 kPa. The patient had no criteria of TSC. Brain CT was not performed. The diagnosis of LAM was established by open lung biopsy. Immunohistochemical studies showed expression of progesterone (but not oestrogen) receptors by LAM cells. Serum levels of oestrogens and progesterone were normal. Therapy with progestative drugs was started, with i.m. medroxyprogesterone 500 mg monthly for 1 yr, then oral nomegestrol 10 mg q.d. Follow-up showed slow impairment of pulmonary function. Oxygen therapy was started in October 2003.

The patient was admitted in December 2003 because of behavioural changes, gait disturbances, and bladder and bowel incontinence. Examination revealed major astasia, symmetric brisk reflexes, apragmatism, and decrease in attention and verbal fluency. Cerebral CT showed a right fronto-temporal tumour, 7 cm in diameter (fig. 1Go), with peritumoural oedema, together with a smaller parasagittal lesion, both suggestive of meningiomas. Surgical resection of the fronto-temporal mass resulted in rapid and complete recovery of the neurological and cognitive status. Histological examination of the tumour showed meningothelial meningioma, with expression of progesterone (but not oestrogen) receptors by tumour cells.



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  		Fig. 1.— Axial gadolinium-enhanced T1-weighted magnetic resonance imaging showing a large right fronto-temporal meningioma, surrounded by oedema and significant mass effect on the brain. Scale bar=5 cm.

 
Since LAM occurs mainly in females of childbearing age, a role of oestrogens in the progression of pulmonary LAM has been suspected. Progesterone treatment is therefore commonly prescribed, despite lack of evidence of beneficial effect. Both in vitro models and epidemiological studies suggest that female sex hormones may increase the risk of meningioma, consistent with a higher incidence among females than males 3, and the accelerated growth of meningioma during pregnancy. A large study recently found a relative risk of meningioma of 2.48 (95% confidence interval 1.29–4.77) in pre-menopausal females who received hormone therapy 4. A total of 50–80% of meningiomas express progesterone receptors 5, with conflicting results regarding the influence of progesterone on the growth of meningioma cells in vitro.

Although the relationship between LAM and meningioma remains to be clarified, a link between the two disorders cannot be excluded. Amplification of S6 kinase (a protein involved in a critical pathway regulating cell growth and proliferation) has been reported in some meningioma cells, thus sharing biological similarities with LAM cells in which S6 kinase is activated 6, 7. Somatic mutations of the TSC2 gene have been found in renal angiomyolipomas and lung LAM cells of patients with sporadic pulmonary LAM 8; it remains to be determined whether similar mutations may be present in meningiomas.

As meningioma may be more than just an incidental finding in patients with lymphangioleiomyomatosis 2, we consider that lymphangioleiomyomatosis patients who are already on hormonal therapy or in whom such treatment is considered undergo brain imaging for screening of meningioma. Furthermore, we suggest that patients should be informed of the potential risk of a growth-enhancing effect of intracranial benign tumours before this treatment, with hitherto no proven benefit in lymphangioleiomyomatosis, is started.

References

  1. Moss J, DeCastro R, Patronas NJ, Taveira-DaSilva A. Meningiomas in lymphangioleiomyomatosis. JAMA 2001;286:1879–1881.[Abstract/Free Full Text]
  2. Franz DN. Meningiomas in women with lymphangioleiomyomatosis. JAMA 2002;287:1397–1398.[Free Full Text]
  3. Longstreth WT Jr, Dennis LK, McGuire VM, Drangsholt MT, Koepsell TD. Epidemiology of intracranial meningioma. Cancer 1993;72:639–648.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  4. Jhawar BS, Fuchs CS, Colditz GA, Stampfer MJ. Sex steroid hormone exposures and risk for meningioma. J Neurosurg 2003;99:848–853.[Web of Science][Medline] [Order article via Infotrieve]
  5. Hsu DW, Efird JT, Hedley-Whyte ET. Progesterone and estrogen receptors in meningiomas: prognostic considerations. J Neurosurg 1997;86:113–120.[Web of Science][Medline] [Order article via Infotrieve]
  6. Cai DX, James CD, Scheithauer BW, Couch FJ, Perry A. PS6K amplification characterizes a small subset of anaplastic meningiomas. Am J Clin Pathol 2001;115:213–218.[Abstract/Free Full Text]
  7. Krymskaya VP. Tumour suppressors hamartin and tuberin: intracellular signalling. Cell Signal 2003;15:729–739.[Web of Science][Medline] [Order article via Infotrieve]
  8. 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 USA 2000;97:6085–6090.[Abstract/Free Full Text]




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