American Journal of Respiratory and Critical Care Medicine

The true prevalence of pulmonary lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex (TSC) is unknown. The prevalence of LAM, radiological features, and lung function in patients with TSC was measured. The presence of LAM, as defined by the presence of cysts by high-resolution chest computed tomography (HRCT) scan, was determined in patients with TSC without prior pulmonary disease (Group 1). To determine the significance of early detection, severity of disease in screened patients (Group 1) was compared with that in patients with TSC with a prior diagnosis of LAM (Group 2). Forty-eight patients with TSC and no prior history of LAM were screened. Of the 38 females, 13 (34%) had LAM; LAM was absent in males. Lung function was preserved in patients with TSC who were found to have LAM by screening. In patients previously known to have LAM, FEV1 and Dl CO correlated inversely with severity of disease as assessed by CT scan. The prevalence of LAM in women with TSC was 34%, ∼ 10-fold that previously reported, consistent with a large hitherto unrecognized subclinical population of patients at risk for pulmonary complications.

Keywords: lymphangioleiomyomatosis; tuberous sclerosis complex; lung function

Tuberous sclerosis complex (TSC), which is characterized by widespread hamartomatous lesions, seizure disorders, and mental retardation, occurs in as many as one in 5,800 live births (1). TSC is both sporadic (∼ 60%) and inherited as an autosomal dominant disorder with variable penetrance; the mosaic nature of organ involvement in TSC suggests that somatic gene mutations contribute to its pathogenesis. Linkage studies and positional cloning led to the identification of two TSC genes, TSC1 and TSC2 (2). Approximately 70% of patients with TSC develop abdominal angiomyolipomas; patients also exhibit two types of lung pathology—noncalcified nodular lesions characterized by multifocal micronodular pneumocyte hyperplasia (MMPH) and cystic lung disease identical in histological appearance to lymphangioleiomyomatosis (LAM), a rare disease (∼ 400 patients in the United States) of unknown etiology occurring primarily in premenopausal women that results in progressive respiratory failure (3). Earlier prevalence studies had found that < 4% of patients with TSC presented with clinical evidence of pulmonary LAM (4).

Cystic lung disease in LAM is characterized by the proliferation of abnormal smooth muscle cells, similar to those found in angiomyolipomas (5). Recently, abnormal smooth muscle cells in renal angiomyolipomas and lung lesions from patients with sporadic LAM were reported to exhibit loss of heterozygosity as well as point mutations in the TSC2 gene (6). In view of the evident molecular basis for sporadic LAM, we asked whether the prevalence of LAM in TSC might have been underestimated. A prospective screening study of patients with TSC was initiated to look for the presence of cystic lung lesions characteristic of LAM. This cohort was then compared to patients with TSC who presented with pulmonary symptoms and were diagnosed with LAM.

The study protocols and consent documents were approved by the National Heart, Lung, and Blood Institute (NHLBI) Institutional Review Board (Protocols 82-H-0032 and 95-H-0186). Two groups of individuals were recruited for the study from a population of patients with TSC registered with the National Tuberous Sclerosis Association (NTSA) or the LAM Foundation, as well as from general referral. Group 1 consisted of individuals with TSC but no prior diagnosis of LAM, who volunteered for screening upon receiving a recruitment letter mailed by the NTSA. Of these patients, 162 contacted our recruitment nurse, and 69 were enrolled in the study (Protocol 82-H-0032). Group 2 comprised patients with TSC and a prior diagnosis of LAM recruited from general referral and the LAM Foundation. Of ∼ 400 patients with LAM in North America, 178 were followed at the NIH under protocol 95-H-0186 (“Natural History of LAM”), and all 21 patients with LAM and TSC (Group 2) were included in the current study.

Patients were admitted for clinical history, physical examination, pulmonary function testing, chest X-ray, and high-resolution computed tomography (HRCT) scan of the chest. Lung diffusion capacity (Dl CO) and forced expiratory volume in 1 s (FEV1) were measured in accordance with American Thoracic Society guidelines. Lung CT scans were performed with standard technique with 10-mm collimation at 1-cm intervals. In addition, HRCT was performed with 1.0-mm collimation at 3-cm intervals. The images were viewed by a single observer (board certified radiologist), and the results were confirmed by an independent rater. To estimate disease severity, the lungs were divided into three equal zones: upper, middle, and lower. The extent of involvement of the lungs with cysts in each zone was graded qualitatively according to the percentage of lung parenchyma judged abnormal as follows: normal, no cysts present; mild, less than one-third of the lungs involved; moderate, one- to two-thirds of the lungs involved; and severe, more than two-thirds of the lungs involved. The grades assigned to each of the three lung zones were averaged to provide a single score for each patient. These measures have been previously used by other authors with low interobserver variability (7-9).

A total of 69 patients were evaluated. Data depicting the demographic characteristics of the female study subjects are presented in Table 1. There was no significant difference in average age, race, smoking, or family history of TSC between Group 1 and Group 2 subjects. In Group 1 patients, the number of smokers, or pack-years smoked did not correlate with the presence of LAM on HRCT of the chest (data not shown).

Table 1.  DEMOGRAPHIC CHARACTERISTICS OF GROUP 1 AND GROUP 2 PATIENTS

Group 1*(n = 38)Group 2(n = 21)
Age, yr ± SEM38 ± 242 ± 2
Smokers, number of patients11   7
Pack-years smoked92115
Race, number of patients
 White36  19
 Asian 2  0
 African American 0  2
Family history of TSC, number of patients 8  11

Definition of abbreviation: TSC = tuberous sclerosis complex.

*Patients with TSC and no known lung disease.

Patients with TSC known to have lymphangioleiomyomatosis.

Not statistically different by two-tailed Student's t test or chi-squared test comparing Group 1 with Group 2.

Forty-eight patients with TSC and no prior history of LAM were screened (Group 1), 10 of whom were male and 38 female. Of the 38 women in Group 1, 13 (34%) exhibited pulmonary parenchymal cysts consistent with the diagnosis of LAM. LAM was not observed in any of the male patients with TSC. Both males and females with TSC exhibited noncalcified lung nodules (1–5 mm) on CT scan, perhaps representing MMPH. All Group 1 patients with LAM (n = 13) had mild disease, and none had experienced pneumothorax or pulmonary symptoms. Of the Group 2 patients (n = 21), three (14%) had mild disease, nine (43%) had moderate disease, and nine (43%) had severe disease as assessed by HRCT scanning of the chest. Nodular lesions were found without or with the cystic lesions characteristic of LAM. Of the 59 females with TSC (Group 1 and Group 2) evaluated in this study, 25 had lung nodules, 18 with LAM and seven without; of the 10 males, two had nodules. The nodular lung lesions found in patients with TSC occurred independently of sex or pulmonary cystic lesions, suggesting that the pathogenesis of these lesions may differ from that of LAM.

Group 1 patients with LAM had significantly higher Dl CO and FEV1 values than patients in Group 2 (Table 2). Group 1 patients without LAM and those with LAM exhibited no significant differences in lung function, indicating that lung function is not a sensitive indicator of early disease. When patients were referred for pulmonary symptoms (Group 2), disease severity as assessed by HRCT scan was inversely correlated with lung function (Figure 1).

Table 2.  RADIOLOGICAL AND PHYSIOLOGICAL CHARACTERISTICS  OF GROUP 1 AND GROUP 2 PATIENTS WITH LAM

Group 1* Group 2
FEV1, % predicted ± SEM100 ± 469 ± 6
Dl CO, % predicted ± SEM112 ± 483 ± 5
CT severity, number of patients
 Mild13 3
 Moderate 0 9
 Severe 0 9
Nodules, number of patients 811

Definition of abbreviations: CT = computed tomography; Dl CO = diffusing capacity of the lung for CO; LAM = lymphangioleiomyomatosis; TSC = tuberous sclerosis complex.

*Patients with TSC and no known lung disease.

Patients with TSC known to have LAM.

p < 0.001 by two-tailed Student's t-test comparing Group 1 and Group 2.

The discovery of a high prevalence of LAM in female patients with TSC brings attention to a subgroup of patients with TSC who are at risk of developing clinical complications of pulmonary LAM. These results are consistent with an association between TSC gene mutations and the development of LAM.

Previous estimates of the prevalence of LAM in TSC were derived from case series (4, 10) or retrospective chart reviews (11), each likely to inadvertently exclude asymptomatic patients. Indeed, our data show that the patients with TSC diagnosed with LAM by screening were asymptomatic, had mild disease by radiological criteria, and exhibited normal lung function by physiological testing.

In contrast to the cystic lung lesions, lung nodules were found in both sexes. The presence of lung nodules in patients with TSC did not correlate with the presence of the cysts characteristic of LAM. In addition, lung nodules were not present in patients with sporadic LAM (7, 12), suggesting that these lesions, perhaps representing MMPH, were independent features of TSC.

Given our findings, of the estimated 20,000–25,000 women with TSC in the United States, 7,500 would be predicted to have LAM. Screening of all women with TSC by HRCT scan of the chest would be indicated to identify patients at risk for the development of pneumothorax, and patients who might be candidates for potential early intervention.

The authors thank Dr. Martha Vaughan for critical review of the manuscript.

1. Osborne JP, Fryer A, Webb DEpidemiology of tuberous sclerosis. Ann NY Acad Sci6151991125127
2. Sampson JR, Harris PCThe molecular genetics of tuberous sclerosis. Hum Mol Genet3199414771480
3. Ryu J. Tuberous sclerosis complex and LAM. In: Moss J, editor. LAM and other diseases characterized by smooth muscle proliferation. New York: Marcel Dekker; 1999. p. 407–418.
4. Castro M, Shepherd CW, Gomez MR, Lie JT, Ryu JHPulmonary tuberous sclerosis. Chest1071995189195
5. Travis WD, Usuki J, Horiba K, Ferrans VJ. Histopathologic studies on lymphangioleiomyomatosis. In: Moss J, editor. LAM and other diseases characterized by smooth muscle proliferation. New York: Marcel Dekker; 1999. p. 171–217.
6. Carsillo T, Astrinidis A, Henske EPMutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA97200060856090
7. Avila NA, Chen CC, Chu SC, Wu M, Jones EC, Neumann RD, Moss JPulmonary lymphangioleiomyomatosis: correlation of ventilation-perfusion scintigraphy, chest radiography, and CT with pulmonary function tests. Radiology2142000441446
8. Aberle DR, Hansell DM, Brown K, Tashkin DPLymphangiomyomatosis: CT, chest radiographic, and functional correlations. Radiology1761990381387
9. Muller NL, Chiles C, Kullnig PPulmonary lymphangiomyomatosis: correlation of CT with radiographic and functional findings. Radiology1751990335339
10. Dwyer JM, Hickie JB, Garvan JPulmonary tuberous sclerosis. Report of three patients and a review of the literature. Q J Med401971115125
11. Costello LC, Hartman TE, Ryu JHHigh frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc752000591594
12. Chu SC, Horiba K, Usuki J, Avila NA, Chen CC, Travis WD, Ferrans VJ, Moss JComprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest115199910411052
Correspondence and requests for reprints should be addressed to Dr. Joel Moss, Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590. E-mail:

Funded by the Intramural Research Division, National Heart, Lung, and Blood Institute, NIH.

Related

No related items
American Journal of Respiratory and Critical Care Medicine
164
4

Click to see any corrections or updates and to confirm this is the authentic version of record