LYMPHANGIOLEIOMYOMATOSIS
Pulmonary lymphangioleiomyomatosis (LAM) is a diffuse, progressive lung disease that affects young women of childbearing age. It occurs as a sporadic disease (S-LAM) or with a tuberous sclerosis complex (TSC-LAM). The incidence and prevalence (two to five per million) of sporadic LAM are unknown. Whites are afflicted much more commonly than other racial groups.
Patients with S-LAM present with dyspnea or fatigue.
Spontaneous pneumothorax occurs in almost two-thirds of cases. It is often
recurrent, may be bilateral, and may necessitate pleurodesis for more definitive
therapy. Hemoptysis occurs and may be life threatening. Chylothorax, caused by
obstruction of the thoracic duct or rupture of the lymphatics in the pleura or
mediastinum by proliferating smooth muscle cells, is characteristic of this
disorder. Chyle is milky white in appearance, has a high triglyceride level (>110
mg/dL), and has chylomicrons. Chyloperitoneum (chylous ascites), chyluria, and
chylopericardium have been reported. Renal angioleiomyomata, a characteristic
pathologic finding in tuberous sclerosis, is also common in LAM (≤50% of subjects).
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The physical examination can be unrevealing or may
demonstrate end-expiratory crackles, hyperinflation, decreased or absent breath
sounds, ascites, and intraabdominal or adnexal masses.
Pathologically, LAM is characterized by proliferation
of atypical smooth muscle around the bronchovascular structures and within the
pulmonary interstitium. The abnormal-appearing smooth muscle–like cells have
loss of heterozygosity and inactivating mutations in the tuberous sclerosis
complex-2 (16p13). In addition, there is diffuse, cystic dilatation of the
terminal airspaces. Hemosiderosis is common and a consequence of low-volume
hemorrhage caused by the rupture of dilated and tortuous venules.
Estrogen appears to play a central role in disease
progression. The disease does not present before menarche and only rarely after
menopause (usually in association with hormonal supplementation). The disease
may accelerate during pregnancy and abate after oophorectomy.
LAM most commonly presents with obstructive physiology
(reduced FEV1 [forced expiratory volume in 1 second], reduced FEV1/FVC
[forced vital capacity] ratio) and gas trapping. Both a loss of elastic recoil
and an increase in airflow resistance contribute to the observed airflow
limitation. A markedly reduced DLCO (diffusing capacity for carbon
monoxide) is a characteristic feature. The alveolar-arterial oxygen difference
is also increased. There is a diminished exercise performance with a reduced
oxygen consumption and low anaerobic threshold in most patients.
The chest radiographic findings in patients with LAM
are variable, ranging from normal early in the course of the disease to
severely emphysematous-like changes in advanced disease. Pneumothorax may be an
early feature, and chylous pleural effusion may develop at any time during the
course. The thin-section high-resolution computed tomography (HRCT) scanning
shows diffuse, homogeneous, small (<1 cm diameter), thin-walled cysts (100% of patients)
and ground-glass opacities (59%) and can be pathognomonic in an appropriate clinical context. The
most common abdominal findings include renal angiomyolipoma (54%), enlarged
abdominal lymph nodes (39%), lymphangiomyoma (16%), ascites (10%), dilatation
of the thoracic duct (9%), and hepatic involvement (4%).
In general, the diagnosis should be strongly suspected
in any young woman who presents with emphysema, recurrent pneumothorax, or a
chylous pleural effusion. LAM can be readily diagnosed by its characteristic
histologic findings on surgical lung biopsy. Immunohistochemical stains specific
for smooth muscle components actin or desmin and HMB-45 have been used to
improve diagnostic sensitivity and specificity.
The most common reasons for hospitalization are for
the management of spontaneous pneumothorax, chylothorax, or renal
angiomyolipomas that are acutely bleeding or at risk for spontaneous
hemorrhage. The prognosis is variable but generally poor, with about 22% to 62%
of patients succumbing to progressive respiratory failure after 10 years from
diagnosis. Long-term survival (>20 years after diagnosis) has been reported. Pregnancy
and the use of supplemental estrogen are known to accelerate the disease
process.
There is no proven role for corticosteroids, cytotoxic
agents, oophorectomy, progesterone, tamoxifen, or luteinizing hormone–releasing
hormone analogues in the treatment of patients with LAM. Lung transplantation
should be considered for any failing patient. There have been reports of
recurrent disease in transplanted lungs and the recurrent LAM cells within the
donor lungs have been shown to be of recipient origin, suggesting metastatic
spread.
TUBEROUS SCLEROSIS
Tuberous sclerosis (TSC) is a rare autosomal dominant
disorder. It affects men and women equally. Mental retardation, seizures, and
facial angiofibroma (adenoma sebaceum) form the classic clinical triad. Up to
30% of female TSC patients have cystic lung changes consistent with LAM
(TSC-LAM). In patients with TSC-LAM, peripheral blood DNA analysis reveals a
single mutation in either TSC1 or TSC2, and the LAM cells in the
lung reveal a second hit (deletion) or loss of heterozygosity for the normal
allele. Pulmonary involvement in TSC carries a poor
prognosis.
