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LYMPHANGIOLEIOMYOMATOSIS

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).

LYMPHANGIOLEIOMYOMATOSIS
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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.