Lymphangioleiomyomatosis (LAM) is a rare, progressive, systemic disease that typically results in cystic lung destruction and predominantly affects women, especially during child bearing years. It occurs in more than 30% of women with tuberous sclerosis complex (TSC-LAM), a heritable syndrome that is associated with seizures, cognitive impairment and benign tumors in multiple tissues. Most LAM patients who present for medical evaluation have the sporadic form of the disease (S-LAM), however, which is not associated with other manifestations of tuberous sclerosis complex. Mild cystic changes consistent with LAM have been described in 10-15% of men with TSC, but symptomatic LAM in males is extremely rare. Sporadic LAM occurs exclusively in women, with one published exception to date. Both TSC-LAM and S-LAM are associated with mutations in tuberous sclerosis genes. Lung destruction in LAM is a consequence of diffuse infiltration by neoplastic smooth muscle-like cells, which invade all lung structures including the lymphatics, airway walls, blood vessels, and interstitial spaces. The consequence of obstruction of the vessels and airways include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. The typical disease course is characterized by progressive dyspnea on exertion, punctuated by recurrent pneumothoraces and, in some patients, chylous pleural effusions or ascites. Modern estimates for median survival in LAM have varied from 10 to 30 years, based on whether hospital based or population based cohorts are studied. Most patients have dyspnea on exertion with daily activities by 10 years after symptom onset and many will require supplemental oxygen over that interval. An FDA approved therapy, sirolimus, is now available for stabilization of lung function decline. Lung transplant remains the option of last resort for patients with advanced disease.
- Shortness of breath
LAM is most commonly detected when a younger woman develops a "pneumothorax", where the lung "pops" and air accumulates around the lung inside the chest wall, causing the lung to collapse. In patients with LAM, this occurs due to the bursting of the cysts that are formed in the lungs. Pneumothorax causes sharp chest pains and shortness of breath, which may be mild to severe. LAM can also be associated with accumulation of a milky fluid around the lungs called "chyle".
LAM occurs in two settings: in the disease tuberous sclerosis complex (TSC-LAM) and in a sporadic form, in women who do not have TSC (sporadic LAM). In both settings, genetic evidence indicates that LAM is caused by inactivating or “loss of function” mutations in the TSC1 or TSC2 genes, which were cloned in 1997 and 1993 respectively. The TSC1 gene is located on chromosome 9q34 and the TSC2 gene is located on chromosome 16p13. TSC-LAM occurs in women who have germline mutations in either the TSC1 or the TSC2 gene.
Sporadic LAM is primarily associated with somatic TSC2 gene mutations. Germline and somatic mutations in LAM include many types of mutations spread across the genes, with no clear “hot spots,” including missense changes, in-frame deletions, and nonsense mutations. Because of the large size of the genes (together they have more than 60 exons) and because mutations can be located virtually anywhere within the genes, mutation detection is often challenging.
On a cellular basis, LAM cells carry bi-allelic inactivation of the TSC2 genes, consistent with the “two-hit” tumor suppressor gene model originally proposed by Alfred Knudson, MD, PhD. The second hit event in LAM cells is often loss of the chromosomal region containing the wild-type copy of the TSC2 gene; this is referred to as loss of heterozygosity or LOH. LOH can be detected in microdissected LAM cells, in angiomyolipomas and lymph nodes from women with LAM, and in LAM cells isolated from the blood and urine, referred to as circulating LAM cells.
Interestingly, angiomyolipomas and pulmonary LAM cells from women with the sporadic form of LAM carry identical mutations in TSC2. This, together with the fact that recurrent LAM after lung transplantation carries the same TSC2 mutations as the original LAM, has led to the “benign metastasis” hypothesis that LAM cells can migrate or metastasize from one site to another.
Although female hormones and pregnancy can aggravate LAM, this is not considered a cause or risk factor for the development of LAM. Often it is a result of a random genetic mutation or occurs in association with an inherited disorder such as TSC
LAM can come to medical attention in several different ways, most of which involve triggering scanning of the chest by CT. Thin walled cystic change in the lungs may be found incidentally on CT scans of the heart, chest or abdomen (on the cuts that include lung bases) obtained for other purposes. Screening of women with TSC with HRCT reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40. LAM is sometimes revealed by chest CT scan in patients who present with an apparent primary spontaneous pneumothorax but more often CT scanning is not ordered (in the United States) until recurrences occur. Progressive dyspnea on exertion without the exacerbations and remissions that are characteristic of asthma or COPD sometimes prompt the astute clinician to order a chest CT. A review of the chest CT by an expert familiar with LAM may increase the diagnostic accuracy. Chylothorax can also bring LAM to attention.
In some cases, the diagnosis of LAM can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma, lymphangioleiomyoma, chylothorax or serum VEGF-D > 800 pg/ml.
If none of these clinical features are present, a biopsy may be necessary to make the diagnosis. Video-assisted thoracoscopic lung biopsy is the most definitive and widely used technique, but transbronchial biopsy has a yield of over 50% and can also be effective. The safety of the latter procedure in patients with diffuse cystic disease and the profusion of cystic change that predicts an informative biopsy are incompletely understood, however. Cytology of chylous fluids, aspirated abdominal nodes or lymphatic masses can also yield the diagnosis. In all cases, review by an expert pathologist who is familiar with LAM is advised.
Survival estimates vary widely, appear to be dependent on mode of presentation or ascertainment, and have generally trended upward over the past few decades, probably due to earlier recognition through more widespread use of CT scanning. In a recent population based cohort ascertained by surveying patients registered with the LAM Foundation, the median survival was found to be 29 years. Data from earlier, large case series indicated that 38% to 78% of patients were alive at 8.5 years from the time of disease onset.
Patients with LAM typically develop progressive airflow obstruction. In a cohort of patients in the United Kingdom, 10 years after symptom onset, 55% of 77 patients were breathless walking on flat ground and 10% were housebound. The average annual rate of decline in FEV1 and DLCO in 275 patients studied in a single pulmonary function laboratory at the NHLBI was 75 ± 9 mL, and 0.69 ± 0.07 mL/min/mm Hg, respectively. In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr. In the MILES trial, patients in the placebo group lost 134 cc/yr. There was some evidence in these studies that rate of decline in lung function correlates with initial DLCO, with menopausal status, and high baseline VEGF-D.
- Medicines (e.g., diuretics, hormone therapy, bronchodilators that relax the muscles around the airways)
- Oxygen therapy - as lung capacity declines, supplemental or full-time oxygen therapy may become necessary
- Procedures to remove air or fluid from the chest or abdominal cavities and prevent it from building up again
- Procedures to remove angiomyolipoma (AML), or benign kidney tumors
- Sirolimus (Repamune) - FDA-approved indication: Treatment of lymphangioleiomyomatosis. Sirolimus blocks the pathway that is affected in LAM cells, which helps stop their uncontrolled growth. The use of sirolimus therapy may be considered in patients with moderate to severe LAM, or those with progressive disease.