| Lymphangioleiomyomatosis | |
|---|---|
| Classification and external resources | |
Micrograph of lymphangioleiomyomatosis. H&E stain. |
|
| ICD-9 | 516.4 |
| ICD-O: | 9174/1 |
| OMIM | 606690 |
| DiseasesDB | 30755 |
| eMedicine | med/1348 radio/415 |
| MeSH | D018192 |
Lymphangioleiomyomatosis (LAM) is a rare lung disease that results in a proliferation of disorderly smooth muscle growth (leiomyoma) throughout the lungs, in the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax) and lymphatics (leading to chylous pleural effusion). LAM occurs in a sporadic form, which only affects females, who are usually of childbearing age. LAM also occurs in patients who have tuberous sclerosis.
Contents |
Sporadic LAM almost always affects women.[1]
The proliferating smooth muscle that occurs in the type of LAM seen in patients with tuberous sclerosis (TSC-LAM) has been shown to represent clones of the smooth muscle in those patients' renal angiomyolipomas. Thus it is believed to represent metastases of this "benign" tumor. There is a female preponderance to TSC-LAM.[2] AM occurs almost exclusively in women. The average age at onset of symptoms is approximately 34 years (5–7). The first symptoms of the disease can occur before an abnormality is detectable with chest plain radiographs or pulmonary function tests; even when such abnormalities exist, the disease may be initially misdiagnosed. There is often a delay between the onset of symptoms and correct diagnosis.
LAM commonly manifests as exertional dyspnea and recurrent pneumothorax. During the course of the illness, there may be nonproductive cough, hemoptysis, chylous pleural effusion, or chylous ascites.[3][4] Obstruction of pulmonary venules causes vascular congestion and hemoptysis, and lymphatic obstruction leads to chylothorax and chylous ascites.
The clinical course of patients with LAM shows considerable variation. The disease is believed to be slowly progressive, leading to respiratory failure and death. The 10-year survival from the start of symptoms in a study at our institution was 49% (7), although reported figures range from an 8.5-year survival probability of 38% to a 10-year survival of 79% (8). Differences in survival rates may be due to improvements in diagnosis, particularly regarding the contribution of high-resolution CT, and do not mean that the progression of the disease has changed substantially. Diagnosis of mild asymptomatic forms may also have contributed to the longer survival rates.[4][5]
Spirometry studies in LAM patients demonstrate chronic airway obstruction with increased lung volume and decreased CO2 diffusion. The radiologic finding of an interstitial pattern with these spirometric results in a young woman narrows the differential diagnosis to some forms of emphysema, Langerhans cell histiocytosis, and sarcoidosis. The information provided by HRCT is essential for differentiating LAM from these conditions.
Numerous therapeutic strategies have been described to treat LAM.[5] In light of the reports of clinical worsening of the disease during pregnancy and with use of exogenous estrogens, many clinicians have applied therapeutic hormone manipulation. Antiestrogen therapy, first used in the early 1980s, consists of surgical castration by oophorectomy or administration of tamoxifen, progesterone, and gonadotropin-releasing hormone agonist or luteinizing hormone–releasing hormone.[3][4] Several studies have reported beneficial effects of antiestrogen hormone therapies for LAM, but careful scrutiny of some of these studies reveals that the treatment improved the chylothorax or chylous ascites, whereas pulmonary involvement seemed to remain stationary or to progress. Since lung transplantation has become available for patients with poor response to therapies, certain treatments must be used with caution. In fact, castration does not clearly demonstrate a beneficial effect on the course of the disease, and the long-term effects of castration, particularly in the postoperative period of lung transplantation, can increase bone complications.
In most cases, chylothorax should be managed conservatively. Chylothorax usually appears early in the course of the disease, when the patient’s functional status is good. Early application of surgical techniques such as pleural abrasion, pleurodesis, or pleurectomy must be avoided because these treatments might limit future lung transplantation. Medical treatment includes tamoxifen, progesterone, and, in some cases, a low-fat diet.[4][5]
When the patient’s functional status declines, bilateral lung transplantation is the best therapeutic option. The guidelines indicating transplantation include progression despite medical treatment, forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of less than 50%, total lung capacity of greater than 130%, and FEV1 of less than 30%. In the largest published series of lung transplantations in LAM patients, the average FEV1 at the time of evaluation for the procedure was 24%.
Common postoperative complications of lung transplantation are bacterial, viral, and fungal infections; acute rejection episodes; and chronic rejection. Complications specific to LAM are pneumothorax of the native lung after single-lung transplantation, chylothorax, recurrence of LAM, and abdominal complications
LAM occurs almost exclusively in women. The average age at onset of symptoms is approximately 34 years (5–7). The first symptoms of the disease can occur before an abnormality is detectable with chest plain radiographs or pulmonary function tests; even when such abnormalities exist, the disease may be initially misdiagnosed. There is often a delay between the onset of symptoms and correct diagnosis.
LAM commonly manifests as exertional dyspnea and recurrent pneumothorax. During the course of the illness, there may be nonproductive cough, hemoptysis, chylous pleural effusion, or chylous ascites.[3][4] Obstruction of pulmonary venules causes vascular congestion and hemoptysis, and lymphatic obstruction leads to chylothorax and chylous ascites.
The clinical course of patients with LAM shows considerable variation. The disease is believed to be slowly progressive, leading to respiratory failure and death. The 10-year survival from the start of symptoms in a study at our institution was 49% (7), although reported figures range from an 8.5-year survival probability of 38% to a 10-year survival of 79% (8). Differences in survival rates may be due to improvements in diagnosis, particularly regarding the contribution of high-resolution CT, and do not mean that the progression of the disease has changed substantially. Diagnosis of mild asymptomatic forms may also have contributed to the longer survival rates.[5]
Spirometry studies in LAM patients demonstrate chronic airway obstruction with increased lung volume and decreased CO2 diffusion. The radiologic finding of an interstitial pattern with these spirometric results in a young woman narrows the differential diagnosis to some forms of emphysema, Langerhans cell histiocytosis, and sarcoidosis. The information provided by HRCT is essential for differentiating LAM from these conditions.
Vascular endothelial growth factor D is elevated in the serum of patients with LAM. In patients with typical cystic changes on high resolution CT scanning serum levels of greater than 800 pg/ml are considered to be diagnostic for LAM.[6]
A lung biopsy may be necessary to make diagnosis in some patients. Video-assisted thoracoscopic biopsy is the most definitive and widely used technique, but transbronchial biopsy can also be effective [7][8] 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 or chylothorax[9]
Numerous therapeutic strategies have been described to treat LAM.[5] In light of the reports of clinical worsening of the disease during pregnancy and with use of exogenous estrogens, many clinicians have applied therapeutic hormone manipulation. Antiestrogen therapy, first used in the early 1980s, consists of surgical castration by oophorectomy or administration of tamoxifen, progesterone, and gonadotropin-releasing hormone agonist or luteinizing hormone–releasing hormone.[3][4] Several studies have reported beneficial effects of antiestrogen hormone therapies for LAM, but careful scrutiny of some of these studies reveals that the treatment improved the chylothorax or chylous ascites, whereas pulmonary involvement seemed to remain stationary or to progress. Since lung transplantation has become available for patients with poor response to therapies, certain treatments must be used with caution. In fact, castration does not clearly demonstrate a beneficial effect on the course of the disease, and the long-term effects of castration, particularly in the postoperative period of lung transplantation, can increase bone complications.
In most cases, chylothorax should be managed conservatively. Chylothorax usually appears early in the course of the disease, when the patient’s functional status is good. Early application of surgical techniques such as pleural abrasion, pleurodesis, or pleurectomy must be avoided because these treatments might limit future lung transplantation. Medical treatment includes tamoxifen, progesterone, and, in some cases, a low-fat diet.[4][5]
When the patient’s functional status declines, bilateral lung transplantation is the best therapeutic option. The guidelines indicating transplantation include progression despite medical treatment, forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of less than 50%, total lung capacity of greater than 130%, and FEV1 of less than 30%. In the largest published series of lung transplantations in LAM patients, the average FEV1 at the time of evaluation for the procedure was 24%.
Common postoperative complications of lung transplantation are bacterial, viral, and fungal infections; acute rejection episodes; and chronic rejection. Complications specific to LAM are pneumothorax of the native lung after single-lung transplantation, chylothorax, recurrence of LAM, and abdominal complications [5](9).
Exact data on survival rates are difficult to collect because LAM is often misdiagnosed as asthma or other more common diseases, and may not be correctly identified until it is in an advanced condition. A comprehensive study of all known British LAM patients found that out of 21 patients that had been observed for 15 years or more since diagnosis, 18 were still alive; and 11 of 12 patients that had been observed for 20 years or more were alive, however, no data is available on respiratory disability.[3]
The association of LAM with women of childbearing age suggests that hormonal stimulation plays a role in the disease process, and several approaches to treatment involve diminishing the effect of estrogen. At one time or another, therapeutic approaches have included
None of these therapies has been shown to be clearly efficacious, and all have undesirable side-effects. There is some evidence which shows that tamoxifen may actually cause worsening of LAM in some patients.[5]
When pulmonary function deteriorates to the point where oxygenation is inadequate, lung transplantation may be considered. Following lung transplant, LAM patients have Kaplan-Meier estimators (survival curves) similar to other lung transplant patients. Although LAM has been reported to recur in the transplanted lung [1], there have been no reported cases of graft failure or death due to recurrence..
A single case report of an apparent response to Doxycycline has recently been reported.[10] However, this therapy has not been proven in a clinical trial.
Sirolimus has recently been tested for the treatment of LAM. The MILES Trial (Multicenter International LAM Efficacy of Sirolimus Trial) was a randomized, double-blind, and placebo-controlled[11]. The primary endpoint was the rate of change in lung function over one year on treatment. A total of 89 patients were enrolled at 13 sites in the United States, Japan and Canada. To be eligible, patients had to have definite LAM and abnormal lung function. In general, patients who enrolled had moderately severe LAM with lung function of about 50% of predicted. Patients were treated with sirolimus or placebo for one year and followed off drug for one year. The data demonstrated that sirolimus stabilized lung function, improved some measures of quality of life and functional performance, and reduced serum VEGF-D in patients with LAM. Side effects were more frequent in the sirolimus group, but serious adverse events were balanced between the groups. The benefit of sirolimus waned when the drug was stopped, and lung function decline resumed. The conclusion of the study was that sirolimus can be considered for treatment of moderately severe LAM. Additional studies are needed to determine the risks and benefits of treatment in patients with milder disease and those who take the drug for longer than 1 year.