What is LAM?
Lymphangioleiomyomatosis (pronounced lim-fan-gee-o-ly-o-my-o-ma-to-sis and often referred to as LAM) is a rare, low-grade neoplasm that primarily affects women. LAM is caused by mutations in tuberous sclerosis genes. LAM manifests as progressive, diffuse cystic lung destruction and causes shortness of breath and recurrent pneumothoraces. Other manifestations of LAM include renal angiomyolipomas, chylous effusions (chylothorax and chylous ascites), lymphangioleiomyomas, and abdominal/retroperitoneal lymphadenopathy.
There are two presentations of LAM: in the sporadic form, sometimes called sporadic LAM or (S-LAM) and in patients with tuberous sclerosis complex, a multi-system genetic disease caused by germline mutations in TSC genes. (TSC-LAM).
Characteristics of LAM
The most common symptom experienced by patients with LAM is progressive dyspnea after exertion, followed by fatigue. Spontaneous pneumothoraces are commonly seen in women with LAM and are often recurrent. Approximately 20% of the patients have lymphatic complications, manifested most commonly by an abundance of chylous fluid, e.g., chylothorax or chylous ascites.
Lung function often declines at approximately two- to three-fold times rate of those without LAM. This is based on an annual drop in forced expiratory volume in one second (FEV1) of 75-120 cc in various reported series.
The prevalence of LAM is estimated at 3.4 – 7.8 per million women, although the true prevalence is probably much higher. Neither LAM nor TSC are known to have a geographical or racial predilection. Conservative estimates suggest that there are approximately 8,000 – 12,000 patients with sporadic LAM and 80,000 – 160,000 patients with TSC-LAM worldwide. Although TSC-LAM appears to be more common, more than 80% of patients with LAM in pulmonary clinics, registries, and trials have sporadic LAM. This paradox remains unexplained but could be attributable to differences in the severity of sporadic LAM compared with TSC-LAM, or because other TSC health priorities divert the focus of patients with TSC and their healthcare providers away from lung manifestations.
Expert radiologists can diagnose pulmonary LAM using a high-resolution CT scan with a reasonable degree (greater than 80%) of certainty. However, to confirm the diagnosis of LAM, especially prior to starting long-term treatment, at least one other diagnostic feature is necessary.
In patients with compatible CT scan findings of cystic lung disease, the presence of any one of the following can help confirm the diagnosis of LAM and obviate the need for a lung biopsy:
- Tuberous Sclerosis Complex
- Chylous effusions
- Elevated serum vascular endothelial growth factor – D (VEGF-D) greater than 800pg/ml
- Histologically confirmed LAM from enlarged lymph nodes
In the absence of the above-mentioned confirmatory features, the diagnosis of LAM requires a lung biopsy for confirmation.
Treatment strategies for LAM
Treatment strategies presently available for LAM are based on the inhibition of the mechanistic target of the rapamycin (mTOR) pathway. The use of sirolimus (also called rapamycin) has been shown to stabilize lung function decline, shrink angiomyolipomas, resolve chylous effusions, and improve quality of life. The use of sirolimus as a treatment of LAM is approved by the United States FDA as well as regulatory agencies in more than 40 other countries worldwide.
Treatment with sirolimus is generally recommended for LAM patients in the following scenarios: abnormal lung function (FEV1 < 70%), progressive lung function decline (FEV1 decline ≥90ml/year), refractory chylous effusions, angiomyolipomas ≥4cm, or other measures suggesting substantial disease burden (abnormal DLCO, air trapping or hyperinflation, the radiological extent of cystic lung disease, or need for supplemental oxygen).
A trial of bronchodilators is often used with LAM patients who have a reversible airflow obstruction based on pulmonary function testing, with continued use dictated by subjective benefit.
Pleurodesis should be performed after the patient’s initial pneumothorax in each hemithorax (the rate of ipsilateral recurrence is more than 70% in the absence of pleurodesis and is reduced to ~30% after pleurodesis).
Lung transplantation is a viable option for women with LAM and can be safely performed by experienced surgeons despite prior unilateral or bilateral pleurodesis. The average post-transplant survival in women with LAM is ~12 years and is better than other chronic lung diseases.
Research and Treatment Progress
Researchers and health care professionals have made great strides in the understanding of LAM biology in the past 3 decades, due in large part to a confluence of scientific discoveries from the tuberous sclerosis complex and signaling biology fields and remarkably effective grassroots patient advocacy from organizations, such as The LAM Foundation and the TSC Alliance.
Major scientific breakthroughs in LAM include:
- Identification of the gene mutation that causes LAM
- Molecular explanation for abnormal smooth muscle cell growth in LAM
- Improved understanding of the natural history of LAM progression
- Discovery and development of VEGF-D as a biomarker that can reduce the need for lung biopsy
- Conduct of several LAM treatment trials and the approval of sirolimus as a treatment for LAM
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