Lymphangioleiomyomatosis

Article Author:
Karam Khaddour
Article Editor:
Maryna Shayuk
Updated:
11/23/2018 10:54:08 AM
PubMed Link:
Lymphangioleiomyomatosis

Introduction

Lymphangioleiomyomatosis (LAM) is a primary disease of the lung parenchyma that is caused by abnormal growth of smooth muscle cells in the lung vasculature, lymphatics, and alveoli that leads to the formation of multiple cysts in the lungs bilaterally and respiratory symptoms, mainly dyspnea on exertion. The main involved organs are the lungs, but it can have extrapulmonary manifestations including in the kidneys causing angiomyolipomas which are benign tumors or can sometimes cause perivascular epithelioid cell tumors with visceral organ involvement.

Etiology

LAM can present sporadically or can be associated with tuberous sclerosis. The sporadic form affects almost only premenopausal women although some cases were reported to occur in men.[1]

Epidemiology

The sporadic form prevalence is unknown; however, one study that was done in 7 countries estimated the prevalence of 3 to 7 cases per million in women.[2] The form it associate which with tuberous sclerosis is prevalent in 30% to 80% of female patients.[3]

Pathophysiology

Estrogen is thought to play an important role in the development of the sporadic form of LAM through stimulation of cell growth that is mediated by estrogen receptors alpha (ERa). Although the mechanism is not entirely understood, researchers hypothesize that estrogen can cause modulation of growth signaling pathways that could lead to uncontrolled cell growth.[4] The observation that patient with LAM have progression of the disease during pregnancy and oral estrogen use supports this. Estrogen use is also known to cause worsening of the disease and in vitro studies have shown that LAM cells express increased ERa.[5] Mutations in tuberous sclerosis complex-2 gene (TSC2) have been proven to have mutations in patients with sporadic LAM.[6] The previously mentioned gene along with TSC1 encodes proteins responsible for inhibition of the mammalian target of rapamycin (mTOR) which is an intracellular signaling pathway the regulated cell proliferation.[7] It affects these 2 genes in the hereditary form of LAM which occurs with tuberous sclerosis.

History and Physical

LAM is insidious but can present with acute respiratory manifestations during pregnancy or after use of oral estrogen in females in reproductive age. Dyspnea is the most common presenting symptom which can occur during rest and increases with exertion. It could be mistaken and treated as chronic obstructive pulmonary disease (COPD) or asthma. Other manifestations that are less common include a productive cough and hemoptysis. Wheezing could be heard on physical examination in some patients. Also, pleural effusions and pneumothorax can occur in a small percentage of patients with LAM.[8]

Evaluation

Laboratory Studies

Patients with LAM do not have abnormal complete blood count (CBC) or comprehensive metabolic panel (CMP) unless they have other medical conditions. There are no definitive tests or biomarkers that can establish the diagnosis of LAM. However, some studies suggest that it could measure vascular endothelial growth factor D (VEGF-D in patients with suspicion of LAM as numbers equal to 800 pg/mL has high sensitivity and specificity.[9] Pleural effusion is present is usually chylomicron due to lymphatic obstruction with the abnormal growth. Triglyceride levels are usually greater than 110 mg/dL.

Pulmonary Function Testing

Most of the patients with LAM have an obstructive pulmonary pattern and expected to have decreased FEV1/FVC and decreased DLCO on spirometry.  Some reversibility could be noticed on the administration of bronchodilators during testing, and that is why some patients with respiratory symptoms could be diagnosed initially as having asthma. It also uses six-minute walk test in clinical practice in patients with LAM to assess for hypoxia and requirements of oxygen.

Imaging

Chest x-ray shows none specific findings in patients with LAM. The cystic disease difficult to recognize on a plain chest x-ray, and it could see only non-specific findings of pneumothorax or pleural effusions if present. High-resolution computed tomography (HRCT) has a high sensitivity and specificity of detecting the disease and has been suggested as a modality for screening patients who suspected of having LAM.[10] On HRCT, many small thin-walled cysts can be seen bilaterally in a diffuse distribution in the lungs. Septal thickening can be seen, and usually, there is no associated lymphadenopathy.

Biopsy

Biopsy remains the gold standard for the diagnosis of LAM where the characteristic abnormal smooth muscle-like cells can be seen under microscopy. The best approach for biopsy is surgically through either video-assisted thoracoscopy, trans-bronchial lung biopsy or surgical wedge resection. There are no guidelines of the best approach for the biopsy. Trans-bronchial lung biopsy has a lower yield and higher false negative compared to surgical biopsy. However, the decision based on the in-site experience, patient comorbidities, and wishes.

Pathology

The characteristic findings of LAM are smooth muscle cell proliferation in the walls of the alveoli and vascular bed in the lung tissue on a hematoxylin-eosin stain (H and E). Pathology could show cystic spaces. Immunohistochemical staining helps to establish the diagnosis and is positive for HMB-45, actin, and myosin. It also finds estrogen and progesterone receptors on the stain of the tissue samples. There have been cases with a diagnosis of LAM through cytology by seeing the smooth muscle-like cells and positive stains, but this remains of low yield compared to tissue biopsy.[11]

Treatment / Management

Management is aimed at controlling the symptoms, improving quality of life and slowing the progression of the disease.

Bronchodilators

Bronchodilators are used for symptomatic control and relief of symptoms in patients who show reversibility on PFTs. Usually, beta-agonists and anticholinergic used in the treatment. Studies have shown benefit and reversibility of airflow obstruction in patients with LAM treated with albuterol and ipratropium after adjusting for smoking and asthmatic status.[12]

Respiratory Rehabilitation

Studies have shown that respiratory rehabilitation in patients with decreased functional capacity and respiratory symptoms benefit from it. It encourages all health care professionals to consider patients with LAM to have respiratory rehabilitation to increase endurance and improve quality of life.[13]

Medication

Sirolimus is the only FDA-approved drug to treat LAM. Sirolimus is a (mTOR) inhibitor that controls the abnormal proliferation and growth of smooth muscle cells in the lung parenchyma and is effective and safe. The medication has shown the ability to prevent the worsening of lung function, respiratory symptoms and improve quality of life.[14] Everolimus is an alternative in patients who cannot tolerate sirolimus or have allergies but has not been approved by FDA for this purpose, and its use is still off-label.

Hormonal modulating therapy has been hypothesized to be an option for treatment given the role of estrogen. Selective estrogen receptor modulator could play a role in the treatment of the disease. However, there have been no clinical trials assessing the efficacy of these medications. One study assesses the safety of letrozole in postmenopausal women with LAM, but the study did not conclude with accurate results given the approval of the sirolimus when letrozole study was recruiting patients.

Lung Transplantation

Lung transplantation remains the best option in a patient who progresses despite supportive and medical treatment and worsening of symptoms and lung function capacities. However, many anecdotal case reports mentioned recurrence with LAM after lung transplantation raising a question to the curative role of this surgical treatment modality.

Prognosis

It has shown mortality to be longer of what has been reported in the previous decade. The median transplant-free survival in patients with LAM estimated to be 29 years from symptom onset and 23 years from diagnosis.[15] Given the possibility of recurrence after lung transplantation, many experts now consider the disease to be a low-grade neoplasm.

Complications

All patients with LAM should be advised to avoid the use of estrogen-containing oral contraceptive pills given the increased rate of worsening of the symptoms with their use. Progesterone based oral contraceptives appear to be safe and could be an alternative. Pregnancy can also increase the risk of worsening of symptoms and complications, but patients with LAM reported to have multiple pregnancies without complications. Patients with LAM should receive influenza and pneumococcal vaccination.

Enhancing Healthcare Team Outcomes

Awareness of the possible complications and drug influence in this conditon is a key concept in the diagnosis and treatment of LAM -lymphangioleiomyomatosis.