Lymphangioleiomyomatosis

Etiology

LAM can present sporadically (S-LAM) or can be associated with tuberous sclerosis complex (TSC-LAM); however, pathologically, these two types are indistinguishable.[1]

The etiology of LAM is not known; however, the genetic and hormonal etiologies have been recently elucidated based on the following:

• The disease is exacerbated by high estrogen states points towards a hormonal role.[2][2]
• The genetic predisposition and various mutations have been linked to both types of LAM (S-LAM and SCL-LAM). [3]
• The sporadic form affects almost only premenopausal women, although some rare cases were reported to occur in men.[4] 
• The most common type of LAM, TSC-LAM, is an autosomal dominant genetic disease and is considered the most common type of LAM.
• TSC genes function as tumor suppressor genes. TSC1 encodes hamartin and TSC2 encodes tuberin. These two key genes are linked to a complex called TBC1D7, which regulates the kinase mechanistic target of the rapamycin (called mTOR).[5]
• The mutations in the TSC genes, such as TSC2 mutation, have been linked to causing overactivation of the mTOR pathway leading to defects in smooth muscle cell proliferation and the formation of benign tumors (angiomyolipomas) in multiple organs that are commonly seen in LAM. [6][7] The mTOR pathway is important for intracellular phosphorylation and extracellular signal-regulated kinase (ERK) hence serving as a regulator for the growth and proliferation of cells. Thus, the targeted inhibition of the mTOR pathway plays a key role in the development of the new therapy for patients with TSC.[5]
• Mutations in TSC2 account for the majority (75%) of TSC cases.[8]

Epidemiology

The prevalence of S-LAM is unknown; however, one study was done in 7 countries and estimated the prevalence of 3 to 7 cases per million in women.[9] Another study revealed that the sporadic form affects 1 in 400,000 adult women.[10][5] The age of most commonly affected individuals is about 35 years old. LAM associated with TSC (TSC-LAM) is more common than S-LAM. One study estimated the incidence to affect 1 in 5000 to 10,000 live births.[1] Patients with both tuberous sclerosis and LAM are much more likely than others to develop angiomyolipomas which may occur in almost 90% and an overall estimate of around 5 million women worldwide.[11][12] The incidence rate increases with age, with the highest rates (as high as 80 %) among women older than 40 years of age.[13] Unlike S-LAM, which occurs predominantly in women, TSC-LAM affects both men and women with TSC. It is estimated that 10 to 30 % of men with TSC have cystic lung disease.[14]

History and Physical

Patients with LAM can present clinically with different manifestations.[5][15] These include the following:

• There can be the development of benign tumors in multiple organs (brain, heart, skin, eyes, kidney, lung, and liver).
• LAM can present with acute respiratory manifestations during pregnancy or after the use of oral estrogen in females of reproductive age.
• Dyspnea is the most common presenting symptom that can occur during rest and increase with exertion. It could easily be mistaken and treated as a chronic obstructive pulmonary disease (COPD) or asthma. Progressive dyspnea and fatigue will be the initial symptom in about two-thirds of patients, one-third will present with spontaneous pneumothorax, and about a quarter will have a pleural effusion.[11] 
• Lymphatic abnormalities (i.e., thoracic duct dilatation, chylothorax, and chylous ascites) are most common in TSC-LAM than in S-LAM.[16]
• Other less common manifestations include a productive cough, chest pain, pulmonary hypertension, and hemoptysis. Wheezing can be heard during physical examination in some patients. 
• Patients with TSC have skin lesions characteristic of the disorder (such as hypopigmented macules, forehead plaques, and facial fibroadenomas) or defected nails (longitudinal nail grooves).
• Epilepsy and cognitive impairment are common in individuals with TSC. 
• Brain lesions such as cortical hamartomas (glioneuronal and subependymal), astrocytoma (a low-grade astrocytic brain tumor within the ventricles of the brain), and heterotopia (which as ectopic collections of neurons). These brain lesions can be asymptomatic and detected radiologically or present clinically as papilledema or hydrocephalus in patients with TSC.[17]
• LAM can be associated with renal angiomyolipomas (which are more frequent in TSC-LAM and often bilateral). [18]
• TSC-LAM may be associated with polycystic kidney disease.[18] 
• Pulmonary symptoms may worsen during menses in a third of women with LAM. Likewise, lung function has been reported to worsen after estrogen administration and during pregnancy.[5]

Evaluation

Laboratory Studies

Patients with lymphangioleiomyomatosis do not have an abnormal complete blood count (CBC) or comprehensive metabolic panel (CMP) unless they have other medical conditions. No definitive tests or biomarkers can definitively establish the diagnosis of LAM. However, some studies suggest that measuring vascular endothelial growth factor D (VEGF-D) in patients suspected of LAM is reasonable as levels greater than or equal to 800 pg/mL have a high sensitivity and specificity for pulmonary lymphangioleiomyomatosis.[19] Pleural effusions, if present, are usually chylomicron due to lymphatic obstruction from abnormal growth. Triglyceride levels are usually greater than 110 mg/dL.

Pulmonary Function Testing

Airflow obstruction is the most common presentation of LAM, but restrictive or mixed patterns can also occur. Most patients with LAM have increased airflow resistance, reversible airflow obstruction, and obstructive pulmonary pattern. Therefore they are expected to have decreased FEV1/FVC and decreased DLCO on pulmonary function testing. Some reversibility can be noticed upon administering bronchodilators during testing, which is why some patients with respiratory symptoms could be diagnosed initially as having asthma. In clinical practice, a six-minute walk test can be used to assess for hypoxia and oxygen requirements in patients with LAM.

Imaging

Chest x-ray shows no specific findings in patients with LAM. The cystic disease is difficult to recognize on a plain chest X-ray, and it may see only non-specific findings of pneumothorax or pleural effusions if present. High-resolution computed tomography (HRCT) has high sensitivity and specificity in detecting the disease and has been suggested as a modality for screening patients suspected of having LAM (strong recommendation).[20][21] The characteristic diagnostic finding in lymphangioleiomyomatosis is the presence of multiple (usually >10), thin-walled (0.1 to 2 mm thick), well-demarcated, bilateral, diffusely distributed pulmonary cysts on high-resolution computed tomography.[10][16] 

Septal thickening may be seen; usually, there is no associated lymphadenopathy. However, as LAM progresses, reticulonodular opacities, pleural thickening, or hyperinflation can be seen. In addition, focal ground-glass opacities can be found due to the proliferation of smooth muscle cells, pulmonary hemorrhage, and lymphatic congestion. Other thoracic radiological findings could include septal thickening, chylothorax, pericardial effusion, thoracic duct dilatation, and mediastinal lymph node enlargement.[5]

Imaging of the kidneys is also strongly recommended due to the frequently associated finding of renal angiomyolipomas in patients with LAM. It is reported that 45% to 60% of all LAM patients will develop renal angiomyolipomas.[11][22][23] CT abdomen and pelvis are recommended to screen for lymphangioleiomyomas and angiomyolipomas. 

A screening CT scan is recommended if women resenting with spontaneous pneumothorax during childbearing age, recurrent pneumothorax, or bilateral pneumothorax, and the presence of TSC. 

Biopsy

Biopsy remains the gold standard for diagnosing 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 on the best approach for the biopsy. Trans-bronchial lung biopsy has a lower yield and higher false-negative rate than surgical biopsy. However, the decision is based on local experience, patient comorbidities, and wishes. The diagnostic yield and safety of transbronchial lung biopsy and transbronchial cryobiopsy require further investigation. 

Pathology and use of biomarkers 

The characteristic pathological findings of pulmonary LAM are smooth muscle cell proliferation in the walls of the alveoli and vascular bed in lung tissue on a hematoxylin-eosin stain (H and E) slide. Pathology can also show cystic spaces. The diagnosis is established by immunohistochemical staining, which will be positive for HMB-45, actin, myosin, estrogen, and progesterone. There have been cases with a diagnosis of LAM through cytology by seeing the smooth muscle-like cells and positive stains, but this remains a low yield compared to tissue biopsy evaluations.[24]

Traditionally to confirm LAM diagnosis, a histopathological test after surgical lung biopsy is required, but the diagnosis can be made clinically through the presence of CT imaging and the presence of one of the following: a diagnosis of TSC, a chylous effusion, lymphangioleiomyoma, renal angiomyolipoma or elevated VEGF-D (strong recommendation).[25][5] The serum VEGF-D test has frequently eliminated the need for biopsy as it has a very low false-positive rate and a high false-negative rate. At a threshold level of 800 pg/mL, the diagnostic threshold reported 100% specificity, which is currently used by the College of American Pathologists/Clinical Laboratory Improvement Amendments laboratory.[26] Thus the elevated VEGF-D level (≥800 pg/mL) can be used to confirm LAM, but low levels (<800 pg/mL) can not exclude LAM. 

Treatment / Management

Management aims to control the symptoms, improve quality of life, and slow disease progression. In addition to medical treatment, supportive care includes smoking cessation and correction of hypoxia with adequate O2 supplementation. The management approach outlined here is evidence-based recommendations according to the American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines. [25](A1)

Bronchodilators

Bronchodilators are used for symptomatic control and relief of symptoms in patients who show reversibility on PFTs. Usually, beta-agonists and anticholinergics are used in the treatment. Studies have shown the benefit and reversibility of airflow obstruction in patients with LAM treated with albuterol and ipratropium after adjusting for smoking and asthmatic status.[27](B2)

Respiratory Rehabilitation

Studies have shown that respiratory rehabilitation in patients with decreased functional capacity and respiratory symptoms benefits from it. It encourages all healthcare professionals to consider patients with LAM to have respiratory rehabilitation to increase endurance and improve their quality of life.[28](A1)

Medication

Sirolimus is approved to treat LAM by the US Food and Drug Administration (FDA), the European Medicines Agency, and drug agencies in other countries. Sirolimus is an (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 in the MILES trial the ability to prevent the worsening of lung function (stabilization of FEV and improvement in FVC) and respiratory symptoms while improving the quality of life and reducing serum VEGF-D levels.[29] The recommended initial dose of sirolimus is 1 mg orally once daily and titration to 2 to maintain a trough level ≤10 ng/mL (usually after the first week of initiating treatment). The adverse effects of sirolimus are reported to occur in the first few months of initiation of therapy, which are generally dose-related.[30] These side effects include diarrhea, stomatitis, dyspepsia, nausea, hypercholesterolemia, and acneiform rash. Other uncommon adverse events include lower extremity edema, renal failure, infection, delayed wound healing, pneumonitis, allergic reaction, and anemia.[31](A1)

Sirolimus can alleviate the lymphatic manifestations of LAM, such as chylous effusions and lymphangioleiomyomas. Sirolimus is considered the first-line treatment for symptomatic patients with LAM with one of the following criteria (strong recommendation): FEV1  <70% of predicted, chylous complications, and rapidly progressive disease such as FEV1 decline ≥90 mL per year, or problematic chylous accumulations. The safety profile of sirolimus is reasonable and includes nonspecific symptoms such as nausea, diarrhea, mucositis, acne, lower-extremity swelling, and hyperlipidemia.[25](A1)

Everolimus is an alternative for patients who cannot tolerate sirolimus or have allergies, but the FDA has not approved it for this purpose, and its use is still off-label. However, everolimus has approval for treating AMLs, central nervous system tumors, and epilepsy due to TSC and renal angiomyolipomas in LAM patients, particularly when associated with tuberous sclerosis.[32][33][34]

Hormonal modulating therapy has been hypothesized to be an option for treatment, given the role of estrogen. Selective estrogen receptor modulators could play a role in treating 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 the letrozole study was recruiting patients. The use of anti-estrogen treatments is not recommended outside of the clinical trial or investigation; hence hormonal therapy is not recommended treatment for LAM (conditional recommendation). Another treatment, such as doxycycline, is not recommended due to weak evidence (conditional recommendation).[25](A1)

Lung Transplantation

Lung transplantation remains the best option for a patient who progresses with worsening symptoms and lung function despite supportive and refractory treatment with an mTOR inhibitor. However, many anecdotal case reports mentioned recurrence with LAM after lung transplantation, raising a question about the curative role of this surgical treatment modality.

Pleurodesis

In refractory cases of pneumothorax related to LAM, chemical pleurodesis using talc is recommended. Due to the potential delay in wound healing associated with sirolimus, it is usually recommended to stop the drug  2 to 4 weeks after the resolution of pneumothorax. 

Differential Diagnosis

Following are some important differentials of lymphangioleiomyomatosis:

• Amyloidosis
• Asthma
• Benign metastasizing myeloma
• Birt-Hogg-Dube syndrome
• Diffuse pulmonary lymphangiomyosis
• Emphysema
• Eosinophilic granuloma
• Follicular bronchiolitis
• Interstitial myofibrosis
• Leiomyosarcoma
• Lymphoid interstitial pneumonia
• Light-chain deposition disease
• Pulmonary Langerhans cell histiocytosis

Prognosis

Now the mortality is found to be longer than what has been reported in the previous decade. The median transplant-free survival in patients with LAM is estimated to be 29 years from symptom onset and 23 years from diagnosis.[35] Given the possibility of recurrence after lung transplantation, many experts now consider the disease to be a low-grade neoplasm. Pleural disease and pneumothorax in LAM are refractory and can recur even after pleurodesis is performed in a third of cases.[36][5] 

Due to the potential of pressure changes associated with air travel, there is an increased risk of pulmonary cysts rupture and spontaneous pneumothorax in patients with LAM. Therefore, patients should be counseled about air travel-associated risks and the possible need for inflight oxygen supplements.[5][36]

Complications

All patients with lymphangioleiomyomatosis should be advised to avoid using estrogen-containing oral contraceptive pills, given the increased rate of worsening 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 symptoms and complications, but patients with LAM reported having multiple pregnancies without complications. Patients with LAM should receive influenza and pneumococcal vaccination.