Lymphangioleiomyomatosis typically presents in women of childbearing age with symptoms of exertional dyspnoea or spontaneous pneumothorax and is characterised by proliferation of atypical smooth muscle cells along lymphatic vessels, and thin-walled cysts uniformly distributed throughout both lungs.
Description
Lymphangioleiomyomatosis (LAM) is a rare lung disease characterised by the abnormal proliferation of smooth muscle-like cells (LAM cells) in the lungs, lymphatic system, and kidneys. These abnormal cells invade the tissue of these organs, leading to the formation of cysts, nodules, and tumours. Over time, the damage caused by LAM can lead to respiratory failure.
Pathogenesis
The pathogenesis of LAM is not entirely understood. However, it’s believed that mutations in the tuberous sclerosis genes (TSC1 and TSC2) result in the formation of LAM cells. These cells exhibit a ‘benign metastasis’ pattern, originating from an unknown source, potentially the uterus, and then migrating and proliferating in the lungs, lymphatic system, and kidneys.
Epidemiology, Risk Factors & Associations
- Almost exclusively affects women, particularly those of childbearing age.
- Prevalence estimated to be around 1 to 5 per million women.
- Seen frequently in 30-40% of individuals with tuberous sclerosis complex (TSC)
- Sporadic LAM is quite rare
Clinical Features
Typical features of LAM include:
- Progressive exertional dyspnea
- Cough
- Recurrent pneumothoraces
- Chylous effusions (chylothorax and chylous ascites)
- Abdominal angiolipomas
- Renal angiomyolipomas
Complications
- Progressive loss of lung function
- Respiratory failure
- Recurrent or spontaenous pneumothorax (spontaneous lung collapse)
- Haemorrhage from renal angiomyolipoma
Subtypes
- TSC-LAM: Associated with tuberous sclerosis complex.
- Sporadic LAM – with no known cause or association. Rare.
Pathological Features
Morphology
Characterised by the presence of diffuse thin-walled lung cysts and the proliferation of atypical smooth muscle cells (LAM cells) within the lung parenchyma.
Histopathology
The abnormal LAM cells express melanoma markers like HMB45, Melan-A, and MITF. They also show positivity for smooth muscle markers such as alpha-smooth muscle actin and desmin.
Genetics
Mutations in the TSC1 and TSC2 genes are the most significant genetic association in LAM. These mutations cause increased activity of the mammalian target of rapamycin (mTOR) pathway, leading to abnormal cell growth and proliferation.
Radiological Features
CT
- Typically shows numerous, diffuse, thin-walled, round cysts scattered throughout both lungs with no zonal predominance.
- Cysts may vary in size.
- Normal intervening lung parenchyma. No associated ground-glass opacities, micronodules, or fibrosis should be present.
- Expiratory phase can help in evaluating small airways disease
- Pneumonthorax
- Chylous pleural effusions (25%)
- May demonstrate bilateral renal angiomylipoma
Lymphangiography
- Obstruction of lymphatic flow at multiple levels
- Dilated lymphatics
- Increased number of lymphatics
- Renal angiomyolipomas
- Chylous ascites, uterine leiomyomas, lymphaticoureteral and lymphaticovenous communications
- Abdominal and pelvic lymph angioleimyomas
- Abdominal lymph nodes
Diagnosis
Confirmatory diagnosis is usually made with tissue biopsy, showing characteristic pathological features of LAM. Genetic testing may be used to identify mutations in the TSC genes.
Differential Diagnosis
- Pulmonary Langerhans Cell Histiocytosis (PLCH): PLCH typically presents in young smokers and shows nodules and cysts with characteristic upper and mid-lung predominance on imaging. Additionally, it may demonstrate a combination of cysts and nodules, while LAM primarily shows diffuse cysts.
- Birt-Hogg-Dubé Syndrome: This is a genetic syndrome associated with skin fibrofolliculomas, renal tumors, and spontaneous pneumothorax. Cysts in Birt-Hogg-Dubé tend to be located in the lower medial and subpleural lung zones, which differentiates it from LAM.
- Cystic Bronchiectasis: This condition is associated with a history of infectious insults and manifests with bronchial wall thickening, bronchial dilatation, and cysts that are usually of variable size and have visible walls. It can be differentiated from LAM by the absence of these bronchiectatic features in LAM.
- Emphysema: Emphysematous changes typically present in smokers and can be differentiated by the characteristic centrilobular and panlobular emphysema patterns, upper lobe predominance, and the absence of the diffuse round cysts that are seen in LAM.
- Lymphocytic Interstitial Pneumonia (LIP): LIP can present with diffuse thin-walled cysts, but it also demonstrates ground-glass opacities and interlobular septal thickening, which help to distinguish it from LAM. Additionally, LIP usually occurs in the setting of autoimmune diseases or Sjogren’s syndrome.
Management
Management of LAM is usually overseen by a pulmonologist or a specialist in rare lung diseases. The key aspects of management include:
- Symptom management: Bronchodilators can help with shortness of breath.
- Slowing disease progression: Sirolimus (Rapamycin) is an mTOR inhibitor that can stabilise lung function and improve quality of life.
- Management of complications: Pneumothoraces are managed with pleurodesis. Large angiomyolipomas may require embolisation or surgery.
- Lung transplantation: In severe cases, lung transplantation may be considered.
- Genetic counselling: Particularly for patients with TSC-LAM.