Lymphangioleiomyomatosis
Updates to Article Attributes
Lymphangioleiomyomatosis (LAM) is a low-grade destructive metastasising PEComatous tumour, resulting from proliferation of LAM cells in lung, kidney and axial lymphatics. Disease is caused by mutations of the TSC2 or TSC1 genes and is most commonly sporadic. Cystic lung disease is the most frequent manifestation.
Epidemiology
Cystic lung disease almost exclusively affects women, with very few reported affected men with tuberous sclerosis (TSC). Diagnosis is typically delayed and advanced cystic lung destruction may be mistaken for emphysema. The true prevalence may be as high as 8:1,000,000 1.
Sporadic LAM (s-LAM) may be a forme fruste of TSC. In s-LAM the mutations are somatic and not heritable, whereas in TSC germline mutations are inherited in an autosomal dominant fashion. Even in TSC, sporadic mutations outnumber inherited disease 2:1. TSC may be under-diagnosed due to the attached stigma.
Clinical presentation
Adult presentation of:
- progressive dyspnoea
- the disease is variable, the average age of onset of symptoms is about 35 years of age and untreated patients become dependent on home oxygen about 10 years afterwards
- pneumothorax
- haemoptysis
- acute abdominal pain due to haemorrhagic renal angiomyolipoma (AML)
Diagnosis
American Thoracic Society/Japanese Respiratory Society guidelines 2017 support a clinical diagnosis of LAM based on typical lung CT and accompanied by any of the following:
- TSC
- renal angiomyolipoma
- cystic lymphangioleiomyoma
- chylous pleural effusions in the chest and/or abdomen
This society also recommends testing for vascular endothelial growth factor D (VEGF D) before resorting to lung biopsy which must be stained appropriately, including for HMB-45.
Pathology
Tissues are infiltrated by smooth muscle-like LAM cells containing inactivating mutations of TSC2 or TSC1 tumour suppressor genes. Consequent activation of the mechanistic target of rapamycin (mTOR) signalling pathway results in proliferation of LAM cells which coat alveolar walls, bronchioles, pleura, venules and lymphatics, causing obstruction and cystic lung destruction. LAM cells express oestrogen receptors and functional decline accelerates during pregnancy. Oestrogen is a driver of LAM cell proliferation and lymphatic dissemination.
Radiographic features
Pulmonary features
Plain radiograph
- large volume lungs with abnormal architecture mimicking emphysema in advanced disease
- chylous pleural effusions
- pneumothorax
CT
- large lungs containing scattered thin-walled rounded empty cysts
- in early disease, the cysts are few and small with normal intervening lung parenchyma
- the cysts progressively enlarge and become more numerous until there is little normal lung remaining
- transient areas of increased lung opacity due to haemorrhage
- small lung nodules representing multifocal micronodular pneumocyte hyperplasia (MMPH)
- pneumothorax
- chylous pleural effusions
- myocardial fatty foci in TSC 12
Extra-pulmonary features
In the abdomen and pelvis:
- multiple renal AMLs, especially common in TSC 2,3
- hepatic or retroperitoneal AMLs
- chylous ascites
- lymphangioleiomyomas: soft cystic/solid masses which can insinuate between normal structures without compressing them
- lymphadenopathy
In bones:
- multiple osteoblastic bone lesions in TSC, similar in appearance to enostoses
Treatment and prognosis
There are few medications which have been shown to benefit patients with LAM, with sirolimus being one of the main treatment options. Sirolimus limits LAM cell proliferation by inhibiting the activated mTOR pathway, thereby improving lung function, at least in the short-term, and often shrinking masses and chylous effusions. Progression resumes on cessation
Other potential therapies, depending on the manifestations expressed, include:
- VATS pleurodesis for recurrent pneumothorax
- lung transplantation for respiratory failure
- genetic counselling if TSC
Complications
- respiratory failure
- recurrent pneumothorax
- haemorrhagic AML
- sirolimus toxicity, including organising pneumonia, cryptogenic organising pneumonia, interstitial pneumonitis, focal fibrosis or alveolar haemorrhage
- sudden death due to obstructing subependymal giant cell astrocytoma in TSC
Differential diagnosis
-
emphysema
- similar in appearance to advanced cystic lung disease in LAM
- in the least affected areas, LAM will have typical cysts separated by normal parenchyma
-
lymphocytic interstitial pneumonitis (LIP)
- in women of child-bearing age, LIP is usually associated with connective tissue disease, especially Sjögren syndrome
- a smaller number of lower zone predominant perivascular cysts, some with internal soft-tissue may coexist with nodules, ground-glass opacity, tree-in bud opacities, lymphoma or amyloid deposits
- lung changes may pre-date typical serological abnormalities
-
light-chain deposition disease
- typically occurs in an older adult with plasma cell dyscrasia (e.g. multiple myeloma) and renal failure with findings of cysts, nodules and lymphadenopathy
-
pulmonary Langerhans cell histiocystosis
- upper zone predominant and bronchocentric cavitating nodules, branching or irregular cysts
- spares costophrenic and costomediastinal angles
- typically a disease of young adult smokers, especially men
-<li>sirolimus toxicity, including <a title="Organising pneumonia" href="/articles/organising-pneumonia">organising pneumonia</a>, <a title="Cryptogenic organising pneumonia" href="/articles/cryptogenic-organising-pneumonia-1">cryptogenic organising pneumonia</a>, <a title="Acute interstitial pneumonitis" href="/articles/acute-interstitial-pneumonitis">interstitial pneumonitis</a>, focal fibrosis or alveolar haemorrhage</li>- +<li>sirolimus toxicity, including <a href="/articles/organising-pneumonia">organising pneumonia</a>, <a href="/articles/cryptogenic-organising-pneumonia-1">cryptogenic organising pneumonia</a>, <a href="/articles/acute-interstitial-pneumonitis">interstitial pneumonitis</a>, focal fibrosis or alveolar haemorrhage</li>
-<a href="/articles/lymphocytic-interstitial-pneumonitis-1"></a>in women of child-bearing age, LIP is usually associated with connective tissue disease, especially <a title="Sjogren disease" href="/articles/sjogren-syndrome-1">Sjögren syndrome</a>- +<a href="/articles/lymphocytic-interstitial-pneumonitis-1"></a>in women of child-bearing age, LIP is usually associated with connective tissue disease, especially <a href="/articles/sjogren-syndrome-1">Sjögren syndrome</a>
Image 13 CT (C+ arterial phase) ( create )
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