Citation, DOI & article data
Lymphangioleiomyomatosis (LAM) is a low-grade destructive metastasising PEComatous tumour 1 resulting from the proliferation of LAM cells in the lung, kidney and axial lymphatics. The disease is caused by mutations of the TSC2 or TSC1 genes and is more commonly sporadic rather than inherited. Cystic lung disease (CLD) is the most frequent manifestation.
Symptomatic CLD almost exclusively affects women and is associated with sporadic lymphangioleiomatosis (s-LAM) or tuberous sclerosis complex (TSC-LAM). The few cases of cystic LAM lung disease in men are associated with TSC-LAM except for one reported case of s-LAM. CLD in men is less severe. CLD may be detected through screening of known TSC cases, but in s-LAM diagnosis is more likely to be delayed and advanced cystic lung destruction may be mistaken for emphysema.
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 transmissible to future generations in an autosomal dominant fashion. Even in TSC, sporadic mutations outnumber inherited disease 2:1 and these cases will have a negative family history. TSC affects about 1:6,000 live births. The true prevalence of s-LAM may be as high as 8:1,000,000.
s-LAM can present in late teens or adulthood with lymphatic or lung disease. TSC LAM commonly presents during childhood with developmental delay, seizures, characteristic skin lesions or tumours. Cystic lung disease and renal angioleiomyoma (AML) are features of both conditions and can present in the following ways:
pneumothorax often precedes diagnosis, occurring in >65% of cases and often recurrent, sometimes bilateral
pneumothorax during pregnancy
progressive dyspnoea: the disease is variable, the average age of onset of symptoms is 33 years of age and untreated patients typically become dependent on home oxygen about 10 years afterwards
acute abdominal pain and shock due to haemorrhagic renal angiomyolipoma
American Thoracic Society/Japanese Respiratory Society guidelines 2017 2 support a clinical diagnosis of LAM based on typical lung CT and accompanied by any of the following:
TSC is characterised by benign tumours in almost any organ which are frequently detected in childhood or, in the case of cardiac rhabdomyomas, in-utero. Children often have developmental delay, seizures and characteristic skin lesions. TSC2 on chromosome 16 codes for tuberin and is more commonly implicated and severe than TSC1 on chromosome 9 which codes for hamartin. Pathological TSC gene mutations are detected in 75-90% of TSC cases 3.
In the absence of a TSC diagnosis, the guidelines recommend testing for vascular endothelial growth factor D (VEGF-D) before resorting to a lung biopsy which must be stained appropriately, including for HMB-45 (other smooth muscle-predominant lesions in the lung do not react with this antibody). VEGF-D levels correlate with the severity of lymphatic involvement and higher levels predict more rapid disease progression and more robust responses to mTOR inhibitors. Serum VEGF-D >800 pg/mL is considered diagnostic. Less severe cases with a normal VEGF-D can be offered transbronchial biopsy which has a diagnostic rate <50%; VATS wedge resection has a higher diagnostic rate but greater morbidity and mortality.
A radiological suspicion without confirmatory findings is insufficient for diagnosis: long-term treatment with sirolimus or everolimus can have serious toxicity, and a wrong diagnosis is a missed opportunity to correctly manage a different condition.
Smooth muscle-like LAM cells contain inactivating mutations of TSC2 or TSC1 tumour suppressor genes with consequent activation of the mechanistic target of rapamycin (mTOR) signalling pathway. This results in proliferation of LAM cells which migrate through lymphatic vessels and infiltrate airways and blood vessels. Lymphatic and vascular obstruction and rupture may result, causing haemorrhage, chylous effusions etc.. The mechanism of cystic lung destruction is uncertain and could involve check-valve obstruction and/or metalloproteinases. LAM cells express oestrogen receptors and functional decline accelerates during pregnancy. Oestrogen is a driver of LAM cell proliferation and lymphatic dissemination.
Lung disease, lymphatic disease and chylous leaks predominate in s-LAM, whereas widespread benign tumours and hamartomas are common in TSC. Epithelioid AML may have a relatively aggressive course and is normally rare, but occurs with greater frequency in s-LAM and TSC-LAM.
The source of the LAM cells is not known, however microscopic uterine LAM cell lesions have a high incidence in LAM patients, but are absent in non-LAM controls.
large volume lungs with abnormal architecture mimicking emphysema in advanced disease
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) especially in tuberous sclerosis
chylous effusions: pleural, pericardial
dilated thoracic duct
myocardial fatty foci in tuberous sclerosis
Abdomen and pelvis
Best delineated by CT or MRI:
single or multiple renal AMLs containing a mixture of fat and soft tissue
>90% incidence in TSC cases which have larger and more numerous AMLs compared with about 30% incidence in s-LAM
hepatic, adrenal or retroperitoneal AMLs
lymphangioleiomyomas: soft cystic/solid masses which can insinuate between normal structures without compressing them
multiple osteoblastic bone lesions in tuberous sclerosis, similar in appearance to enostoses
Treatment and prognosis
Median survival is approximately 30 years following diagnosis. There are few medications that have been shown to benefit patients with LAM, with mTOR inhibitors (e.g. sirolimus or everolimus) being one of the main treatment options. mTOR inhibitors limit 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 generally resumes on cessation.
Other potential therapies, depending on the manifestations include:
bronchodilators, response seen in ~20%
VATS pleurodesis for recurrent pneumothorax, the method affects perioperative haemorrhage at transplantation
lung transplantation for respiratory failure
recurrent LAM in transplanted lungs carries the original tuberous sclerosis mutation
embolisation or nephron-sparing surgery for large, rapidly growing or haemorrhagic AMLs
surgery is contraindicated for lymphatic masses, as it can result in persistent chyle leaks
genetic counselling for TSC cases
pneumococcus and influenza vaccines are advised
haemorrhagic AML, potentially fatal
sirolimus or everolimus toxicity, including organising pneumonia, cryptogenic organising pneumonia, interstitial pneumonitis, focal fibrosis or alveolar haemorrhage, Pneumocystis jirovecii pneumonia, cardiac failure
sudden death due to obstructing subependymal giant cell astrocytoma in TSC
osteoporosis may occur in immobile patients
advanced emphysema can appear similar to advanced cystic lung disease in LAM
fibrosis may mimic cyst walls
emphysema distribution depends on aetiology
LAM will have typical cysts separated by normal parenchyma in the least affected areas
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, delaying diagnosis
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
fewer cysts with characteristic subpleural distribution and characteristic cyst shapes
autosomal dominant inheritance:
family history of pneumothorax or renal tumours
characteristic skin lesions
folliculin gene mutation
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