Lymphangioleiomyomatosis

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.

Epidemiology

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 by screening in 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 subsequently inherited in an autosomal dominant fashion. Even in TSC, sporadic mutations outnumber inherited disease 2:1 and these cases 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.

Clinical presentation

s-LAM can present in late teens or adulthood and lymphatic and lung disease predominate:

• 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
• haemoptysis
• acute abdominal pain and shock 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:

• tuberous sclerosis complex (TSC)
• renal angiomyolipoma (AML)
• cystic lymphangioleiomyoma
• chylothorax and/or chyloperitoneum

TSC is characterised by benign tumours in almost any organ which are frequently detected in childhood or, in the case of cardiac rhabdomyomas, even 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.

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.

Pathology

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 causing obstruction, cystic lung destruction and haemorrhage. 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 has 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.

Radiographic features

Chest

Plain radiograph

• large volume lungs with abnormal architecture mimicking emphysema in advanced disease
• chylothorax
• 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) especially in tuberous sclerosis
• pneumothorax
• chylous effusions: pleural, pericardial
• lymphadenopathy
• 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 AMLscompared with about 30% incidence in s-LAM
• hepatic, adrenal or retroperitoneal AMLs
• chylous ascites
• lymphangioleiomyomas: soft cystic/solid masses which can insinuate between normal structures without compressing them
• lymphadenopathy

Skeletal

• 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

Complications

• respiratory failure
• recurrent pneumothorax 
• bilateral pneumothorax
• 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

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
• pulmonary Langerhans cell histiocytosis
  • 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
• Birt-Hogg-Dubé Syndrome
  • autosomal dominant inheritance:
  • family history of pneumothorax or renal tumours
  • characteristic skin lesions
  • folliculin gene mutation