Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a low-grade destructive metastasising PEComatous tumour, 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 most commonly sporadic. Cystic lung disease is the most frequent manifestation.

Epidemiology

Cystic lung disease almost exclusively affects women, and the majority of symptomatic lung disease occurs in sporadic LAM (s-LAM). Diagnosis is typically delayed and advanced cystic lung destruction may be mistaken for emphysema. The true prevalence of s-LAM may be as high as 8:1,000,000 ¹. 

The prevalence of tuberous sclerosis (TSC) is 1:6,000 births, however, cystic lung disease is frequently asymptomatic. The few cases of cystic LAM lung disease in men are in this category, except for one reported case of s-LAM.

S-LAM may be a 'forme fruste' of tuberous sclerosis. In s-LAM, the mutations are somatic and not heritable, whereas in tuberous sclerosis germline mutations are inherited in an autosomal dominant fashion. Even in tuberous sclerosis, sporadic mutations outnumber inherited disease 2:1. Tuberous sclerosis may be underdiagnosed due to the attached stigma.

Clinical presentation

S-LAM presents in late teens or adulthood and lung and lymphatic disease predominate:

• pneumothorax, which 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 become dependent on home oxygen about 10 years afterwards
• 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:

• tuberous sclerosis
• 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 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. Higher levels predict more rapid disease progression and more robust responses to mTOR inhibitors¹⁷.

One-third of TSC cases are inherited by autosomal dominant transmission and frequently present in childhood with developmental delay and seizures. TSC2 on chromosome 16 codes for tuberin and is more common and severe than TSC1 on chromosome 9 which codes for hamartin.

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 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 tuberous sclerosis.

Radiographic features

Chest

Radiography

• 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) in tuberous sclerosis
• pneumothorax
• chylous effusions: pleural, pericardial
• lymphadenopathy
• dilated thoracic duct
• myocardial fatty foci in tuberous sclerosis ¹²

Abdomen and pelvis

Best delineated by CT or MR.

• single or multiple renal epithelioid AMLs containing a mixture of fat and soft tissue. >90% incidence in TSC cases which have larger and more numerous AMLs¹⁵ compared with about 30% incidence in s-LAM. 
• hepatic 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 about 30 years following diagnosis. There are few medications that have been shown to benefit patients with LAM, with mTOR inhibitors being one of the main treatment options. Sirolimus or everolimus limit LAM cell proliferation by inhibiting the activated mTOR pathway, thereby improving lung function, at least in the short-term, and often shrinking masses¹³ and chylous effusions. Progression generally resumes on cessation.

About 20% respond to bronchodilators. Pneumococcus and influenza vaccines are advised. Osteoporosis may occur in immobile patients.

​Other potential therapies, depending on the manifestations include:

• VATS pleurodesis for recurrent pneumothorax. The method affects perioperative haemorrhage at transplantation ¹⁶
• lung transplantation for respiratory failure. Recurrent LAM in transplanted lungs carries the original tuberous sclerosis mutation ¹⁴
• 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 tuberous sclerosis cases

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 

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 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