Lymphangioleiomyomatosis

A low grade metastasising neoplasm of perivascular epithelioid cells (LAM cells) that causes progressive diffuse cystic destruction of the lungs, chylous effusions, abdominal lymphatic masses and renal angiomyolipomas.

• Almost exclusively women of reproductive age (mean age at diagnosis about 35 to 40 years); incidence is about 3 to 5 per million women; two forms: sporadic (somatic TSC2 mutations) and tuberous sclerosis complex associated (germline TSC1 or TSC2 mutation, with lung cysts in about 30 to 40% of women with the complex).
• Mechanism: loss of tuberin or hamartin leads to constitutive activation of the mechanistic target of rapamycin (mTOR) pathway, cell proliferation, vascular endothelial growth factor D release, and lymphatic invasion.
• Oestrogen exposure appears to accelerate disease.

Progressive exertional dyspnoea, cough, wheeze, haemoptysis, chest pain; recurrent pneumothorax (about 65% have at least one) often leading to diagnosis.

• Chylous pleural effusion, chylous ascites or chyluria in about 10 to 30%.
• Renal angiomyolipoma (about 30 to 50% in sporadic disease and about 90% with tuberous sclerosis) with flank pain or bleeding (Wunderlich syndrome); abdominal and retroperitoneal lymphangioleiomyomas.
• Tuberous sclerosis features: facial angiofibromas, ungual fibromas, shagreen patches, seizures, cognitive impairment.
• Differential diagnosis: pulmonary Langerhans cell histiocytosis, emphysema, Birt-Hogg-Dube syndrome, lymphoid interstitial pneumonia, Sjogren syndrome, amyloidosis, light chain deposition disease, asthma and chronic obstructive pulmonary disease.
• Complications: recurrent pneumothorax, chylothorax, respiratory failure, haemorrhage from angiomyolipoma, pulmonary hypertension, lymphoedema, meningioma, and venous thromboembolism.

High-resolution CT: numerous (more than 10) thin walled round cysts of 2 to 5 mm (up to 30 mm), uniformly distributed with normal intervening lung and including the lung bases.

• Diagnosis without biopsy when typical cysts are accompanied by one of: tuberous sclerosis complex, renal angiomyolipoma, serum vascular endothelial growth factor D of more than 800 pg/mL, chylous effusion, or lymphangioleiomyoma.
• Biopsy (transbronchial, thoracoscopic or from a lymphatic mass) when none is present: HMB-45, smooth muscle actin, oestrogen receptor and progesterone receptor positive spindle and epithelioid cells.
• Spirometry (obstruction, reduced FEV1), diffusing capacity (often reduced out of proportion), 6 minute walk with oximetry, echocardiogram.
• Abdominal and pelvic CT or MRI for angiomyolipoma and lymphatic masses; genetic testing for TSC1 and TSC2; brain MRI in tuberous sclerosis.

Sirolimus (mTOR inhibitor) for FEV1 less than 70% predicted, rapid decline (FEV1 loss more than 90 mL a year), symptomatic chylous effusion, or large angiomyolipoma:

• Start 2 mg orally once daily with a trough target of 5 to 15 ng/mL, checked after 2 weeks; reduce to 1 mg daily if mouth ulcers or other effects occur; it stabilises FEV1 in most, but decline resumes if stopped.
• Check full blood count, lipids, creatinine, urinalysis (proteinuria) and glucose every 3 months; avoid grapefruit and strong CYP3A4 inhibitors or inducers.
• Adverse effects: mouth ulcers, peripheral oedema, dyslipidaemia, proteinuria, infection, impaired wound healing, pneumonitis (rare), and teratogenicity.
• Everolimus 10 mg daily (or 2.5 to 5 mg for lung disease) is an alternative.

```{=html} <!-- --> ``` - Bronchodilators: salbutamol 100 micrograms as needed, tiotropium 18 micrograms daily, or formoterol with budesonide when obstruction responds.

• Pneumothorax: chest drain followed by surgical pleurodesis or pleurectomy after the first episode, because recurrence is about 70% without it (lung transplant eligibility remains).
• Chylous effusion: sirolimus 2 mg daily (trough 5 to 15 ng/mL), a low fat diet with medium chain triglycerides, therapeutic drainage when breathless, thoracic duct embolisation or pleurodesis for refractory cases.
• Angiomyolipoma: sirolimus or everolimus for tumours of 3 cm or more; selective arterial embolisation for bleeding or tumours more than 4 cm with aneurysms (more than 5 mm); nephron sparing surgery as a last resort.
• Avoid oestrogen: stop oestrogen-containing contraceptives, hormone replacement and fertility treatment; use progesterone only or barrier methods (evidence for hormonal anti-oestrogen therapy is limited).
• Supportive: oxygen to keep SpO2 90% or more at rest and exertion, pulmonary rehabilitation, annual influenza and pneumococcal conjugate vaccine, bone density scan and calcium and vitamin D, and avoidance of air travel unless risk of pneumothorax is discussed.
• Lung transplantation for FEV1 less than 30% predicted, severe hypoxaemia or pulmonary hypertension; 5 year survival after transplant is about 65 to 70%.
• Special groups: pregnancy (high risk: pneumothorax, chylothorax, angiomyolipoma bleeding; stop sirolimus before conception (at least 12 weeks), and plan care with respiratory and obstetric teams); children and tuberous sclerosis (everolimus for angiomyolipoma, seizures, giant cell astrocytoma, with screening of girls from adolescence); elderly (slower progression); renal impairment (monitor proteinuria on sirolimus); surgery (continue sirolimus with a dose pause of 1 to 2 weeks around major surgery).
• Red flags: sudden chest pain and breathlessness (pneumothorax), flank pain or haematuria (angiomyolipoma bleed), milky effusion, rapid FEV1 fall, haemoptysis, pregnancy.
• Follow-up: spirometry and diffusing capacity every 3 to 6 months, CT of the chest yearly (or at change), abdominal imaging every 1 to 2 years, sirolimus level at 2 weeks and every 3 to 6 months; the 10 year survival is about 85%.