Lymphangioleiomyomatosis (ORPHA:538)
A rare, multiple cystic lung disease characterized by progressive cystic destruction of the lung and lymphatic abnormalities, frequently associated with renal angiomyolipomas (AMLs).
Epidemiology
Sporadic lymphangioleiomyomatosis (LAM) affects around 1/129 000 - 385 000 adult women in Europe. However, LAM may occur as a feature of tuberous sclerosis complex (TSC) and is present in up to 30-40% of adult TSC cases. Sporadic LAM affects almost exclusively females.
Clinical description
Defining manifestations of the disease are respiratory and include progressive dyspnea, pneumothorax and chylothorax. LAM may lead to chronic respiratory failure. A common extra-pulmonary manifestation is a high incidence of AMLs, mostly localized to the kidneys and usually asymptomatic (hemorrhage is rare). Chylous ascites, abdominal and thoracic lymphadenopathy and lymphangioleiomyomas (especially retroperitoneal) can be observed. Symptoms may worsen during pregnancy.
Etiology
Sporadic LAM is due to somatic mutations in the tuberous sclerosis genes TSC2 and/or TSC1, that encode the major signaling proteins tuberin and hamartin. Mutations result in excessive proliferation of LAM cells. In contrast, TSC is due to germline mutations.
Diagnostic methods
For a definite LAM diagnosis, a high resolution computed tomography (HRCT) scan shows typical lung cysts with diffuse distribution and may be associated together with one of the following: TSC; a lung biopsy showing cysts and abnormal immature smooth muscle-like cells (LAM cells); AMLs in the kidney; thoracic or abdominal chylous effusion; lymphangioleiomyoma; elevation of serum level of vascular endothelial growth factor D (VEGF-D) greater than 800 mg/L. The diagnosis of LAM is possible when only characteristic lung cysts are present.
Differential diagnosis
The two main differential diagnoses are adult pulmonary Langerhans cell histiocytosis and emphysema. Less frequent differential diagnoses include hypersensitivity pneumonitis, light chain-deposition disease, Birt-Hogg-Dubé syndrome and Sjögren syndrome.
Genetic counseling
Sporadic LAM is not inherited. In contrast, TSC may be inherited or result from de novo germline mutations of TSC1 or TSC2.
Management and treatment
LAM patients who develop respiratory symptoms should have periodic pulmonary function testing. Management of air flow obstruction is essential and a quarter of patients respond to inhaled bronchodilators. Patients should be informed of the risk of pneumothorax. Pleurodesis may be performed at first pneumothorax to prevent increased risk of recurrent pneumothorax. Surgical pleurodesis is often necessary for a recurrent pneumothorax or chylothorax. Single/bilateral lung transplantation is performed when other options have proven unsuccessful. The mTOR inhibitor sirolimus may be used in expert centers to stabilize or improve pulmonary function in cases with altered lung function (forced expiratory volume in one second [FEV1] < 70% of predicted value) or declining lung function (FEV1 decline > 90 mL/year). Asymptomatic AMLs < 4cm in diameter do not usually need to be treated but should be monitored. AMLs > 4 cm or with microaneurysms > 0.5 cm or bleeding risk should be treated by selective arterial embolization, sirolimus or everolimus therapy, or nephron sparing surgery. Estrogen therapy should be avoided.
Prognosis
Disease progression rate and severity is highly variable. The main predictor of prognosis is the rate of decline in pulmonary function.

                            Last update: 
                            May 2022


                            - Expert reviewer(s): 
                            Pr Vincent COTTIN | ERN-LUNG*


                                * European Reference Network