Guideline sources The following summarized guidelines for the evaluation and management of pulmonary lymphangioleiomyomatosis (pulmonary LAM) are prepared by our editorial team based on guidelines from the Japanese Respiratory Society (JRS/ATS 2017; 2016), the Tuberous Sclerosis Complex International (TSCi 2013), and the European Respiratory Society (ERS 2010). 1 2 3 4 Calculator ITS diagnostic criteria for tubero Guidelines https://web.pathway.md/diseases/rec3unhjBL4F9EtAG 1/7 6/29/23, 11:36 PM Pulmonary lymphangioleiomyomatosis Pathway 1. Screening and diagnosis Indications for screening: As per ITS 2013 guidelines, obtain clinical screening for lymphangioleiomyomatosis symptoms, including exertional dyspnea and shortness of breath, at each clinic visit of patients with tuberous sclerosis. Review counseling regarding smoking risk and estrogen use at each clinic visit of patients at risk of lymphangioleiomyomatosis. E Show 3 more As per ERS 2010 guidelines, do not screen asymptomatic patients for lymphangioleiomyomas during the course of the disease since a proven therapeutic intervention is not currently available for lymphangioleiomyomas. D Show 6 more 2. Diagnostic investigations History and physical examination: elicit a thorough personal and family history concerning the manifestations of tuberous sclerosis complex in patients presenting with lymphangioleiomyomatosis. Perform a physical examination by a physician familiar with the manifestations of tuberous sclerosis complex to assess the skin, retina, and nervous system. B Chest imaging: As per ATS 2017 guidelines, avoid using HRCT features in isolation to make a clinical diagnosis of lymphangioleiomyomatosis in patients with cystic changes on chest HRCT characteristic of lymphangioleiomyomatosis but not having additional confirmatory features of lymphangioleiomyomatosis (clinical, radiologic, or serologic). D As per ERS 2010 guidelines: Obtain chest HRCT using thin collimation, high spatial reconstruction algorithm in patients with suspected lymphangioleiomyomatosis. E Consider obtaining imaging with sequential scanning (images with 1 mm collimation at 1- cm intervals) or low-dose spiral multidetector CT. E Pulmonary function tests: obtain spirometry, bronchodilator testing, and TLCO in the initial evaluation of patients with lymphangioleiomyomatosis (including tuberous sclerosis complex- lymphangioleiomyomatosis). B Show 2 more Blood gas analysis: Consider obtaining blood gases in the initial evaluation of patients with lymphangioleiomyomatosis to obtain a baseline value, and in the assessment of patients with severe disease including before transplant referral. E Obtain blood gases to assess the indication for oxygen therapy in patients with advanced disease. E Cardiopulmonary exercise testing: Consider obtaining cardiopulmonary exercise testing to provide additional information over standard lung function tests in symptomatic patients. C https://web.pathway.md/diseases/rec3unhjBL4F9EtAG 2/7 6/29/23, 11:36 PM Pulmonary lymphangioleiomyomatosis Pathway Consider obtaining the 6-minute walk test in the evaluation of disability, disease progression, and response to treatment in symptomatic patients. E Serum VEGF-D: obtain VEGF-D to establish the diagnosis of lymphangioleiomyomatosis before lung biopsy in patients with CT findings of cystic abnormalities characteristic of lymphangioleiomyomatosis but not having clinical or extrapulmonary radiologic features of lymphangioleiomyomatosis. B Genetic testing: Refer patients with lymphangioleiomyomatosis and bilateral angiomyolipoma, and other patients where doubt remains, to a clinical geneticist for a full evaluation. B Do not obtain a routine genetic analysis in patients with sporadic lymphangioleiomyomatosis. D Abdominal imaging: obtain abdominopelvic CT at diagnosis or during work-up to identify angiomyolipoma and other abdominal lesions in all patients with suspected or confirmed lymphangioleiomyomatosis. B Show 2 more Brain imaging: Consider obtaining brain MRI as a baseline evaluation for comparison during follow-up as well as in the presence of symptoms compatible with meningioma. C Obtain brain MRI screening for meningioma in patients with lymphangioleiomyomatosis receiving progestogen therapy or planning to receive such treatment. E Screening for pulmonary hypertension: Do not screen patients with non-severe lymphangioleiomyomatosis for pulmonary hypertension. D Consider obtaining echocardiography to assess pulmonary artery pressure in patients with severe disease, requiring long-term oxygen therapy, or considered for lung transplantation. C Screening for osteoporosis: obtain periodic evaluation of bone mineral density in patients with lymphangioleiomyomatosis, especially in postmenopausal patients. B 3. Diagnostic procedures Lung biopsy: consider performing transbronchial lung biopsy before surgical lung biopsy when a definitive diagnosis is required in patients with parenchymal cysts on HRCT characteristic of lymphangioleiomyomatosis but not having additional confirmatory features of lymphangioleiomyomatosis (clinical, radiologic or serologic). C Histopathology: examine pathological samples from patients with suspected lymphangioleiomyomatosis (or any diffuse parenchymal lung disease) by a pathologist experienced in lymphangioleiomyomatosis. E Show 2 more 4. Medical management https://web.pathway.md/diseases/rec3unhjBL4F9EtAG 3/7 6/29/23, 11:36 PM Pulmonary lymphangioleiomyomatosis Pathway mTOR inhibitors: As per ATS 2016 guidelines: Initiate sirolimus rather than offering observation in patients with lymphangioleiomyomatosis with abnormal/declining lung function. B Consider initiating sirolimus before invasive management in patients with lymphangioleiomyomatosis with symptomatic chylous fluid accumulations. C As per ITS 2013 guidelines, consider initiating mTOR inhibitors in patients with lymphangioleiomyomatosis with moderate-to-severe lung disease or rapid progression. E As per ERS 2010 guidelines, do not use sirolimus routinely for pulmonary LAM outside clinical trials. Encourage patients with lymphangioleiomyomatosis to participate in clinical trials whenever possible. D Show 2 more Hormone therapy: As per ATS 2016 guidelines, avoid using hormonal therapy for the treatment of patients with lymphangioleiomyomatosis. D As per ERS 2010 guidelines, do not use oral or IM progesterone routinely in patients with lymphangioleiomyomatosis. D Show 4 more Inhaled bronchodilators: offer a trial of inhaled bronchodilators in patients with airflow obstruction and continue if a response is observed. B Doxycycline: avoid using doxycycline for the treatment of patients with lymphangioleiomyomatosis. D Management of osteoporosis: Treat osteoporosis in patients with lymphangioleiomyomatosis as in other patients with osteoporosis. B Initiate early aggressive therapy for osteoporosis in patients with lymphangioleiomyomatosis with severe lung disease and osteopenia at any bone site in view of the rapid deterioration in bone mineral density observed after lung transplantation. Encourage weight-bearing exercises and strength training in addition to pharmacotherapy. B 5. Nonpharmacologic interventions Pulmonary rehabilitation: consider offering pulmonary rehabilitation in patients with lymphangioleiomyomatosis limited by dyspnea. E 6. Therapeutic procedures Management of pneumothorax: As per ATS 2017 guidelines, consider offering ipsilateral pleurodesis after the initial pneumothorax episode rather than waiting for a recurrent pneumothorax before intervening with a pleural symphysis procedure in patients with lymphangioleiomyomatosis. C https://web.pathway.md/diseases/rec3unhjBL4F9EtAG 4/7 6/29/23, 11:36 PM Pulmonary lymphangioleiomyomatosis Pathway As per ERS 2010 guidelines, manage pneumothorax in lymphangioleiomyomatosis ideally jointly by a chest physician and thoracic surgeon. B Show 2 more Management of chylothorax: Decide on the decision to intervene and the choice of technique for symptomatic chylous pleural effusions on an individual basis based on clinical evaluation, including the amount of chyle collected, recurrence of chylothorax, respiratory condition of the patient, and consideration of future lung transplantation. E Consider offering a fat-free diet with supplementation of mid-chain triglycerides in patients with chylothorax. E 7. Surgical interventions Lung transplantation: As per ATS 2017 guidelines, avoid viewing previous unilateral or bilateral pleural procedures (pleurodesis or pleurectomy) as a contraindication to lung transplantation in patients with lymphangioleiomyomatosis. D As per ITS 2013 guidelines, recognize that patients with tuberous sclerosis complex with lymphangioleiomyomatosis are candidates for lung transplantation but tuberous sclerosis complex comorbidities may impact transplant suitability. E As per ERS 2010 guidelines, offer lung transplantation in patients with NYHA functional class III or IV with hypoxemia at rest, severe impairment in lung function, and exercise capacity (VO2 max < 50% of predicted). B Show 7 more 8. Specific circumstances Pregnant patients: counsel all patients, including patients with few or no symptoms, that there is a greater risk of pneumothorax and chylous effusion during pregnancy. E Show 5 more Patients with renal angiomyolipoma: do not treat patients with asymptomatic renal angiomyolipoma < 4 cm, rather obtain annual ultrasound assessments unless symptoms occur. Obtain CT or MRI if ultrasound measurements are unreliable due to technical factors. D Show 5 more 9. Patient education General counseling: As per ITS 2013 guidelines, counsel adolescent and adult female patients on smoking risks and estrogen use. E As per ERS 2010 guidelines: https://web.pathway.md/diseases/rec3unhjBL4F9EtAG 5/7 6/29/23, 11:36 PM Pulmonary lymphangioleiomyomatosis Pathway Inform patients with both sporadic and tuberous sclerosis complex- lymphangioleiomyomatosis, including patients with no or minimal symptoms, of the risk of pneumothorax and advise them to seek urgent medical attention in the event of symptoms of pneumothorax. B Advise patients to seek urgent medical attention in the presence of symptoms of bleeding angiomyolipoma. B Counseling on air travel: Discourage patients from air travel in the following situations: new, unevaluated respiratory symptoms B known untreated pneumothorax B pneumothorax treated within the previous month. B Show 3 more 10. Preventative measures Routine immunizations: offer influenza and pneumococcal vaccination in patients with lymphangioleiomyomatosis. E 11. Follow-up and surveillance Assessment of disease progression: consider repeating lung function tests at 3-6 monthly intervals during the first year following diagnosis, and at 3-12 monthly intervals thereafter depending on the severity and progression of the disease. C Show 5 more Post-transplant management: Administer the same post-transplant regimen of immunosuppression in patients with lymphangioleiomyomatosis as for other indications. B Do not perform a routine biopsy for the evaluation of recurrent lymphangioleiomyomatosis post-transplantation. D Clinical findings Patient demographics Symptoms Female sex Abdominal pain Back pain Past medical history Bloating Chest pain Osteoporosis Cough Pulmonary hypertension Hemoptysis Tuberous sclerosis complex Pelvic pain Respiratory exam Shortness of breath Sputum production Wheezing Vital signs https://web.pathway.md/diseases/rec3unhjBL4F9EtAG 6/7 6/29/23, 11:36 PM Pulmonary lymphangioleiomyomatosis Pathway Lab findings Hypoxemia O2 saturation serum VEGF-D Abdominal exam Genetic testing Abdominal distension Tsc1 gene mutation Ascites Tsc2 gene mutation Imaging findings Pleural effusion Pneumothorax Pulmonary cysts Diagnostic procedures Chylothorax pleural fluid triglycerides References 1. Nishant Gupta, Geraldine A Finlay, Robert M Kotloff et al. Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017 Nov 15;196 10 1337 1348. Open 2. S R Johnson, J F Cordier, R Lazor et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010 Jan;35 1 14 26. Open 3. Francis X McCormack, Nishant Gupta, Geraldine R Finlay et al. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med. 2016 Sep 15;194 6 748 61. Open 4. Darcy A Krueger, Hope Northrup, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct;49 4 255 65. Open https://web.pathway.md/diseases/rec3unhjBL4F9EtAG 7/7