Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Lymphangioleiomyomatosis: diagnosis and emerging therapies

  Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease that predominantly affects women during their reproductive years. It can occur with tuberous sclerosis complex (TSC), while most cases are sporadic. Breathlessness, recurrent pneumothorax and chylous pleural effusions are important clues.

  Diagnosis combines high-resolution computed tomography (HRCT), pulmonary function testing and exclusion of other causes of diffuse cystic lung disease. Genetic findings, clinical context and serum VEGF-D can reduce the need for biopsy. Symptoms often precede clear imaging abnormalities by years.

  No drug currently cures LAM. The mTOR inhibitor sirolimus slows lung-function decline in selected patients, while supportive care addresses airflow obstruction, oxygen needs, pneumothorax and pleural fluid. Everolimus can be considered when sirolimus is unsuitable, and transplantation remains an option for end-stage disease. For APSR 2022 delegates, separating established treatment from unproven approaches is essential.

  In Australia, expertise is concentrated in Melbourne, Sydney, Brisbane and Adelaide, making telehealth and travel support central for rural and remote patients. The Pharmaceutical Benefits Scheme covers sirolimus for eligible LAM under specialist prescribing, while Medicare rebates and public specialist services affect access to diagnostic work-up. Culturally safe pathways and peer support remain especially important for Aboriginal and Torres Strait Islander patients and families.

  Sporadic and TSC-associated LAM

  Feature	Sporadic LAM	TSC-associated LAM
  Underlying association	No clinical evidence of TSC; most LAM cases	Inherited TSC, usually involving a germline TSC1 or TSC2 variant
  Common clues	Diffuse lung cysts, chylothorax and renal angiomyolipoma	Typical cysts with seizures, skin lesions, renal abnormalities or brain findings
  Family impact	No usual familial TSC pattern	Screening and reproductive counselling may affect relatives
  Care emphasis	Exclude other cystic lung diseases and manage complications	Coordinate respiratory, renal, neurological, dermatology and genetics review

  The distinction is not simply classificatory. TSC-associated LAM requires coordinated assessment for brain, renal, dermatological and genetic manifestations, including screening relatives where appropriate. Sporadic LAM still requires careful exclusion of inherited syndromes and alternative cystic lung disorders.

  A TSC diagnosis makes characteristic lung cysts highly persuasive. Without TSC, the radiological pattern and clinical exclusions carry more weight. A multidisciplinary team can prevent both delayed diagnosis and unnecessary tissue sampling.

  Making the diagnosis

  A structured assessment should establish symptom onset, smoking history, occupational exposures, pregnancy history, episodes of pneumothorax and features of TSC. Spirometry may show obstruction, while diffusion capacity and exercise testing help quantify impairment. HRCT typically shows thin-walled, round cysts distributed diffusely through both lungs.

  Important mimics include pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, emphysema and infection-related cysts. Smoking history, cyst distribution, skin or renal findings, family history and targeted genetic testing help separate them. Serum VEGF-D above 800 pg/mL supports LAM in a compatible setting but does not exclude it when low.

  Biopsy is unnecessary when the overall evidence is conclusive, although it may be justified if imaging and genetics leave substantial uncertainty. Before treatment, clinicians should record baseline forced vital capacity, FEV1, diffusion capacity, oxygen needs and six-minute walk distance. These measurements establish severity and provide a reference for meaningful follow-up.

  Therapeutic options and emerging directions

  Sirolimus is established care when disease is progressive, symptomatic or associated with complications such as troublesome chylothorax or angiomyolipoma. It stabilises rather than restores lost lung function. Monitoring must cover blood counts, lipids, glucose, infection risk, drug interactions and adverse effects such as mouth ulcers.

  Bronchodilators, oxygen, pulmonary rehabilitation, vaccination, smoking cessation and management of pneumothorax or chylous effusions should accompany disease-directed treatment. Pregnancy requires specialist counselling because outcomes can influence both maternal health and LAM progression.

  Several plausible candidates have not become standard care. The letrozole and simvastatin trials did not show convincing overall benefit, and doxycycline has not proved disease-modifying efficacy. Research now emphasises selective mTOR dosing, combination strategies, biomarkers and new anti-fibrotic mechanisms. Until evidence changes, clinical trials or established mTOR therapy remain preferable to unproven supplements.

  Australian specialist care and practical preparation

  Australian services should establish a regional referral pathway before suspicion becomes advanced. HRCT, complete pulmonary function tests and TSC assessment may require a metropolitan respiratory centre, while follow-up can occur through telehealth and local imaging. Sirolimus prescribing criteria should be checked at each PBS renewal, and access to genetics services may involve additional waiting time.

  Australasian guidance supports early specialist referral and shared decisions about mTOR inhibition. The LAM Foundation of Australia can assist with peer support, travel planning and family education. For Aboriginal and Torres Strait Islander patients, cultural safety, interpreter access and flexible appointment planning can be decisive. Genetic counselling should address implications for relatives and reproductive decisions.

  Clinical checklist

  • Record pneumothorax, chylothorax, pregnancy and TSC history at referral.
  • Request HRCT, spirometry, DLCO and six-minute walk testing where needed.
  • Use telehealth or a regional pathway when local expertise is limited.
  • Coordinate respiratory, genetics, renal and neurology review for suspected TSC.

  Patient and family checklist

  • Bring previous images, reports, medicines and family history to appointments.
  • Request a written plan for monitoring, treatment, vaccination and emergencies.
  • Use The LAM Foundation of Australia for peer and navigation support.
  • Discuss family testing with a genetics service before extending testing to relatives.

  The next phase of LAM care

  The research agenda includes earlier diagnosis, better outcome measures and equitable access to clinical trials. Australian and New Zealand registries can preserve longitudinal data, while international collaboration exposes differences in genetics, disease progression and treatment response.

  A reliable care pathway should connect respiratory assessment with treatment review, research opportunities and advanced care planning. Lung transplantation remains effective for selected end-stage disease, with referral considered before severe disability and respiratory failure become irreversible.

  For a patient with unexplained diffuse lung cysts, recurrent pneumothorax or chylothorax, the next concrete step is referral to a respiratory physician at a tertiary Australian centre experienced in diffuse cystic lung disease.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)