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Abstract
A female of reproductive age presents to the emergency department with progressive dyspnoea due to pneumothorax. She has a history of lymphangioleiomyomatosis (LAM) diagnosed by lung biopsy 15 years ago following incidental finding of pneumothorax. Despite various procedural and medicinal treatments, she continued to have recurrent pneumothorax, with three hospital admissions over the preceding 3 months. LAM is a rare cystic lung disease affecting the lymphatic system, which most commonly affects women of childbearing age. It can be diagnosed via imaging or tissue biopsy (gold standard). Treatment can be difficult, and it often requires highly specialised care by pulmonologists and often confers significant limitations to patients’ independence and quality of life. Family physicians are often part of multidisciplinary team to provide care to patients with rare chronic conditions.
- Respiratory system
- General practice / family medicine
- Pneumothorax
- Respiratory medicine
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Background
Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease, which can occur sporadically or in conjunction with tuberous sclerosis complex (TSC).1 The estimated prevalence of LAM is 3–7 cases per million women, with an estimated 15% of cases associated with tuberous sclerosis complex.2 Tuberous sclerosis complex can be diagnosed with the identification of either a TSC1 or TSC2 pathogenic mutation or from clinical diagnostic criteria.3 LAM primarily affects the lung parenchyma but can affect other organs, including the kidneys, brain and liver.4 The most common presenting symptom is dyspnoea, which can easily be mistaken for more common diagnoses like asthma or Chronic Obstructive Pulmonary Disease (COPD) in the emergency department or primary care setting.5 Interdisciplinary management of rare diseases, such as LAM, is required to assist primary care physicians in the diagnosis and treatment of such illnesses.
Case presentation
A female in her 30s presented to the emergency department experiencing progressive dyspnoea, non-productive cough and left-sided chest pain. This was her third presentation during a 3-month period, with multiple prior pneumothoraxes resolved following chest tube placement over the past 15 years. She has a medical history of sporadic-LAM (S-LAM) and allergic rhinitis, and no significant family history of cardiopulmonary disease. Her social history includes one alcoholic unit per week and no history of tobacco, vaping or other inhaled substances. Her vital signs were significant for tachycardia with a pulse of 112 beats per minute, tachypnoea of 22 breaths per minute and an oxygen saturation (SpO2) of 89% in room air. Her physical exam was notable for diminished breath sounds on the left side without wheezes, rales or crackles. Chest radiograph demonstrated a new left-sided pneumothorax and stable loculated pneumothorax on the right side with underlying cystic lung disease. An interventional pulmonologist was consulted for acute management of her spontaneous pneumothorax. CT chest after placement of left-sided pigtail catheter showed small residual left-sided pneumothorax in the medial posterior pleural space with stable loculated right pneumothorax (figure 1). Cardiac enzymes were negative, and ECG demonstrated normal sinus rhythm with right atrial enlargement.
Coronal view CT chest.
Investigations
The patient was first diagnosed with sporadic LAM 15 years ago. A CT abdomen and pelvis without contrast was suggested to evaluate abdominal pain and it showed a haemorrhagic exophytic left renal mass and incidental finding of right pneumothorax. Subsequent CT chest showed diffuse scattered cystic changes with well-defined walls. No other lung abnormalities were noted. Given the persistence of the patient’s pneumothorax and concern for LAM, a lung biopsy was performed during a video-assisted thoracic surgery (VATS) procedure. Immunostaining was focally positive for HMB-45 and Desmin and negative for Mart-1, which is consistent with the diagnosis of LAM. An ophthalmologist evaluated the patient during initial hospitalisation and did not find stigmata of TSC. Brain MRI was also obtained to evaluate intracranial tumours and was found to be normal other than a non-specific right frontal subcortical white matter hyperintense focus.
Pulmonary function tests demonstrated a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio of 71%, FVC of 2.91 L (69% predicted), FEV1 of 2.05 L (61% predicted and decreased from 2.5 L previously), total lung capacity of 4.4 L (83% predicted) and a diffusion capacity of carbon monoxide of 18.9 mL/mm Hg/min (71% predicted).
An echocardiogram revealed that the left ventricle was found to be decreased in size (consistent with decreased filling), with normal wall thickness, wall motion and left ventricular diastolic filling. The left ventricular ejection fraction was 70%. The right ventricle was normal in size, with normal systolic function and trace tricuspid regurgitation. Right ventricular systolic pressure was not calculated.
The patient has not undergone genetic testing for TSC. However, she does not have additional clinical stigmata of TSC. The left renal mass present on the CT on initial presentation 15 years ago was consistent with angiomyolipoma (a finding in LAM) versus clear cell–cell carcinoma. The patient underwent embolisation of this lesion. This lesion was never biopsied but remained stable in size on subsequent imaging, confirming the presence of malignancy less likely. The diagnostic criterion for LAM requires the presence of ≥2 angiomyolipoma, which this patient does not meet. Additionally, a combination of two major clinical features (LAM and angiomyolipomas) without other features does not meet the criteria for definite diagnosis of TSC. Therefore, the patient does not meet the clinical diagnostic criteria for definite diagnosis of TSC.3
Differential diagnosis
Although the patient’s history of LAM was the most likely cause for her pneumothorax, it is imperative to consider other causes of her pneumothorax to prevent future events. Typically, the differential for pneumothorax is divided into three categories.6 The first is trauma, often from blunt or penetrating chest trauma such as a motor vehicle accident. The second is iatrogenic, caused by a healthcare procedure such as a central line insertion. The third is spontaneous, in which no specific cause is identified. A subcategory of spontaneous pneumothorax is secondary in which the patient has an underlying lung condition. Cystic lung diseases, such as LAM, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dube syndrome, amyloidosis and lymphocytic interstitial pneumonia, can increase risk of spontaneous pneumothorax.7
The absence of recent trauma or healthcare procedures, no smoking or vaping history and imaging studies negative for other lung pathologies make pathology other than LAM to be the unlikely cause of this patient’s recurrent pneumothorax. This is supported by the definitive diagnoses of LAM by positive biopsy and CT findings of multiple thin-walled cysts, consistent with LAM.
Treatment
The patient was managed in the acute setting with placement of an anterolateral left-sided chest tube. The chest tube was slowly transitioned from suction to water seal and then removed following resolution of her pneumothorax. No significant changes were made to her medication regimen at the time of discharge.
Outcome and follow-up
The patient underwent a doxycycline pleurodesis and later a betadine pleurodesis with resolution of her pneumothorax. She was able to return to her daily life, though with continued reduced exercise tolerance. 2 months after hospitalisation, repeat pulmonary function tests demonstrated reduced lung function. She was unable to join clinical trials for LAM due to her recent pneumothoraxes. Sirolimus, an established pharmacotherapy for LAM, was suggested by the pulmonology team to stabilise her pulmonary function though it was initially deferred per patient’s preference due to the concerns for side effects. After experiencing a recurrent spontaneous pneumothorax (the fifth one of the year), sirolimus, an established therapy for LAM which affects the mTOR pathway, was initiated.8 Follow-up pulmonary function testing and CT scan demonstrated that her pulmonary disease was stable following initiation of the daily sirolimus. She has not had a recurrent pneumothorax in over 1 year.
Discussion
LAM is a rare cystic lung disease affecting the lungs and lymphatic system. It can occur either in combination with tuberous sclerosis or alone.1 It mainly affects women of childbearing age and is characterised by pulmonary cystic changes, recurrent spontaneous pneumothorax and chylous pleural effusions, and can proceed to progressive respiratory failure.9 It can also include abdominal manifestations such as lymphadenopathy, lymphatic masses and angiomyolipomas, which may cause abdominal pain. Throughout the disease process, LAM cells (smooth muscle) accumulate in the lungs, resulting in cystic changes and progressive loss of healthy lung tissue. LAM cells also accumulate in the lymphatics, resulting in the thickening of lymphatic vessel lumen and cystic dilation.10 Diagnosis is often delayed but can be achieved by obtaining pulmonary function tests and CT scan imaging of the chest. Pulmonary function tests typically demonstrate airflow obstruction (often with a bronchodilator response), normal total lung capacity and decreased diffusion capacity.11 CT scans will demonstrate many thin-walled cysts throughout the lungs.10 If CT findings and other typical manifestations of LAM are present, then tissue biopsy is often not needed for diagnosis. The diagnostic gold standard is a lung/lymphatics biopsy demonstrating LAM cells or nodular infiltration by abnormal smooth muscle cells and specific immunohistochemical staining for smooth muscle marker and melanoma-related antigen HMB45.12 Treatment includes managing acute symptoms of pneumothorax, typically with chest tube placement. It can also include pleurodesis to help reduce spontaneous pneumothorax frequency. Sirolimus, an immune modulator acting on the mTOR pathway which is responsible for part of the pathophysiology of LAM, has been shown to be an effective therapy for stabilising lung function.8 Ultimately, some patients require lung transplant.
Patient’s perspective
Living with Llymphangioleiomyomatosis (LAM) for the past 14 years has been a profound journey, one that has tested my resilience as an individual. Throughout this journey, my spiritual connection with God has deepened, providing me with strength and comfort as I navigate the challenges of this chronic illness.
Despite the lifestyle changes and uncertainties, I am immensely grateful and feel blessed to be alive today. I am incredibly thankful for the exceptional care and support provided by the medical professionals. Their collaborative approach and dedication to my well-being have played a pivotal role in managing my condition and achieving the best possible outcomes.
Acknowledgement is also due to the LAM Foundation, whose tireless efforts in research, fundraising, and information dissemination have significantly contributed to advancing understanding and treatment options for LAM. Their commitment to organizing conferences and forums has been instrumental in fostering a supportive community and providing access to valuable resources.
Lastly, I want to express my heartfelt gratitude to my family and friends for their unwavering love and support throughout this journey. Their encouragement and presence have been invaluable in helping me face the challenges of LAM with courage and optimism.
Learning points
It is important for primary care physicians to be aware of rare diseases as to be able toso they can direct patients to appropriate specialists and ongoing clinical trials to improve outcomes.
Lymphangioleiomyomatosis is a rare cystic lung disease that should be considered in young women of childbearing agoe who have spontaneous pneumothorax or progressive pulmonary decline of unclear origin.
Sirolimus can be considered for the treatment of LAM in patients with recurrent respiratory symptoms, including pneumothorax.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors All the authors participated in the clinical care of the patient, contributed to the writing of the manuscript and edited clinical images. They also gave final approval of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.