The Case

A 31-year-old woman with no past medical history presented to the Emergency Department (ED) with worsening shortness of breath. On examination and plain radiography, she was unexpectedly found to have a moderate-sized left pneumothorax. A thoracostomy tube was placed resulting in immediate relief of symptoms. The patient had a computed tomography (CT) scan done as a part of the work-up and she was told that she had some blebs and mild emphysema. Once the lung was fully expanded, the chest tube was removed and the patient was sent home with no specific follow-up instructions, except to see her primary care physician. 

Three days later, the patient returned to the same ED with similar symptoms and again was found to have a left pneumothorax that required chest tube placement. At this time, another chest CT was obtained, and a pulmonology consultation was requested. The consulting physician explained to the patient that she had some small cysts and blebs in her chest. After this second episode of spontaneous pneumothorax, she was discharged to her home after the chest tube was removed.

Two weeks later, the patient was found on the floor of her kitchen by her husband with severe respiratory distress and a very thready pulse. He called 911. After hearing her recent history, paramedics immediately placed a needle in her left chest which gave prompt relief of symptoms and restored hemodynamic stability, strongly suggesting she had had another episode of left-sided pneumothorax with tamponade physiology (also known as a tension pneumothorax). She was taken to a different ED this time, where she had another chest CT. The ED physician was concerned by the CT scan and requested another pulmonary consultation. This time, the on-call pulmonary physician diagnosed cystic lung disease based on the CT findings, and decided to transfer the patient to an advanced lung center for further immediate work-up and treatment.

On arrival at the referral center, the patient had a left-sided chest tube in place with no air leak and a fully expanded lung. The patient’s CT scan showed classic features of lymphangioleiomyomatosis (LAM), a rare cystic lung disease that is most often seen in young women.

After careful evaluation, the patient underwent video-assisted thoracoscopic surgery (VATS) pleurodesis on the left side. At the same time, a biopsy was performed to confirm the diagnosis. After surgery, the patient required about 2 liters/minute of oxygen by nasal cannula to prevent dyspnea and hypoxia with exertion. She was started on sirolimus to prevent progression of her bilateral extensive cystic disease, and she is now doing well, with no recurrences of pneumothorax, and being followed regularly through a comprehensive Advanced Lung Disease and Lung Transplant program.

The Commentary

By Narath Carlile, MD, MPH, Soheil El-Chemaly, MD, MPH, and Gordon D. Schiff, MD

Lymphangioleiomyomatosis or LAM is a rare cystic lung disease that occurs primarily in women of reproductive age. It can occur sporadically or in the context of the Tuberous Sclerosis Complex (TSC). Two forms of LAM have been described. The sporadic form, which occurs in 3.3-7.7/million women, and the inherited form of LAM, which may occur in up to 80% of women with TSC.¹ From diagnosis, the medium lifespan of LAM patients is over 20 years.

Patient presentations vary from asymptomatic disease detected incidentally on chest CT to severe pulmonary disease including pneumothorax or even chylothorax. One third of patients present with pneumothorax, and the incidence of pneumothorax in patients with LAM is 1000 times higher than in the general female population.²

Cystic lung diseases like LAM have specific CT findings - thin-walled cysts typically scattered through both lungs, with no predilection for upper vs. lower lobes (i.e., without specific geographic distribution). The diagnosis of LAM can be made based on these characteristic CT findings along with blood testing for VEGF-D³ (vascular endothelial growth factor D), which is specific for LAM if it is higher than 800pg/ml. About 70% of patients with LAM have a high VEGF-D level. It is also appropriate to check alpha-1 antitrypsin levels and rule out other connective tissue diseases such as Sjogren’s disease that can manifest with cystic lung disease. Besides LAM, other rare causes of cystic lung disease include Birt-Hogg-Dube, a genetic condition affecting the folliculin gene and manifesting with benign skin hamartomas, pulmonary cysts and spontaneous pneumothorax, and an increased risk of  renal cell carcinoma.

Because LAM and other treatable underlying causes often cannot be detected on plain chest x-rays, it has been recommended⁴ that clinicians consider ordering a CT scan of the chest for patients presenting with an unexplained spontaneous pneumothorax. This practice is likely to be cost effective⁵ to prevent negative downstream consequences for patients. In this case, at the initial ED presentation, the CT scan would likely have demonstrated diffuse cystic lung disease, which in retrospect appears to have been misdiagnosed by the ED physician, radiologist, and first pulmonary consultant as “mild emphysema” with “small cysts and blebs.” Had the lung lesions been more accurately framed as “cystic lung disease,” the clinicians’ premature closure on a diagnosis of emphysema might have been avoided.⁶ In the second ED presentation three days later, providers at the same ED “anchored” on the incorrect diagnosis and failed to consider alternative diagnoses, such as LAM. This cognitive failure inappropriately limited further investigation.

Given the low pre-test probability of emphysema in a young non-smoking woman, particularly if testing for alpha-1 antitrypsin deficiency was normal, a search for alternate diagnoses should have been undertaken in this case. Educating physicians interpreting CT scans about the distinction between cystic lung diseases and other parenchymal lucencies that may mimic cysts (such as blebs or bullae, which are more characteristic of emphysema) could reduce the likelihood of a diagnosis such as LAM being missed or delayed.

Since LAM occurs in young women and asthma is a common cause of dyspnea in this population, it is not unusual for women to be misdiagnosed for many years as having asthma prior to finally being diagnosed with LAM.⁵ A pneumothorax can occur in up to 70% of women with LAM.⁷ On average, patients experience 2.2 pneumothoraxes before the diagnosis of LAM is made.⁸ In patients who experience a first pneumothorax, the majority will develop another pneumothorax.⁷ Because of the high rate of recurrence, a pneumothorax in a patient with LAM needs to be managed with pleurodesis, as finally occurred in this case. In one study, the rate of recurrence decreased from more than 60% to 27% after pleurodesis.⁷

Given the risk of recurrence for this patient, the management of the second spontaneous pneumothorax was not sufficient. An important dictum in diagnostic safety is to reconsider the initial diagnosis (and in this case the underlying etiology) when a patient unexpectedly returns unimproved or with a recurrence. For patients with recurrent pneumothorax, aggressive management of the pneumothorax with additional imaging and referral to a lung specialty center is necessary to identify the cause and to consider additional treatments such as pleurodesis.

The disease is caused by atypical smooth muscle-like cells called LAM cells that carry mutations in the TSC1 or TSC2 genes that lead to activation of the mammalian/mechanistic target of rapamycin (mTOR). The mTOR pathway is active in a significant percentage of human cancers. LAM is included in the group of proliferative lesions known as perivascular epithelioid cell tumors. These tumors are characterized by the co-expression of myogenic and melanogenesis-related markers.⁹

Untreated LAM can progress to respiratory failure requiring lung transplant. However, sirolimus (originally named rapamycin) has been shown to be effective in halting the lung function decline in most patients¹⁰ and has been approved by the FDA for treatment of this disease. Therefore, timely referral to a lung center where treatment can be initiated is important. Unfortunately, the initial pulmonary consultant in this case apparently did not consider the potential of this diagnosis and thus definitive treatment for the patient’s serious condition was delayed.

Finally, clinicians should understand the principles of diagnostic uncertainty as they apply to patients with unusual but serious presentations. How can we improve the diagnosis of rarer conditions, and also avoid needlessly working up every patient for diagnoses that are uncommon or unlikely? This remains a fundamental challenge in diagnostic quality and safety, but following certain principles and strategies can help minimize and mitigate errors and delays.¹¹ First, clinicians need to maintain a non-dismissive open-mind, and seek additional information and consultation when a patient’s course or response to therapy does not proceed as expected.  Creating more systematic and proactive follow-up safety nets to ensure patients are improving rather than worsening can help operationalize such an open-minded culture and decrease the likelihood that unresolved or unexplained problems are overlooked. Although increasing clinicians’ knowledge about rarer diseases such as LAM via traditional education methods (CME courses, journal reading, etc.) can improve awareness of the disease and potentially increase clinical recognition, relying on education and human memory are considered among the weaker interventions for ensuring more reliable performance.¹² Providing real-time, automated reminders to consider the diagnosis, e.g. CT reports that are automatically populated with a differential diagnosis that features LAM for CT’s in young women with cystic lung disease, is another strategy that could be implemented to improve especially the timeliness of diagnosing LAM.

Take-Home Points

• Given the incidence of underlying conditions requiring special treatment, spontaneous pneumothorax without a clear etiology should be evaluated with a CT scan.
• Recurrent spontaneous pneumothorax without a clear underlying etiology should be urgently evaluated for rare, but serious, underlying diseases such as LAM.
• Cystic lung diseases are identifiable through characteristic findings on CT scans that should be recognized by physicians interpreting CT scans, and these findings warrant referral to a lung specialist.
• LAM is a rare cystic lung disease that occurs more commonly in young women. These patients have a high risk of recurrence of spontaneous pneumothorax, and referral to a lung center with specialists experienced in diagnosis and treatment of these patients, such as with pleurodesis is indicated.
• Educating providers who see patients with spontaneous pneumothorax, as well as patients who have these conditions, are recommended measures to increase awareness of LAM and trigger specialized evaluation and treatment of this condition. Beyond educational efforts, achieving more timely, reliable diagnoses for rare conditions will likely require innovative forms of decision support and reminders that alert clinicians to consider such rare diagnoses.

Narath Carlile, MD, MPH
Brigham and Women’s Hospital
Harvard Medical School

Soheil El-Chemaly, MD, MPH
Brigham and Women’s Hospital
Harvard Medical School

Gordon D. Schiff, MD
Brigham and Women’s Hospital
Harvard Medical School

Acknowledgements:

The long-standing process for submitting PSNet WebM&M case submissions is anonymous. Users may contribute by submitting a case at the following link: https://psnet.ahrq.gov/webmm/submit-case

Periodically, the Primary-Care Research in Diagnosis Errors (PRIDE) Learning Network, a collaborative project convened by the Brigham and Women’s Hospital Center for Patient Safety Research and Practice, and the State of Massachusetts Betsy Lehman Center for Patient Safety, contributes cases and commentaries from their monthly discussions of diagnosis error cases to PSNet. PRIDE is funded by a grant from the Gordon and Betty Moore Foundation. This case was produced in cooperation with the PRIDE Learning Network. We acknowledge the assistance of the PRIDE project director Maria Mirica, PhD, in preparing this case discussion.

References

1. Taveira-DaSilva AM, Moss J.  Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis. Expert Opin Orphan Drugs. 2016;4(4):369-378. doi:10.1517/21678707.2016.1148597

2. Gonano C, Pasquier J, Daccord C, et al. Air travel and incidence of pneumothorax in lymphangioleiomyomatosis. Orphanet J Rare Dis. 2018;13(1):222. Published 2018 Dec 13. doi:10.1186/s13023-018-0964-6

3. Daccord C, Aubert V, Félix N, Lazor R. Serum VEGF-D level as a diagnostic biomarker of lymphangioleiomyomatosis in clinical practice. Poster Walks. Chest Joint Congress. DOI:https://doi.org/10.1016/j.chest.2017.04.142.

4. Baumann MH, Strange C, Heffner JE, Light R, Kirby TJ, Klein J, Luketich JD, Panacek EA, Sahn SA; AACP Pneumothorax Consensus Group. Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest. 2001 Feb;119(2):590-602. doi: 10.1378/chest.119.2.590. PMID: 11171742.

5. Gupta N, et al. Chest Computed Tomographic Image Screening for Cystic Lung Diseases in Patients with Spontaneous Pneumothorax Is Cost Effective. Annals of the American Thoracic Society. 2017;14(1):17-25. doi: 10.1513/AnnalsATS.201606-459OC

6. Richardson WS. Five uneasy pieces about pre-test probability. J Gen Intern Med. 2002;17(11):882-883. doi:10.1046/j.1525-1497.2002.20916.x

7. Johnson SR. Lymphangioleiomyomatosis. In: Cottin V, Cordier JF, Richeldi L, editors. Orphan Lung Diseases. 2015. Springer, London. https://doi-org.ezp-prod1.hul.harvard.edu/10.1007/978-1-4471-2401-6_17

8. Chidharla A, et al. A woman with dyspnea and recurrent pneumothorax: when dyspnea is not asthma. Journal of Community Hospital Internal Medicine Perspectives. 2020:10(4):334-337. doi: 10.1080/20009666.2020.1771125

9. Krymskaya VP, McCormack FX. Lymphangioleiomyomatosis: A Monogenic Model of Malignancy. Annu Rev Med. 2017;68:69-83. doi:10.1146/annurev-med-050715-104245.

10. McCormack FX, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England Journal of Medicine. 2011;364(17):1595-1606. doi: 10.1056/NEJMoa1100391

11. Schiff GD, Martin SA, Eidelman DH, Volk LA, Ruan E, Cassel C, Galanter W, Johnson M, Jutel A, Kroenke K, Lambert BL, Lexchin J, Myers S, Miller A, Mushlin S, Sanders L, Sheikh A. Ten Principles for More Conservative, Care-Full Diagnosis. Ann Intern Med. 2018 Nov 6;169(9):643-645. doi: 10.7326/M18-1468. Epub 2018 Oct 2. PMID: 30285046.

12. Woods DM, Holl JL, Angst D, et al. Improving Clinical Communication and Patient Safety: Clinician-Recommended Solutions. In: Henriksen K, Battles JB, Keyes MA, et al., editors. Advances in Patient Safety: New Directions and Alternative Approaches (Vol. 3: Performance and Tools). Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Aug. Table 3, Hierarchy of interventions. Available from: https://www.ncbi.nlm.nih.gov/books/NBK43654/table/advances-woods_78.t3/