The first symptoms of pulmonary LAM, such as shortness of breath during exercise, coughing and chest pain, usually occur between the ages of 25 and 35 years [1] [2]. Because LAM is rare and its onset insidiously, the symptoms may be misdiagnosed as asthma, pulmonary emphysema, chronic bronchitis, chronic obstructive pulmonary disease or sarcoidosis and the correct diagnosis may be delayed for several years [1] [3]. As the disease progresses, progressive dyspnea, pneumothorax, and chylothorax occur [4] [5]. TSC-LAM has symptoms of TSC.

• Fatigue

  Adverse events were mostly grade 1−2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. [doi.org]

  CASE PRESENTATION A 32-year-old woman presented with a four-month history of progressive fatigue and exertional dyspnea. She had no history of a cutaneous disorder, seizures, or renal or cranial tumours. She was a lifelong nonsmoker. [ncbi.nlm.nih.gov]

  The consensus clinical definition of LAM includes multiple symptoms: Fatigue Cough Coughing up blood (rarely massive) Chest pain Chylous complications arising from lymphatic obstruction, including Chylothorax Chylous ascites Chylopericaridium Chyloptysis [en.wikipedia.org]

  George's Respiratory Questionnaire, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), the Functional Performance Inventory, the General Well-Being Questionnaire, and the EuroQOL visual-analogue scales assessing fatigue, dyspnea, and [nejm.org]

• Lymphedema

  Kazakov, Giant angiofibromas in tuberous sclerosis complex: A possible role for localized lymphedema in their pathogenesis, Journal of the American Academy of Dermatology, 67, 6, (1319), (2012). Daniel F. Dilling, Emily R. Gilbert, Maria M. [doi.org]

  […] of LAM are dyspnea, cough, chest pain, chyloptysis, chylothorax, hemoptysis [8], spontaneous pneumothorax [9], pleural effusion [10], chylous ascites, lymphangiomyoma masses, chylous vaginal discharge, chyluria, uterine fibroids, and lower-extremity lymphedema [lungindia.com]

• Chest Discomfort

  A young nonsmoking woman presented with severe dyspnea, exercise desaturation, and chest discomfort. Pathologic and histochemical findings revealed pulmonary lymphangioleiomyomatosis (LAM) as the primary abnormality. [ncbi.nlm.nih.gov]

• Dyspnea

  We report a case of a 29-year-old woman who presented with abrupt right chest pain and progressive dyspnea. [ncbi.nlm.nih.gov]

  Thus, sirolimus, as an mTOR inhibitor, could stabilize the pulmonary function and improve dyspnea. [spandidos-publications.com]

  Right: 7 years later, presenting with exertional dyspnea upon referral. Figure 1 Axial CT scan of the chest. Left: prior to fertility treatment. Right: 7 years later, presenting with exertional dyspnea upon referral. [academic.oup.com]

• Pleural Effusion

  Clinical examination revealed bilateral basal crackles with signs suggestive of left side pleural effusion, chest x-ray showed left sided pleural effusion, and diffuse bilateral basal pulmonary shadowing. [ncbi.nlm.nih.gov]

  Pneumothorax was seen in only two patients; pleural effusion was seen in two patients. CT examination of patients with LAM reveals neither a uniform nor a pathognomonic appearance. [link.springer.com]

  Later on patient developed bilateral pleural effusions (Figure 2, right image). Diagnostic pleural tap was done which came out to be chylous. [panafrican-med-journal.com]

  Both ThinPrep cytological test (TCT) and cell block analysis for the pleural effusion were performed to detect if there were malignant cells. [jtd.amegroups.com]

• Cough

  A 28 years old female admitted to our hospital with complaint of dry cough, exertional dyspnoea and chest pain for last 2 years. [lungindia.com]

  A 55-year-old white woman with pulmonary lymphangioleiomyomatosis (LAM) presented to the emergency department with odynophagia and subplatysmal emphysema after a paroxysm of coughing. [ncbi.nlm.nih.gov]

• Hemoptysis

  We describe a patient presenting with hemoptysis post-LTx for PLAM. Computed tomography (CT) scan demonstrated no pulmonary abnormality, but identified a retroperitoneal mass confirmed as angiomyolipoma by CT-guided core biopsy. [ncbi.nlm.nih.gov]

  Symptoms are dyspnea, cough, chest pain, and hemoptysis; spontaneous pneumothorax is common. Diagnosis is suspected on the basis of symptoms and chest x-ray findings and is confirmed by high-resolution CT. [msdmanuals.com]

  Hemoptysis occurred less frequently [ 1, 4 ]. Our patient presented only with hemoptysis. On a chest radiograph, LAMP is characterized by an increased number of interstitial markings in the presence of normal lung volumes or hyperinflation. [omicsonline.org]

  The clinical features include dyspnea, hemoptysis, recurrent pneumothorax, chylothorax, and chylous ascites. [doi.org]

• Exertional Dyspnea

  Patients with pulmonary lymphangioleiomyomatosis most commonly present with exertional dyspnea and a cough. Pneumothorax is almost always found on the initial chest radiograph. [ncbi.nlm.nih.gov]

  Right: 7 years later, presenting with exertional dyspnea upon referral. Figure 1 Axial CT scan of the chest. Left: prior to fertility treatment. Right: 7 years later, presenting with exertional dyspnea upon referral. [academic.oup.com]

  Patients usually present with exertional dyspnea and recurrent episodes of pneumothorax are common 8. [radiopaedia.org]

• Odynophagia

  A 55-year-old white woman with pulmonary lymphangioleiomyomatosis (LAM) presented to the emergency department with odynophagia and subplatysmal emphysema after a paroxysm of coughing. [ncbi.nlm.nih.gov]

  […] lesions suggestive of pulmonary lymphangioleiomyomatosis (LAM) in patients who received a diagnosis [ncbi.nlm.nih.gov] Pulmonary Barotrauma A 55-year-old white woman with pulmonary lymphangioleiomyomatosis (LAM) presented to the emergency department with odynophagia [symptoma.com]

• Left Flank Pain

  CASE PRESENTATION: A 38-year-old woman presented with a dry cough and left flank pain. She had a right nephrectomy for renal angiomyolipoma 17 years ago. A magnetic resonance imaging scan demonstrated a round mass in the left kidney. [ncbi.nlm.nih.gov]

  Case presentation A 38-year-old woman presented with a dry cough and left flank pain. She had a right nephrectomy for renal angiomyolipoma 17 years ago. A magnetic resonance imaging scan demonstrated a round mass in the left kidney. [bmcpulmmed.biomedcentral.com]

• Chest Pain

  Due to an increase in frequency of her intermittent pleuritic chest pain, a CT thorax was organised by her GP which picked up a 4mm cyst in the right midzone of her lung. [imj.ie]

  We present the case of a 46-year-old female patient with chest pain, cough, sputum, and dyspnea on exertion for three weeks. Minimal pneumothorax was noted, and the patient was referred to our center for further investigation and treatment. [ncbi.nlm.nih.gov]

  Symptoms are dyspnea, cough, chest pain, and hemoptysis; spontaneous pneumothorax is common. Diagnosis is suspected on the basis of symptoms and chest x-ray findings and is confirmed by high-resolution CT. [msdmanuals.com]

• Darier's Sign

  [en.wikipedia.org] lymphangioleiomyomatosis ). [5] A pseudo- Darier sign may be present. [symptoma.com]

• Sweating

  She denied any cough, wheeze, night sweats and weight loss. Her past history include hypothyroidism and liver haemangioma. She has a family history of ischaemic heart disease and works in a launderette. Examination and CXR was normal. [imj.ie]

• Night Sweats

  She denied any cough, wheeze, night sweats and weight loss. Her past history include hypothyroidism and liver haemangioma. She has a family history of ischaemic heart disease and works in a launderette. Examination and CXR was normal. [imj.ie]

• Grunting

  Grunt TW, Mariani GL (2012) Targeting the PI3K/AKT/mTOR pathway in breast cancer. Curr Cancer Drug Targets 21:177–184 Google Scholar 64. [doi.org]

The physical examination is often nonspecific but may reveal evidence of pleural effusion, ascites, pericardial effusion or pneumothorax, if present. High-resolution computed tomography (HR-CT) is the most sensitive method for diagnosing LAM. The typical findings are diffuse round, thin-walled cysts of varying sizes evenly distributed in all lung fields [3]. Other imaging results depend on the affected structures. Pulmonary function testing may be normal or may show obstructive, restrictive, or mixed patterns [5]. An increase of serum vascular endothelial growth factor D (VEGF-D) greater than 800 mg/L is common [6] [7] [8]. A LAM diagnosis without lung biopsy can be made in patients with typical cystic changes on pulmonary HR-CT scanning and findings of tuberous sclerosis, angiomyolipoma, lymphangioleiomyoma, thoracic or abdominal chylous effusion or serum VEGF-D > 800 mg/L, otherwise, a lung biopsy may be necessary [9].

• Pneumoperitoneum

  Other less frequent symptoms are hemoptysis, chylous pleural effusions, chylous ascites, pericardial effusion, pneumoperitoneum, acute abdomen, and lymphedema. [scielo.br]

• Pleural Effusion

  Clinical examination revealed bilateral basal crackles with signs suggestive of left side pleural effusion, chest x-ray showed left sided pleural effusion, and diffuse bilateral basal pulmonary shadowing. [ncbi.nlm.nih.gov]

  Pneumothorax was seen in only two patients; pleural effusion was seen in two patients. CT examination of patients with LAM reveals neither a uniform nor a pathognomonic appearance. [link.springer.com]

  Later on patient developed bilateral pleural effusions (Figure 2, right image). Diagnostic pleural tap was done which came out to be chylous. [panafrican-med-journal.com]

  Both ThinPrep cytological test (TCT) and cell block analysis for the pleural effusion were performed to detect if there were malignant cells. [jtd.amegroups.com]

General care depends on the manifestation and may include treatment of pleural effusions, and for airway disease bronchodilators and supplemental oxygen [10]. Sirolimus, an mTOR inhibitor, stabilizes lung function, reduces symptoms, the size of angiomyolipomas, lymphangioleiomyomas, and chylous effusions, and improves life quality [11] [12] [13] [14] [15] [16]. If lung function markedly declines, in some patients lung transplantation may be required [17].

Survival estimates vary widely. Sporadic LAM is generally more severe than TSC-LAM.

To date, the cause of LAM is not fully understood. LAM occurs sporadically (S-LAM) or as a complication of tuberous sclerosis (TSC-LAM) [18]. TSC is an autosomal dominant genetic disorder associated with development of hamartomas and dysplastic lesions in several organs.

Overall, the disease is very rare and the international frequency of pulmonary LAM is unknown. TSC-LAM is present in up to 40% of women with tuberous sclerosis complex [19] [20].

The proliferation of abnormal cells leads to airflow obstruction, overdistention of distal air spaces, bullae, and the formation of pneumothoraces.

No guidelines present.

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease affecting almost exclusively in women of reproductive age [5] [21]. LAM was first described in a patient affected by TSC who presented with bilateral spontaneous pneumothorax in 1918 [22] and the spontaneous form in a patient without TSC in 1937 [23]. The disorder is characterized by abnormal smooth muscle cell proliferation that results in functional obstruction of vessels, lymphatics, and airways.

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease that usually affects women of childbearing age. It is characterized by an abnormal growth of cells, particularly of smooth muscle-like cells, in the lungs. There are two forms of the disorder - sporadic LAM (S-LAM) and TSC-LAM, which can be inherited with tuberous sclerosis complex.

Lymphangioleiomyomatosis may cause a wide variety of symptoms including progressive shortness of breath with exertion and recurrent episodes of collapsed lung, which are similar to those of other lung diseases such as asthma, emphysema, and bronchitis, thus the correct diagnosis is often delayed.

A high-resolution computed tomography (HRCT) chest scan, pulmonary function tests, a blood test for vascular endothelial growth factor D (VEGF-D) and in some cases a lung biopsy may be needed to provide an accurate diagnosis.

In some counties, the drug sirolimus (Rapamune) was approved to treat LAM. In addition, bronchodilators and supplemental oxygen may be necessary. Lung transplantation may be considered for patients with very advanced disease.

1. Taylor JR, Ryu J, Colby TV, et al. Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med 1990; 323: pp. 1254-1260
2. Kitaichi M, Nishimura K, Itoh H, et al. Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med 1995; 151: pp. 527-533
3. Chu SC, Horiba K, Usuki J, et al. Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest 1999; 115: pp. 1041-1052
4. Johnson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK. Thorax 2000; 55: pp. 1052-1057
5. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006; 173: pp. 105-111
6. Seyama K, Kumasaka T, Souma S, et. al. Vascular endothelial growth factor D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol 2006; 4: pp. 143-152.
7. Young LR, Vandyke R, Gulleman PM, et. al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138: pp. 674-681.
8. Young L, Lee HS, Inoue Y, et al. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013;1(6):445–452.
9. Johnson SR. Cordier JF. Lazor R, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010; 35(1):14-26
10. Taveira-DaSilva AM, Hedin C, Stylianou MP, et al. Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2001; 164(6):1072-6
11. Adams DM, Trenor CC, Hammill AM, et. al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics 2016; 137: e201153257.
12. Aghaeimeybodi F, Najafizadeh K, Razavi-Ratki SK, et al. Effects of Sirolimus on Lung function in patients with Lymphangioleiomyomatosis. Caspian J Intern Med. 2019;10(1):7–10.
13. Martirossian A, Shah S, Carrete L, et al. Durability of Sirolimus for Lymphangioleiomyomatosis. Am J Med Sci. 2017 Dec;354(6):603-607
14. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364(17):1595–1606.
15. Bissler JJ, McCormack FX, Young LR et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008; 358(2):140-51
16. Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med. 2011;154(12):797–293.
17. Ando K, Okada Y, Akiba M, et al. Lung Transplantation for Lymphangioleiomyomatosis in Japan. PLoS One. 2016;11(1):e0146749
18. McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008; 133: pp. 507-516
19. Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 2001; 164: pp. 661-668
20. Costello LC, Hartman TE, and Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000; 75: pp. 591-594
21. Kalassian K, Doyle R, Kao P, et al. Lymphangioleiomyomatosis: new insights. Am J Respir Crit Care Med 1997; 155: pp. 1183-1186
22. Lautenbacher R. Dysembriomes metotipiques des reins, carcinose submiliere aigue puomon avec amphyseme generalise et double pneumothorax. Ann Med Interne (Paris) 1918; 5: pp. 435-450
23. von Stossel E. Uber muskulare Cirrhose der Lunge (Muscular cirrhosis of the lung). Beitr Klin Tuberk 1937; 90: pp. 432-442