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Lymphangioleiomyomatosis

LAM

Lymphangioleiomyomatosis (LAM) is a rare disease affecting lung, kidney, and axial lymphatics that occurs almost exclusively in women of reproductive age. It is usually progressive and characterized by abnormal smooth muscle cell proliferation.


Presentation

The first symptoms of 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]. LAM can lead to chronic respiratory insufficiency. Other possible symptoms include chylous ascites, abdominal and thoracic lymphadenopathy and abdominal tumors including angiomyolipomas of the kidney and lymphangiomyomas [5]. TSC-LAM has symptoms of TSC.

Pain
  • We report a case of a 23-year-old woman who presented with diffuse, but increasing abdominal pain. Transabdominal ultrasound showed multiple cystic formations.[ncbi.nlm.nih.gov]
Lymphedema
  • We report the case of a 45-year-old woman with sporadic LAM, successfully treated with sirolimus, in whom the first manifestation of the disease was chyloperitoneum and after three and nine years, respectively, lymphedema of the left lower extremity and[ncbi.nlm.nih.gov]
  • […] duct wall invasion, lymphangioleiomyomaformation, chylous fluidcollections in the peritoneal, pleural, andpericardial spaces, chyloptysis, chylocolporrhea/chylometrorrhea, chyle leak from theumbilicus, chylous pulmonary congestion,and lower extremity lymphedema[journals.uair.arizona.edu]
  • […] 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]
  • 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]
Fatigue
  • George's Respiratory Questionnaire, SGRQ), dyspnoea (modified Medical Research Council dyspnoea scale, mMRC) and fatigue (Multidimensional Fatigue Inventory, MFI-20).[ncbi.nlm.nih.gov]
  • Often misdiagnosed as asthma or emphysema, most LAM sufferers experience shortness of breath, collapsed lung, chest pain, and fatigue. LAM is a progressive disease, and there is no known cure.[uabmedicine.org]
  • Fatigue Risks Causes and Risk Factors of Lymphangioleiomyomatosis (LAM) LAM results from mutations, or changes, in two genes called TSC1 and TSC2. A hereditary form of the disease also occurs in patients who have tuberous sclerosis disease.[loyolamedicine.org]
Soft Tissue Mass
  • Detecting lymphangiomyomas as soft tissue masses of fat density on CT scanning can strengthen the diagnosis of LAM when a tissue biopsy has not been performed.[doi.org]
  • Extrapulmonary features include lymph node masses, cystic soft tissue masses, 26 27 and chylous ascites in up to a third of patients. 1 25 Uterine fibroids (leiomyomas) 8 and renal angiomyolipomas 28 29 are also seen; angiomyolipomas are often asymptomatic[thorax.bmj.com]
High Fever
  • Case 4: A 47-year-old woman, who underwent right single LTx, developed repeated high fevers. She developed an acute abdomen, and swollen subcutaneous lymph nodes were found.[ncbi.nlm.nih.gov]
Dyspnea
  • A 41-year-old woman with pulmonary lymphangioleiomyomatosis presented with exertional dyspnea. A chest computed tomographic scan showed hyperinflation with diffuse cystic lesions throughout both lung fields.[ncbi.nlm.nih.gov]
  • The common symptom is shortness of breath (dyspnea) A multifocal neoplasm with perivascular epithelioid cell differentiation affecting almost exclusively females of child-bearing age.[icd9data.com]
Pleural Effusion
  • Chylous pleural effusion and ascites occasionally appear during the course of the disease. There are only a few reports on the cytologic findings in this disease.[ncbi.nlm.nih.gov]
  • PNEUMOTHORAX AND PLEURAL EFFUSION Pneumothorax was common and frequently required surgical intervention.[doi.org]
Cough
  • A 32-year-old primigravida presented with cough and dyspnea at 16 weeks' gestation. Chest roentgenogram revealed a large pleural effusion and diffuse interstitial infiltrates.[ncbi.nlm.nih.gov]
Hemoptysis
  • Pneumothorax, chylous effusions and hemoptysis were frequent complications.[ncbi.nlm.nih.gov]
  • Pneumothorax, chylous effusions, and hemoptysis are frequent complications. The roentgenographic appearance is characteristic although not . . .[doi.org]
Sputum
  • She was diagnosed with chyloptysis and chylous pulmonary congestion by sputum analysis.[ncbi.nlm.nih.gov]
  • Initial diagnosis was based primarily on clinical signs and symptoms and treatment was started despite the negative result of the sputum microscopy for acid fast bacilli.[pesquisa.bvsalud.org]
  • Coughing up blood-stained sputum or blood (hemoptysis) is less frequent. Course: LAM is generally progressive, leading to increasingly impaired lung function. The rate of development can vary considerably among patients.[medicinenet.com]
  • Natural History, Complications and Prognosis Natural history Patients will have a history of [2] [11] [12] [13] : Dyspnea Bluish discoloration of lips ( cyanosis ) Cough Chest pain Weight loss Blood in sputum Headache Pain abdomen Complications Ascites[wikidoc.org]
Abdominal Pain
  • We report a case of a 23-year-old woman who presented with diffuse, but increasing abdominal pain. Transabdominal ultrasound showed multiple cystic formations.[ncbi.nlm.nih.gov]
  • One woman experienced clinical resolution of her abdominal pain and distension but did not have confirmatory follow-up imaging due to financial constraints.[mja.com.au]
Abdominal Distension
  • In one woman, temporary cessation of everolimus resulted in recurrence of abdominal distension, requiring reinstitution of therapy. Lung function Lung function was abnormal in all five patients at presentation.[mja.com.au]
  • Lymphangioleiomyomas can occur in the abdomen, pelvis and retroperitoneum with correlated symptoms such as abdominal distension and nausea. In patients that have TSC, neurological symptoms are also common.[jtd.amegroups.com]
  • Symptoms associated with lymphangioleiomyomas are nausea, bloating, abdominal distension, peripheral oedema and urinary symptoms 23.[erj.ersjournals.com]
Chest Pain
  • Lung is the most common site of involvement, and patients usually present with dyspnea, chest pain, and cough. Chylous pleural effusion and ascites occasionally appear during the course of the disease.[ncbi.nlm.nih.gov]
  • 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]
  • Often misdiagnosed as asthma or emphysema, most LAM sufferers experience shortness of breath, collapsed lung, chest pain, and fatigue. LAM is a progressive disease, and there is no known cure.[uabmedicine.org]
Exertional Chest Pain
  • The symptoms of LAM may include: Shortness of breath Breathlessness during physical exertion Chest pain Cough Coughing up viscous white sputum Coughing up blood (haemoptysis) Progressive worsening of symptoms over time.[betterhealth.vic.gov.au]
Osteoporosis
  • Many cases of LAM are associated with osteoporosis, a condition characterized by progressive thinning of the bones. Causes The exact cause of LAM is not known.[rarediseases.org]
  • Care for your bones Some women who have LAM may be at risk for osteoporosis if they have undergone permanent hormonal therapy such as oophorectomy or are receiving certain hormone therapy medicines.[nhlbi.nih.gov]
  • The available treatment options include: Oxygen therapy Pulmonary rehabilitation Removal of air or fluid from lungs or abdomen to help you breathe better Surveillance and treatment of osteoporosis (weak bones) Standard vaccinations to prevent respiratory[foundation.chestnet.org]
  • Grade: B; Quality: low; Benefit: substantial; Consensus: very good. 2) Those with osteoporosis should be treated the same as other patients with osteoporosis.[doi.org]
  • […] cyanosis ) Cough Chest pain Weight loss Blood in sputum Headache Pain abdomen Complications Ascites Pleural effusion pneumothorax Chylothorax H emoptysis Chyloptysis Chyluria Haematuria Pericardial effusion Pneumoperitoneum Lymphedema Respiratory failure Osteoporosis[wikidoc.org]
Shagreen Patch
  • Besides facial angiofibromas and shagreen patches over the back, no other physical signs such as those referable to the respiratory system were noted. Chest X-ray performed did not show any abnormality.[nature.com]
  • patch Forehead plaque Retinal hamartoma Laboratory Findings Pulmonary function tests are used to assess the lung damage caused by lymphangiomyomatosis.[wikidoc.org]
  • Angiogenesis in TSC Patients with TSC may present with skin lesions such as forehead fibrous plaques, facial angiofibromas, ungual fibromas and Shagreen patches, in addition to brain and other manifestations [ 40, 41 ].[doi.org]
  • Subungual fibromas, facial angiofibromas and shagreen patches are all detectable clinically but may be misdiagnosed or overlooked in milder cases, and hypomelanotic patches require examination under Woods (ultraviolet) light for reliable detection.[erj.ersjournals.com]
Flank Pain
  • We report the case of a 25-year-old woman who presented with abdominal and flank pain with two successive pregnancies and was diagnosed of giant bilateral renal AMLs and pulmonary LAM associated with TSC in the post-partum of her second pregnancy.[ncbi.nlm.nih.gov]
  • Renal angiomyolipomas, although usually asymptomatic, can cause bleeding if they grow large (eg, 4 cm), usually manifesting as hematuria or flank pain.[msdmanuals.com]
  • A major complication of them is hemorrhage that may present with flank pain or shock [ 6 ].[ajronline.org]
  • Pain (see Flank Pain, [[Flank Pain]]) Hematuria (see Hematuria, [[Hematuria]]): risk of hemorrhage increases with size Renin-Dependent Hypertension (see Hypertension, [[Hypertension]]): may occur Renal Mass (see Renal Mass, [[Renal Mass]]): often with[mdnxs.com]
Hematuria
  • Renal angiomyolipomas, although usually asymptomatic, can cause bleeding if they grow large (eg, 4 cm), usually manifesting as hematuria or flank pain.[msdmanuals.com]
  • (see Hematuria, [[Hematuria]]): risk of hemorrhage increases with size Renin-Dependent Hypertension (see Hypertension, [[Hypertension]]): may occur Renal Mass (see Renal Mass, [[Renal Mass]]): often with areas of fat attenuation on CT Chyluria (see Chyluria[mdnxs.com]
  • In some cases, they may cause flank pain, blood in the urine (hematuria) or bleeding into the abdomen (abdominal hemorrhaging).[rarediseases.org]
  • The extra-pulmonary manifestations of the disease may be renal angiomyolipomas, slowly growing masses from 1 mm to 20 cm that can be asymptomatic or can lead to renal failure, hematuria, flank pain and retroperitoneal hemorrhage ( 24 ).[jtd.amegroups.com]
Kidney Failure
  • Symptoms of LAM may include: Abdominal bleeding Abdominal pain Acute kidney failure Breathing problems, such as shortness of breath Chest pains Coughing up blood Fainting Fatigue Fluid buildup in the abdomen, chest and pelvis (chylous ascites) Persistent[loyolamedicine.org]
  • These can cause pain, bleeding, or kidney failure. In a few people with LAM, discovery of these benign tumors outside the lungs is the first sign of LAM lung disease.[webmd.com]

Workup

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].

Pericardial Effusion
  • 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.[symptoma.com]
  • Pleural effusion Pneumothorax Ground-glass opacities Pericardial effusion Chylothorax Mediastinal lymphadenopathy Dilated thoracic duct Cystic lymph nodal lesions Renal angiolipomas in 50% of cases.[wikidoc.org]
  • Less commonly patients can present with chest pain, pleural or pericardial effusion and lymphedema.[bib.irb.hr]
  • Other less frequent symptoms are hemoptysis, chylous pleural effusions, chylous ascites, pericardial effusion, pneumoperitoneum, acute abdomen, and lymphedema.[scielo.br]
  • Tsc1 –/– embryos were also paler and edematous, and often had pericardial effusions.[doi.org]
Atelectasis
  • (see Rounded Atelectasis, [[Rounded Atelectasis]]) Epidemiology : case reports describe rounded atelectasis occurring in the setting of LAM-associated pneumothorax and chylothorax Small Airways Disease (see Obstructive Lung Disease, [[Obstructive Lung[mdnxs.com]
  • The effusions may be large and may cause atelectasis, dyspnea, cough, and chest pain [ 7, 8 ].[ajronline.org]
  • Kishi K, Homma S, Miyamoto A, Kurosaki A, Motoi N, Kohno T, et al: Rounded atelectasis associated with pulmonary lymphangioleiomyomatosis. Intern Med 2005;44:625-627.[karger.com]
  • Pulmonary lymphangioleiomyomatosis and rounded atelectasis. JBR-BTR. 2004;87(3):152-3. Finlay G. The LAM cell: what is it, where does it come from, and why does it grow? Am J Physiol Lung Cell Mol Physiol. 2004;286(4):L690-3.[malattierare.regione.veneto.it]
Pneumoperitoneum
  • ] : Dyspnea Bluish discoloration of lips ( cyanosis ) Cough Chest pain Weight loss Blood in sputum Headache Pain abdomen Complications Ascites Pleural effusion pneumothorax Chylothorax H emoptysis Chyloptysis Chyluria Haematuria Pericardial effusion Pneumoperitoneum[wikidoc.org]
  • Other less frequent symptoms are hemoptysis, chylous pleural effusions, chylous ascites, pericardial effusion, pneumoperitoneum, acute abdomen, and lymphedema.[scielo.br]
Kerley A Lines
  • If Kerley B lines are present, they may be the result of interstitial edema related to lymphatic obstruction. Multiple cysts become visible as they enlarge. Occasionally, patients may present with pneumothorax or chylous pleural effusion.[emedicine.com]
Pleural Effusion
  • Chylous pleural effusion and ascites occasionally appear during the course of the disease. There are only a few reports on the cytologic findings in this disease.[ncbi.nlm.nih.gov]
  • PNEUMOTHORAX AND PLEURAL EFFUSION Pneumothorax was common and frequently required surgical intervention.[doi.org]

Treatment

General care depends on the manifestation and may include treatment of pleural effusions and ascites, 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].

Prognosis

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

Etiology

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.

Epidemiology

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

Sex distribution
Age distribution

Pathophysiology

The proliferation of abnormal cells leads to airflow obstruction, overdistention of distal air spaces, bullae, and the formation of pneumothoraces. Obstruction of lymphatics due to infiltration by smooth muscle cells may result in chylothorax, and chylous ascites.

Prevention

No guidelines present.

Summary

Lymphangioleiomyomatosis (LAM) is a rare disease affecting lung, kidney, and axial lymphatics that occurs 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.

Patient Information

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, lymphatic system and kidneys. 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.

References

Article

  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

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Last updated: 2019-07-11 20:39