Lymphangiomyomatosis: Difference between revisions

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{{SI}}
'''For patient information, click [[Lymphangiomyomatosis (patient information)|here]].'''
'''For patient information, click [[Lymphangiomyomatosis (patient information)|here]].'''


{{CMG}}; {{AOEIC}} {{VK}} {{Ammu}}
{{CMG}}; {{AOEIC}} {{JSS}}


{{SK}} Lymphangioleiomyomatosis; LAM; Pulmonary lymphangioleiomyomatosis; Pulmonary lymphangiomyomatosis
{{SK}} Lymphangioleiomyomatosis; LAM; Pulmonary lymphangioleiomyomatosis; Pulmonary lymphangiomyomatosis


==Overview==
==Overview==
Lymphangiomyocytosis is defined as a multifocal neoplasm with differentiation of the perivascular epithelioid cell and has a female prepondrance, especially females of child-bearing age. On microscopic histopathological analysis, smooth muscle and epithelioid cells and by the proliferation of lymphatic vessels are characteristic findings of lmphangiomyomatosis. Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as [[asthma]], spontaneous pneumothorax, [[emphysema]], [[interstitial pulmonary fibrosis]], [[eosinophilic granuloma]] (EG), Birt-Hogg-Dube syndrome, [[lymphangiomas]], pulmonary lymphangiectasis, and [[leiomyosarcoma]]. Symptoms of lymphangiomyomatosis  may include [[constipation]], [[dyspnea]], and [[cough]]. The mainstay of therapy for lymphangiomyomatosisis include [[sirolimus]], medroxyprogesterone, gonadotropin-releasing hormone agonists, and [[tamoxifen]].
Lymphangiomyomatosis is a disorder resulting from proliferation of abnormal [[Smooth muscle cell|smooth muscle]] like cells, mostly in the lungs but can also occur in other body parts such as [[kidney]], [[mediastinum]] or axial [[Lymphatic system|lymphatics]]. Lymphangiomyomatosis is characterized by small [[Mediastinum|mediastinal]] or retro- peritoneal tumors which involve the [[Thoracic duct|thoracic duc]]<nowiki/>t and consist of numerous [[smooth muscle]] bundles interspersed with lymphatic channels. Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as [[asthma]], [[Pneumothorax|spontaneous pneumothorax]], [[emphysema]], interstitial [[pulmonary fibrosis]], [[eosinophilic granuloma]] (EG), Birt-Hogg-Dube syndrome, [[lymphangiomas]], pulmonary lymphangiectasis, and [[leiomyosarcoma]]. Symptoms of lymphangiomyomatosis  may include [[constipation]], [[dyspnea]], and [[cough]]. The mainstay of therapy for lymphangiomyomatosisis include [[sirolimus]], [[Medroxyprogesterone acetate|medroxyprogesterone]], [[gonadotropin]]-releasing hormone agonists, and [[tamoxifen]]. The most effective treatment is [[lung transplant]].


==Historical Perspective==
==Historical Perspective==
It was first described by Van Stossel in the year 1937.


==Classification==
==Classification==
Lymphangiomyomatosis is classified into:
Lymphangiomyomatosis is classified into:
* Sporadic lymphangiomyomatosis, when it occurs without tuberous sclerosis.
* Sporadic lymphangiomyomatosis, (when it occurs without [[tuberous sclerosis]])<ref name="pmid9105053">{{cite journal| author=Kalassian KG, Doyle R, Kao P, Ruoss S, Raffin TA| title=Lymphangioleiomyomatosis: new insights. | journal=Am J Respir Crit Care Med | year= 1997 | volume= 155 | issue= 4 | pages= 1183-6 | pmid=9105053 | doi=10.1164/ajrccm.155.4.9105053 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9105053  }} </ref>.
* Lymphangiomyomatosis with tuberous sclerosis, when it occurs in patients of tuberous sclerosis.
* Lymphangiomyomatosis with [[tuberous sclerosis]], (when it occurs in patients of [[tuberous sclerosis]]).


==Pathophysiology==
==Pathophysiology==
* Lymphangiomyomatosis is a disorder resulting from proliferation of abnormal smooth muscle like cells, mostly in the lungs but can also occur in other body parts such as kidney, mediastinum or axial lymphatics.
* Lymphangiomyomatosis is a disorder resulting from proliferation of abnormal smooth muscle like cells, mostly in the lungs but can also occur in other body parts such as kidney, mediastinum or axial lymphatics<ref name="pmid9872207">{{cite journal| author=Sullivan EJ| title=Lymphangioleiomyomatosis: a review. | journal=Chest | year= 1998 | volume= 114 | issue= 6 | pages= 1689-703 | pmid=9872207 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9872207  }} </ref><ref name="pmid10325903">{{cite journal| author=Johnson S| title=Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms. | journal=Thorax | year= 1999 | volume= 54 | issue= 3 | pages= 254-64 | pmid=10325903 | doi= | pmc=1745441 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10325903  }} </ref><ref name="pmid11070117">{{cite journal| author=Matsui K, Tatsuguchi A, Valencia J, Yu Zx, Bechtle J, Beasley MB et al.| title=Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases. | journal=Hum Pathol | year= 2000 | volume= 31 | issue= 10 | pages= 1242-8 | pmid=11070117 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11070117  }} </ref>.


* Lymphangiomyomatosis is characterized by small mediastinal or retro- peritoneal tumors which involve the thoracic duct and consist of numerous smooth muscle bundles interspersed with lymphatic channels.
* Lymphangiomyomatosis is characterized by small mediastinal or retro- peritoneal tumors which involve the [[thoracic duct]] and consist of numerous smooth muscle bundles interspersed with lymphatic channels<ref name="pmid17362325">{{cite journal| author=Kebria M, Black D, Borelli C, Modica I, Hensley M, Chi DS| title=Primary retroperitoneal lymphangioleiomyomatosis in a postmenopausal woman: a case report and review of the literature. | journal=Int J Gynecol Cancer | year= 2007 | volume= 17 | issue= 2 | pages= 528-32 | pmid=17362325 | doi=10.1111/j.1525-1438.2007.00785.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17362325  }} </ref>.


* It can occur in a sporadic form, which only affects females, who are usually of childbearing age.
* It can occur in a sporadic form, which only affects females, who are usually of childbearing age.
* It can also occur in patients who have [[tuberous sclerosis]]..
* It can also occur in patients who have [[tuberous sclerosis]]..
* Renal angiomyolipomas are present in 50 % of cases of sporadic lymphangiomyomatosis.
* [[Angiolipoma|Renal angiolipomas]] are present in 50 % of cases of sporadic lymphangiomyomatosis<ref name="pmid11863203">{{cite journal| author=Hancock E, Osborne J| title=Lymphangioleiomyomatosis: a review of the literature. | journal=Respir Med | year= 2002 | volume= 96 | issue= 1 | pages= 1-6 | pmid=11863203 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11863203  }} </ref>.
*The ''tuberous sclerosis complex (TSC)'' gene mutation has been associated with the development of lymphangiomyomatosis.  
*The ''tuberous sclerosis complex (TSC)'' gene mutation has been associated with the development of lymphangiomyomatosis.  
*TSC1 and TSC2 genes located on chromosome 9q34 and 16p13, are involved in the pathogenesis.
*TSC1 and TSC2 genes located on chromosome 9q34 and 16p13, are involved in the pathogenesis.
*TSC1 gene is responsible for the production of hamartin protein and TSC2 for the production of tuberin protein.
*TSC1 gene is responsible for the production of hamartin protein and TSC2 for the production of tuberin protein.
*The loss of these proteins along with the influence of estrogen allows the cell to grow and divide in an uncontrolled way, resulting in the tumors and cysts associated with lymphangiomyomatosis.
*The loss of these proteins along with the influence of [[estrogen]] allows the cell to grow and divide in an uncontrolled way, resulting in the [[Tumor|tumors]] and [[Cyst|cysts]] associated with lymphangiomyomatosis.
*This proliferation of immature muscle cells starts covering alveolar walls, bronchioles, pleura and vessels, including lymphatic routes.
*This proliferation of immature muscle cells starts covering alveolar walls, [[Bronchiole|bronchioles]], [[Pleural cavity|pleura]] and vessels, including [[Lymphatic system|lymphatic]] routes.
*Excessive proteolytic activity from the proliferation of the smooth muscle cells result in lung destruction and formation of cysts.
*Excessive [[Proteolysis|proteolytic]] activity from the proliferation of the smooth muscle cells result in lung destruction and formation of cysts.
*These cysts are called lymphangioleiomyomas.  
*These cysts are called lymphangioleiomyomas.  
*Obstruction of lymphatics may result in chylothorax, and chylous ascites.
*Obstruction of lymphatics may result in [[chylothorax]], and [[chylous ascites]]<ref name="pmid23111591">{{cite journal| author=Richter MJ, Baumgartner R, Leuchte HH| title=[Chylothorax in an 87-year-old patient]. | journal=Internist (Berl) | year= 2013 | volume= 54 | issue= 1 | pages= 105-9 | pmid=23111591 | doi=10.1007/s00108-012-3158-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23111591  }} </ref><ref name="pmid12576391">{{cite journal| author=Ryu JH, Doerr CH, Fisher SD, Olson EJ, Sahn SA| title=Chylothorax in lymphangioleiomyomatosis. | journal=Chest | year= 2003 | volume= 123 | issue= 2 | pages= 623-7 | pmid=12576391 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12576391  }} </ref>.
*As the cysts develop throughout the lungs, lymphangiomyomatosis causes breathing problems similar to emphysema.
*As the cysts develop throughout the lungs, lymphangiomyomatosis causes breathing problems.
*The abnormal poliferation and formation of cysts, causes obstructive pattern of lung disease.
*The abnormal proliferation and formation of cysts, causes obstructive pattern of lung disease<ref name="pmid8616568">{{cite journal| author=Crausman RS, Jennings CA, Mortenson RL, Ackerson LM, Irvin CG, King TE| title=Lymphangioleiomyomatosis: the pathophysiology of diminished exercise capacity. | journal=Am J Respir Crit Care Med | year= 1996 | volume= 153 | issue= 4 Pt 1 | pages= 1368-76 | pmid=8616568 | doi=10.1164/ajrccm.153.4.8616568 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8616568  }} </ref>.
*
*
==Causes==
==Causes==
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* Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as:
* Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as:
:*[[Asthma]]
:*[[Asthma]]
:*Spontaneous pneumothorax
:*[[Spontaneous pneumothorax]]
:*[[Emphysema]]
:*[[Emphysema]]
:*[[Interstitial pulmonary fibrosis]]
:*[[Interstitial lung disease|Interstitial pulmonary fibrosis]]
:*[[Eosinophilic granuloma]] (EG)
:*[[Eosinophilic granuloma]] (EG)
:*Birt-Hogg-Dube syndrome
:*Birt-Hogg-Dube syndrome
:*[[Lymphangiomas]]
:*[[Lymphangiomas]]
:*Pulmonary lymphangiectasis
:*Pulmonary [[Lymphangiectasia|lymphangiectasis]]
:*Langerhans cell histiocytosis (LCH)
:*[[Langerhans cell histiocytosis]] (LCH)
:*
:*
==Epidemiology and Demographics==
==Epidemiology and Demographics==
* The incidence of lymphangiomyomatosis is 0.2 per 100000 individuals.
* The incidence of lymphangiomyomatosis is 0.2 per 100000 individuals<ref name="pmid17587419">{{cite journal| author=Hayashida M, Seyama K, Inoue Y, Fujimoto K, Kubo K, Respiratory Failure Research Group of the Japanese Ministry of Health, Labor, and Welfare| title=The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors. | journal=Respirology | year= 2007 | volume= 12 | issue= 4 | pages= 523-30 | pmid=17587419 | doi=10.1111/j.1440-1843.2007.01101.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17587419  }} </ref>.
===Age===
===Age===
*Lymphangiomyomatosis is more commonly observed among female patients aged 15-45 years old.
*Lymphangiomyomatosis is more commonly observed among female patients aged 15-45 years old.
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=== Natural history ===
=== Natural history ===
Patients will have a history of:
Patients will have a history of<ref name="pmid9872207">{{cite journal| author=Sullivan EJ| title=Lymphangioleiomyomatosis: a review. | journal=Chest | year= 1998 | volume= 114 | issue= 6 | pages= 1689-703 | pmid=9872207 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9872207  }} </ref><ref name="pmid25078640">{{cite journal| author=Baldi BG, Freitas CS, Araujo MS, Dias OM, Pereira DA, Pimenta SP et al.| title=Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre. | journal=Sarcoidosis Vasc Diffuse Lung Dis | year= 2014 | volume= 31 | issue= 2 | pages= 129-35 | pmid=25078640 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25078640  }} </ref><ref name="pmid9463158">{{cite journal| author=Nagy B, Nábrády Z, Nemes Z| title=Pulmonary lymphangiomyomatosis in a preadolescent girl. | journal=N Engl J Med | year= 1998 | volume= 338 | issue= 7 | pages= 473-4 | pmid=9463158 | doi=10.1056/NEJM199802123380715 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9463158  }} </ref><ref name="pmid11083892">{{cite journal| author=Johnson SR, Tattersfield AE| title=Clinical experience of lymphangioleiomyomatosis in the UK. | journal=Thorax | year= 2000 | volume= 55 | issue= 12 | pages= 1052-7 | pmid=11083892 | doi= | pmc=1745654 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11083892  }} </ref>:
* Dyspnea
* [[Dyspnea]]
* Bluish discoloration of lips (cyanois)
* Bluish discoloration of lips ([[cyanosis]])
* Cough
* [[Cough]]
* Chest pain
* [[Chest pain]]
* Weight loss
* [[Weight loss]]
* Blood in sputum
* [[Hemoptysis|Blood in sputum]]
* Headache
* [[Headache]]
* Pain abdomen
* [[Abdominal pain|Pain abdomen]]


=== Complications ===
=== Complications ===
* Ascites
* [[Ascites]]
* Pleural effusion
* [[Pleural effusion]]
* [[pneumothorax]]
* [[pneumothorax]]
* Chylothorax
* [[Chylothorax]]
* H[[hemoptysis|emoptysis]]
* H[[hemoptysis|emoptysis]]
* Chyloptysis
* Chyloptysis
* Chyluria
* [[Chyluria]]
* Haematuria
* [[Hematuria|Haematuria]]
* Pericardial effusion
* [[Pericardial effusion]]
* Pneumoperitoneum
* [[Pneumoperitoneum]]
* Lymphedema
* [[Lymphedema]]
* Respiratory failure
* [[Respiratory failure]]
* Osteoporosis
* [[Osteoporosis]]
* Meningioma.
* [[Meningioma]].


=== Prognosis ===
=== Prognosis ===
* The prognosis of lymphangiomyomatosis is poor, with 70% of patients not surviving more than 10 years after diagnosis.
* The prognosis of lymphangiomyomatosis is poor, with 70% of patients not surviving more than 10 years after diagnosis.
* Poor prognostic factors include:
* Poor prognostic factors include:
** Reduced FEV1.
** Reduced [[FEV1]].
** Reduced diffusion lung capacity to carbon monoxide.
** Reduced diffusion lung capacity to carbon monoxide.
** Formation of cysts in lungs.
** Formation of cysts in lungs.
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== Diagnosis ==
== Diagnosis ==
=== Symptoms ===
=== Symptoms ===
*Symptoms of lymphangiomyomatosis  may include the following:
*Symptoms of lymphangiomyomatosis  may include the following<ref name="pmid9927387">{{cite journal| author=| title=NHLBI Workshop Summary. Report of workshop on lymphangioleiomyomatosis. National Heart, Lung, and Blood Institute. | journal=Am J Respir Crit Care Med | year= 1999 | volume= 159 | issue= 2 | pages= 679-83 | pmid=9927387 | doi=10.1164/ajrccm.159.2.9803107 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9927387  }} </ref><ref name="pmid10325903">{{cite journal| author=Johnson S| title=Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms. | journal=Thorax | year= 1999 | volume= 54 | issue= 3 | pages= 254-64 | pmid=10325903 | doi= | pmc=1745441 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10325903  }} </ref><ref name="pmid19447921">{{cite journal| author=Taveira-DaSilva AM, Steagall WK, Rabel A, Hathaway O, Harari S, Cassandro R et al.| title=Reversible airflow obstruction in lymphangioleiomyomatosis. | journal=Chest | year= 2009 | volume= 136 | issue= 6 | pages= 1596-1603 | pmid=19447921 | doi=10.1378/chest.09-0624 | pmc=2818851 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19447921  }} </ref>:
**Dyspnea
**[[Dyspnea|Difficulty in breathing]]
** Bluish discoloration of lips (cyanois)
** Bluish discoloration of lips ([[cyanosis]])
** Cough
** [[Cough]]
** Chest pain
** [[Chest pain]]
** Weight loss
** [[Weight loss]]
** Blood in sputum
** [[Hemoptysis|Blood in sputum]]
** Headache
** [[Headache]]
** Pain abdomen
** [[Abdominal pain|Pain abdomen]]
=== Physical Examination ===
=== Physical Examination ===
*Physical examination may be remarkable for:
*Physical examination may be remarkable for:
:*Crackles
:*[[Rales|Crackles]]
:*Wheezes
:*Wheezes
:*[[Pleural effusion]]
:*[[Pleural effusion]]
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:*Facial angiofibromas
:*Facial angiofibromas
:*Periungual fibromas
:*Periungual fibromas
:*Hypomelanotic macules, ash-leaf spots
:*Hypomelanotic [[Macule|macules]], ash-leaf spots
:*Shagreen patch  
:*Shagreen patch  
:*Forehead plaque
:*Forehead [[plaque]]
:*Retinal hamartoma
:*Retinal [[hamartoma]]


=== Laboratory Findings ===
=== Laboratory Findings ===
*Pulmonary function tests are used to assess the lung damage caused by lymphangiomyomatosis.
*Pulmonary function tests are used to assess the lung damage caused by lymphangiomyomatosis.
**Reduced FEV1.
**Reduced FEV1.
**Reduced diffusion lung capacity to carbon monoxide.
**Reduced diffusion lung capacity to [[carbon monoxide]].
**Increased residual volume.
**Increased [[Lung volumes|residual volume.]]
**Obstructive pattern on spirometry.
**Obstructive pattern on [[spirometry]].
**Reduced SpO2 ( <95%).
**Reduced SpO2 ( <95%).
* Vascular endothelial growth factor-D (VEGF-D) is diagnostic for LAM if the level is greater than or equal to 800 pg/mL.
* [[Vascular endothelial growth factor]]-D (VEGF-D) is diagnostic for LAM if the level is greater than or equal to 800 pg/mL.


===Imaging Findings===
===Imaging Findings===
* CT scan is used to daignose lymphangiomyomatosis.
* CT scan is used to diagnose lymphangiomyomatosis<ref name="pmid8466360">{{cite journal| author=Warren SE, Lee D, Martin V, Messink W| title=Pulmonary lymphangiomyomatosis causing bilateral pneumothorax during pregnancy. | journal=Ann Thorac Surg | year= 1993 | volume= 55 | issue= 4 | pages= 998-1000 | pmid=8466360 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8466360  }} </ref><ref name="pmid1146965">{{cite journal| author=Corrin B, Liebow AA, Friedman PJ| title=Pulmonary lymphangiomyomatosis. A review. | journal=Am J Pathol | year= 1975 | volume= 79 | issue= 2 | pages= 348-82 | pmid=1146965 | doi= | pmc=1912658 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1146965  }} </ref><ref name="pmid2215609">{{cite journal| author=Taylor JR, Ryu J, Colby TV, Raffin TA| title=Lymphangioleiomyomatosis. Clinical course in 32 patients. | journal=N Engl J Med | year= 1990 | volume= 323 | issue= 18 | pages= 1254-60 | pmid=2215609 | doi=10.1056/NEJM199011013231807 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2215609  }} </ref><ref name="pmid26938102">{{cite journal| author=Lama A, Ferreiro L, Golpe A, Gude F, Álvarez-Dobaño JM, González-Barcala FJ et al.| title=Characteristics of Patients with Lymphangioleiomyomatosis and Pleural Effusion: A Systematic Review. | journal=Respiration | year= 2016 | volume= 91 | issue= 3 | pages= 256-64 | pmid=26938102 | doi=10.1159/000444264 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26938102  }} </ref>.
* Lymphangiomyomatosis appears as well-circumscribed lobular, thin or thick-walled masses without evidence of necrosis or hemorrhage.
* Lymphangiomyomatosis appears as well-circumscribed lobular, thin or thick-walled masses without evidence of [[necrosis]] or [[Bleeding|hemorrhage]].
* Other findings are:
* Other findings are:
** Diffuse thin-walled cysts.
** Diffuse thin-walled [[Cyst|cysts]].
** Adenopathy and thoracic duct dilatation.
** [[Lymphadenopathy|Adenopathy]] and [[Thoracic duct|thoracic duct dilatation]].
** Pleural effusion
** [[Pleural effusion]]
** Pneumothorax
** [[Pneumothorax]]
** Ground-glass opacities  
** Ground-glass opacities  
** Pericardial effusion
** [[Pericardial effusion]]
** Chylothorax
** [[Chylothorax]]
** Mediastinal lymphadenopathy  
** [[Mediastinum|Mediastinal]] [[lymphadenopathy]]
** Dilated thoracic duct
** Dilated [[thoracic duct]]
** Cystic lymph nodal lesions
** Cystic lymph nodal lesions
** Renal angiolipomas in 50% of cases.
** Renal angiolipomas in 50% of cases.
** Features of interstitial lung disease
** Features of [[interstitial lung disease]]


=== Other diagnostic studies ===
=== Other diagnostic studies ===
* Transbronchial lung biopsy
* Transbronchial lung biopsy<ref name="pmid8616568">{{cite journal| author=Crausman RS, Jennings CA, Mortenson RL, Ackerson LM, Irvin CG, King TE| title=Lymphangioleiomyomatosis: the pathophysiology of diminished exercise capacity. | journal=Am J Respir Crit Care Med | year= 1996 | volume= 153 | issue= 4 Pt 1 | pages= 1368-76 | pmid=8616568 | doi=10.1164/ajrccm.153.4.8616568 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8616568  }} </ref>.


*Surgical lung biopsy
*Surgical lung biopsy
*On biopsy, the histopathological findings are:
**Proliferation of spindle-shaped myoid cells that are arranged in short fascicles around [[Arteriole|arterioles]], [[Venule|venules]], and [[Lymphatic system|lymphatics]] which causes thickening of [[Alveolus|alveola]]<nowiki/>r septa and formation of cysts.
**The spindle cell proliferation can result in formation of [[Nodule (medicine)|nodules]].
**The tumor cells may invade [[Lymphatic system|lymphatics]] and blood vessels causing secondary [[Bleeding|hemorrhage]] and destruction of the septal wall.
*Immunohistopathological results of the biopsy are:
*Immunohistopathological results of the biopsy are:
**Reactivity with anti–alpha-smooth actin antibodies, which is consistent with smooth-muscle differentiation.
**Reactivity with anti–alpha-smooth [[actin]] [[antibodies]], which is consistent with [[Smooth muscle|smooth-muscle]] differentiation.
**Estrogen and progesterone receptors
**[[Estrogen]] and [[progesterone]] receptors.
**VEGF-D
**[[Vascular endothelial growth factor|VEGF]]-D reactivity.
**HMB-45 antibod
**[[HMB-45|HMB]]-45 antibody reactivity.


== Treatment ==
== Treatment ==


=== Medical Therapy ===
=== Medical Therapy ===
*Sirolimus is used for medical treatment of lymphangiomyomatosis in a dose of 2 mg/day PO for 10-20 days.
*[[Sirolimus]] is used for medical treatment of lymphangiomyomatosis in a dose of 2 mg/day PO for 10-20 days.
*Other medications used are [[Medroxyprogesterone acetate|medroxyprogesterone]], [[gonadotropin-releasing hormone]] agonists, and [[tamoxifen]]<ref name="pmid8623516">{{cite journal| author=Zanella A, Toppan P, Nitti D, Lise M| title=Pulmonary lymphangioleiomyomatosis: a case report in postmenopausal woman treated with pleurodesis and progesterone (medroxyprogesterone acetate). | journal=Tumori | year= 1996 | volume= 82 | issue= 1 | pages= 96-8 | pmid=8623516 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8623516  }} </ref>.


=== Surgery ===
=== Surgery ===
*Lung transplant is performed for patients with recurrent lymphangiomyomatosis resitant to medical therapy.
*[[Lung transplantation|Lung transplan]]<nowiki/>t is performed for patients with recurrent lymphangiomyomatosis resistant to medical therapy<ref name="pmid16685019">{{cite journal| author=Almoosa KF, Ryu JH, Mendez J, Huggins JT, Young LR, Sullivan EJ et al.| title=Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. | journal=Chest | year= 2006 | volume= 129 | issue= 5 | pages= 1274-81 | pmid=16685019 | doi=10.1378/chest.129.5.1274 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16685019  }} </ref>.


=== Prevention===
=== Primary Prevention ===
* Lymphangiomyomatosis cannot be prevented as it is caused due to mutations.
* Lymphangiomyomatosis cannot be prevented as it is caused due to gene mutations, mechanism of which is unknown.


* However, the lung damage can be reduced by using the following measures:
==Secondary Prevention===
** Bronchodilators
* Effective measures for secondary prevention of  lymphangiomyomatosis is reducing lung damage. The lung damage can be reduced by using the following measures:<ref name="pmid16268919">{{cite journal| author=Yen KT, Putzke JD, Staats BA, Burger CD| title=The prevalence of acute response to bronchodilator in pulmonary lymphangioleiomyomatosis. | journal=Respirology | year= 2005 | volume= 10 | issue= 5 | pages= 643-8 | pmid=16268919 | doi=10.1111/j.1440-1843.2005.00762.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16268919  }} </ref>
** Supplemental oxygen
** [[Bronchodilators]]
** Supplemental [[oxygen]]
** Pulmonary rehabilitation
** Pulmonary rehabilitation
** Smoking cessation
** [[Smoking cessation]]
** Standard vaccination for respiratory infections
** Standard vaccination for respiratory infections


Latest revision as of 18:45, 17 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Jogeet Singh Sekhon, M.D. [2]

Synonyms and keywords: Lymphangioleiomyomatosis; LAM; Pulmonary lymphangioleiomyomatosis; Pulmonary lymphangiomyomatosis

Overview

Lymphangiomyomatosis is a disorder resulting from proliferation of abnormal smooth muscle like cells, mostly in the lungs but can also occur in other body parts such as kidney, mediastinum or axial lymphatics. Lymphangiomyomatosis is characterized by small mediastinal or retro- peritoneal tumors which involve the thoracic duct and consist of numerous smooth muscle bundles interspersed with lymphatic channels. Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as asthma, spontaneous pneumothorax, emphysema, interstitial pulmonary fibrosis, eosinophilic granuloma (EG), Birt-Hogg-Dube syndrome, lymphangiomas, pulmonary lymphangiectasis, and leiomyosarcoma. Symptoms of lymphangiomyomatosis may include constipation, dyspnea, and cough. The mainstay of therapy for lymphangiomyomatosisis include sirolimus, medroxyprogesterone, gonadotropin-releasing hormone agonists, and tamoxifen. The most effective treatment is lung transplant.

Historical Perspective

It was first described by Van Stossel in the year 1937.

Classification

Lymphangiomyomatosis is classified into:

Pathophysiology

  • Lymphangiomyomatosis is a disorder resulting from proliferation of abnormal smooth muscle like cells, mostly in the lungs but can also occur in other body parts such as kidney, mediastinum or axial lymphatics[2][3][4].
  • Lymphangiomyomatosis is characterized by small mediastinal or retro- peritoneal tumors which involve the thoracic duct and consist of numerous smooth muscle bundles interspersed with lymphatic channels[5].
  • It can occur in a sporadic form, which only affects females, who are usually of childbearing age.
  • It can also occur in patients who have tuberous sclerosis..
  • Renal angiolipomas are present in 50 % of cases of sporadic lymphangiomyomatosis[6].
  • The tuberous sclerosis complex (TSC) gene mutation has been associated with the development of lymphangiomyomatosis.
  • TSC1 and TSC2 genes located on chromosome 9q34 and 16p13, are involved in the pathogenesis.
  • TSC1 gene is responsible for the production of hamartin protein and TSC2 for the production of tuberin protein.
  • The loss of these proteins along with the influence of estrogen allows the cell to grow and divide in an uncontrolled way, resulting in the tumors and cysts associated with lymphangiomyomatosis.
  • This proliferation of immature muscle cells starts covering alveolar walls, bronchioles, pleura and vessels, including lymphatic routes.
  • Excessive proteolytic activity from the proliferation of the smooth muscle cells result in lung destruction and formation of cysts.
  • These cysts are called lymphangioleiomyomas.
  • Obstruction of lymphatics may result in chylothorax, and chylous ascites[7][8].
  • As the cysts develop throughout the lungs, lymphangiomyomatosis causes breathing problems.
  • The abnormal proliferation and formation of cysts, causes obstructive pattern of lung disease[9].

Causes

  • Lymphangiomyomatosis is caused due to mutations in TSC1 and TSC2 genes.

Differentiating Lymphangiomyomatosis from other Diseases

  • Lymphangiomyomatosis must be differentiated from other diseases that cause similar clinical features, such as:

Epidemiology and Demographics

  • The incidence of lymphangiomyomatosis is 0.2 per 100000 individuals[10].

Age

  • Lymphangiomyomatosis is more commonly observed among female patients aged 15-45 years old.

Gender

  • Lymphangiomyomatosis affects women exclusively who are of reproductive age group.

Race

  • There is no racial predilection for lymphangiomyomatosis.

Natural History, Complications and Prognosis

Natural history

Patients will have a history of[2][11][12][13]:

Complications

Prognosis

  • The prognosis of lymphangiomyomatosis is poor, with 70% of patients not surviving more than 10 years after diagnosis.
  • Poor prognostic factors include:
    • Reduced FEV1.
    • Reduced diffusion lung capacity to carbon monoxide.
    • Formation of cysts in lungs.

Diagnosis

Symptoms

Physical Examination

  • Physical examination may be remarkable for:

Laboratory Findings

Imaging Findings

Other diagnostic studies

  • Transbronchial lung biopsy[9].
  • Surgical lung biopsy
  • On biopsy, the histopathological findings are:
    • Proliferation of spindle-shaped myoid cells that are arranged in short fascicles around arterioles, venules, and lymphatics which causes thickening of alveolar septa and formation of cysts.
    • The spindle cell proliferation can result in formation of nodules.
    • The tumor cells may invade lymphatics and blood vessels causing secondary hemorrhage and destruction of the septal wall.
  • Immunohistopathological results of the biopsy are:

Treatment

Medical Therapy

Surgery

  • Lung transplant is performed for patients with recurrent lymphangiomyomatosis resistant to medical therapy[21].

Primary Prevention

  • Lymphangiomyomatosis cannot be prevented as it is caused due to gene mutations, mechanism of which is unknown.

Secondary Prevention=

  • Effective measures for secondary prevention of lymphangiomyomatosis is reducing lung damage. The lung damage can be reduced by using the following measures:[22]

References

  1. ↑ Kalassian KG, Doyle R, Kao P, Ruoss S, Raffin TA (1997). "Lymphangioleiomyomatosis: new insights". Am J Respir Crit Care Med. 155 (4): 1183–6. doi:10.1164/ajrccm.155.4.9105053. PMID 9105053.
  2. ↑ 2.0 2.1 Sullivan EJ (1998). "Lymphangioleiomyomatosis: a review". Chest. 114 (6): 1689–703. PMID 9872207.
  3. ↑ 3.0 3.1 Johnson S (1999). "Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms". Thorax. 54 (3): 254–64. PMC 1745441. PMID 10325903.
  4. ↑ Matsui K, Tatsuguchi A, Valencia J, Yu Zx, Bechtle J, Beasley MB; et al. (2000). "Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases". Hum Pathol. 31 (10): 1242–8. PMID 11070117.
  5. ↑ Kebria M, Black D, Borelli C, Modica I, Hensley M, Chi DS (2007). "Primary retroperitoneal lymphangioleiomyomatosis in a postmenopausal woman: a case report and review of the literature". Int J Gynecol Cancer. 17 (2): 528–32. doi:10.1111/j.1525-1438.2007.00785.x. PMID 17362325.
  6. ↑ Hancock E, Osborne J (2002). "Lymphangioleiomyomatosis: a review of the literature". Respir Med. 96 (1): 1–6. PMID 11863203.
  7. ↑ Richter MJ, Baumgartner R, Leuchte HH (2013). "[Chylothorax in an 87-year-old patient]". Internist (Berl). 54 (1): 105–9. doi:10.1007/s00108-012-3158-7. PMID 23111591.
  8. ↑ Ryu JH, Doerr CH, Fisher SD, Olson EJ, Sahn SA (2003). "Chylothorax in lymphangioleiomyomatosis". Chest. 123 (2): 623–7. PMID 12576391.
  9. ↑ 9.0 9.1 Crausman RS, Jennings CA, Mortenson RL, Ackerson LM, Irvin CG, King TE (1996). "Lymphangioleiomyomatosis: the pathophysiology of diminished exercise capacity". Am J Respir Crit Care Med. 153 (4 Pt 1): 1368–76. doi:10.1164/ajrccm.153.4.8616568. PMID 8616568.
  10. ↑ Hayashida M, Seyama K, Inoue Y, Fujimoto K, Kubo K, Respiratory Failure Research Group of the Japanese Ministry of Health, Labor, and Welfare (2007). "The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors". Respirology. 12 (4): 523–30. doi:10.1111/j.1440-1843.2007.01101.x. PMID 17587419.
  11. ↑ Baldi BG, Freitas CS, Araujo MS, Dias OM, Pereira DA, Pimenta SP; et al. (2014). "Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre". Sarcoidosis Vasc Diffuse Lung Dis. 31 (2): 129–35. PMID 25078640.
  12. ↑ Nagy B, Nábrády Z, Nemes Z (1998). "Pulmonary lymphangiomyomatosis in a preadolescent girl". N Engl J Med. 338 (7): 473–4. doi:10.1056/NEJM199802123380715. PMID 9463158.
  13. ↑ Johnson SR, Tattersfield AE (2000). "Clinical experience of lymphangioleiomyomatosis in the UK". Thorax. 55 (12): 1052–7. PMC 1745654. PMID 11083892.
  14. ↑ "NHLBI Workshop Summary. Report of workshop on lymphangioleiomyomatosis. National Heart, Lung, and Blood Institute". Am J Respir Crit Care Med. 159 (2): 679–83. 1999. doi:10.1164/ajrccm.159.2.9803107. PMID 9927387.
  15. ↑ Taveira-DaSilva AM, Steagall WK, Rabel A, Hathaway O, Harari S, Cassandro R; et al. (2009). "Reversible airflow obstruction in lymphangioleiomyomatosis". Chest. 136 (6): 1596–1603. doi:10.1378/chest.09-0624. PMC 2818851. PMID 19447921.
  16. ↑ Warren SE, Lee D, Martin V, Messink W (1993). "Pulmonary lymphangiomyomatosis causing bilateral pneumothorax during pregnancy". Ann Thorac Surg. 55 (4): 998–1000. PMID 8466360.
  17. ↑ Corrin B, Liebow AA, Friedman PJ (1975). "Pulmonary lymphangiomyomatosis. A review". Am J Pathol. 79 (2): 348–82. PMC 1912658. PMID 1146965.
  18. ↑ Taylor JR, Ryu J, Colby TV, Raffin TA (1990). "Lymphangioleiomyomatosis. Clinical course in 32 patients". N Engl J Med. 323 (18): 1254–60. doi:10.1056/NEJM199011013231807. PMID 2215609.
  19. ↑ Lama A, Ferreiro L, Golpe A, Gude F, Álvarez-Dobaño JM, González-Barcala FJ; et al. (2016). "Characteristics of Patients with Lymphangioleiomyomatosis and Pleural Effusion: A Systematic Review". Respiration. 91 (3): 256–64. doi:10.1159/000444264. PMID 26938102.
  20. ↑ Zanella A, Toppan P, Nitti D, Lise M (1996). "Pulmonary lymphangioleiomyomatosis: a case report in postmenopausal woman treated with pleurodesis and progesterone (medroxyprogesterone acetate)". Tumori. 82 (1): 96–8. PMID 8623516.
  21. ↑ Almoosa KF, Ryu JH, Mendez J, Huggins JT, Young LR, Sullivan EJ; et al. (2006). "Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications". Chest. 129 (5): 1274–81. doi:10.1378/chest.129.5.1274. PMID 16685019.
  22. ↑ Yen KT, Putzke JD, Staats BA, Burger CD (2005). "The prevalence of acute response to bronchodilator in pulmonary lymphangioleiomyomatosis". Respirology. 10 (5): 643–8. doi:10.1111/j.1440-1843.2005.00762.x. PMID 16268919.
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