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Lymphangioleiomyomatosis

Changed by Rohit Sharma, 25 Oct 2021
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Lymphangioleiomyomatosis (LAM) is a low-grade destructive metastasising PEComatous tumour, resulting from proliferation of LAM cells in lung, kidney and axial lymphatics. Disease is caused by mutations of the TSC2 or TSC1 genes and is most commonly sporadic. Cystic lung disease is the most frequent manifestation.

Epidemiology

Cystic lung disease almost exclusively affects women, with very few reported affected men with tuberous sclerosis (TSC). Diagnosis is typically delayed and advanced cystic lung destruction may be mistaken for emphysema. The true prevalence may be as high as 8:1,000,0001.

Sporadic LAM (s-LAM) may be a forme fruste of TSC. In s-LAM the mutations are somatic and not heritable, whereas in TSC germ-linegermline mutations are inherited in an autosomal dominant fashion. Even in TSC, sporadic mutations outnumber inherited disease 2:1. TSC may be under-diagnosed due to the attached stigma.

Clinical presentation

WomanAdult presentation of child-bearing age with:

  • Progressiveprogressive dyspnoea
    • the disease is variable, the average age of onset of symptoms is about 35 years of age and untreated patients become dependent on home oxygen about 10 years afterwards
  • Pneumothoraxpneumothorax
  • Haemoptysishaemoptysis
  • Acuteacute abdominal pain due to haemorrhagic renal angiomyolipoma (AML) 

Diagnosis

American Thoracic Society/Japanese Respiratory Society guidelines 2017 support a clinical diagnosis of LAM based on typical lung CT and accompanied by any of the following:

  • TSC
  • Renalrenal angiomyolipoma
  • Cysticcystic lymphangioleiomyoma
  • Chylouschylous pleural effusions in the chest and/or abdomen

TheyThis society also recommendrecommends testing for vascular endothelial growth factor D (VEGF D) before resorting to lung biopsy which must be stained appropriately, including for HMB-45.

Pathology

​Tissues are infiltrated by smooth muscle-like LAM cells containing inactivating mutations of TSC2 or TSC1 tumour suppressor genes. Consequent activation of the mechanistic target of rapamycin (mTOR) signalling pathway results in proliferation of LAM cells which coat alveolar walls, bronchioles, pleura, venules and lymphatics, causing obstruction and cystic lung destruction. LAM cells express oestrogen receptors and functional decline accelerates during pregnancy. Oestrogen is a driver of LAM cell proliferation and lymphatic dissemination.

Radiographic features

Chest:Pulmonary features
Radiography:Plain radiograph
  • Largelarge volume lungs with abnormal architecture mimicking emphysema in advanced disease
  • Chylouschylous pleural effusions
  • Pneumothoraxpneumothorax
CT:
  • Largelarge lungs containing scattered thin-walled rounded empty cysts. Early on
    • in early disease, the cysts are few and small with normal intervening lung parenchyma. The
    • the cysts progressively enlarge and become more numerous until there is little normal lung remaining.
  • Transienttransient areas of increased lung opacity due to haemorrhage.
  • Smallsmall lung nodules representing multifocal micronodular pneumocyte hyperplasia (MMPH)
  • Pneumothoraxpneumothorax
  • Effusions (chylous)chylous pleural effusions
  • myocardial fatty foci in TSC12
AbdomenExtra-pulmonary features

In the abdomen and pelvis:

  • Multiplemultiple renal AMLs, especially common in TSC2,3
  • Hepatichepatic or retroperitoneal AMLs
  • Ascites (chylous)chylous ascites
  • Lymphangioleiomyomaslymphangioleiomyomas: soft cystic/solid masses which can insinuate between normal structures without compressing them
  • Lymphadenopathylymphadenopathy
Bone

In bones:

  • Multiplemultiple osteoblastic bone lesions in TSC, similar in appearance to enostoses

Treatment and prognosis

  • The disease is variable

    There are few medications which have been shown to benefit patients with LAM, with sirolimus being one of the average age of onset of symptoms is about 35 years of age and untreated patients become dependent on home oxygen about 10 years afterwards

  • Menopause: decline in lung function slows after menopause or oophorectomy 
  • main treatment options. Sirolimus limits LAM cell proliferation by inhibiting the activated mTOR pathway, thereby improving lung function, at least in the short-term, and often shrinking masses and chylous effusions. Progression resumes on cessation
  • Chloroquine may kill TSC2-deficient cells and is being trialled as an adjunct to Sirolimus
  • Letrozole is an aromatase inhibitor that inhibits

    ​Other potential therapies, depending on

     the conversion of androgens to oestrogen and is undergoing trials as a treatment for LAM
    • manifestations expressed, include:
  • VATS pleurodesis for recurrent pneumothorax  
  • Lunglung transplantation for respiratory failure
  • TSC patients should receive genetic counselling if TSC

Complications

  • Respiratoryrespiratory failure
  • Recurrentrecurrent pneumothorax 
  • Haemorrhagichaemorrhagic AML
  • Sirolimussirolimus toxicity, including organizingorganising pneumonia, BOOPcryptogenic organising pneumonia, interstitial pneumonitis, focal fibrosis or alveolar haemorrhage, which may be dose-related and reversible
  • Suddensudden death due to obstructing subependymal giant cell astrocytoma in TSC 

Differential diagnosis

  • Emphysemaemphysema is
    • similar in appearance to advanced cystic lung disease in LAM. In
    • in the least affected areas, LAM will have typical cysts separated by normal parenchyma
  • Lymphocyticlymphocytic interstitial pneumonitis (LIP) in
    • ​in women of child-bearing age, LIP is usually associated with connective tissue disease, especially Sjögren's syndrome. A
    • a smaller number of lower zone predominant perivascular cysts, some with internal soft-tissue may coexist with nodules, ground-glass opacity,  tree-in bud opacities, lymphoma or amyloid deposits. Lung
    • lung changes may pre-date typical serological abnormalities
  • Lightlight-chain deposition disease
    • Pulmonary Langerhans cell histiocystosis is usually smoking-related in young adults, often male, and is typically upper zone predominant, sparing costophrenic and costomediastinal angles. Bronchocentric nodular inflammation leads to bronchial wall destruction and irregular branching cystic cavities
    • light-chain deposition disease typically occurs in an older adult with plasma cell dyscrasia (e.g. multiple myeloma) and renal failure with findings of cysts, nodules and lymphadenopathy
  • pulmonary Langerhans cell histiocystosis
    • upper zone predominant and bronchocentric cavitating nodules, branching or irregular cysts
    • spares costophrenic and costomediastinal angles
    • typically a disease of young adult smokers, especially men
  • -<p><strong>Lymphangioleiomyomatosis (LAM)</strong> is a low-grade destructive metastasising <a title="PEComatous tumor" href="/articles/perivascular-epithelioid-cell-tumours-pecomas-1">PEComatous</a><a title="PEComatous tumour" href="/articles/pecomatous-tumour"> tumour</a>, resulting from proliferation of LAM cells in lung, kidney and axial lymphatics. Disease is caused by mutations of the TSC2 or TSC1 genes and is most commonly sporadic. Cystic lung disease is the most frequent manifestation.</p><h4><strong>Epidemiology</strong></h4><p>Cystic lung disease almost exclusively affects women, with very few reported affected men with <a title="tuberous sclerosis (TSC)" href="/articles/tuberous-sclerosis-tsc">tuberous sclerosis (TSC)</a>. Diagnosis is typically delayed and advanced cystic lung destruction may be mistaken for <a title="Emphysema of lung - general" href="/articles/pulmonary-emphysema">emphysema</a>. The true prevalence may be as high as 8:1,000,000<sup>1</sup>. </p><p>Sporadic LAM (s-LAM) may be a <em>forme</em> <em>fruste</em> of TSC. In s-LAM the mutations are somatic and not heritable, whereas in TSC germ-line mutations are inherited in an autosomal dominant fashion. Even in TSC, sporadic mutations outnumber inherited disease 2:1. TSC may be under-diagnosed due to the attached stigma.</p><h4>Clinical presentation</h4><p>Woman of child-bearing age with:</p><ul>
  • -<li>Progressive dyspnoea</li>
  • -<li>Pneumothorax</li>
  • -<li>Haemoptysis</li>
  • -<li>Acute abdominal pain due to haemorrhagic renal <a title="Renal angiomyolipoma (AML)" href="/articles/renal-angiomyolipoma">angiomyolipoma (AML)</a> </li>
  • +<p><strong>Lymphangioleiomyomatosis (LAM)</strong> is a low-grade destructive metastasising <a href="/articles/perivascular-epithelioid-cell-tumours-pecomas-1">PEComatous</a><a href="/articles/pecomatous-tumour"> tumour</a>, resulting from proliferation of LAM cells in lung, kidney and axial lymphatics. Disease is caused by mutations of the <em>TSC2</em> or <em>TSC1</em> genes and is most commonly sporadic. Cystic lung disease is the most frequent manifestation.</p><h4>Epidemiology</h4><p>Cystic lung disease almost exclusively affects women, with very few reported affected men with <a href="/articles/tuberous-sclerosis-tsc">tuberous sclerosis (TSC)</a>. Diagnosis is typically delayed and advanced cystic lung destruction may be mistaken for <a href="/articles/pulmonary-emphysema">emphysema</a>. The true prevalence may be as high as 8:1,000,000 <sup>1</sup>.</p><p>Sporadic LAM (s-LAM) may be a <em>forme</em> <em>fruste</em> of TSC. In s-LAM the mutations are somatic and not heritable, whereas in TSC germline mutations are inherited in an autosomal dominant fashion. Even in TSC, sporadic mutations outnumber inherited disease 2:1. TSC may be under-diagnosed due to the attached stigma.</p><h4>Clinical presentation</h4><p>Adult presentation of:</p><ul>
  • +<li>progressive dyspnoea<ul><li>the disease is variable, the average age of onset of symptoms is about 35 years of age and untreated patients become dependent on home oxygen about 10 years afterwards</li></ul>
  • +</li>
  • +<li>pneumothorax</li>
  • +<li>haemoptysis</li>
  • +<li>acute abdominal pain due to haemorrhagic renal <a href="/articles/renal-angiomyolipoma">angiomyolipoma (AML)</a> </li>
  • -<li>Renal angiomyolipoma</li>
  • -<li>Cystic lymphangioleiomyoma</li>
  • -<li>Chylous pleural effusions in the chest and/or abdomen</li>
  • -</ul><p>They also recommend testing for vascular endothelial growth factor D (VEGF D) before resorting to lung biopsy which must be stained appropriately, including for HMB-45.</p><h4>Pathology</h4><p>​Tissues are infiltrated by smooth muscle-like LAM cells containing inactivating mutations of TSC2 or TSC1 tumour suppressor genes. Consequent activation of the mechanistic target of rapamycin (mTOR) signalling pathway results in proliferation of LAM cells which coat alveolar walls, bronchioles, pleura, venules and lymphatics, causing obstruction and cystic lung destruction. LAM cells express oestrogen receptors and functional decline accelerates during pregnancy. Oestrogen is a driver of LAM cell proliferation and lymphatic dissemination.</p><h4>Radiographic features</h4><h5>Chest:</h5><h6>Radiography:</h6><ul>
  • -<li>Large volume lungs with abnormal architecture mimicking emphysema in advanced disease</li>
  • -<li>Chylous effusions</li>
  • -<li>Pneumothorax</li>
  • -</ul><h6>CT:</h6><ul>
  • -<li>Large lungs containing scattered thin-walled rounded empty cysts. Early on, the cysts are few and small with normal intervening lung parenchyma. The cysts progressively enlarge and become more numerous until there is little normal lung remaining.</li>
  • -<li>Transient areas of increased lung opacity due to haemorrhage.</li>
  • -<li>Small lung nodules representing <a title="Multifocal micronodular pneumocyte hyperplasia (MMPH)" href="/articles/multifocal-micronodular-pneumocyte-hyperplasia">multifocal micronodular pneumocyte hyperplasia (MMPH)</a>
  • -</li>
  • -<li>Pneumothorax</li>
  • -<li>Effusions (chylous)</li>
  • -<li>
  • -<a title="Myocardial fatty foci" href="/articles/myocardial-fatty-foci">Myocardial fatty foci</a> in TSC<sup>12</sup>
  • -</li>
  • -</ul><h5>Abdomen and pelvis:</h5><ul>
  • -<li>Multiple renal AMLs, especially common in TSC<sup>2,3</sup>
  • -</li>
  • -<li>Hepatic or retroperitoneal AMLs</li>
  • -<li>Ascites (chylous)</li>
  • -<li>Lymphangioleiomyomas: soft cystic/solid masses which can insinuate between normal structures without compressing them</li>
  • -<li>Lymphadenopathy</li>
  • -</ul><h5>Bone</h5><ul><li>Multiple osteoblastic bone lesions in TSC, similar in appearance to enostoses</li></ul><h4>Treatment and prognosis</h4><ul>
  • -<li>The disease is variable, the average age of onset of symptoms is about 35 years of age and untreated patients become dependent on home oxygen about 10 years afterwards</li>
  • -<li>Menopause: decline in lung function slows after menopause or oophorectomy </li>
  • -<li>Sirolimus limits LAM cell proliferation by inhibiting the activated mTOR pathway, thereby improving lung function, at least in the short-term, and often shrinking masses and chylous effusions. Progression resumes on cessation</li>
  • -<li>Chloroquine may kill TSC2-deficient cells and is being trialled as an adjunct to Sirolimus</li>
  • -<li>Letrozole is an aromatase inhibitor that inhibits the conversion of androgens to oestrogen and is undergoing trials as a treatment for LAM</li>
  • +<li>renal angiomyolipoma</li>
  • +<li>cystic lymphangioleiomyoma</li>
  • +<li>chylous pleural effusions in the chest and/or abdomen</li>
  • +</ul><p>This society also recommends testing for vascular endothelial growth factor D (VEGF D) before resorting to lung biopsy which must be stained appropriately, including for HMB-45.</p><h4>Pathology</h4><p>​Tissues are infiltrated by smooth muscle-like LAM cells containing inactivating mutations of <em>TSC2</em> or <em>TSC1</em> tumour suppressor genes. Consequent activation of the mechanistic target of rapamycin (mTOR) signalling pathway results in proliferation of LAM cells which coat alveolar walls, bronchioles, pleura, venules and lymphatics, causing obstruction and cystic lung destruction. LAM cells express oestrogen receptors and functional decline accelerates during pregnancy. Oestrogen is a driver of LAM cell proliferation and lymphatic dissemination.</p><h4>Radiographic features</h4><h5>Pulmonary features</h5><h6>Plain radiograph</h6><ul>
  • +<li>large volume lungs with abnormal architecture mimicking emphysema in advanced disease</li>
  • +<li>chylous pleural effusions</li>
  • +<li>pneumothorax</li>
  • +</ul><h6>CT</h6><ul>
  • +<li>large lungs containing scattered thin-walled rounded empty cysts<ul>
  • +<li>in early disease, the cysts are few and small with normal intervening lung parenchyma</li>
  • +<li>the cysts progressively enlarge and become more numerous until there is little normal lung remaining</li>
  • +</ul>
  • +</li>
  • +<li>transient areas of increased lung opacity due to haemorrhage</li>
  • +<li>small lung nodules representing <a href="/articles/multifocal-micronodular-pneumocyte-hyperplasia">multifocal micronodular pneumocyte hyperplasia (MMPH)</a>
  • +</li>
  • +<li>pneumothorax</li>
  • +<li>chylous pleural effusions</li>
  • +<li>
  • +<a href="/articles/myocardial-fatty-foci">myocardial fatty foci</a> in TSC <sup>12</sup>
  • +</li>
  • +</ul><h5>Extra-pulmonary features</h5><p>In the abdomen and pelvis:</p><ul>
  • +<li>multiple renal AMLs, especially common in TSC <sup>2,3</sup>
  • +</li>
  • +<li>hepatic or retroperitoneal AMLs</li>
  • +<li>chylous ascites</li>
  • +<li>lymphangioleiomyomas: soft cystic/solid masses which can insinuate between normal structures without compressing them</li>
  • +<li>lymphadenopathy</li>
  • +</ul><p>In bones:</p><ul><li>multiple osteoblastic bone lesions in TSC, similar in appearance to enostoses</li></ul><h4>Treatment and prognosis</h4><p>There are few medications which have been shown to benefit patients with LAM, with sirolimus being one of the main treatment options. Sirolimus limits LAM cell proliferation by inhibiting the activated mTOR pathway, thereby improving lung function, at least in the short-term, and often shrinking masses and chylous effusions. Progression resumes on cessation</p><p>​Other potential therapies, depending on the manifestations expressed, include:</p><ul>
  • -<li>Lung transplantation for respiratory failure</li>
  • -<li>TSC patients should receive genetic counselling</li>
  • -</ul><p><strong>Complications</strong></p><ul>
  • -<li>Respiratory failure</li>
  • -<li>Recurrent pneumothorax </li>
  • -<li>Haemorrhagic AML</li>
  • -<li>Sirolimus toxicity, including organizing pneumonia, BOOP, interstitial pneumonitis, focal fibrosis or alveolar haemorrhage, which may be dose-related and reversible</li>
  • -<li>Sudden death due to obstructing subependymal giant cell astrocytoma in TSC </li>
  • +<li>lung transplantation for respiratory failure</li>
  • +<li>genetic counselling if TSC</li>
  • +</ul><h5>Complications</h5><ul>
  • +<li>respiratory failure</li>
  • +<li>recurrent pneumothorax </li>
  • +<li>haemorrhagic AML</li>
  • +<li>sirolimus toxicity, including <a title="Organising pneumonia" href="/articles/organising-pneumonia">organising pneumonia</a>, <a title="Cryptogenic organising pneumonia" href="/articles/cryptogenic-organising-pneumonia-1">cryptogenic organising pneumonia</a>, <a title="Acute interstitial pneumonitis" href="/articles/acute-interstitial-pneumonitis">interstitial pneumonitis</a>, focal fibrosis or alveolar haemorrhage</li>
  • +<li>sudden death due to obstructing subependymal giant cell astrocytoma in TSC </li>
  • -<a href="/articles/pulmonary-emphysema">Emphysema</a> is similar in appearance to advanced cystic lung disease in LAM. In the least affected areas, LAM will have typical cysts separated by normal parenchyma</li>
  • +<a href="/articles/pulmonary-emphysema">emphysema</a><ul>
  • +<li>similar in appearance to advanced cystic lung disease in LAM</li>
  • +<li>in the least affected areas, LAM will have typical cysts separated by normal parenchyma</li>
  • +</ul>
  • +</li>
  • +<li>
  • +<a href="/articles/lymphocytic-interstitial-pneumonitis-1">lymphocytic interstitial pneumonitis (LIP</a><a href="/articles/lymphocytic-interstitial-pneumonitis-1">)</a><ul>
  • -<a href="/articles/lymphocytic-interstitial-pneumonitis-1">L</a><a href="/articles/lymphocytic-interstitial-pneumonitis-1">ymphocytic interstitial pneumonitis (LIP</a><a href="/articles/lymphocytic-interstitial-pneumonitis-1">)</a> in women of child-bearing age is usually associated with connective tissue disease especially Sjögren's syndrome. A smaller number of lower zone predominant perivascular cysts, some with internal soft-tissue may coexist with nodules, ground-glass opacity,  tree-in bud opacities, lymphoma or amyloid deposits. Lung changes may pre-date typical serological abnormalities</li>
  • -<li><a href="/articles/light-chain-deposition-disease">Light-chain deposition disease</a></li>
  • +<a href="/articles/lymphocytic-interstitial-pneumonitis-1">​</a>in women of child-bearing age, LIP is usually associated with connective tissue disease, especially <a title="Sjogren disease" href="/articles/sjogren-syndrome-1">Sjögren syndrome</a>
  • +</li>
  • +<li>a smaller number of lower zone predominant perivascular cysts, some with internal soft-tissue may coexist with nodules, ground-glass opacity,  tree-in bud opacities, lymphoma or amyloid deposits</li>
  • +<li>lung changes may pre-date typical serological abnormalities</li>
  • +</ul>
  • +</li>
  • -<a href="/articles/pulmonary-langerhans-cell-histiocystosis">Pulmonary Langerhans cell histiocystosis</a> is usually smoking-related in young adults, often male, and is typically upper zone predominant, sparing costophrenic and costomediastinal angles. Bronchocentric nodular inflammation leads to bronchial wall destruction and irregular branching cystic cavities</li>
  • +<a href="/articles/light-chain-deposition-disease">light-chain deposition disease</a><ul><li>typically occurs in an older adult with plasma cell dyscrasia (e.g. multiple myeloma) and renal failure with findings of cysts, nodules and lymphadenopathy</li></ul>
  • +</li>
  • -<a title="light-chain deposition disease" href="/articles/light-chain-deposition-disease">light-chain deposition disease </a>typically occurs in an older adult with plasma cell dyscrasia (e.g. multiple myeloma) and renal failure with findings of cysts, nodules and lymphadenopathy </li>
  • +<a href="/articles/pulmonary-langerhans-cell-histiocystosis">pulmonary Langerhans cell histiocystosis</a><ul>
  • +<li>upper zone predominant and bronchocentric cavitating nodules, branching or irregular cysts</li>
  • +<li>spares costophrenic and costomediastinal angles</li>
  • +<li>typically a disease of young adult smokers, especially men</li>
  • +</ul>
  • +</li>

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