Lymphangiomyomatosis

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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:

• Sporadic lymphangiomyomatosis, (when it occurs without tuberous sclerosis).
• Lymphangiomyomatosis with tuberous sclerosis, (when it occurs in patients of tuberous sclerosis).

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 characterized by small mediastinal or retro- peritoneal tumors which involve the thoracic duct and consist of numerous smooth muscle bundles interspersed with lymphatic channels.

• 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.
• 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.
• As the cysts develop throughout the lungs, lymphangiomyomatosis causes breathing problems.
• The abnormal proliferation and formation of cysts, causes obstructive pattern of lung disease.

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:

• Asthma
• Spontaneous pneumothorax
• Emphysema
• Interstitial pulmonary fibrosis
• Eosinophilic granuloma (EG)
• Birt-Hogg-Dube syndrome
• Lymphangiomas
• Pulmonary lymphangiectasis
• Langerhans cell histiocytosis (LCH)

Epidemiology and Demographics

• The incidence of lymphangiomyomatosis is 0.2 per 100000 individuals.

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:

• Dyspnea
• Bluish discoloration of lips (cyanosis)
• Cough
• Chest pain
• Weight loss
• Blood in sputum
• Headache
• Pain abdomen

Complications

• Ascites
• Pleural effusion
• pneumothorax
• Chylothorax
• Hemoptysis
• Chyloptysis
• Chyluria
• Haematuria
• Pericardial effusion
• Pneumoperitoneum
• Lymphedema
• Respiratory failure
• Osteoporosis
• Meningioma.

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

• Symptoms of lymphangiomyomatosis may include the following:
  • Difficulty in breathing
  • Bluish discoloration of lips (cyanosis)
  • Cough
  • Chest pain
  • Weight loss
  • Blood in sputum
  • Headache
  • Pain abdomen

Physical Examination

• Physical examination may be remarkable for:

• Crackles
• Wheezes
• Pleural effusion
• Pneumothorax
• Ascites
• Facial angiofibromas
• Periungual fibromas
• Hypomelanotic macules, ash-leaf spots
• Shagreen patch
• Forehead plaque
• Retinal hamartoma

Laboratory Findings

• Pulmonary function tests are used to assess the lung damage caused by lymphangiomyomatosis.
  • Reduced FEV1.
  • Reduced diffusion lung capacity to carbon monoxide.
  • Increased residual volume.
  • Obstructive pattern on spirometry.
  • 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.

Imaging Findings

• CT scan is used to diagnose lymphangiomyomatosis.
• Lymphangiomyomatosis appears as well-circumscribed lobular, thin or thick-walled masses without evidence of necrosis or hemorrhage.
• Other findings are:
  • Diffuse thin-walled cysts.
  • Adenopathy and thoracic duct dilatation.
  • Pleural effusion
  • Pneumothorax
  • Ground-glass opacities
  • Pericardial effusion
  • Chylothorax
  • Mediastinal lymphadenopathy
  • Dilated thoracic duct
  • Cystic lymph nodal lesions
  • Renal angiolipomas in 50% of cases.
  • Features of interstitial lung disease

Other diagnostic studies

• Transbronchial lung biopsy.

• 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:
  • Reactivity with anti–alpha-smooth actin antibodies, which is consistent with smooth-muscle differentiation.
  • Estrogen and progesterone receptors.
  • VEGF-D reactivity.
  • HMB-45 antibody reactivity.

Treatment

Medical Therapy

• 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, gonadotropin-releasing hormone agonists, and tamoxifen.

Surgery

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

Prevention

• 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:
  • Bronchodilators
  • Supplemental oxygen
  • Pulmonary rehabilitation
  • Smoking cessation
  • Standard vaccination for respiratory infections