Lymphangiomyomatosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Varun Kumar, M.B.B.S. [2] Ammu Susheela, M.D. [3]

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

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.

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 angiomyolipomas 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 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 similar to emphysema.
• The abnormal poliferation 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
• Leiomyosarcoma
• Langerhans cell histiocytosis (LCH)

Epidemiology and Demographics

• Till date, 1500 cases of sporadic cases of lymphangiomyomatosis was estimated to be in United States.

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

• Common complications of lymphangiomyomatosis include ascitis, chylous pleural effusion, pneumothorax, hemoptysis, chyloptysis, chyluria, hematuria, pericardial effusion, pneumoperitoneum, lymphedema, respiratory failure, osteoporosis, and meningioma.

Diagnosis

Symptoms

• Symptoms of lymphangiomyomatosis may include the following:

• Constipation
• Dyspnea
• Cough

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

• There are no specific laboratory findings associated with lymphangiomyomatosis.

Imaging Findings

• With lmphangiomyomatosis, there is diffuse replacement of the pulmonary parenchyma by thin-walled cysts measuring 2-20 mm in diameter, with equal involvement of upper and lower lung zones. On chest X-rays, superimposition of the cysts gives a reticulonodular pattern of interstitial lung disease.

Other Diagnostic Studies

• Lymphangiomyomatosis may also be diagnosed using immunohistochemistry.
• Findings on immunohistochemistry include Flt-4 (VEGFR-3).

Treatment

Medical Therapy

• The mainstay of therapy for lymphangiomyomatosisis include sirolimus, medroxyprogesterone, gonadotropin-releasing hormone agonists, and tamoxifen.

Surgery

• Surgical intervention can only be performed for patients with receuurent lymphangiomyomatosis resitant to medical therapy.