Pulmonary Lymphangiomatosis

Overview

Diffuse pulmonary lymphangiomatosis is a disease in which the overgrowth (proliferation) of lymphatic vessels (lymphangiomatosis) occurs in the lungs, pleura and typically the surrounding soft tissue of the chest (mediastinum). Lymphatic vessels are part of the lymphatic system, which includes lymph nodes, the small nodules where certain white blood cells (lymphocytes) and other cells participate in the immune regulatory system of the body. When fluid leaves arteries and enters the soft tissue and organs of the body, it does so without red or white blood cells. This thin watery fluid is known as lymph. The lymphatic system consists of a network of tubular channels (lymph vessels) that transport lymph back into the bloodstream. Lymph accumulates between tissue cells and contains proteins, fats, and lymphocytes. As lymph moves through the lymphatic system, it passes through the network of lymph nodes that help the body to deactivate sources of infection (e.g., viruses, bacteria, etc.) and other potentially injurious substances and toxins. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes; and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. 

Lymphangiomatosis can potentially affect any part of the body except the brain. The disorder can be widespread, affecting multiple areas simultaneously, as in the case of diffuse pulmonary lymphangiomatosis, or be isolated to one area (i.e. the lungs and chest). The specific symptoms and severity vary, depending in part upon the size and the specific location of the abnormalities. Diffuse pulmonary lymphangiomatosis causes functional impairment of the lungs and when the chest wall is involved, may be associated with disfigurement. The exact cause of diffuse pulmonary lymphangiomatosis is unknown.

Pulmonary lymphangiomatosis has two histologic patterns, conventional and Kaposiform, and in both is a bilateral process. 

Symptoms

The symptoms and severity of diffuse pulmonary lymphangiomatosis can vary from one person to another and here is no typical or standard presentation for the disorder. Generally, pulmonary lymphangiomatosis progresses faster in children than adults. Some individuals may eventually experience life-threatening complications, while others have mild symptoms that can go undiagnosed well until adulthood. Consequently, it is important to note that one person’s experience can vary dramatically from another’s. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. 

The specific symptoms associated with diffuse pulmonary lymphangiomatosis depend upon the size and exact location of affected lymphatic vessels. The disorder often causes a variety of general, nonspecific symptoms including fatigue and nausea as well as symptoms more directly related to the chest, including chest pain, wheezing, shortness of breath (dyspnea), chronic cough, and coughing up blood (hemoptysis). Chest tightness, recurrent respiratory infections and recurrent pneumonia have also been reported in individuals with diffuse pulmonary lymphangiomatosis. Some individuals give a history of asthma. 

Diffuse pulmonary lymphangiomatosis can eventually cause compression of nearby structures in the chest, bony destruction leading to the appearance of "holes" in adjacent bones (lytic bone lesions), and other complications such as the accumulation of lymph fluid (chyle) in the space between the lung surface and chest wall (pleural space), a condition known as chylous pleural effusions. A collapsed lung (pneumothorax) can also occur. Some of these complications can be life-threatening e.g. when chylous pleural effusions become large enough to make breathing difficult, and when chyle accumulates in the sac around the heart (pericardial effusion) and makes it difficult for the heart to pump blood. The excess fluid in the lungs and other spaces also can lead to severe infection, as bacteria can rest in these excess fluid pockets.

Causes

The exact cause of diffuse pulmonary lymphangiomatosis is unknown. Lymphangiomatosis in general is believed to result from abnormalities in the development of the lymphatic vascular system during embryonic growth. No environmental, immunological or genetic risk factors that may play a role in the development of the disorder have been identified. 

The symptoms of diffuse pulmonary lymphangiomatosis are caused by complications due to the overproduction (proliferation), widening (dilation), and thickening of lymphatic vessels throughout the lungs. 

Researchers are studying whether vascular endothelial growth factor receptor 3 (VEGFR-3) plays a role in the development of lymphangiomatosis. Researchers have determined that affected tissue in individuals with lymphangiomatosis have high levels of VEGFR-3, a chemical that most likely promotes the growth of lymphatic vessels. A better understanding of such underlying mechanisms should lead to targeted therapies for individuals with lymphangiomatosis.

Diagnosis

Pulmonary lymphangiomatosis has two histologic patterns, conventional and Kaposiform, and in both is a bilateral process. The more conventional appearance is with marked widening of the pleura, interlobular septa, and bronchovascular bundles by proliferated and somewhat dilated lymphatic channels. These channels are often accompanied by bundles of smooth muscle and small lymphoid aggregates, similar to those seen in lymphangiomatous lesions elsewhere in the body.

In the Kaposiform variant, the lymphatic channels may be difficult to identify in a background of proliferated fibrous stroma, lymphatic endothelial hyperplasia, and hemosiderin deposition. Both forms are progressive with gradual limitation of lung volume and restrictive changes; although the lung parenchyma is constricted, it is not actually encroached on by the proliferated lymphatics and perilymphatic tissues. There is currently no effective therapy short of lung transplatation, which cannot be used in the Kaposiform variant due to the intense pleural scarring that these patients manifest.

A diagnosis of diffuse pulmonary lymphangiomatosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Because of the disorder’s rarity and varying presentation in each individual, obtaining a correct diagnosis can be challenging.

Pulmonary function tests may be used to help diagnose diffuse pulmonary lymphangiomatosis. This group of tests can evaluate how well the lungs are functioning. Affected individuals often have a restrictive pattern or a mixed restrictive and obstructive pattern of lung function. 

Lymphoscintigraphy is a specialized procedure in which small amounts of radioactive material is used to help create pictures (called scintigrams) of the lymphatic system. Lymphoscintigraphy is used to help obtain a diagnosis of lymphatic disease and/or to assess the extent of the disease. 

Surgical removal and microscopic examination of affected lung tissue (lung biopsy) may be used to confirm a diagnosis of diffuse pulmonary lymphangiomatosis. However, a lung biopsy is not always possible and can be associated with complications such as the accumulation of chyle within the thoracic cavity and around the lungs (chylothorax). If an area of bone is affected, a bone biopsy may be performed. 

Various imaging techniques including plain x-rays, ultrasound, computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to determine the location, behavior and extent of the disorder. Plain x-rays can reveal snow-white patches (infiltrates) or chylous effusions. During and ultrasound, high-frequency radio waves are used to create a picture of internal organs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.

Treatment

The treatment of diffuse pulmonary lymphangiomatosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, pulmonologists, radiologists, and other healthcare professionals may need to systematically and comprehensively plan effective treatment. In extremely rare cases, spontaneous remission, in which symptoms go away on their own, has been reported. 

Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the size and location of the lymphatic abnormalities; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient or parents based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. 

A wide variety of potential therapies have been tried in individuals with diffuse pulmonary lymphangiomatosis. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with diffuse pulmonary lymphangiomatosis. 

Surgical removal (excision) of affected tissue can be performed and has been effective in some cases when the disease is more localized. However this is typically not the case in diffuse pulmonary lymphangiomatosis. When surgery is attempted, diseased lymphatic tissue is often difficult to distinguish from healthy tissue, making it challenging to completely remove all affected tissue. Any diseased tissue left behind can cause recurrence of the disorder. In addition, it may be impossible to remove all of the diseased lymphatic tissue because of its location near or around vital organs. 

Sclerotherapy is a procedure in which a solution, called a sclerosant or sclerosing agent, is injected directly into the lesion. This solution causes scarring within the lesion, eventually causing it to shrink or collapse. In most cases, the antibiotic doxycycline is the sclerosing agent used. Sclerotherapy may require multiple sessions to be effective and has demonstrated good results in some cases. Again, however, this is of limited value in a widespread disease such as diffuse pulmonary lymphangiomatosis. 

A variety of drugs have been reported in the medical literature for the treatment of individuals with diffuse pulmonary lymphangiomatosis. Two commonly used drugs are interferon alfa 2b and glucocorticoids. Other medications that have been tried include bisphosphates, thalidomide, and rapamycin. Recently, researchers have reported encouraging results with drugs that inhibit, either directly or indirectly, the production of vascular endothelial growth factor receptor 3 (VEGFR-3), specifically the drugs propranolol and bevacizumab. 

Radiotherapy, or the use of radiation to destroy affected tissue, has also been tried in individuals with diffuse pulmonary lymphangiomatosis where surgery is not an option. 

Some individuals have been treated by dietary adjustments such as restricting fat, except for a particular type of fat known as medium chain triglycerides. Dietary treatments, however, have generally proven ineffective. Drainage of fluid around lungs and heart may be necessary in some cases (pleural or pericardial drainage). Some individuals have also undergone artificial destruction of the pleural space (pleurodesis) to prevent fluid accumulation there. Surgical removal of part of the pleura has also been tried (pleurectomy). Lung transplantation has been used to treat some patients with severe disease that has not responded to any other therapy, but due to the extensive nature of the disease in the chest, this surgery can be very challenging.

Resources

Lymphangiomatosis & Gorham's Disease Alliance