Rare Lung Disease II

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General Information

Rare Lung Disease Week II

Generalized lymphatic anomaly (GLA), also known as lymphangiomatosis, is a rare heterogeneous non-hereditary disorder that affects people of all ages, race and sex, but primarily children and young adults. When the disease affects the lung, it may be referred to as Diffuse Pulmonary Lymphangiomatosis (DPL). First described in 1838 by Jackson as a ”boneless arm,” Gorham-Stout disease (GSD) is related to GLA. In 1955, Gorham and Stout described thin-walled nonmalignant lymphatic vascular channel proliferation that replaced bone and soft tissue. Any organ system may be affected. The exact etiology of the diseases is unknown. Perhaps increased osteoclast activity and hydrolytic enzyme expression promote bone resorption in GSD. Vascular proliferative factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor and platelet-derived growth factor (PDGF) have been implicated in GLA.


Clinically, thoracic disease resulting from GLA and GSD may include bronchiole compression, pleural and pericardial chylous effusions, scoliosis, pain, and thoracic cage instability. Patients may present with fatigue, dyspnea, bronchorrhea, wheezing, chest pain, or respiratory failure. In Kaposiform lymphangiomatosis, lymphatic spindle cells invade bronchoalveolar bundles and pulmonary septae, resulting in hemoptysis and hemothorax; thrombocytopenia and anemia may be associated with a positive disseminated intravascular coagulation (DIC) panel. Any bone may be involved, but those with a shared joint, such as the shoulder or pelvis, may be particularly susceptible. Minor trauma may precede painless early disease; eventually, pain and swelling ensue. Complications include fracture, poor healing and bone infection.  In addition to mobile teeth, pain, and clinically obvious facial deformity, of concern from a pulmonary standpoint, is that involvement of the maxillofacial facial bone in GSD causes malocclusion, which may result in obstructive sleep apnea syndrome. Abdominal involvement may result is chylous ascites, bowel obstruction, and splenic cysts.   Although spontaneous regression of bone lesions has been described, the medical literature reports that the diseases have a 16% overall fatality rate; in the case of thoracic involvement, mortality may be greater than 50%. Children have a worse prognosis.


Serum alkaline phosphatase may be elevated in GSD, but serum testing is not helpful in making the diagnosis, which is suspected by x-ray, CT or MRI demonstrating bone findings that initially appear similar to osteoporosis. In both GSD and GLA, imaging may reveal progressive bone destruction, effusions, or what appear to be mediastinal masses; effusions are often chylous, but may be serosanguinous or hemorrhagic.  Pathologically, thin-walled vascular channel proliferation with fibrous connective tissue and cellular infiltrates are evident, followed by fibrous tissue replacement of bone with local soft tissue atrophy.  Lymphatic endothelial cells typically express platelet endothelial cell adhesion molecule (CD31),   lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and possibly Prospero homeobox protein 1 (PROX-1) or Podoplanin (D2-40).


There is no definitive treatment for GLA. Pleurodesis, pleurectomy, thoracic duct ligation and lung transplantation may be effective in some cases. Studies with therapy targeting growth factors such as bevacizumab against VEGF and the tyrosine kinase inhibitor imitinib mesylate against PDGFR-β have demonstrated varying success when used alone or in combination. Sirolimus, an mTOR (mammalian target of rapamycin) pathway inhibitor that is effective in lymphangioleiomyomatoisis, is currently under investigation in GLA treatment.


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Four Facts About Lymphangiomatosis & Gorham’s Disease

  1. Lymphangiomatosis and Gorham’s disease are thought to be a spectrum of disease:
    1. Lymphangiomatosis, recently classified as generalized lymphatic anomaly (GLA) is marked by the presence of cysts that result from an increase both in the size and number of thin-walled lymphatic channels that are abnormally interconnected and dilated.  Disease is poorly understood.  Studies are just beginning.
    2. Gorham’s disease (recently classified as Gorham-Stout disease) is thought to result from a derangement of osteoclast activity that is always accompanied by vascular anomaly (often lymphatic in origin and having the same features characteristic of lymphangiomatosis) that may extend into the soft tissues, particularly in the chest.  Pathology is poorly understood and requires further study.
  2. When it involves the lungs, lymphangiomatosis or Gorham-Stout may cause chylothorax, chylopericardium, or interstitial disease that result in chronic respiratory failure.  Pulmonary lymphangiomatosis is often very aggressive in the young.
  3. Affects males and females of all ethnicities equally and most commonly presents by age 20 years
    1. Lymphangiomatosis  (GLA) affecting the lung is commonly misdiagnosed as asthma; and can be confused with lymphangiolieomyomatosis (LAM)
    2. Gorham’s disease (GSD) may be misdiagnosed as Paget’s disease, fibrous dysplasia, osteogenesis imperfecta in children; in adults it may be misdiagnosed as osteoporosis.
  4. Pulmonary lymphangiomatosis is separate and distinct from lymphangiectasis, lymphangioleiomyomatosis (LAM), pulmonary capillary hemangiomatosis, Kaposi’s sarcoma, and kaposiform hemangioendothelioma.