Rare Lung Disease

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General Information

Rare Lung Disease Week

Generalized lymphatic anomaly (GLA), formerly known as lymphangiomatosis, is a rare condition in which the lymphatic vessels proliferate abnormally in some areas of the body. [1-3] GLA and GSD can affect almost all organs, including the lung, heart, liver, spleen, and bones.[1,4], and are typically sporadic and non-hereditary[7]. In some cases, congenital abnormalities in the developing lymphatic system play a major role in pathogenesis of the condition, with lymphatic cysts and dilation progressing after birth. The condition tends to present before age 20, and approximately three-quarters of patients have involvement of more than one organ. [5] The thoracic lymphatic disorders typically present with symptoms of cough, shortness of breath, chyloptysis, or expectoration of branching casts. Typical pulmonary manifestations of the thoracic lymphatic disorders include chylous effusions, peribronchiolar interstitial infiltrates, and mediastinal masses.

Symptoms are often due to compression of tissues by dilated lymphatic channels or by the accumulation of lymph and chyle in body cavities such as the pleura (chylothorax), pericardium (chylopericardium), or abdominal cavity (chyloascites.)  Chylothorax can be either unilateral or bilateral. [6]

Gorham-Stout disease (GSD) is related to GLA; lymphatic proliferation occurs predominantly in the bones, producing cortical bone loss and progressive bony resorption. Patients may present with bone pain, weakness, or pathological fractures. The shoulder, skull, and pelvic girdle are most commonly affected. [5] In patients, loss of structural integrity in the rib cage or chronic chylous effusion can result in chronic respiratory failure and death.

The terminology of these conditions can be challenging to patients and practitioners alike:

  • A number of synonyms of GSD have been used, including vanishing bone disease, phantom bone disease, disappearing bone disease, Gorham's disease, Gorham-Stout syndrome, massive osteolysis, and acute spontaneous absorption of bone.

  • GLA has also been referred to as lymphangiomatosis, generalized cystic lymphangiomatosis, or cystic angiomatosis. A number of other conditions have similar names but are not related to GLA, such as pulmonary lymphangioleiomyomatosis (LAM), lymphangiectasis, yellow nail syndrome, and plastic bronchitis.

Although GLA and GSD were first described in the 19th century, understanding of the conditions has lagged behind more common disorders. It is still not entirely clear if GLA and GSD represent the same underlying disorder, with GSD more prominently affecting bones. [1,6] There is reason for hope, however.  The molecular basis of  ymphatic disorders are being uncovered at a thrilling rate, including mutations in Flt4 and VEGF-C in hereditary lymphedema, FOXC2 in yellow nail syndrome and lymphedema-distichiasis, and ITGA9 in fetal chylothorax.

There are no standardized treatments for GLA and GSD. External beam radiation therapy, surgical therapy, interferon alpha-2b, lung transplantation, and bisphosphonates have been employed but none have been validated in controlled trials. Ligation of the thoracic duct, with or without concomitant pleurodesis may be required to manage chylothorax. [5, 8] The emergence of sophisticated imaging techniques that characterize abnormal lymphatic flow promises to improve the classification and therapeutic approaches to the thoracic lymphatic disorders [9-11]. Embolization can be curative for the frightening and sometimes near asphyxiating expectoration of bronchial casts that occurs in plastic bronchitis.

The Lymphangiomatosis and Gorham's Disease Alliance (LGDA) provides education, support and hope through research to patients with these conditions, and also serves physicians and scientists with an interest in the conditions. The LGDA website contains valuable resources including medical information, community connections, and news about recent scientific developments and upcoming conferences related to the conditions.

References:

  1. Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G. Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation. Skeletal Radiol. 2013 Jul;42(7):917-24.
  2. Blei F. Lymphangiomatosis: clinical overview. Lymphat Res Biol. 2011;9(4):185-90.
  3. Tazelaar HD, Kerr D, Yousem SA, Saldana MJ, Langston C, Colby TV. Diffuse pulmonary lymphangiomatosis. Hum Pathol. 1993 Dec;24(12):1313-22.
  4. Satria MN, Pacheco-Rodriguez G, Moss J. Pulmonary lymphangiomatosis. Lymphat Res Biol. 2011;9(4):191-3.
  5. Hu P, Yuan XG, Hu XY, Shen FR, Wang JA. Gorham-Stout syndrome in mainland China: a case series of 67 patients and review of the literature. J Zhejiang Univ Sci B. 2013 Aug;14(8):729-35.
  6. Venkatramani R, Ma NS, Pitukcheewanont P, Malogolowkin MH, Mascarenhas L. Gorham's disease and diffuse lymphangiomatosis in children and adolescents. Pediatr Blood Cancer. 2011 Apr;56(4):667-70.
  7. Dupond JL, Bermont L, Runge M, de Billy M. Plasma VEGF determination in disseminated lymphangiomatosis-Gorham-Stout syndrome: a marker of activity? A case report with a 5-year follow-up. Bone. 2010 Mar;46(3):873-6.
  8. Kinnier CV, Eu JP, Davis RD, Howell DN, Sheets J, Palmer SM. Successful bilateral lung transplantation for lymphangiomatosis. Am J Transplant. 2008 Sep;8(9):1946-50
  9. Dori Y, Keller MS, Rome JJ, Gillespie MJ, Glatz AC, Dodds K, Goldberg DJ,Goldfarb S, Rychik J, Itkin M.Percutaneous Lymphatic Embolization of Abnormal Pulmonary Lymphatic Flow as Treatment of Plastic Bronchitis in Patients WithCongenital Heart Disease. Circulation. 2016 Mar 22;133(12):1160-70
  10. Itkin M. Lymphatic intervention is a new frontier of IR. J Vasc Interv Radiol.2014 Sep;25(9):1404-5.
  11. Itkin M, McCormack FX. Nonmalignant adult thoracic lymphatic disorders. In Clinics in Chest Medicine. In Press.

Four Facts About Lymphangiomatosis & Gorham's Disease

  1. Lymphangiomatosis, recently classified as generalized lymphatic anomaly (GLA), and Gorham-Stout disease (GSD) are thought to be a spectrum of disease, one aspect of which may affect the lungs and other organs of the thorax.  Another related complex lymphatic anomaly that has features of GLA and GSD, along with hemorrhagic effusions, called Kaposiform lymphangiomatosis (KLA), was described in 2014.

  2. Pulmonary disease in GLA, GSD, and KLA is often most aggressive in younger patients and is separate and distinct from lymphangiectasia, lymphangioleiomyomatosis (LAM), pulmonary capillary hemangiomatosis, Kaposi's sarcoma, and kaposiform hemangioendothelioma.

  3. GLA, GSD, or KLA affecting the lung may be misdiagnosed as asthma, and can be confused with lymphangiolieomyomatosis (LAM). 

  4. Thoracic disease in GLA, GSD, or KLA may cause chylothorax, chylopericardium, or interstitial disease that result in chronic respiratory failure.