Rare Lung Disease II

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General Information About LGD

Rare Lung Disease Week II

Lymphangiomatosis is a very rare disorder in which the lymphatic vessels tend to abnormally proliferate.1 Lymphangiomatosis can occur in all organs of the body including the brain, lung, heart, spleen, liver and bones. Gorham-Stout disease (GSD) is a variant of lymphangiomatosis where these characteristic lesions occur predominantly in the bones causing bone destruction. In extreme circumstances, the complete loss of bony structures has led to the name “vanishing bone disease”.1, 2, 5 Because lymphangiomatosis is an extremely rare disease, most of our knowledge has evolved from case reports and a few case series. It has been known to occur in all age groups including the very young, adolescents and adults. There does not seem to be a sex predilection for this disease unlike lymphangioleiomyomatosis (LAM), which affects women. Symptoms at the time of presentation are dependent on the organ system affected by the disease. Lymphangiomatosis can be localized (e.g. splenic, pulmonary) or diffuse with lesions in multiple organ systems.

Pulmonary lymphangiomatosis can cause shortness of breath, chest-tightness, cough, chylous effusions, and rarely – expectoration of lymphatic contents (chyloptysis), depending on the extent of the lung involvement.3, 4 Imaging of the lung can show different patterns of involvement. Most common is interstitial and septal thickening in the lung periphery, and ground glass opacities can occur around the bronchovascular bundles. The other presentation is with chylous collections in the mediastinum, parenchyma, pleural space, and/or the chest wall. In diffuse lymphangiomatosis, the characteristic cystic bony lesions also tend to be detected on the chest tomogram.3

Expectedly, in patients with pulmonary lymphangiomatosis, the pulmonary function tests (PFTs) tend to demonstrate restrictive and obstructive patterns, but without the severe hyperinflation and air-trapping noted in advanced stages of LAM.3, 6, 7 The characteristic lesions noted in biopsy specimens are notable for the presence of ‘lymphangiomas’, which are essentially collections of thin-walled lymphatic channels with spaces in between the channels filled with chylous material. Clusters of spindle cells have been described in the lesions. The lesions stain for lymphatic markers: LYVE-1, VEGFR-3, and smooth muscle markers: vimentin and desmin. The important difference between the histopathology of LAM and lymphangiomatosis is that the lesions in the latter are not reactive to HMB-45, which is a monoclonal antibody against the protein gp100, present in LAM lesions.1, 3, 8 Table 1 lists the differences between LAM and Lymphangiomatosis.

The disease course tends to be progressive with respiratory failure being a leading cause of mortality. Non pulmonary lymphangiomatosis, like GSD tends to have a less ominous course with some case reports even noting spontaneous remission after the initial presentation. There have been anecdotal reports of response to various biologics including interferon-α, bevacizumab, corticosteroids, imatinib mesylate and sirolimus.1 Sirolimus, a mammalian target of rapamycin (m-TOR) pathway inhibitor, is currently being investigated as a potential therapeutic option.9 Therapeutic options for GSD at this time are focused on organ specific involvement with radiation, bisphosphonate therapy and in advanced cases surgical/orthopedic resections and graft placements to address bony and soft tissue lesions.5 Because of some of the histological similarities between LAM and lymphangiomatosis, therapeutic breakthroughs for LAM, such as with m-TOR inhibition could open the doors for potential treatment options for this rare and challenging disease.

Table 1. Differences between lymphangioleiomyomatosis and lymphangiomatosis

Clinico-radio-pathological features

Lymphangioleiomyomatosis

Lymphangiomatosis

Age

Mean age of onset and diagnosis tends to be in the fourth decade

Can present at all ages – ranging from the very young to adulthood.

Sex

Females

Males and Females

Presentation/Syndromes

S-LAM or TSC-LAM

Can present as localized or diffuse lymphangiomatosis. GSD has predominantly bony involvement.

Histopathology

Proliferating lesions composed of smooth muscle cells and epithelioid cells.

Proliferating lymphatic channels and spindle cells with intervening spaces filled with chylous material

Immunohistochemistry

Characteristically stain for melanocyte markers (HMB-45, Melan-A, Tyrosinase, NKI/C3) and smooth muscle markers (Actin, Desmin, Vimentin)

Stain for smooth muscle markers (Actin, Desmin, Vimentin) and lymphatic markers (LYVE-1, VEGFR-3)

HRCT characteristics

Empty cystic lesions in lung parenchyma, pneumothorax, chylous effusions.

Extra-pulmonary imaging can reveal AMLs that can have a very specific CT signature.

Varied appearance ranging from interstitial/septal thickening, ground glass opacities, chylous collections in the mediastinum, parenchyma, pleural space, and/or the chest wall,

AMLs not seen in Lymphangiomatosis but other renal, peri-renal, liver and bony lesions can be noted in diffuse lymphangiomatosis

Spirometry characteristics

Obstructive and restrictive patterns with hyperinflation and air-trapping in advanced disease

Obstructive and restrictive patterns without evidence of hyperinflation or air-trapping.

Therapy

Sirolimus and other m-TOR inhibitors

Anecdotal reports of success with interferon-α, bevacizumab, steroids, imatinib and sirolimus

Prognosis

Tends to be slowly progressive without therapy, eventually resulting in respiratory failure

Progressive pulmonary involvement can eventually result in respiratory failure. Respiratory failure is one of the leading causes of mortality.

Abbreviations: S-LAM: Sporadic LAM, TSC-LAM: Tuberous sclerosis associated LAM, GSD: Gorham-Stout disease, AML: Angiomyolipoma.

References

  1. Blei F. Lymphangiomatosis: Clinical overview. Lymphat Res Biol. 2011;9(4):185-190. doi: 10.1089/lrb.2011.0020; 10.1089/lrb.2011.0020.

  2. Patel DV. Gorham's disease or massive osteolysis. Clin Med Res. 2005;3(2):65-74.

  3. Satria MN, Pacheco-Rodriguez G, Moss J. Pulmonary lymphangiomatosis. Lymphat Res Biol. 2011;9(4):191-193. doi: 10.1089/lrb.2011.0023; 10.1089/lrb.2011.0023.

  4. Nair LG, Kurtz CP. Lymphangiomatosis presenting with bronchial cast formation. Thorax. 1996;51(7):765-766.

  5. Ruggieri P, Montalti M, Angelini A, Alberghini M, Mercuri M. Gorham-stout disease: The experience of the rizzoli institute and review of the literature. Skeletal Radiol. 2011;40(11):1391-1397. doi: 10.1007/s00256-010-1051-9; 10.1007/s00256-010-1051-9.

  6. Baldi BG, Albuquerque AL, Pimenta SP, Salge JM, Kairalla RA, Carvalho CR. Exercise performance and dynamic hyperinflation in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2012;186(4):341-348. doi: 10.1164/rccm.201203-0372OC; 10.1164/rccm.201203-0372OC.

  7. Burger CD, Hyatt RE, Staats BA. Pulmonary mechanics in lymphangioleiomyomatosis. Am Rev Respir Dis. 1991;143(5 Pt 1):1030-1033. doi: 10.1164/ajrccm/143.5_Pt_1.1030.

  8. Tazelaar HD, Kerr D, Yousem SA, Saldana MJ, Langston C, Colby TV. Diffuse pulmonary lymphangiomatosis. Hum Pathol. 1993;24(12):1313-1322.

  9. Safety and efficacy study of Sirolimus in complicated vascular Anomalies.


Four Facts About LGD

  1. Lymphangiomatosis and Gorham’s disease are thought to be a spectrum of disease:
    • 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.
    • Gorham’s disease (recently classified as Gorham-Stout disease) - it is believed results 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 must be studied further.
  2. When it involves the lungs, lymphangiomatosis or Gorham-Stout causes chylothorax, chylopericardium, and interstitial disease that result in chronic respiratory failure.  Pulmonary lymphangiomatosis is very aggressive in the young.
  3. Affects males and females of all ethnicities equally and most commonly presents by age 20 years
  4. Pulmonary lymphangiomatosis is separate and distinct from lymphangiectasis, lymphangioleiomyomatosis (LAM), pulmonary capillary hemangiomatosis, Kaposi’s sarcoma, and kaposiform hemangioendothelioma.