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Pulmonary Capillary HemangiomatosisPulmonary Capillary Hemangiomatosis: The Puzzle Takes Shape FREE TO VIEW

David Langleben, MD
Author and Funding Information

From the Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital; and McGill University.

Correspondence to: David Langleben, MD, Room E-206, Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, QC, H3T 1E2, Canada; e-mail: david.langleben@mcgill.ca


Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):197-199. doi:10.1378/chest.13-2513
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In 1987, the late Dr Judah Folkman proposed the term “angiogenic diseases” for a group of disorders that seemed nonneoplastic but which involved persistent angiogenesis.1 This concept followed a rapid expansion in the identification and understanding of endothelial growth factors, vascular cell biology, and the essential role of the microvasculature in health and disease. It was recognized that the microvasculature seemed designed to remain mainly quiescent for many decades, with tight controls limiting capillary growth but with the ability to switch to rapid capillary proliferation in response to hormonal factors, inflammation and injury, or stimuli from tumors.1

Shortly after Dr Folkman’s publication, the first case of familial pulmonary capillary hemangiomatosis (PCH) was described, and another family was described in 2011.2,3 PCH is a rare disorder that was first reported in 1978, with only seven nonrelated cases having been reported by 1998 and a little more than 100 by 2011.2,4,5 The diagnostic histologic feature is the proliferation of capillaries in the pulmonary interstitium.5 However, another essential feature is evidence of invasion by the capillaries into one or more of the pulmonary veins and arteries, alveolar walls and alveolar space, intralobular fibrous septa, and bronchi. Affected areas tend to have a patchy distribution within the lung, and reticulonodular infiltrates may be seen on radiography. Less frequently, the capillaries invade pericardium, pleura, and mediastinal lymph nodes. The first case report described endothelial nuclear pleomorphism and hyperchromasia and suggested that PCH was a form of endothelial neoplasia.4 The clinical picture varies depending on the affected lung structures; therefore, PCH may mimic idiopathic pulmonary arterial hypertension, pulmonary veno-occlusive disease, or atypical interstitial lung disease and may result in a misdiagnosis as airways disease. Once symptoms appear, the course usually is fulminant and fatal. Ultimately, the diagnosis is made by lung biopsy or at lung transplantation or autopsy. Case reports appeared suggesting therapeutic success with interferon-α and doxycycline, but consistently effective therapy remained elusive.6,7 It is interesting to note that both reported therapies affect angiogenesis. However, the cause of PCH remained a mystery.

Twenty-five years after the description of the first family, the mystery is well on its way to being solved. In a landmark study, initially published online in CHEST on October 17, 2013, and now in the current print issue of CHEST (see page 231), Best and colleagues8 describe mutations in the gene for eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in a family with PCH and in two other patients with sporadic PCH. EIF2KA4 expression, or lack thereof, contributes to the regulation of angiogenesis, affecting endothelial proliferation and apoptosis resistance. Thus, as was proposed many years ago, PCH may truly be an endothelial neoplasia of the lung.4 The family with the EIF2AK4 mutations transmitted them in an autosomal recessive pattern, as was seen in the original family.2 The authors also studied another patient with familial PCH that had been transmitted in an autosomal dominant pattern and eight other patients with sporadic PCH, but none of them had mutations in EIF2AK4. This does not diminish the significance of the findings; rather, it should spur deeper analysis of EIF2AK4 and its signaling pathways as well as the search for other genes. Indeed, it is now understood that heritable pulmonary arterial hypertension can result from mutations in five different genes, with likely more awaiting discovery.9 Thus, EIF2AK4 mutations should not be expected to account for all cases of PCH. However, just as the recognition of the gene mutations in heritable pulmonary arterial hypertension provided insight into its development, understanding the role of EIF2AK4 will help explain the pathogenesis of PCH. The frequency of PCH in the general population is unknown. In an autopsy series, nearly 6% of subjects had histologic lesions consistent with PCH.10 Presumably, overt disease never develops in most individuals. However, de novo PCH was detected in the lungs from a previously healthy lung donor 3 months after the lungs were used for transplantation.11

The leading current hypothesis for the development of pulmonary arterial hypertension is that the pulmonary microvascular endothelium is injured, or factors necessary for its viability and health are altered, followed by emergence of apoptosis-resistant endothelial populations that are dysfunctional and proliferative and that gradually choke off the microcirculation. Plexiform lesions are seen. This process may be considered neoplastic.12 In the current classification of pulmonary hypertension, PCH (group 1') is linked to but not part of pulmonary arterial hypertension (group 1).13 Given the presence of abnormal endothelial proliferation in both, that linkage seems appropriate. Given that PCH involves capillary proliferation, whereas pulmonary arterial hypertension affects mainly the small arteries, and the two disorders have different histologic abnormalities, the separation within the classification is also appropriate.

In a remarkable confluence of events, another major piece has just been fitted into the puzzle. Pulmonary veno-occlusive disease (PVOD), also a rare disorder, causes intimal cellular proliferation and fibrosis of pulmonary venules.14,15 PVOD may be familial,16 and other suspected triggers include infections, autoimmune disorders, and drugs and toxins. The nature of the cellular proliferation has not yet been characterized to the same degree as for pulmonary arterial hypertension and PCH, and it is not known if the involved cells are mainly endothelial. Nevertheless, the intimal thickening in the veins has many parallels to that seen in arterioles in PAH. For these reasons, PVOD was also classified in group 1', with PCH.

Eyries and colleagues17 have just described 13 families with PVOD and found that all had EIF2AK4 mutations. Moreover, five of 20 seemingly sporadic PVOD cases had the same mutation. Thus, EIF2AK4 represents a clear link between PCH and PVOD. Indeed, histologic overlap of features has previously been described and was again seen in the recent report,17,18 although PCH must not be confused with congested capillaries, as might be seen with downstream venous obstruction. The question is whether PCH and PVOD are distinct disorders or simply different or overlapping manifestations of the same disorder. The reports by Best and colleagues8 and Eyries and colleagues17 would suggest that they are a single disease with a spectrum of pathologies, at least for the autosomal recessive cases. Fitting these pieces of the puzzle marks the beginning of progress toward understanding and being able to attack these devastating illnesses.

Finally, a word of appreciation for our geneticist, the late Dr Naomi Fitch. In an era before the tools of modern molecular biology and with only a small family available for analysis, she correctly deduced that the inheritance pattern was autosomal recessive. Our predecessors did so much with so little.

References

Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235(4787):442-447. [CrossRef] [PubMed]
 
Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. [CrossRef] [PubMed]
 
Wirbelauer J, Hebestreit H, Marx A, Speer CP. Familial pulmonary capillary hemangiomatosis early in life. Case Rep Pulmonol. 2011;2011:827591. [PubMed]
 
Wagenvoort CA, Beetstra A, Spijker J. Capillary haemangiomatosis of the lungs. Histopathology. 1978;2(6):401-406. [CrossRef] [PubMed]
 
Langleben D. Pulmonary capillary hemangiomatosis.. In:Peacock AJ, Naeije R, Rubin LJ., eds. Pulmonary Circulation: Diseases and Their Treatment.3rd ed. London, England: Hodder Arnold; 2011:447-453.
 
White CW, Sondheimer HM, Crouch EC, Wilson H, Fan LL. Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Engl J Med. 1989;320(18):1197-1200. [CrossRef] [PubMed]
 
Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJ. Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline. Chest. 2003;124(5):2017-2022. [CrossRef] [PubMed]
 
Best DH, Sumner KL, Austin ED, et al. EIF2AK4mutations in pulmonary capillary hemangiomatosis. Chest. 2014;145(2):231-236. [originally published online October 17, 2013].
 
Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361. [CrossRef] [PubMed]
 
Havlik DM, Massie LW, Williams WL, Crooks LA. Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases. Am J Clin Pathol. 2000;113(5):655-662. [CrossRef] [PubMed]
 
de Perrot M, Waddell TK, Chamberlain D, Hutcheon M, Keshavjee S. De novo pulmonary capillary hemangiomatosis occurring rapidly after bilateral lung transplantation. J Heart Lung Transplant. 2003;22(6):698-700. [CrossRef] [PubMed]
 
Rai PR, Cool CD, King JA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178(6):558-564. [CrossRef] [PubMed]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1)(suppl):S43-S54. [CrossRef] [PubMed]
 
Cockrill BA, Hales CA. Pulmonary veno-occlusive disease.. In:Peacock AJ, Naeije R, Rubin LJ., eds. Pulmonary Circulation. Disease and Their Treatment. London, England: Hodder Arnold, 2011:435-446.
 
Clardy PF, Mandel J. Pulmonary veno-occlusive disease.. In:Yuan JX-J, Garcia JGN, Hales CA, Rich S, Archer SL., eds. Textbook of Pulmonary Vascular Disease. New York, NY: Springer, 2011:1169-1181.
 
Davies P, Reid L. Pulmonary veno-occlusive disease in siblings: case report and morphometric study. Hum Pathol. 1982;13(10):911-915. [CrossRef] [PubMed]
 
Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension [published online ahead of print December 1, 2013]. Nat Genet. doi:10.1038/ng.2844.
 
Lantuejoul S, Sheppard MN, Corrin B, et al. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30(7):850-857.
 

Figures

Tables

References

Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235(4787):442-447. [CrossRef] [PubMed]
 
Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. [CrossRef] [PubMed]
 
Wirbelauer J, Hebestreit H, Marx A, Speer CP. Familial pulmonary capillary hemangiomatosis early in life. Case Rep Pulmonol. 2011;2011:827591. [PubMed]
 
Wagenvoort CA, Beetstra A, Spijker J. Capillary haemangiomatosis of the lungs. Histopathology. 1978;2(6):401-406. [CrossRef] [PubMed]
 
Langleben D. Pulmonary capillary hemangiomatosis.. In:Peacock AJ, Naeije R, Rubin LJ., eds. Pulmonary Circulation: Diseases and Their Treatment.3rd ed. London, England: Hodder Arnold; 2011:447-453.
 
White CW, Sondheimer HM, Crouch EC, Wilson H, Fan LL. Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Engl J Med. 1989;320(18):1197-1200. [CrossRef] [PubMed]
 
Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJ. Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline. Chest. 2003;124(5):2017-2022. [CrossRef] [PubMed]
 
Best DH, Sumner KL, Austin ED, et al. EIF2AK4mutations in pulmonary capillary hemangiomatosis. Chest. 2014;145(2):231-236. [originally published online October 17, 2013].
 
Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361. [CrossRef] [PubMed]
 
Havlik DM, Massie LW, Williams WL, Crooks LA. Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases. Am J Clin Pathol. 2000;113(5):655-662. [CrossRef] [PubMed]
 
de Perrot M, Waddell TK, Chamberlain D, Hutcheon M, Keshavjee S. De novo pulmonary capillary hemangiomatosis occurring rapidly after bilateral lung transplantation. J Heart Lung Transplant. 2003;22(6):698-700. [CrossRef] [PubMed]
 
Rai PR, Cool CD, King JA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178(6):558-564. [CrossRef] [PubMed]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1)(suppl):S43-S54. [CrossRef] [PubMed]
 
Cockrill BA, Hales CA. Pulmonary veno-occlusive disease.. In:Peacock AJ, Naeije R, Rubin LJ., eds. Pulmonary Circulation. Disease and Their Treatment. London, England: Hodder Arnold, 2011:435-446.
 
Clardy PF, Mandel J. Pulmonary veno-occlusive disease.. In:Yuan JX-J, Garcia JGN, Hales CA, Rich S, Archer SL., eds. Textbook of Pulmonary Vascular Disease. New York, NY: Springer, 2011:1169-1181.
 
Davies P, Reid L. Pulmonary veno-occlusive disease in siblings: case report and morphometric study. Hum Pathol. 1982;13(10):911-915. [CrossRef] [PubMed]
 
Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension [published online ahead of print December 1, 2013]. Nat Genet. doi:10.1038/ng.2844.
 
Lantuejoul S, Sheppard MN, Corrin B, et al. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30(7):850-857.
 
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