—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 2 - Pulmonary Capillary Hemangiomatosis

Carlyne D. Cool
Department of Pathology
University of Colorado Health Sciences Center
Denver, CO


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Diagnosis:
Pulmonary Capillary Hemangiomatosis (PCH)

Lung findings:
The autopsy lung specimen on cut sections demonstrates nodular, punctate areas of red congestion. Microscopic examination reveals interstitial proliferations of small, capillary-sized vascular channels in a lobular and patchy distribution. Occasionally, the vascular proliferations are more prominent around bronchovascular bundles and in the pleura. If there is a prominent venous component, reactive intimal fibrosis and secondary veno-occlusive disease can occur. At low power, the histologic pattern is striking because of the very patchy appearance to the apparent congestion. On high power, the areas of congestion can now be seen to be multiple layers of capillary-sized vessels that expand the septa. The adjacent thin septa contain the normal single layer of capillaries. The endothelial cells lining the capillary-like spaces are cytologically bland and stain with the usual endothelial cell markers, such as CD31 and Factor VIII-related antigen. Because of the longstanding congestion, there can be secondary changes including foci of interstitial fibrosis and hemosiderosis. Hemosiderosis can lead to the entity of 'endogenous pneumoconiosis', in which iron encrusted elastic fibers are engulfed by giant cells.


Case 2 - Slide 1
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Case 2 - Figure 1
Low power magnification illustrating a patchy area of congestion. The surrounding alveolar septa are thin and delicate. No significant inflammatory infiltrates are identified. No airspace abnormalities are present.
Case 2 - Figure 2
An area of apparent congestion with red blood cells and hemosiderin-laden macrophages within airspaces.
Case 2 - Figure 3
High power magnification demonstrating increased density of capillary-like vessels within the septa. There are numerous hemosiderin-laden macrophages within airspaces.

Case 2 - Figure 4
Another high power field illustrates the numerous capillary-like vessels within the septa. There is no cytologic atypia or mitoses.
Case 2 - Figure 5
A cluster of multinucleated giant cells engulf an iron coated elastic fiber. There is a surrounding cuff of chronic inflammatory cells with occasional eosinophils. Additional iron coated fibers are present in the upper right and lower left fields of the image.


Discussion:
PCH was first recognized in 1978 by Wagenvoort and colleagues. Since then, there have been scattered case reports (approximately 50 reported cases). PCH has recently been reclassified in the WHO classification scheme (see Tables 1 and 2). PCH can occur in congenital, familial and sporadic forms. The sporadic form is the most common (4 cases per million individuals) and can present at all ages, although the disease typically presents in the 20-40 year age group (M=F) with symptoms that mimic classic pulmonary arterial hypertension (PAH).

This case of PCH demonstrates the typical clinical scenario of severe pulmonary hypertension unresponsive to therapies for PAH. In fact, prostacyclins, which are used to treat severe PAH, are contraindicated in PCH because patients can develop massive, fatal pulmonary edema (If the pulmonary muscular arteries and arterioles are dilated and yet the pulmonary vein resistance remains fixed, the increased transcapillary hydrostatic pressure leads to massive transudation of fluid into the lung parenchyma). Patients initially present with progressive dyspnea and cough. They can develop hemoptysis (30% of patients) and hemorrhagic pleural effusions (25% of patients). Hemoptysis and pleural effusions are almost never seen in PAH and are rarely seen in PVOD, and consequently their presence should raise the possibility of PCH. The clinical presentation is often deceptive and patients can be misdiagnosed as having PAH. Biopsies are dangerous in these patients because of the possibility of massive hemorrhage and poor wound repair. The histological findings are most often found at autopsy, as was seen in this case.

PCH is a rare (4 cases/million) manifestation of pulmonary hypertension that is characterized by patchy proliferations of capillary-sized vessels within the interstitium. Most commonly, the vascular proliferations occur in the septa, but they can also occur in the bronchovascular bundles and in the pleura. The pulmonary arteries may show mild to moderate medial hypertrophy, but no plexiform lesions are seen in PCH. There is debate about whether PCH is related to pulmonary veno-occlusive disease or a separate, distinct entity. Often, there are foci of capillary hemangiomatosis in PVOD and foci of venous occlusion in PCH. The distinction is likely arbitrary; both disorders portend a poor prognosis, with most patients dying within 2 to 3 years of diagnosis, unless lung transplantation is performed.

Mimics of PCH include congestion, which can lead to a prominence of alveolar capillaries, but the increased density of capillaries found in PCH is lacking. Congestion is also usually diffuse, while PCH is nodular. Patchy atelectasis can simulate PCH at low power, but higher power examination reveals the capillary proliferation. PCH can have PVOD areas, but widespread venous occlusion is not present.

There are few reports regarding potential etiologies. In fact, it is still unclear whether PCH represents a reactive, neoplastic, or congenital process. Although the histology is that of a low-grade capillary neoplasm, immunohistochemical studies have failed to demonstrate abnormal endothelial cells. An immunohistochemical comparison between idiopathic PAH and PCH demonstrated that while the endothelial cells of plexiform and PCH lesions both express markers of cell proliferation (Ki-67) and angiogenesis (vascular endothelial growth factor), the endothelial cells of PCH, but not idiopathic PAH, retain markers of cell growth suppression such as peroxisome proliferator-activated receptor-gamma and caveolin-1. Data from Lantuejoul et al suggest that most cases of PCH represent a secondary angioproliferative process caused by postcapillary obstruction, though the cause of the venous obliteration could not be identified. Kradin et al found reduced endothelial nitric oxide synthase in a majority of cases of PCH. A recent report by Assaad et al that utilized microdissection of nodules of proliferating capillaries in PCH to analyze gene expression, identified upregulation of platelet-derived growth factor (PDGF) B and PDGFR-beta genes in the lesions. PDGF-B has a central role in angiogenesis. These studies suggest that antiproliferative therapy may be a useful therapeutic strategy in this angioproliferative disease.

Table 1. 1998 WHO Nomenclature and Classification of Pulmonary Hypertension
1 Pulmonary Arterial Hypertension
1.1 Primary Pulmonary Hypertension
(a) Sporadic
(b) Familial
1.2 Related to:
(a) Collagen Vascular Disease
(b) Congenital Systemic to Pulmonary Shunts
(c) Portal Hypertension
(d) HIV Infection
(e) Drugs/Toxins
(1) Anorexigens
(2) Other
(f) Persistent Pulmonary Hypertension of the Newborn
(g) Other

2 Pulmonary Venous Hypertension
2.1 Left-Sided Atrial or Ventricular Heart Disease
2.2 Left-Sided Valvular Heart Disease
2.3 Extrinsic Compression of Central Pulmonary Veins
(a) Fibrosing Mediastinitis
(b) Adenopathy/Tumors
2.4 Pulmonary Veno-Occlusive Disease
2.5 Other

3 Pulmonary Hypertension Associated with Disorders of the Respiratory System and/or Hypoxemia
3.1 Chronic Obstructive Pulmonary Disease
3.2 Interstitial Lung Disease
3.3 Sleep Disordered Breathing
3.4 Alveolar Hypoventilation Disorders
3.5 Chronic Exposure to High Altitude
3.6 Neonatal Lung Disease
3.7 Alveolar-Capillary Dysplasia
3.8 Other

4 Pulmonary Hypertension due to Chronic Thrombotic and/or Embolic Disease
4.1 Thromboembolic Obstruction of Proximal Pulmonary Arteries
4.2 Obstruction of Distal Pulmonary Arteries
(a) Pulmonary Embolism (Thrombus, Tumor, OVA and/or parasites, Foreign Material
(b) In-situ Thrombosis
(c) Sickle Cell Disease

5 Pulmonary Hypertension due to Disorders Directly Affecting the Pulmonary Vasculature
5.1 Inflammatory
(a) Schistosomiasis
(b) Sarcoidosis
(c) Other
5.2 Pulmonary Capillary Hemangiomatosis

(From Executive Summary from the World Symposium on Primary Pulmonary Hypertension 1998, Evian, France, 6-10 September 1998)

Table 2. 2003 Revised Nomenclature and Classification of Pulmonary Hypertension
Pulmonary Arterial Hypertension (PAH)
  1. Idiopathic (IPAH)

  2. Familial (FPAH)

  3. Associated with:
    1. Collagen vascular disease

    2. Congenital systemic to pulmonary shunts (large, small, repaired or nonrepaired)

    3. Congenital systemic to pulmonary shunts (large, small, repaired or nonrepaired)

    4. Portal hypertension

    5. HIV infection

    6. Drugs and toxins

    7. Other (glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)

  4. Associated with significant venous or capillary involvement
    1. Pulmonary veno-occlusive disease

    2. Pulmonary capillary hemangiomatosis
Pulmonary venous hypertension
  1. Left-sided atrial or ventricular heart disease

  2. Left-sided valvular heart disease
Pulmonary hypertension associated with hypoxemia
  1. Chronic obstructive pulmonary disease

  2. Interstitial lung disease

  3. Sleep-disordered breathing

  4. Alveolar hypoventilation disorders

  5. Chronic exposure to high altitude
Pulmonary hypertension due to chronic thrombotic and/or embolic disease
  1. Thromboembolic obstruction of proximal pulmonary arteries

  2. Thromboembolic obstruction of distal pulmonary arteries

  3. Pulmonary embolism (tumor, parasites, foreign material)
Miscellaneous
Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

(Adapted from the WHO World Symposium on PAH, Venice, 2003.)

References:
  1. Wagenvoort CA, Beetstra A, Spijker J. Capillary haemangiomatosis of the lung. Histopathology. 1978;2:401-406.

  2. Tron V, Magee F, Wright JL, Colby T, Churg A. Pulmonary capillary hemangiomatosis. Hum Pathol. 1986.;17:1144-1149.

  3. Faber CN, Yousem SA, Dauber JH, Griffith BP, Hardest RL, Pradis IL. Pulmonary capillary hemangiomatosis: a report of three cases and a review of the literature. Am Rev Respir Dis. 1989;140:808-813.

  4. Almagro P, Julia J, Sanjaume M, et al. Pulmonary capillary hemangiomatosis associated with primary pulmonary hypertension. Medicine. 2002;81:417-424.

  5. Frazier AA, Franks TJ, Mohammed T-L, Ozbudak IH, Galvin JR. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. RadioGraphics 2007;27:867-882.

  6. Sullivan A, Chmura K, Cool CD, Voelkel N, Chan ED. Pulmonary capillary hemangiomatosis: an immunohistochemical analysis of vascular remodeling in a fatal case. Chest 2005;128:576.

  7. El-Gabaly ME, Farver CF, Budev MA, Mohammed T-LH. Pulmonary capillary hemangiomatosis imaging findings and literature update. Comput Assist Tomogr. 2007;31:608-610.

  8. Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109:106-109.

  9. Kradin R, Matsubar O, Mark EJ. Endothelial nitric oxide synthase expression in pulmonary capillary hemangiomatosis. Exp Mol Pathol. 2005;79:194-197.

  10. Lantuejoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30:850-857.

  11. Assaad AM, Kawut SM, Arcasoy SM, et al. Platelet-derived growth factor is increased in pulmonary capillary hemangiomatosis. Chest. 2007;131:850-855.