Pulmonary Capillary Hemangiomatosis: A Rare Cause of Pulmonary Hypertension.
CLINICAL PRESENTATION AND CLASSIFICATION
The most common presenting symptom of PCH is progressive dyspnea. (3-10) Other complaints include cough, chest pain, and fatigue. (4,7) These symptoms are nonspecific and can be seen in every form of pulmonary hypertension, including peripheral venoocclusive disease (PVOD), which makes diagnosis by clinical means difficult if not impossible. Symptoms that have been suggested to be more specific for PCH include hemoptysis, (4,10) which is thought to be a result of hemorrhage into alveolar spaces from the fragile capillary walls. Age at presentation is variable, ranging from infancy to 71 years. (4)
Findings on pulmonary function tests include normal forced vital capacity and normal forced expiratory volume with a markedly reduced diffusion capacity. Right heart catheterization shows elevated pressures indicative of pulmonary hypertension. Pulmonary capillary wedge pressures are normal, reflecting normal postcapillary pressures and left atrial function. Alveolar lavage frequently shows increased hemosiderin-laden macrophages. (3,8,10,11)
In the 2003 Venice clinical classification of pulmonary hypertension, (12) PCH was included with PVOD as a subtype of pulmonary arterial hypertension based on the involvement of venules or arterioles seen in both entities. In the most recent classification system, the 2008 Dana Point revision, (12) PCH and PVOD are placed in their own category, group 10, which is closely related to but distinct from the pulmonary arterial hypertension group (Table). Clinically, PCH and PVOD are indistinguishable; therefore, histology has been the only reliable means of establishing the diagnosis. (12) Although they are still considered distinct entities, recent thinking suggests they may be different manifestations of a spectrum of disease. (4)
Radiographic findings are typically nonspecific and include changes consistent with pulmonary hypertension (bilateral interstitial infiltrates, cardiomegaly, and enlargement of the pulmonary arteries (10,11)). Depending on the extent of disease, diffuse bibasilar reticulonodular or micronodular areas of opacity can be seen. This finding in addition to lymphadenopathy is thought to be more suggestive of PCH as opposed to PVOD, although discrimination between these entities is generally not possible based solely on imaging studies. (3,11)
On computed tomography scan, the hallmark of well-developed PCH is diffuse centrilobular ground-glass nodular opacities. (5,8,11) The periphery is generally spared, and the distribution of lesions is typically bilateral and involving all lobes. As on radiography, changes associated with pulmonary hypertension are also present.
The most frequently reported gross findings are multiple, red-brown, ill-defined nodular lesions seen throughout the lung parenchyma. (3,8,11,13) Other less specific findings include a congested and edematous appearance without significant fibrosis.
Histologically, sections of lung involved by PCH show preserved architecture with patchy areas of capillary congestion. At higher power, PCH lesions are composed of an abnormal proliferation of small, thin-walled capillaries causing expansion of the alveolar septae (Figure 1, A and B). The endothelial cell nuclei within these lesions are bland, without cytologic atypia or mitotic activity. To make the diagnosis, at least 2 layers of these aberrant capillaries within an alveolar wall should be seen (Figure 1, C). The capillary proliferations are typically centered around bronchovascular bundles and create a nodular appearance, lending to the characteristic computed tomographic scan findings and gross appearance. These proliferations can extend along septal lines and infiltrate small muscular pulmonary arteries and interlobular veins, causing occlusion. Lumens of the capillaries are frequently dilated, and capillary congestion is present. Hemosiderin-laden macrophages are often present in the alveolar spaces. As in other forms of pulmonary hypertension, intimal thickening and medial hypertrophy of small muscular arteries can be seen (Figure 1, D). Plexiform lesions, which are frequently seen in other forms of pulmonary hypertension, are not observed in PCH. (1,4,8,9)
Although special stains and immunohistochemistry are not necessary to confirm the diagnosis of PCH, they can help to visualize confounding features. An endothelial cell marker such as CD31 or CD34 will highlight the proliferative capillary endothelial cells within the alveolar septa (Figure 2, A and B), assisting in differentiating PCH from capillary congestion and atelectasis. (5,9) Dilated capillaries in PVOD can mimic PCH, but a trichrome or a Movat pentachrome stain will highlight the supporting collagen of loop lesions and occluded veins seen in PVOD but not in PCH. (11)
The etiology of PCH is largely unknown. It was once believed to be a neoplastic process, but clonality has not been demonstrated. (6,14) Because PCH has been seen in association with left-sided heart failure and localized venous obstruction, it has been postulated that chronic passive congestion can lead to capillary proliferation. (15,16) This theory is supported by the fact that PCH changes are frequently found in conjunction with histologic evidence of PVOD. Another frequently suggested etiology is chronic inflammation or infectious agents causing upregulation of local growth factors. (5,9) A familial case has been reported, (17) but the genetics are still unknown. Multiple descriptions of incidentally discovered cases of PCH-like foci in patients without pulmonary hypertension have also been reported. (13) It is unclear whether these represent early stages of disease or are truly incidental findings.
Clinically, PCH is difficult to distinguish from many other causes of pulmonary hypertension and is impossible to distinguish from PVOD. Therefore, histology has been the sole reliable means of diagnosis, and this remains true only with adequate sampling. Because of this issue, many cases of PCH are diagnosed at autopsy or following transplant surgery. (4) Common misdiagnoses include pulmonary arteriopathy and PVOD. (10,13) Pulmonary arteriopathy shows the same medial thickening and intimal hypertrophy seen in PCH but without the hallmark capillary proliferation. Typically, PVOD shows dilated capillaries without proliferation, as well as small veins blocked by organizing thrombi rather than infiltrating capillaries. (13)
TREATMENT AND PROGNOSIS
Treatments used for other causes of pulmonary hypertension, including angiotensin-converting enzyme inhibitors, diuretics, corticosteroids, and warfarin, are also used to treat PCH. However, these drugs have proven relatively ineffective, and prognosis remains poor. The median survival after onset of symptoms is only 3 years. (6,10) Interferon a-2a has been suggested to be effective, although this has only been shown in in a few case reports. (3,10,18) Of note, prostacyclins such as epoprostenol, which are routinely used in the treatment of pulmonary hypertension, have been reported to have disastrous effects in patients with PCH. Several groups (2,3,10,12) have reported sudden onset pulmonary edema and respiratory arrest after administration; thus, the use of these drugs is contraindicated. The only definitive treatment for PCH is lung transplantation; however, a case report (6) of recurrence after transplantation has been published.
Pulmonary capillary hemangiomatosis is a rare cause of pulmonary hypertension that seems closely related to POVD. It is marked by proliferation of thin-walled capillaries within the alveolar septae, which can infiltrate the walls of small arteries and veins. The stimulus for this proliferation is currently unknown. Recognition and diagnosis of this disease are important because severe reactions to prostacyclins, typically used in treatment of pulmonary hypertension, have been reported.
Please Note: Illustration(s) are not available due to copyright restrictions.
We thank Carlyne Cool, MD, for her assistance in reviewing the manuscript.
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Mary C. O'Keefe, MD; Miriam D. Post, MD
Accepted for publication December 3, 2013.
From the Department of Pathology, University of Colorado, Aurora.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Miriam D. Post, MD, Department of Pathology, University of Colorado, Mail Stop F768, 12605 E 16th Ave, Aurora, CO 80045 (e-mail: Miriam.Post@ucdenver.edu).
Caption: Figure 1. A, Thickened alveolar septae expanded by a capillary proliferation. B, Marked septal expansion by congested capillary loops. Alveolar spaces are filled with hemosiderin-laden macrophages. C, Single alveolar septum expanded by more than 4 layers of capillaries. D, Septal arteriole with muscularized wall and narrowed lumen (hematoxylin-eosin, original magnifications X40 [A], X100 [B], X400 [C], and X200 [D]).
Caption: Figure 2. A, CD34 staining highlights the exuberant septal capillary proliferation (upper left) compared with more normal-appearing thin septa (bottom right). B, Single alveolar septum expanded with multiple layers of capillaries (CD34, original magnifications X100 [A] and x400 [B]).
Dana Point 2008 Classification of Pulmonary Hypertension (3) 1. Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH 1.2 Heritable 1.2.1 BMPR2 1.2.2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia) 1.2.3 Unknown 1.3 Drug- and toxin-induced 1.4 Associated with 1.4.1 Connective tissue diseases 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1.4.6 Chronic hemolytic anemia 1.4.7 Persistent pulmonary hypertension of the newbor 1'. Pulmonary veno-occlusive disease (PVOD) and/o pulmonary capillary hemangiomatosis (PCH) 2. Pulmonary hypertension owing to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 3. Pulmonary hypertension owing to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities 4. Chronic thromboembolic pulmonary hypertensioi (CTEPH) 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Hematologic disorders: myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis (a) Reprinted from Simonneau et al (12) with permission from Elsevier.
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|Author:||O'Keefe, Mary C.; Post, Miriam D.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Feb 1, 2015|
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