Case 2 -

Chronic Pulmonary Venous Hypertension Secondary to Pulmonary Vein Stenosis Complicating Catheter Ablation of Atrial Fibrillation Kelly J. Butnor Fletcher Allen Health Care Burlington, VT

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Clinical Summary: A 50-year-old male with an insignificant remote smoking history (3 pack years) presented with persistent dyspnea, left-sided pleuritic pain, and recurrent hemoptysis for the past two months that was unresponsive to antibiotics. His past medical history was significant for atrial fibrillation, for which he had undergone radiofrequency catheter ablation five years earlier. He was employed as a nuclear plant technician and had a pet cockatoo for the past ten years. Serial CT scans of the chest disclosed migratory nodular ground glass opacities involving the left upper lobe. A VATS biopsy of the left upper lobe was performed. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The lung wedge resection exhibited brown discoloration. Histologic examination was notable for dilated pulmonary veins and patchy hemorrhage and hemosiderosis (Fig. 1). Movat's stain highlighted pulmonary venous medial hypertrophy (Figs. 2–3). Features of chronic alveolar hemorrhage manifested as alveolar hemosiderin-laden macrophages (Fig. 4), which stained intensely for Prussian blue (Fig. 5). In addition, the pulmonary arteries showed mild hypertensive changes in the form of intimal fibrosis and medial hypertrophy (Figs. 6–7). Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 Low power view of the lung wedge resection showing dilated pulmonary veins, arterial hypertrophy, and patchy hemorrhage and hemosiderosis. H&E Case 2 - Figure 2 A Movat's stain highlights medial hypertrophy of pulmonary veins within an interlobular septum. Movat's Case 2 - Figure 3 A Movat's stain highlights medial hypertrophy of pulmonary veins within an interlobular septum. Movat's Case 2 - Figure 4 Patchy hemosiderosis, characterized by alveolar macrophages containing globular golden brown refractile pigment, is evidence of chronic alveolar hemorrhage. H&E Case 2 - Figure 5 Hemosiderin-laden macrophages are highlighted by Prussian blue staining for iron. Prussian blue Case 2 - Figure 6 Pulmonary arteries show mild hypertensive changes. H&E Case 2 - Figure 7 Movat's staining discloses intimal fibrosis and medial hypertrophy of pulmonary arteries. Movat's Differential Diagnoses: Alveolar hemorrhage syndrome Pulmonary veno-occlusive disease (PVOD) Chronic pulmonary venous hypertension Pulmonary arterial hypertension Final Diagnosis: Chronic pulmonary venous hypertension secondary to pulmonary vein stenosis complicating catheter ablation of atrial fibrillation Case Discussion: Based on the histologic findings, it was recommended that the patient be evaluated for cardiac or other extrapulmonary causes of pulmonary hypertension. CT angiography disclosed stenosis of the left superior pulmonary vein that had not been present prior to his ablative procedure for atrial fibrillation. In the 18 months since undergoing lung biopsy, the patient has not reported recurrence of his pulmonary symptoms. Review of the Literature/Treatment Options: This case illustrates a complication of radiofrequency catheter ablation (RFA) of atrial fibrillation. RFA is a relatively new technique for treating drug–refractory atrial fibrillation. Arrhythmogenic foci that cause atrial fibrillation are often located in the pulmonary veins. Although highly successful in terminating arrhythmias, catheter ablation of ectopic foci in the pulmonary veins can cause dense fibrosis and scarring, resulting in pulmonary vein stenosis in about 1–3% of cases in contemporary series [1, 2]. The presentation of pulmonary vein stenosis following RFA of atrial fibrillation varies widely and depends on the extent of occlusion and the number of veins involved [2]. In the largest series to date on the clinical aspects of this condition, the most frequently reported symptom was dyspnea on exertion (83%), followed by cough (39%), dyspnea at rest (30%), pleuritic chest pain (26%), flu- like symptoms (13%), and hemoptysis (13%) [3]. Patients' symptoms are often initially erroneously attributed to common respiratory conditions, such as pneumonia, asthma, pulmonary embolism, or lung cancer, resulting in delayed and sometimes inappropriate treatment [3, 4]. Successful treatment of pulmonary vein stenosis depends on early recognition of the problem before occlusion is complete. Diagnosis is confirmed by pulmonary vein angiography. Balloon angioplasty or endovascular stenting can be used to treat incomplete occlusions, but restenosis rates are in the range of 30–50% [1]. Conclusion(s): Detailed accounts of the histopathologic findings in the lungs of patients who develop pulmonary vein stenosis following RFA of atrial fibrillation are sparse, but the features described in three prior reports in the literature are similar to those seen in the present case [5, 6, 7] . Congestive vasculopathy is the term that encompasses the morphologic changes seen in the lungs not only of patients with pulmonary vein stenosis following RFA of atrial fibrillation, but also from other causes of chronic pulmonary venous hypertension (Table 1) [8, 9]. Table 1. Causes of Pulmonary Venous Hypertension (WHO Classification) Left-sided atrial or ventricular heart disease (e.g. congestive heart failure) Left-sided valvular heart disease (e.g. mitral stenosis) Extrinsic compression of central pulmonary veins Fibrosing mediastinitis Adenopathy and/or tumors Pulmonary veno-occlusive disease Others (e.g. pulmonary vein stenosis following RFA of atrial fibrillation) Chronic pulmonary venous hypertension induces pathologic changes in nearly every component of the lung, with perhaps the exception of the airways (Table 2) [10, 11]. The pulmonary veins develop medial smooth muscle hypertrophy, along with intimal and adventitial fibrosis. In some cases, the veins undergo "arterialization", in which a distinct external elastic lamina develops, separated from the internal elastic lamina by a layer of circular smooth muscle [11] . Pulmonary lymphatics become dilated and the interlobular fibrous septa are expanded by interstitial edema. Dilatation and congestion of the pulmonary capillaries is also seen. In patients with chronic pulmonary venous hypertension, increased pressures are transmitted to the pulmonary arterial system and as a result, the pulmonary arteries commonly undergo medial hypertrophy. Arterial intimal fibrosis, which is said to be eccentric in most instances, also occurs [11] . Adventitial fibrosis can be seen as well. Muscularization of the pulmonary arterioles, in which a distinct layer of smooth muscle forms between internal and external elastic laminae, is also a feature. Another finding in chronic pulmonary venous hypertension is hemosiderosis, in which hemosiderin derived from extravasated erythrocytes accumulates in alveolar macrophages and the pulmonary interstitium, particularly around blood vessels, airways, and interlobular septa. Hemosiderin deposition manifests grossly as "brown induration" of the lungs. Elastic fibers in the alveolar septa and pulmonary blood vessels sometimes become encrusted by hemosiderin–derived iron and occasionally, calcium, which can incite a giant cell response. The confusing term "endogenous pneumoconiosis" has been applied to this phenomenon, which some authors have suggested replacing with a more descriptive designation of "mineralizing pulmonary elastosis" [12] . Other findings that can be seen in chronic pulmonary venous hypertension include osseous metaplasia and alveolar microlithiasis. Table 2. Pathologic Manifestations of Chronic Pulmonary Venous Hypertension Pulmonary Veins Medial hypertrophy Arterialization Intimal and adventitial fibrosis Pulmonary Arteries & Arterioles Medial hypertrophy Intimal and adventitial fibrosis Arteriolar muscularization Pulmonary Lymphatics Dilatation Pulmonary Parenchyma Interstitial edema and fibrosis Hemorrhage and hemosiderosis Osseous metaplasia Alveolarmicrolithiasis Endogenous pneumoconiosis Pulmonary Capillaries Dilatation and congestion Erythrocyte extravasation Adapted from Refs. 9,10 [9, 10] Hemorrhage and hemosiderosis can be so severe in chronic pulmonary venous hypertension as to simulate a bland alveolar hemorrhage syndrome. While difficult to discern on routine histopathologic examination, elastic stains can highlight the abnormal vessels that distinguish chronic pulmonary venous hypertension from alveolar hemorrhage syndromes. The differential diagnosis of chronic pulmonary venous hypertension also includes pulmonary veno–occlusive disease (PVOD) and pulmonary arterial hypertension. Although venous intimal fibrosis is a feature of chronic pulmonary venous hypertension, it is usually not severe and in contrast to PVOD, is never obstructive. In pulmonary arterial hypertension, the venous system is not involved, unlike chronic pulmonary venous hypertension, which affects both the veins and arteries. Another distinction from pulmonary arterial hypertension is that plexiform and dilatation lesions are not seen in uncomplicated chronic pulmonary venous hypertension. References: Holmes DR, Monahan KH, Packer D. Pulmonary vein stenosis complicating ablation for atrial fibrillation: clinical spectrum and interventional considerations. JACC Cardiovasc Interv 2009;2:267-76. Purerfellner H, Martinek M. Pulmonary vein stenosis following catheter ablation of atrial fibrillation. Curr Opin Cardiol 2005;20:484-90. Packer DL, Keelan P, Munger TM, et al. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation 2005;111:546-54. Qureshi AM, Prieto LR, Latson LA, et al. Transcatheter angioplasty for acquired pulmonary vein stenosis after radiofrequency ablation. Circulation 2003;108:1336-42. Yang HM, Lai CK, Patel J, et al. Irreversible intrapulmonary vascular changes after pulmonary vein stenosis complicating catheter ablation for atrial fibrillation. Cardiovasc Pathol 2007;16:51-5. Ernst S, Ouyang F, Goya M, et al. Total pulmonary vein occlusion as a consequence of catheter ablation for atrial fibrillation mimicking primary lung disease. J Cardiovasc Electrophysiol 2003;14:366-70. Nehra D, Liberman M, Vagefi PA, et al. Complete pulmonary venous occlusion after radiofrequency ablation for atrial fibrillation. Ann Thorac Surg 2009;87:292-5. Executive summary from the World Symposium on Primary Pulmonary Hypertension. World Health Organization, 1998. (Accessed at Available at: http://www.who.int/ncd/cvd/pph/html.) Wagenwoort C, Mooi W. Biopsy Pathology of the Pulmonary Vasculature. London: Chapman Hall Medical; 1989. Cool C. Vascular diseases. In: Zander D, Farver C, eds. Pulmonary Pathology. Philadelphia: Churchill Livingstone Elsevier; 2008:102-7. Kay J. Pulmonary vascular disease. In: Churg A, Myers J, Tazelaar H, Wright J, eds. Thurlbeck's Pathology of the Lung. 3rd ed. New York: Thieme; 2005:893-905. Pai U, McMahon J, Tomashefski JF. Mineralizing pulmonary elastosis in chronic cardiac failure. "Endogenous pneumoconiosis" revisited. Am J Clin Pathol 1994;101:22-8.