Case 1 -

Pulmonary Arterial Hypertension, Plexiform Type, Secondary to Systemic Lupus Erythematosus Kevin O. Leslie Mayo Clinic Scottsdale

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Clinical History A 36 year old married Caucasian woman, with systemic lupus erythematosus for 20 years, presented with symptomatic depression and suicidal thoughts. The patient's clinical course had been marked with episodes of hypoxia and a variably severe skin rash. Her pulmonary disease and skin manifestations responded inconsistently to systemic corticosteroid therapy during flare-ups, in part secondary to patient compliance issues. During the final hospitalization the patient's pulmonary status declined progressively and she expired from cardiopulmonary failure. An autopsy was performed. (Autopsy material courtesy of Thomas V. Colby, MD) Case 1 - Figure 1 - Scanning magnification photomicrograph of the H&E stained section of lung showing thick-walled pulmonary arteries and a bone marrow embolus (likely an agonal event). Case 1 - Figure 2 - Closer inspection of the arteries shows medial thickening. Case 1 - Figure 3 - Concentric luminal compromise Case 1 - Figure 4 - Nicely accentuated by an elastic tissue stain (EVG) Case 1 - Figure 5 - Eccentric subendothelial lesions are also highlighted by the EVG stain Case 1 - Figure 6 - Two plexiform lesions (PLX), each present adjacent to a pulmonary artery branch, are present in this photomicrograph. Dilated blood-filled thin-walled vascular spaces--so called angiomatoid lesions (dark arrows), can be seen surrounding the plexiform lesion at the top of the photograph. Case 1 - Figure 7 - A transverse section through a plexiform lesion nicely illustrates the relationship of these complex endovascular lesions to the parent artery. Case 1 - Figure 8 - Note the thin muscle layer (sm) present above and below the lesion, and the apparent focal nature of the process. The EVG stain outlines an attenuated elastica. Case 1 - Figure 9 - The EVG stain highlights the relationship of the angiomatoid and plexiform lesions to the parent artery. Note the relative absence of a well-defined elastic lamina in these lesions. Case 1 - Figure 10 - The triumvirate of pulmonary artery (PA) branch, plexiform lesion (PLX), and angiomatoid (dilatation) lesion (arrows) is well-illustrated in this photomicrograph. Diagnosis Pulmonary Arterial Hypertension, Plexiform Type, Secondary to Systemic Lupus Erythematosus. Lung Findings At scanning magnification the lung tissue is remarkable for thick-walled pulmonary artery branches (Figure 1) some of which have bone marrow emboli. The arteries are thickened, often with luminal compromise (Figure 6). Adjacent to many arteries are cellular hyperchromatic nodules (Figures 7 & 8) that on closer inspection are composed of slit-like vascular channels and many redundant endothelial cells (Figure 9). These are plexiform lesions. Adjacent to some of the plexiform lesions, thin-walled congested vascular channels can be seen (Figure 10). These are so-called "dilatation" or angiomatoid lesions (resembling blood filled, thin-walled angiomas) always appear adjacent to plexiform lesions but may not be present in every plane of section. The elastic-van Gieson method is essential to the evaluation of pulmonary vascular diseases, highlighting the arterial elastic lamina and thereby providing useful information on the location of cells (or matrix) that narrow the vascular lumens. The pulmonary veins in this patient are also abnormal, with subendothelial sclerosis, but no occlusive lesions are seen. Discussion Pulmonary arterial hypertension is defined by the presence of sustained systolic pulmonary arterial pressures exceeding 40 mm Hg or a mean arterial pressure of greater than 25 mm. Hg. Primary and secondary forms exist, with the primary form being sufficiently rare that pathologists typically encounter cases as part of seminars rather than in daily practice. Secondary forms include those caused by systemic collagen vascular diseases, congenital pulmonary shunts, portal hypertension, human immunodeficiency virus infection (HIV), drugs/toxins, persistent pulmonary hypertension of the newborn, and miscellaneous other rare causes. The 1975 World Health Organization (WHO) classification of pulmonary hypertension was based solely on pathology, dividing pulmonary hypertension into plexogenic, veno-occlusive, and thromboembolic types. In 1998 the WHO conducted a world symposium resulting in a new classification with integration of clinical data, epidemiology and pathology (Table 1). Table 1 1998 WHO (Evian) 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. Human immunodeficiency virus 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 disorder to 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 diseases      4.1 Thromboembolic obstruction of proximal pulmonary arteries     4.2 Obstruction of distal to 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   Rich, S: Primary pulmonary hypertension. Executive summary from the world symposium. Primary Pulmonary Hypertension. World Health Organisation Publications 1998. A 2003 world symposium on pulmonary hypertension, convened in Venice Italy, reviewed the impact of the Evian classification. and after seeking input from a group of 56 international experts, proposed a few modifications (Table 2). These included the desirability for a genetic classification, the elimination of the term "primary pulmonary hypertension" in favor of "idiopathic pulmonary hypertension", the reclassification of veno-occlusive disease and capillary hemangiomatosis into "pulmonary occlusive venopathy, and pulmonary microvasculopathy (each modified by histopathologic features), updated entries on new risk factors for pulmonary hypertension, and finally reassessment of the congenital systemic-to-pulmonary shunts category [1, 2] . Table 2 2003 Vienna Third World Symposium on Pulmonary Arterial Hypertension [2]. 1. Pulmonary arteriopathy (pre- and intra-acinar arteries)        Subsets         Pulmonary arteriopathy with isolated medial hypertrophy        Pulmonary arteriopathy with medial hypertrophy and intimal thickening (cellular, fibrotic)          Concentric laminar         Eccentric, concentric non-laminar       Pulmonary arteriopathy with plexiform and/or dilatation lesions or arteritis        Pulmonary arteriopathy with isolated arteritis  1a. As above but with coexisting venous-venular changes (cellular and/or fibrotic intimal thickening, muscularization)        The presence of the following changes should be noted:       Adventitial thickening; thrombotic lesions (fresh, organized, recanalized, colander lesions); necrotizing or lympho-monocytic arteritis; elastic artery changes (fibrotic or atheromatous intimal plaques, elastic laminae degeneration); bronchial vessel changes, ferruginized encrustation, calcifications, foreign body emboli, organized infarct, or avascular lymphocytic infiltrates.    2. Pulmonary occlusive venopathy (veins of various size and venules) with or without coexisting arteriopathy        Histopathologic features:       Venous changes: Intimal thickening/obstruction (cellular, fibrotic); obstructive fibrous luminal septa (recanalization).       Adventitial thickening (fibrotic); muscularization; iron and calcium encrustation with foreign body reaction       Capillary changes: Dilated, congested capillaries; angioma-like lesions       Interstitial changes: Edema; fibrosis; hemosiderosis; and lymphocytic infiltrates       Others: Dilated lymphatics; alveoli with hemosiderin-laden macrophages; type 2 cell hyperplasia   3. Pulmonary micro-vasculopathy with or without coexisting arteriopathy and/or venopathy        Histopathologic features:       Microvessel changes: Localized capillary proliferations within pulmonary interstitium; obstructive capillary proliferation in dense and venular walls       Venous-venular intimal fibrosis       Interstitial changes: Edema, fibrosis, hemosiderosis       Others: Dilated lymphatics; alveoli with hemosiderin-laden macrophages; type 2 cell hyperplasia   4. Unclassifiable    The exact mechanism(s) for pulmonary hypertension in the autoimmune setting remains unknown. Newer molecular and genetic studies may shed light on pathogenesis and potentially, etiology for many forms of PAH (see reference #1 for a current review). Grading of pulmonary hypertension using the Heath-Edwards scheme is of little value outside of the setting of congenital heart disease. Importantly, severity of vascular pathology does not always correlate with severity of clinical findings. References Farber HW, Loscalzo J: Pulmonary arterial hypertension. NEJM 2004 351:1655-65. Simonneau G, et al: Clinical classification of pulmonary hypertension. J Am Coll Cardiol, 2004; 43:5S-12S. Pietra GG, et al: Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol, 2004; 43: 25S-32S. Voelkel NF, Cool C.:Pathology of pulmonary hypertension. Cardiol Clin. 2004 Aug;22(3):343-51. Dorfmuller P, Humbert M, Capron F, Muller KM. Pathology and aspects of pathogenesis in pulmonary arterial hypertension. Sarcoidosis Vasc Diffuse Lung Dis. 2003 Mar;20(1):9-19. Meyrick B. The pathology of pulmonary artery hypertension. Clin Chest Med. 2001 Sep;22(3):393-404.. Rubin LJ. Pathology and pathophysiology of primary pulmonary hypertension. Am J Cardiol. 1995 Jan 19;75(3):51A-54A. Burke AP, Farb A, Virmani R. The pathology of primary pulmonary hypertension. Mod Pathol. 1991 Mar;4(2):269-82. Edwards WD. Pathology of pulmonary hypertension. Cardiovasc Clin. 1988;18(2):321-59. Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc. 1985 Jan;60(1):16-25.