Pulmonary Vascular Diseases

Abstract

Two major categories of pulmonary vascular diseases are discussed in this chapter: noninflammatory vascular disorders and inflammatory vascular diseases (vasculitis). Noninflammatory vascular disorders encompass pulmonary hypertension of diverse causes with corresponding heterogeneity in histopathologic features. Inflammatory vascular disease or vasculitides comprise mainly granulomatosis with polyangiitis (formerly Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), and microscopic polyangiitis. These three forms of vasculitis are often referred to as antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitides, and they are frequently characterized by some combination of parenchymal necrosis, hemorrhage, and necrotizing vasculitis.

Two major categories of pulmonary vascular diseases are discussed in this chapter: noninflammatory vascular disorders and inflammatory vascular diseases (vasculitis). Noninflammatory vascular disorders encompass pulmonary hypertension of diverse causes with corresponding heterogeneity in histopathologic features. Inflammatory vascular disease or vasculitides comprise mainly granulomatosis with polyangiitis (formerly Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), and microscopic polyangiitis. These three forms of vasculitis are often referred to as antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitides, and they are frequently characterized by some combination of parenchymal necrosis, hemorrhage, and necrotizing vasculitis.

Noninflammatory Vascular Disorders

Current classification schemes for pulmonary hypertension are based on a number of factors, including clinical presentation, hemodynamic studies, cytogenetic and molecular testing in selected patients, and occasionally histopathology. Pulmonary arterial hypertension in adults includes idiopathic (primary) pulmonary hypertension, pulmonary hypertension associated with various underlying conditions (e.g., systemic connective tissue disease, portal hypertension, HIV infection), and pulmonary veno-occlusive disease and/or capillary hemangiomatosis (Table 10.1). Evidence of pulmonary hypertension is more commonly seen in surgical specimens from patients with underlying lung disease and/or hypoxia. Chronic thrombotic pulmonary hypertension is less common but should be separated from the other categories of disease because of important differences in therapeutic strategies. Occasionally evidence of pulmonary hypertension can be more localized as a result of regional abnormalities, including obstructing neoplasms.

Table 10.1 Adult pulmonary hypertension classification

All forms of pulmonary hypertension may demonstrate some common pathologic changes, such as medial hypertrophy and intimal hyperplasia in small pulmonary arteries. However, occasionally there are distinct histologic findings that can be helpful in identifying a specific etiology or phenotype. Features suggestive of idiopathic (primary) arterial hypertension (Figs. 10.1, 10.2, 10.3 and 10.4) include severe concentric thickening of the vascular wall, concentric intimal fibrosis, plexiform lesions, and angiomatoid lesions; however, the diagnosis of idiopathic pulmonary arterial hypertension requires exclusion of other phenotypes and causes of pulmonary hypertension (Figs. 10.5, 10.6, 10.7, 10.8, 10.9 and 10.10). Pulmonary veno-occlusive disease (PVOD) (Figs. 10.11, 10.12, 10.13, 10.14, 10.15 and 10.16) and pulmonary capillary hemangiomatosis (Fig. 10.17) are two rare and overlapping conditions with clinical presentations that resemble other forms of pulmonary arterial hypertension. The histologic findings in these conditions show considerable overlap with chronic venous hypertension in patients with left-sided heart disease and venous outflow obstruction in conditions like fibrosing mediastinitis (Figs. 10.18 and 10.19). For that reason, correlation with clinical information is necessary before rendering either of these diagnoses. Chronic thrombotic pulmonary hypertension is another form of pulmonary hypertension with distinct histologic findings helpful in separating it from other types of pulmonary hypertension (Fig. 10.20).

Fig. 10.1

Pulmonary arterial hypertension . (a) Photomicrograph of routinely stained section showing severe intimal hyperplasia and fibrosis with medial hypertrophy in a muscular pulmonary artery, leading to marked luminal narrowing. (b) An elastic tissue stain highlights the double elastic layers of the artery, with both intimal and medial thickening

Fig. 10.2

Pulmonary arterial hypertension. (a) In this example, a photomicrograph of a routinely stained section demonstrates more prominent intimal fibrosis leading to near complete obliteration of the lumen. (b) An elastic tissue stain highlights the thickened intima

Fig. 10.3

Pulmonary arterial hypertension. (a) Photomicrograph showing a plexiform lesion, which in this example is a diverticular outpouching of the artery into perivascular connective tissue characterized by a proliferation of small vascular spaces and hyperplastic endothelial cells resulting in a glomeruloid appearance, often with associated fibrin thrombi resembling organized and recanalized thrombi. (b) Photomicrograph showing a plexiform lesion forming a glomeruloid proliferation of small vascular spaces with plump endothelial cells involving the wall of a small muscular artery. (c) Photomicrograph of an elastic tissue stained section from the same biopsy showing that the plexiform lesion penetrates from the intima through the vessel wall

Fig. 10.4

Severe pulmonary arterial hypertension with necrotizing arteritis. Photomicrograph showing a small muscular pulmonary artery in which the arterial wall shows marked fibrinoid necrosis with an acute inflammatory infiltrate. This is an uncommon finding that only occurs in severe pulmonary hypertension

Fig. 10.5

Hypertensive changes in chronic fibrotic disease. High-magnification photomicrograph of a routinely stained section showing severe intimal and medial thickening in a small muscular pulmonary artery in a patient with usual interstitial pneumonia. Note the dense collagen fibrosis and honeycomb change (arrow) in the background

Fig. 10.6

Fat emboli. Photomicrograph showing an oil red O stain in which multiple fat droplets are situated within the lumina of small pulmonary arterioles. This 70-year-old man underwent a hip arthroplasty for a femoral head fracture. Fat droplets within the bone marrow space circulated to the pulmonary artery through the heart, embolizing to small arterioles resulting in acute pulmonary hypertension. Fat emboli are a rare cause of acute pulmonary hypertension and not usually accompanied by the morphologic features characteristic of chronic pulmonary hypertension

Fig. 10.7

Intravenous (IV) drug abusers’ lung. IV injection of pulverized oral medications can result in embolization of inert fillers (excipients), commonly used as binding agents, in small pulmonary vessels, eliciting a foreign body giant cell reaction. In some patients, this may cause a syndrome of chronic pulmonary hypertension. In this example, a low-magnification photomicrograph shows patchy nodular lesions that seem to follow a lymphangitic distribution. Foreign body granulomatous reactions are visible at low magnification

Fig. 10.8

IV drug abusers’ lung. A higher-magnification photomicrograph shows foreign body granulomas affiliated with plate-like, pale-gray particulates of microcrystalline cellulose expanding the vessel wall

Fig. 10.9

IV drug abusers’ lung. (a) High-magnification view showing mainly large, elongated, pale-gray microcrystalline cellulose, which is a common filler in drugs intended for oral use. (b) The same microscopic field viewed at the same magnification using polarized light. The microcrystalline cellulose particles show strong birefringence under polarized light

Fig. 10.10

IV drug abusers’ lung. (a) A high-magnification view showing giant cells containing deeply basophilic crospovidone, another filler common in oral medications and dietary supplements. Microcrystalline cellulose particles and associated giant cells are also present. (b) Crospovidone is not birefringent when viewed with polarized light

Fig. 10.11

Pulmonary veno-occlusive disease (PVOD). Low-magnification photomicrograph shows congested lung parenchyma and several pulmonary veins that are narrowed or occluded by fibrosis (arrows). These vessels do not have accompanying airways and are situated within interlobular septa, a finding helpful in identifying them as veins

Fig. 10.12

PVOD. A high-magnification photomicrograph showing a vein completely occluded by fibrosis

Fig. 10.13

PVOD. A high-magnification photomicrograph showing a small vein nearly occluded by fibrous thickening of its wall

Fig. 10.14

PVOD. An elastic tissue stain reveals the single elastic layer of this nearly occluded vein

Fig. 10.15

PVOD. A high-magnification photomicrograph shows chronic congestive changes, including thickened alveolar septa with capillary hemangiomatosis-like changes (upper right) and a narrowed vein in the center. The wall of the narrowed vein demonstrates deeply basophilic elastic lamina resulting from encrustation by hemosiderin and calcium deposits, a finding referred to historically as endogenous pneumoconiosis. These are signs of severe chronic venous congestion, which can be caused by PVOD, left-sided heart disease, and extrapulmonary venous outflow obstruction

Fig. 10.16

PVOD. High-magnification photomicrograph of a Prussian blue iron-stained section showing iron deposition in the elastic lamina of a vein with fibrosis and a narrowed lumen

Fig. 10.17

Capillary hemangiomatosis. Intermediate-magnification photomicrograph showing expansion of alveolar septa by redundant blood-filled capillary loops. The changes can also be seen in PVOD and chronic venous hypertension caused by left-sided heart disease and venous outflow obstruction. The absence of fibrous obliterations of veins is the key to ruling out PVOD

Fig. 10.18

Capillary hemangiomatosis-like change in venous outflow obstruction. High-magnification photomicrograph showing visceral pleura expanded by proliferating blood-filled capillary loops resembling capillary hemangiomatosis (capillary hemangiomatosis-like change) in a patient with fibrosing mediastinitis causing venous outflow obstruction

Fig. 10.19

Chronic congestive changes. Alveolar space containing numerous hemosiderin-laden macrophages and thickened alveolar septa with redundant capillaries that are features of chronic venous congestion; this can be seen in any condition causing venous hypertension, including PVOD, pulmonary capillary hemangiomatosis, left-sided heart disease, and venous outflow obstruction. In some patients, the thickened alveolar septa may mimic nonspecific interstitial pneumonia and can be affiliated with radiologic abnormalities resembling other forms of diffuse lung disease

Fig. 10.20

Chronic thrombotic pulmonary hypertension. (a) Photomicrograph showing enlarged small muscular pulmonary arteries with multiple lumens (vascular webs) representing recanalized thrombi. The presence of these vascular webs combined with acute and organizing thrombi is an important clue to the diagnosis of chronic thrombotic pulmonary hypertension. An organizing thrombus occludes one of the lumens in the vessel on the right. (b) Photomicrograph from the same patient showing another recanalized thrombus involving a small muscular artery with an organizing thrombus and endothelial hyperplasia resembling a plexiform lesion (arrow)

Granulomatosis with Polyangiitis

Granulomatosis with polyangiitis (GPA , formerly Wegener granulomatosis ) is a systemic vasculitis that commonly involves the upper respiratory tract, the lung, and the kidney. It is part of a family of ANCA-associated vasculitides, the others comprising eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) and microscopic polyangiitis; they have in common a propensity to involve smaller vessels. The lung is sometimes the only organ involved in GPA. ANCA testing is particularly important in the laboratory evaluation of patients suspected of having GPA; a positive cytoplasmic (C)-ANCA corresponding to an antileukocyte proteinase 3 (PR3) autoantibody is highly specific for GPA, although positive results can occur in other conditions, including most importantly inflammatory bowel disease and rheumatoid arthritis. For that reason, interpreting the significance of a positive C-ANCA/PR3 test remains heavily dependent on the clinical context. Most patients with systemic GPA are C-ANCA/PR3 positive, but patients with localized GPA are more commonly negative, which does not preclude the diagnosis in patients with characteristic histologic findings. Occasional cases are positive for perinuclear (P)-ANCA corresponding to an antimyeloperoxidase (MPO) autoantibody; this is less specific and more typical of patients with EGPA and microscopic polyangiitis.

In addition to classic GPA (Figs. 10.21, 10.22, 10.23, 10.24, 10.25, 10.26 and 10.27), other histologic subtypes include bronchiolitis obliterans organizing pneumonia (BOOP)-like, hemorrhage with capillaritis, and eosinophilic variants (Figs. 10.28, 10.29 and 10.30). Hemorrhage with capillaritis refers to necrotizing vasculitis centered on alveolar septal capillaries (capillaritis) with associated alveolar hemorrhage. It is a common focal finding in otherwise classical GPA. In some patients this histology may dominate or be the sole manifestation of disease. In the absence of any other features to establish a histologic diagnosis of GPA, hemorrhage with capillaritis is nonspecific in that it also occurs in other vasculitic syndromes such as microscopic polyangiitis and systemic lupus erythematosus. Rare patients with diffuse alveolar hemorrhage and capillaritis have no other clinical or laboratory evidence of systemic vasculitis.

Fig. 10.21

Granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis), classic type. (a) Low-magnification photomicrograph showing the typical necrotizing granulomatous inflammation with irregular, geographic, basophilic dirty necrosis and background dense inflammatory infiltrates and fibrosis. (b) Higher-magnification view showing collagen necrosis as well as granular, basophilic nuclear debris. The necrotic area is surrounded by epithelioid histiocytes and rare multinucleated giant cells

Fig. 10.22

Classic GPA. High-magnification photomicrograph showing a granulomatous microabscess characterized by a small focus of necrotic neutrophils surrounded by epithelioid histiocytes, multinucleated giant cells, and a mixed inflammatory infiltrate. Granulomatous microabscesses with these features are an extremely helpful finding in establishing a histologic diagnosis of GPA

Fig. 10.23

Classic GPA. High-magnification photomicrograph showing another smaller and more subtle granulomatous microabscess with multinucleated giant cells demonstrating the hyperchromatic nuclei characteristic of GPA

Fig. 10.24

Classic GPA. Large and/or small airways are commonly involved in GPA and when a dominant feature has been referred to by some as a bronchocentric variant. (a) High-magnification photomicrograph showing granulomatous inflammation with giant cells involving and partially destroying a cartilaginous airway. (b) Photomicrograph showing a small bronchiole circumferentially involved by a mixed inflammatory infiltrate that includes multinucleated giant cells resulting in a vaguely granulomatous appearance

Fig. 10.25

Vasculitis in classic GPA. (a) Low-magnification photomicrograph showing necrotizing granulomatous inflammation involving several blood vessels. (b) High-magnification view of a small muscular artery involved by necrotizing granulomatous inflammation with fibrinoid necrosis, necrotic neutrophils, and a multinucleated giant cell

Fig. 10.26

Vasculitis in classic GPA. High-magnification photomicrograph showing another small muscular pulmonary artery involved by necrotizing inflammation with prominent karyorrhexis and granulomatous microabscesses

Fig. 10.27

Vasculitis in classic GPA. In this example, the blood vessel is involved by necrotizing inflammation with abundant neutrophils and eosinophils but without well-developed granulomatous features

Fig. 10.28

BOOP-like GPA. (a) Low-magnification photomicrograph showing extensive organizing pneumonia, a lesion referred to historically as bronchiolitis obliterans organizing pneumonia (BOOP). (b) Higher-magnification photomicrograph showing a granulomatous microabscess typical of GPA in which there is central necrosis with prominent karyorrhexis of neutrophils surrounded by a mixed inflammatory infiltrate that includes palisaded and multinucleated macrophages. (c) Photomicrograph showing a pulmonary vein in the same biopsy in which there is necrotizing vasculitis characterized by a transmural infiltrate of inflammatory cells with fibrinoid necrosis and karyorrhexis

Fig. 10.29

Hemorrhage and necrotizing capillaritis in GPA. (a) Low-magnification photomicrograph showing prominent intra-alveolar hemorrhage and thickened alveolar septa with hemosiderin and inflammatory cells. (b) High-magnification view showing capillaritis characterized by expansion of alveolar septa predominantly by neutrophils, with karyorrhexis and occasional eosinophils. This variant may lack the necrotizing granulomas, granulomatous microabscesses, and giant cells typical of classic GPA. In the absence of classic features, the diagnosis of GPA cannot be made on the basis of histology alone because hemorrhage with capillaritis may occur in patients with other vasculitic syndromes, including microscopic polyangiitis and systemic lupus erythematosus

Fig. 10.30

Eosinophilic variant of GPA. (a) Low-magnification photomicrograph shows necrotizing granulomatous inflammation with dirty basophilic necrosis typical of GPA. (b) At higher magnification, there is prominent eosinophilia, a relatively common finding that does not by itself suggest eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) as an alternative. Because eosinophils are nearly universal in GPA, prominent eosinophilia simply reflects an extreme in the histologic spectrum of classic GPA, although others separate these as eosinophilic variants

Eosinophilic Granulomatosis with Polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis that occurs in patients with asthma and blood eosinophilia. A minority of patients are P-ANCA/MPO positive. Common extrapulmonary sites involved by EGPA include the skin, nerve, muscle, and heart. The diagnosis of EGPA (Figs. 10.31, 10.32 and 10.33) on a lung biopsy relies on finding the combination of eosinophilic pneumonia, necrotizing granulomatous inflammation, and necrotizing vasculitis. Of these, the most common biopsy finding is eosinophilic pneumonia, which is not by itself diagnostic but is supportive in the appropriate clinical context.

Fig. 10.31

Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome). (a) Low-magnification photomicrograph showing necrotizing granulomatous inflammation with prominent eosinophilic infiltrates. (b) High-magnification view of a granuloma composed of a necrotic center, palisading epithelioid histiocytes, and multinucleated giant cells. The surrounding inflammatory cells are rich in eosinophils

Fig. 10.32

EGPA. Photomicrograph showing eosinophilic pneumonia characterized by intra-alveolar accumulation of eosinophils and macrophages in a patient with EGPA

Fig. 10.33

Vasculitis in EGPA. (a) High-magnification photomicrograph showing necrotizing vasculitis in which the vascular wall is infiltrated by an eosinophil-rich mixed inflammatory infiltrate with associated vessel wall necrosis and fibrin thrombus. (b) Photomicrograph showing another example of vasculitis in EGPA in which the blood vessel is partially destroyed by necrosis with an eosinophil-rich inflammatory infiltrate. Note the background eosinophilic pneumonia characterized by intra-alveolar accumulation of eosinophils and macrophages