Vascular Diseases


Introduction

Pulmonary vascular diseases encompass a wide range of disorders of the lung. Abnormalities of the pulmonary vasculature not only cause lung disease, but can also result from secondary involvement by nonvascular pulmonary diseases. Many of the primary vascular diseases of the lung are severe, have no adequate available therapy, and pose dilemmas to both the clinician and pathologist. Diseases of the pulmonary vasculature can affect all compartments of the pulmonary vascular tree, including arteries, arterioles, capillaries, and veins. Patients who have these diseases typically present with insidious symptoms, including dyspnea upon exertion, fatigue, syncope, and lower extremity edema. Most patients with pulmonary vascular disease will not undergo lung biopsies because the risk of the procedure may outweigh any benefits to the patient; thus many cases are diagnosed either clinically or postmortem. However, it is important to understand and be able to evaluate the pulmonary vessels because some of these entities can be easily overlooked in biopsy specimens. This chapter deals with the most common of the vascular diseases (edema, congestive vasculopathy, and thromboembolism), as well as those entities rarely seen (idiopathic pulmonary arterial hypertension [PAH], venoocclusive disease, pulmonary capillary hemangiomatosis [PCH], lymphangiomatosis, and arteriovenous malformation).

Edema

Edema—Fact Sheet

Definition

  • Leakage of fluid from the vascular compartment into the interstitium and alveoli of the lung, most often due to cardiogenic or permeability factors

Incidence

  • Any age

  • Common with heart failure and ARDS

Mortality

  • Related to the underlying etiology

  • 20% mortality in ICU patients

Clinical Features

  • Acute: Breathlessness, anxiety, feelings of drowning

  • Chronic: Dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, cough

Radiologic Features

  • Butterfly pattern of bilateral infiltrates

  • Pleural effusions

  • Kerley B lines

  • Loss of normal sharp definition of pulmonary vasculature

Prognosis and Therapy

  • Prognosis is dependent on etiology

  • Most cardiogenic patients are treated with drug therapy

  • Ventilatory support is required for permeability pulmonary edema due to ARDS

Edema—Pathologic Features

Gross Findings

  • Acute: heavy lungs with frothy exudate and dark blue-red appearance

  • Chronic: firm, brown appearance (“brown induration”)

Microscopic Findings

  • Acute: pink homogeneous fluid fills airspaces, capillaries are congested, leakage of blood into airspaces

  • Chronic: hemosiderin-laden macrophages within airspaces, alveolar septal thickening and fibrosis, changes of pulmonary venous hypertension

Pathologic Differential Diagnosis

  • Diffuse alveolar damage

  • Fibrin exudates

  • Pulmonary alveolar proteinosis

  • Pneumocystis jiroveci pneumonia

Congestion and edema of the lungs is common in heart failure and in areas of inflammation of the lung. Pulmonary edema is the leakage of fluid from the vascular compartment into the interstitium and alveoli of the lung. There are four major causes of pulmonary edema: (1) increased capillary hydrostatic pressure, (2) increased capillary permeability, (3) decreased plasma oncotic pressure, and (4) lymphatic obstruction. Recall that the fluid fluxes in the lung are governed by the Starling equation: the net fluid movement is dependent on the interrelationship between the capillary and interstitial hydrostatic and oncotic pressures. If the net fluid movement is positive, then fluid will leave the capillaries. If negative, fluid will tend to enter the capillaries.

Clinical Features

Pulmonary edema may be found at any age. The most common cause of pulmonary edema, though, is cardiogenic. Cardiogenic pulmonary edema is caused by elevated pulmonary capillary hydrostatic pressure, which leads to a transudate of fluid into the interstitium and alveoli. Both left atrial outflow impairment and left ventricular dysfunction can lead to cardiogenic pulmonary edema. Permeability pulmonary edema, on the other hand, results from injury to the capillary endothelial cells. Intravascular hydrostatic pressures are normal, but the endothelial cells lose their integrity and no longer provide a semipermeable membrane. Most of these patients suffer from acute respiratory distress syndrome (ARDS). High-altitude pulmonary edema is an example of noncardiogenic permeability pulmonary edema, which most often occurs in young individuals who have rapidly ascended from sea level to altitudes greater than 2500 m (8000 ft).

Patients with pulmonary edema, if acute in onset, develop breathlessness, anxiety, and feelings of drowning. In those patients with a more gradual onset of symptoms, the most common complaints include dyspnea upon exertion, orthopnea, and paroxysmal nocturnal dyspnea. Cough may also be present. Patients with severe disease may present with pink, frothy sputum.

Because the causes and severity of pulmonary edema are so varied, the morbidity and mortality of the disease are more related to the underlying etiology. However, the mortality may be as high as 20% in patients admitted to intensive care units.

Radiologic Features

Chest x-rays usually show classic features and thus are very helpful in distinguishing pulmonary edema from other causes of dyspnea. Alveolar edema is characterized by bilateral infiltrates in a butterfly pattern, along with pleural effusions ( Fig. 7.1 ). Other helpful features include loss of sharp definition of pulmonary vasculature, haziness of hilar shadows, and thickening of interlobular septa (Kerley B lines). However, it may take up to 12 hours to develop these classic chest x-ray signs.

FIG. 7.1, Pulmonary edema: chest x-ray findings. Chest radiograph illustrates the blunting of the costophrenic angles by pleural effusions, as well as the bilateral infiltrates, characterized by ill-defined opacities.

Pathologic Features

Gross Findings

The gross appearance can take two forms in pulmonary edema, depending on the acuity of the process. In acute pulmonary edema, the lungs are heavy, become dark blue-red, and exude a frothy pink material from the airways and the cut lung surfaces. The Kerley B lines that are visible on chest x-ray correspond to widened, edematous interlobular septa. In the more chronic form of the disease, the lungs may become firm and take on a brown hue, the so-called brown induration. The brown color is due to the numerous hemosiderin-laden macrophages (“heart failure cells”) that accumulate within airspaces ( Fig. 7.2 ).

FIG. 7.2, Pulmonary edema. Chronic leakage and uptake of hemosiderin by alveolar macrophages can lead to a grossly brown appearance of the lung due to the abundant golden-brown hemosiderin. The alveolar septa can become thickened due to this chronic hemorrhage.

Microscopic Findings

Morphologically, pulmonary edema is recognized as a pink homogeneous fluid that fills the alveolar spaces ( Fig. 7.3 ). The capillaries are congested and dilated, and there may be leakage of blood into alveolar spaces. In the chronic forms, the leakage and breakdown of red blood cells lead to the formation of golden-brown granules of hemosiderin accumulating within macrophage cytoplasm ( Fig. 7.4 ). These macrophages may be called heart failure cells if associated with pulmonary congestion due to congestive heart failure. Additionally, in chronic, long-standing examples of pulmonary edema, there may be a mild associated thickening and fibrosis of the alveolar septa. Pulmonary veins are also commonly affected in chronic pulmonary edema. The histologic changes associated with chronic pulmonary venous hypertension are described in the next section.

FIG. 7.3, Pulmonary edema. The alveolar spaces are filled with pink, homogeneous material characteristic of pulmonary edema.

FIG. 7.4, Pulmonary edema. (A) This is a high-power view of the golden-brown, chunky hemosiderin granules within airspace macrophages. (B) An iron stain highlights the intense deposition of hemosiderin that can be seen in longstanding heart failure.

Differential Diagnosis

The differential diagnosis of pulmonary edema chiefly includes diffuse alveolar damage (DAD), fibrin exudates, pulmonary alveolar proteinosis (PAP), and Pneumocystis jiroveci pneumonia (PJP). DAD is a disease characterized by hyaline membrane formation. The hyaline membranes diffusely line alveolar septa but do not fill the alveoli. It may be difficult on occasion to differentiate the two, because DAD (clinically, ARDS) begins with pulmonary edema. Fibrin exudates can appear similar to pulmonary edema, but fibrin exudates are denser and more eosinophilic, and other features of acute lung injury are often present. PAP can be difficult to distinguish from pulmonary edema. However, pulmonary edema lacks the granularity, acicular spaces, and foam cells of PAP. Periodic acid–Schiff (PAS) stains can also help distinguish PAP from pulmonary edema, because PAP contains PAS-positive, diastase-resistant material. PJP is associated with a frothy-appearing eosinophilic exudate that can be mistaken for pulmonary edema. PJP can be distinguished primarily by the more amphophilic appearance of the alveolar material, as well as by the frothy, foamy appearance. Silver stains, of course, will highlight the Pneumocystis organisms.

Prognosis and Therapy

The prognosis of pulmonary edema is entirely dependent on the etiology. Many patients can be treated adequately with pharmacotherapy. The drugs used to treat pulmonary edema depend on the cause. Cardiogenic pulmonary edema is treated with various drugs, including preload reducers, afterload reducers, catecholamines, and phosphodiesterase inhibitors. Some patients may require surgical intervention with intraaortic balloon pump insertion in order to obtain hemodynamic stabilization before definitive therapy. Patients with permeability pulmonary edema often require ventilatory support during the course of their disease.

Congestive Vasculopathy and Chronic Passive Congestion

Congestive Vasculopathy and Chronic Passive Congestion—Fact Sheet

Definition

  • End result of long-standing edema and congestion due to various etiologies, including chronic congestive heart failure and recurring pulmonary edema. Leads to pulmonary venous hypertension

Incidence

  • Any age

  • Occurs most commonly in patients with chronic congestive heart failure and/or recurring pulmonary edema

  • Mitral stenosis is another common cause

Mortality

  • Related to the underlying etiology

Clinical Features

  • Orthopnea and paroxysmal nocturnal dyspnea

  • Eventually, exertional dyspnea

Radiologic Features

  • Increase in size of the major vessels in the upper lobes

  • Cardiomegaly

  • Pulmonary edema pattern

  • Enlarged left atrial appendage (if mitral stenosis is present)

Prognosis and Therapy

  • Prognosis is dependent on etiology

  • Pulmonary vascular changes may persist even after clinical resolution of the underlying etiology

Congestive Vasculopathy and Chronic Passive Congestion—Pathologic Features

Gross Findings

  • “Brown induration” of chronic congestion and edema

Microscopic Findings

Pulmonary Veins

  • Medial hypertrophy

  • Arterialization (acquisition of an external elastic lamina)

  • Adventitial fibrosis

Pulmonary Lymphatics

  • Dilatation

Pulmonary Arteries

  • Medial hypertrophy

  • Intimal fibrosis, often eccentric

Pulmonary Arterioles

  • Muscularization

Alveolar Parenchyma

  • Edema

  • Alveolar septal thickening

  • Hemosiderin-laden macrophages within air spaces

  • Possible endogenous pneumoconiosis

Pathologic Differential Diagnosis

  • Alveolar hemorrhage syndromes

  • Pulmonary arterial hypertension

  • Pulmonary venoocclusive disease

Congestive vasculopathy and chronic passive congestion are the result of long-standing edema and congestion, often due to elevated left atrial pressure with consequent elevated pulmonary venous pressure. Over time, chronic passive congestion leads to fibrosis of the alveolar septa, along with hemosiderin deposition, the so-called brown induration described earlier. Not only are the septa affected, but the pulmonary veins, arteries, and arterioles can also become remodeled.

Clinical Features

Patients with a history of chronic congestive heart failure and/or recurring pulmonary edema may develop pulmonary venous hypertension. Pulmonary venous hypertension is the most common cause of pulmonary hypertension in clinical practice. These patients may develop orthopnea and paroxysmal nocturnal dyspnea before the development of exertional dyspnea. The clinical picture may become complicated because some of these patients remodel their pulmonary veins and arteries in response to the elevated left-sided pressures, leading to further elevations in pulmonary artery pressures and eventually right-sided heart failure.

Radiologic Features

The radiographic picture of pulmonary venous hypertension is characterized by a change in the apparent size of major vessels in the upper lobes compared with the lower lobes. Normally, when patients are upright, the upper lobe vessels are smaller than the lower vessels. With pulmonary venous hypertension, the upper lobe vessels became at least as large as, if not larger than, the lower lobe vessels. This can be a subtle finding. Other radiographic features can include cardiomegaly (because most congestive vasculopathies are due to left ventricular failure) and the findings of pulmonary edema described earlier. If mitral stenosis is present, then the chest x-ray shows prominence of the left atrial appendage.

Pathologic Features

Gross Findings

The gross findings in congestive vasculopathy are typified by the brown induration of the lung due to chronic hemosiderin deposition.

Microscopic Findings

Because the pressure changes are relayed to the pulmonary veins, arteries, and arterioles, all can show changes of vascular remodeling. The pulmonary veins become thickened by smooth muscle hypertrophy of the media. Additionally, elastic tissue stains demonstrate the acquisition of an external elastic lamina such that veins now resemble arteries ( Fig. 7.5 ). Venous adventitia often become fibrotic. Lymphatics within the interlobular septa often become dilated ( Fig. 7.6 ). The increased venous pressures translate to increased arterial/arteriolar pressures. Thus the pulmonary arteries become hypertrophied by both medial and intimal expansion. The medial hypertrophy can become quite pronounced ( Fig. 7.7 ), and the intimal fibrosis is often eccentric rather than circumferential ( Fig. 7.8 ). The arterioles may become muscularized. Other changes in the lung include hemosiderin-laden macrophages within air spaces. In fact, this may become so severe in diseases such as mitral stenosis that the changes may mimic a bland alveolar hemorrhage syndrome. If the hemosiderin load is large, there may be encrustation of elastic fibers by iron and calcium deposits with resultant engulfment by foreign-body–type giant cells. This appearance can also be seen in other causes of chronic pulmonary hemosiderosis (eg, idiopathic pulmonary hemosiderosis) and has been termed endogenous pneumoconiosis ( Fig. 7.9 ). Iron and von Kossa stains will highlight this feature. Additional histologic findings may include septal thickening due to chronic edema and congestion.

FIG. 7.5, Pulmonary venous hypertension: arterialization of interlobular vein. A vein within the interlobular septum displays arterialization of its wall, with an additional elastic lamina, medial hypertrophy, and mild intimal fibrosis. These changes are best appreciated with elastic tissue stains, such as this Movat or pentachrome stain. Note the absence of an accompanying airway, which would be seen with a true artery.

FIG. 7.6, Pulmonary venous hypertension: dilated lymphatic. As a consequence of venous hypertension, lymphatics become dilated, as illustrated here. This lymph channel is located within an interlobular septum.

FIG. 7.7, Pulmonary venous hypertension: medial hypertrophy of pulmonary artery. Pulmonary arteries can be secondarily affected by venous hypertension such that their medial layer becomes hypertrophied.

FIG. 7.8, Pulmonary venous hypertension: eccentric intimal fibrosis of pulmonary artery. In contrast to other causes of hypertension, pulmonary venous hypertension leads to an eccentric, rather than concentric, intimal changes in pulmonary arteries. This is a high-power view of a Movat-stained section, illustrating an artery with the left side showing minimal intimal change, whereas the right side shows more marked intimal hyperplasia, along with focal loss of the internal elastic lamina. The aqua color indicates myofibroblastic change.

FIG. 7.9, Pulmonary venous hypertension: chronic pulmonary hemosiderosis. (A) This hematoxylin and eosin (H&E) stain illustrates the encrustation of the vascular elastic fibers by calcium and iron deposits. The coated fibers take on a gray hue. Adjacent hemosiderin granules and vascular congestion are present. (B) In the center of this image, a multinucleated giant cell is seen engulfing some of the coated elastic fibers. This has given rise to the term endogenous pneumoconiosis. (C) Iron staining highlights the iron composition of the encrusted elastic fibers. Von Kossa stains can also be used to highlight the calcium composition.

Differential Diagnosis

If hemosiderosis is severe, particular attention should be paid to the vessels, because severe pulmonary venous hypertension can mimic alveolar hemorrhage syndromes. The only distinguishing feature may be the markedly abnormal vessels found in pulmonary venous hypertension. PAH does not affect the venous system; thus careful attention will distinguish the two. Additionally, plexiform lesions and arteritis are not features of pulmonary venous hypertension. Pulmonary venoocclusive disease (PVOD) can be particularly difficult to distinguish from congestive vasculopathy associated with chronic passive congestion, especially in the adult population. Occlusion of veins in interlobular septa is a helpful distinguishing feature in PVOD.

Prognosis and Therapy

The underlying etiology must be treated in order to affect the pulmonary venous hypertension. However, the pulmonary vascular findings may persist even after the clinical cause of the venous hypertension is resolved. There have been rare reports of complete regression of the histologic lesions.

Thromboembolism

Thromboembolism—Fact Sheet

Definition

  • Occlusion of pulmonary arteries, which is usually embolic (most emboli arise from deep venous thrombi), and less often thrombotic in origin

Incidence

  • Any age

  • Common in hospitalized patients

Mortality

  • Major contributor to death in 10% of patients dying in a hospital setting

Clinical Features

  • Most frequently asymptomatic

  • Sudden death is unusual

  • Can cause acute or chronic pulmonary hypertension and right-sided heart failure with its associated symptoms

Radiologic Features

  • Enlargement of central pulmonary arteries

  • Patchy decreased vascularity (mosaic oligemia)

  • Right-sided heart enlargement

  • Ventilation-perfusion scans sensitive, but not specific

  • Spiral CT with contrast best for chronic thromboembolic disease

Prognosis and Therapy

  • May develop pulmonary hypertension, cor pulmonale, and sudden death

  • Anticoagulants are the standard approach to prevention

  • Pulmonary thromboendarterectomy can be performed for large vessel clots

Thromboembolism—Pathologic Features

Gross Findings

  • Early: fibrin and blood loosely adherent to vessel wall

  • Late: fibrous intravascular webs visible in larger arteries

Microscopic Findings

  • Early (72 hours): fibrin and blood within arteries

  • Mid (1 week): endothelial cells cover the clot and grow into the embolus

  • Mid (second week): fibroblasts and capillaries form within the embolus

  • Late (third to fourth week): collagen fibers form, recanalization begins

  • Depending on size of vessel and blood supply, infarcts may occur

  • Nonblood clots can embolize to the pulmonary arteries, including megakaryocytes, bone marrow, adipose tissue, skin, hair, air, and gas; most are incidental findings

  • Tumor emboli can cause pulmonary hypertension

  • Foreign body emboli can cause pulmonary hypertension

Pathologic Differential Diagnosis

  • Plexiform lesions of pulmonary arterial hypertension

Pulmonary embolism is perhaps the most common cause of pulmonary vascular disease and likely the most clinically significant as well. Pulmonary emboli have been documented in up to half of all autopsied patients. Pulmonary embolism is a major contributing cause of death in up to 10% of patients dying in a hospital setting.

Clinical Features

Thrombosis can occur in a number of disease settings. Hypercoagulability, injury, and inactivity can all lead to peripheral venous thrombosis and subsequent embolism to the pulmonary vasculature. Although occlusions of pulmonary arteries are almost always embolic in origin (more than 95% arise from thrombi within lower leg veins), in situ thrombosis of small pulmonary arteries may occasionally lead to pulmonary hypertension. It should be cautioned that in situ thrombosis can occur in response to DAD and should not be interpreted as recurrent thromboembolic disease. Acute pulmonary thromboembolism rarely causes pulmonary hypertension except in massive cases, such as saddle embolism. Recurrent pulmonary thromboembolism, a subtle and difficult entity to diagnose, however, can often lead to sustained pulmonary hypertension. Diagnosis typically is made via spiral computed tomography (CT) scan, ventilation-perfusion scan, or pulmonary angiography. However, occasionally such cases are diagnosed by a fortuitous lung biopsy.

Additionally, emboli of foreign or endogenous material, such as intravenous drug particles, tumor or fat emboli, and ova/parasites, may lead to pulmonary artery obstruction. Sickle cell disease can result in recurrent microvascular obstruction, leading to the development of pulmonary hypertension. Pulmonary hypertension is among the most common cause of death in patients with sickle cell disease. These patients often present with progressive dyspnea.

Radiologic Features

Radiologic features of thromboembolism include enlargement of central pulmonary arteries, patchy areas of decreased vascularity (mosaic oligemia), and right-sided heart enlargement. Ventilation-perfusion scan is sensitive, but not specific, in diagnosing thromboembolic pulmonary hypertension. Spiral CT scans with contrast enhancement are the current procedure of choice for evaluating patients with suspected chronic thromboembolic pulmonary disease.

Pathologic Features

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