Chapter 26: Pathology of Atelectatic, Vascular, and Iatrogenic Diseases of the Lungs and Pleural Space

Atelectasis describes a reduction in lung volume due to incomplete expansion of airspaces or, more commonly, the collapse of previously inflated pulmonary parenchyma. In atelectasis, perfusion of such nonventilated lung creates a physiological shunt that mixes inadequately oxygenated blood from pulmonary arteries with better oxygenated blood in the pulmonary veins (Chap. 9). If the ventilation-perfusion mismatch is sufficiently severe, systemic hypoxemia results. Additionally, atelectatic lung is more likely to become infected. Atelectasis can be subdivided by its pathogenesis.

In resorption atelectasis (also known as obstruction atelectasis), air is prevented from reaching distal airspaces because of airway obstruction. Then, as more distal air is absorbed, the previously expanded lung collapses. The extent of involvement is determined by the level of obstruction: Obstruction of a major airway can result in collapse of an entire lobe. Most commonly, a mucous or mucopurulent plug is responsible for the obstruction, although any physical obstruction will suffice. In resorption atelectasis, the mediastinum shifts toward the affected side.

In compression atelectasis (also known as passive atelectasis and as relaxation atelectasis), accumulation of space-occupying material within the pleural space mechanically compresses the lung parenchyma (Fig. 26.1). Compression atelectasis complicates pleural effusion and pneumothorax (see below), as well as pleural tumors (Chap. 31). Additionally, compression atelectasis of basal lung zones complicates peritoneal effusion (ascites) and frequently occurs in bedridden patients due to diaphragmatic elevation. In compression atelectasis, the mediastinum shifts away from the affected side.

Microatelectasis complicates adult and neonatal respiratory distress syndromes (Chaps. 23 and 39) as well as interstitial inflammatory lung diseases (Chap. 23). Its pathogenesis involves a complex set of events, the most important being deactivation of surfactant in the mature lung or its inadequate synthesis in neonatal lung.

In the setting of localized or generalized pulmonary fibrosis, the foci of fibrosis contract largely due to the action of myofibroblasts, collapsing adjacent lung tissue and resulting in contraction atelectasis or cicatrization atelectasis.

Generally, resorption atelectasis, compression atelectasis, and microatelectasis are reversible, while contraction atelectasis is not.

When edema develops in the lung, the excess fluid rapidly moves from the interstitium to the airspaces (Chaps. 7 and 28). While there are many specific causes of pulmonary edema (see Table 7.2), it is generally due to a change in hemodynamics (perfusion vs interstitial pressures) or to microvascular injury. Congestive heart failure is the most common cause of an increase in pulmonary venous pressure and the resultant pulmonary edema. Less commonly, reduction of plasma oncotic pressure will result in egress of fluid from the vascular space into the interstitium and then the alveoli. Alternatively, an increase in the permeability of capillaries, as occurs in the setting of alveolar and microvascular injury, can result in edema (Chap. 28).

Gross manifestations of pulmonary edema include increase in lung weight and a wet cut surface with frothy fluid visible in larger airways. Microscopically, pulmonary edema is characterized by pale, eosinophilic, glassy or finely granular intra-alveolar precipitate [Fig. 26.2 (a)]. In the setting of pulmonary edema secondary to elevation of venous pressure, alveolar septal capillaries will show congestion characterized by engorgement with blood. Due to the delicate nature of alveolar septa, congestion is typically accompanied by occasional rupture of capillaries, resulting in microhemorrhages that release formed blood elements into alveolar spaces. As erythrocytes are cleared by macrophages, hemoglobin is progressively catabolized to hemosiderin, which persists in macrophage cytoplasm. Thus, the presence of hemosiderin-laden macrophages (or siderophages) reflects remote hemorrhage and implies chronic congestion [Fig. 26.2 (b)]. While any form of pulmonary hemorrhage will eventually show siderophages, the most common cause of pulmonary congestion and hemorrhage is congestive heart failure. This has led to widespread usage of the term "heart failure cells" to describe such intra-alveolar hemosiderin-laden macrophages.

A large majority of pulmonary emboli are thrombotic in origin. Therefore, unless otherwise specified, the term "pulmonary embolus" typically refers to pulmonary thromboembolus. Pulmonary thromboembolism is involved in approximately 10% of hospital deaths. In more than 95% of cases, the source of pulmonary thromboemboli is a thrombus in a deep vein of the lower extremity (Chap. 27). Risk factors for venous thrombosis and pulmonary thromboembolus include prolonged bed rest (especially in the setting of lower extremity immobilization), severe trauma, burns, congestive heart failure, and hypercoagulable states (Table 26.1).

When a venous thrombus embolizes, it travels in progressively larger systemic veins toward the right heart. Upon ejection from the right ventricle, fragments of the embolism move into progressively smaller branches of the pulmonary artery until they reach vessels too small to allow passage. At that point the thromboemboli occlude a pulmonary artery or arteriole and increase pulmonary vascular resistance and can induce vasospasm. When a major vessel is occluded, the resulting pulmonary hypertension can reduce cardiac output and induce cor pulmonale and death. If death does not result, pulmonary thromboembolism results in hypoxemia due to ventilation-perfusion mismatch with increased dead space ventilation (Chap. 8). The ischemia may also reduce surfactant release and cause pleuritic pain that add to the work of breathing (Chaps. 5 and 6). Despite the lung's systemic blood supply (Chap. 2), pulmonary thromboembolism can result in lung parenchymal ischemia and pulmonary infarction. In patients with patent foramen ovale (~30% of all people), pulmonary arterial thrombotic occlusion can cause right-to-left shunting and subsequent paradoxic embolism, in which a venous thrombus enters and embolizes systemic arteries and cause distal ischemia.

Grossly, a pulmonary thromboembolus is a serpentine blood clot impacted in a pulmonary arterial branch [Fig. 26.3 (a)]. A very large thromboembolus occluding the main pulmonary arteries is typically referred to as a "saddle embolus." Microscopically, the thromboembolus is characterized by alternating layers of fibrin (eosinophilic) and erythrocytes. Ischemic lung damage is characterized by intra-alveolar hemorrhage [Fig. 26.3 (b)]. A pulmonary infarct will be conical (or, on cut section, wedge-shaped) and hemorrhagic [Fig. 26.4 (a)]. Initially, the infarct is red-blue. It becomes paler and later red-brown as erythrocytes lyse and hemoglobin is degraded to hemosiderin. Next, as fibroblasts progressively replace necrotic tissue with scar, the infarct shows a gray-white peripheral zone. Microscopically, infarcted lung tissue shows coagulative necrosis with loss of nuclear basophilia, although alveolar hemorrhage often dominates the microscopic appearance [Fig. 26.4 (b), (c)]. In cases of sudden death due to saddle embolus, there are typically no gross or microscopic changes to the lung.

Clinically, 60%-80% of pulmonary thromboemboli are asymptomatic; approximately 5% cause acute cor pulmonale, shock, or sudden death; and 10%-15% affect medium-sized arteries and, through an unknown mechanism, cause dyspnea. In the presence of an underlying risk factor, a patient who has had pulmonary thromboembolism has a 30% chance of recurrent pulmonary thromboembolism. A minority (<3% of patients with recurrent pulmonary thromboembolism develop pulmonary hypertension (see below), chronic cor pulmonale, vascular sclerosis, and worsening dyspnea. Treatment of pulmonary thromboembolism involves thrombolysis and anticoagulation. If anticoagulation is contraindicated or not sufficient, a filter (Greenfield filter, umbrella) can be placed in the inferior vena cava; thromboemboli caught in the filter will undergo fibrinolysis.

In addition to venous thrombi, the student should remember that embolism of the lung can be caused by air, bone marrow, fat, foreign bodies, and amniotic fluid. In most instances, the hemodynamic effects from such materials resemble those caused by thrombi (Chap. 27). However, the duration of such effects and the severity of pulmonary compromise they cause may be transient (as for the nitrogen in air), or may persist (as has been noted for crystals of talcum used to "cut" certain drugs before their intravenous abuse). Amniotic fluid embolism is a devastating event, often resulting in maternal death in the peripartum period.

Normally, pulmonary arterial pressure is approximately one-eighth that of systemic arterial pressure. Pulmonary hypertension is defined as a pulmonary arterial blood pressure greater than or equal to one-fourth systemic arterial blood pressure. Pulmonary hypertension can be a primary disorder or a disorder secondary to an underlying condition. Primary pulmonary hypertension is less common than secondary forms and is typically sporadic, though familial forms exist.

In some cases of primary pulmonary hypertension, the pathogenesis involves a mutation in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), a cell surface protein (in the TGF-β superfamily) that binds many cytokines (including TGF-β, BMP, activin, and inhibin). In vascular smooth muscle cells of the tunica media, normal BMPR2 signaling decreases proliferation and increases apoptosis. An inactivating mutation of the BMPR2 gene, thus, results in smooth muscle proliferation. Such a mutation is present in approximately one-half of patients with familial primary pulmonary hypertension and approximately one-fourth of patients with sporadic primary pulmonary hypertension.

In secondary pulmonary hypertension, endothelial cell dysfunction results from increased shear and mechanical force, due to increased flow and/or increased pressure, or from biochemical injury (eg, due to effects of fibrin in the setting of thromboembolism). Subsequent to endothelial injury, reduction in prostacyclin and NO leads to pulmonary vasoconstriction, platelet adhesion, and platelet activation, while various growth factors and cytokines induce migration and replication of vascular smooth muscle cells. Many conditions cause increased pulmonary blood flow, increased pulmonary vascular resistance, or increased left heart resistance to blood flow and result in secondary pulmonary hypertension (Table 26.2).

The morphology of pulmonary hypertension—primary or secondary—is manifest throughout the pulmonary arterial tree. Main elastic arteries develop atheromata; medium-sized arteries develop hyperplasia of the tunica intima and the tunica media, resulting in thickening of the arterial wall and luminal stenosis (Fig. 26.5); small arteries and arterioles develop medial hypertrophy with reduplication of elastic membranes.

Clinically, primary pulmonary hypertension affects young (20- to 40-year old) patients, more commonly women, and presents with fatigue, syncope (especially on exertion), dyspnea on exertion, and chest pain. Eventually, patients develop severe respiratory insufficiency and cyanosis, with death within 2-5 years in more than three quarters of cases. The clinical scenario in secondary pulmonary hypertension varies by the underlying disease, though respiratory insufficiency and right heart failure eventually develop.

Goodpasture syndrome is an autoimmune disease characterized by the simultaneous development of proliferative glomerulonephritis (typically crescentic) and necrotizing, hemorrhagic interstitial pneumonitis. Epidemiologically, it is associated with certain HLA subtypes and shows a male predominance; presentation is typically in the teens or twenties. Pathogenetically, IgG autoantibodies are directed against an epitope on the α₃ chain of collagen IV. Collagen IV is non-fibrillar and is a key component of basement membranes. The autoantibody-induced basement membrane damage results in clinically significant glomerular and pulmonary injury. With respect to gross pulmonary disease, lungs are heavy, consolidated, and discolored red-brown. Microscopically, the Goodpasture syndrome lung shows focal alveolar wall necrosis with intra-alveolar acute hemorrhage and alveolar septal fibrotic thickening (Fig. 26.6).

Clinically, the presentation of Goodpasture syndrome typically involves hemoptysis with the subsequent development of rapidly progressive renal insufficiency. Therapy involves removal of the pathologic autoantibodies by plasmapheresis and reduction of autoantibody production through immunosuppression.

Wegener's granulomatosis is a systemic vasculitis with a peak incidence in the fifth decade. Pathogenetically, it is likely a form of hypersensitivity, and patients typically have anti-neutrophil cytoplasmic antibodies with cytoplasmic localization (c-ANCA). Simplistically, the antibodies activate neutrophils, which then attack vascular luminal surfaces, resulting in vasculitis of small and medium-sized vessels. Like Goodpasture syndrome, the clinical scenario in Wegener's granulomatosis is dominated by simultaneous pulmonary and renal disease. Morphologically, respiratory tract involvement in Wegener's granulomatosis includes upper tract vasculitis, mucosal granulomata, and ulcers rimmed by granulomatous inflammation as well as lower tract necrotizing granulomatous inflammation (often with cavitation) and necrotizing or granulomatous vasculitis (Fig. 26.8). Renal involvement is typified by necrotizing glomerulonephritis, typically with crescent formation (extracapillary proliferation).

Idiopathic pulmonary hemosiderosis is a disease of children and young adults characterized by the insidious development of hemoptysis, anemia, and weight loss. Morphologically, lungs are heavy, consolidated, and discolored red to red-brown. Microscopically, lungs show alveolar epithelial degeneration, shedding, and hyperplasia; intra-alveolar siderophages; marked congestion of alveolar septal capillaries; and varying degrees of fibrosis.

Many drugs induce lung disease, the morphology of which varies with each compound. The most significant among these are summarized in Table 26.5.

Ionizing radiation injury to the lung can complicate therapeutic irradiation of the lungs, mediastinum, esophagus, and breast. Acute radiation pneumonitis occurs 1-6 months after radiation therapy in 10%-20% of patients receiving therapeutic irradiation involving the lung fields. The pneumonitis in these patients is characterized clinically by fever, dyspnea, and infiltrates on chest x-rays corresponding to the site of previous irradiation. Morphologically, lungs show diffuse alveolar damage (Chap. 23), often with severe atypia of hyperplastic type II alveolar epithelial cells. Some patients with acute radiation pneumonitis will, after about 6 months, progress to chronic radiation pneumonitis that is characterized by interstitial fibrosis in the previously irradiated areas (Fig. 26.10).

With lung transplantation, maintaining graft survival and function involves balancing the two major complications of transplantation: infection and rejection. Powerful immune suppression reduces the incidence of rejection while raising the incidence of infection. Decreased immunosuppression reduces the incidence of infection while raising the incidence of rejection. Lung transplant patients are at risk for bacterial, viral (especially CMV), and fungal infections (including candidiasis, aspergillosis, and Pneumocystis jiroveci pneumonia; Chap. 34). Acute rejection typically occurs within 3 months of transplantation and is characterized by fever, dyspnea, cough, and chest radiograph infiltrate. Since the symptoms and signs of acute rejection mimic those of infection, lung biopsy may be required to establish the diagnosis. The histologic hallmark of acute rejection in the pulmonary allograft is a perivascular lymphocytic inflammatory infiltrate [Fig. 26.11 (a)]. Chronic rejection can present 6-12 months after transplantation and is present in more than one-half of lung transplant recipients within 5 years of transplantation. The histologic hallmark of chronic rejection is bronchiolitis obliterans, in which bronchiolar lumina are obstructed by an inflammatory fibrous exudate [Fig. 26.11 (b)]. Long-standing chronic rejection can result in bronchiectasis (Chap. 20).

A pleural effusion is excess fluid in the pleural space and can be inflammatory or non-inflammatory (Chap. 19). Inflammatory pleural effusions typically occur in the setting of pleuritis, which can be due to infection of the lung (Chap. 34), collagen vascular disorders, uremia, systemic infection, or metastatic cancer. Empyema is a purulent pleural effusion and can be due to spread of an intrapulmonary infection to the pleural space or from lymphohematogenous spread of infection. Typically, empyema undergoes organization, with the development of fibrous adhesions that obliterate the pleural space. In hemorrhagic pleuritis, pleural effusion is sanguineous; underlying conditions include hemorrhagic diathesis, rickettsial disease, and neoplastic involvement of the pleural space. Other pleural effusions include hydrothorax (typically in the setting of congestive heart failure), hemothorax (blood in pleural space), and chylothorax (lymph fluid in pleural space; typically left-sided and due to thoracic duct trauma or obstruction).

Pneumothorax describes air in the pleural space and can be secondary to trauma, interstitial emphysema (Chap. 20), asthma (Chap. 21), tuberculosis (Chap. 36), or a lung abscess (Chap. 34) communicating with the pleural space. Tension pneumothorax, a medical emergency, is a pneumothorax wherein the defect acts as a valve, such that air enters the pleural cavity on inspiration but is prevented from leaving the pleural cavity on expiration.