The chronic restrictive lung diseases are also called diffuse interstitial lung diseases, because changes in the interstitium dominate the morphologic appearance, and diffuse infiltrative diseases, because chest radiographs show diffuse infiltrates. Chronic restrictive lung diseases are a heterogeneous group of disorders without uniform classification, without uniform terminology, and often without known etiology or pathogenesis. Nevertheless, they share many clinical and morphological features and, at end-stage, they may be indistinguishable from each other. Clinically, patients with chronic restrictive lung diseases have dyspnea, tachypnea, end-inspiratory crackles, and eventual cyanosis (Chap. 24). Later, these patients often develop secondary pulmonary hypertension (Chap. 26) and right heart failure with cor pulmonale. Pathogenetically, many of the chronic restrictive lung diseases begin with alveolitis, leading to distortion of alveolar structure and release of mediators that incite cell injury and induce fibrosis. Morphologically, many of the chronic restrictive lung diseases, particularly in later stages, are characterized by interstitial fibrosis. The end-stage of many of the chronic restrictive lung diseases is the classic honeycomb lung.
Idiopathic pulmonary fibrosis (IPF) is a poorly understood, idiopathic, nongranulomatous chronic restrictive lung disease that morphologically is characterized by diffuse interstitial fibrosis. Although many alternate names for the disease exist, cryptogenic fibrosing alveolitis is the one most frequently encountered. The pathogenesis of IPF is poorly understood but appears to involve repeated cycles of alveolitis (due to an unidentified agent) that are followed by wound healing with fibroblast proliferation. Grossly, lungs with well-developed IPF have a pleural surface with a cobblestone appearance due to wound contraction in interlobular septa. The cut surface of IPF lungs shows rubbery-to-firm, white patches in subpleural regions and in the interlobular septa (Fig. 23.3).
Usual interstitial pneumonia in idiopathic pulmonary fibrosis. Pale regions represent fibrosis with cystic change (honeycomb pattern) and are concentrated in the lower lobe and in the subpleural zone of the upper lobe (left of image). The darker parenchyma represents portions of lung with little or no fibrosis. From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002.
Histologically, the morphology of IPF is described as usual interstitial pneumonia (UIP) (Fig. 23.4). Although required for a diagnosis of IPF, UIP is not specific and can be seen in other diseases (eg, collagen vascular diseases, asbestosis; see below). UIP is characterized by regional and temporal heterogeneity where different lung foci show different stages of disease. In addition to interstitial fibrosis, magnified in subpleural zones and interlobular septa, UIP includes characteristic fibroblastic foci and typically shows prominent type 2 pneumocyte hyperplasia. End-stage UIP shows dilatated airspaces lined by cuboidal or low columnar epithelium separated by inflamed fibrous tissue. Patients with IPF typically present in the fifth to eighth decade with increasing dyspnea on exertion and dry cough, followed by hypoxemia, cyanosis, and digital clubbing. Progression of IPF is unpredictable, but the mean survival time is approximately three years. The only definitive therapy for IPF is lung transplantation.
Usual interstitial pneumonia in idiopathic pulmonary fibrosis. (a) Cystically dilatated airspaces are separated by fibrotic and thickened septa. (b) A characteristic finding in UIP is the fibroblastic focus (arrow). (b): From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002.
CLINICAL CORRELATION 23.1
By turning up the brightness on a computed tomogram, the resulting CT images of the lungs can demonstrate severity of interstitial disease. The settings used to image lung parenchyma are the lung windows and blur detail in surrounding soft tissue. Fig. 23.5(a) is high-resolution CT of UIP, with subpleural distribution of abnormalities. Fig. 23.5(b) is an HRCT of end-stage UIP with honeycombing that is more pronounced on the patient's left side (right side of image).
See Clinical Correlation 23.1 for details. From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002.
Nonspecific interstitial pneumonia (NSIP) is an idiopathic, nongranulomatous lung disease without the defining diagnostic features of better-characterized diseases. Histologically, NSIP can show a cellular pattern with mild to moderate expansion of the interstitium by lymphocytes and plasma cells with either a uniform or patchy distribution [Fig. 23.6(a)]. Alternatively, a fibrosing pattern with diffuse or patchy interstitial fibrosis is noted [Fig. 23.6(b)]. In contrast to UIP, the fibrosing pattern of NSIP does typically not show fibroblastic foci or the regional/temporal heterogeneity of disease.
Nonspecific interstitial pneumonia. (a) The cellular pattern of NSIP in which moderate mononuclear inflammatory infiltrate expands the interstitium. (b) The fibrosing pattern of NSIP, in which interstitial fibrosis expands alveolar septa. From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002.
Sarcoidosis is an idiopathic multisystem disease characterized by granulomatous inflammation (typically noncaseating) in many tissues and organs. Since there are many causes of granulomatous inflammation—including foreign body, mycobacterial infection, and fungal infection—sarcoidosis is a diagnosis of exclusion. Though its presentation can include involvement of virtually any organ, patients typically have bilateral hilar lymphadenopathy and/or lung involvement. Sarcoidosis shows a racial bias (black:white of about 10:1) and a female gender bias. Though the etiology of sarcoidosis is unknown, its pathogenesis likely involves a type IV hypersensitivity reaction (cell-mediated, delayed) to a currently unknown antigen. Familial and racial clustering and association with certain HLA subtypes imply that development of sarcoidosis may require a genetic predisposition. Many features of sarcoidosis suggest that it is an infectious disease, but there is no unequivocal evidence that sarcoidosis has an infectious etiology. The morphology of sarcoidosis is nonspecific: noncaseating granulomatous inflammation (Fig. 23.7). A granuloma is a circumscribed collection of epithelioid histiocytes [Fig. 23.7(c)]; the term "epithelioid" is used to describe cells that have more cytoplasm than typical histiocytes, imparting a resemblance to squamous epithelial cells. Epithelioid histiocytes can merge with each other, producing a multinucleated giant cell. While multinucleated giant cells are common in granulomata, not all granulomata contain them. In sarcoidosis, the granulomata often contain Schaumann bodies [laminated concretions of calcium and protein, Fig. 23.7(d)] and asteroid bodies [stellate inclusions within giant cells, Fig. 23.7(e)]. However, neither Schaumann bodies nor asteroid bodies are specific for sarcoidosis.
Sarcoidosis. (a) Grossly, numerous white nodules are associated with bronchovascular bundles. (b) At low magnification, the numerous granulomata appear as eosinophilic nodules. (c) At higher magnification, these nodules are seen to be composed of epithelioid histiocytes and multinucleated giant cells (arrow). Though nonspecific, Schaumann bodies [(d), arrow] and asteroid bodies [(e), arrow] also can be present. (a), (b), (d), and (e): From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002. (c): From Klatt. Robbins and Cotran Atlas of Pathology, 2nd ed. 2010.
As mentioned above, the granulomata in sarcoidosis can involve virtually any organ but typically involve the pulmonary interstitium and hilar lymph nodes. Pulmonary involvement is often complicated by interstitial fibrosis. Other organs that are commonly involved include skin, eyes, lacrimal glands, salivary glands, spleen, liver, and skeletal muscle. Clinically, sarcoidosis is often asymptomatic. If symptomatic, sarcoidosis ranges from progressive chronicity to periods of activity separated by periods of remission. Presentation is typically due to respiratory involvement, with dyspnea, cough, chest pain, and hemoptysis; alternatively, constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats) may dominate the clinical scenario. Specific symptoms at presentation are markedly variable due to the complex of sites showing involvement. Approximately 65%-70% of patients recover spontaneously or with steroid therapy and have minimal or no residual disease, ~20% of patients develop permanent lung dysfunction or visual impairment, and 10%-15% develop progressive pulmonary fibrosis with subsequent cor pulmonale or central nervous system damage.
Hypersensitivity pneumonitis is typically an occupational disease that begins with alveolar damage from exposure to an organic antigen. The acute phase of the disease occurs 4-6 hours after antigen exposure in a previously sensitized host, likely represents a type III hypersensitivity reaction (immune complex), and is typified by diffuse and nodular infiltrates on chest radiograph, restrictive pattern of pulmonary function tests, and neutrophilic inflammation. With continuous antigen exposure, the disease enters its chronic phase with respiratory failure, dyspnea, cyanosis, decreased lung compliance, and decreased total lung capacity. The chronic phase is a type IV hypersensitivity reaction (delayed, cell-mediated) characterized histologically by lymphocytes, plasma cells, and foamy histiocytes in alveoli, alveolar walls, and around terminal bronchioles; interstitial fibrosis; obliterative bronchiolitis; and, in about two-thirds of cases, granulomata. Of note, the eosinophilia that is typical of type I hypersensitivity reactions is not a significant feature of hypersensitivity pneumonitis. If the offending antigen is removed during the acute phase, the disease resolves in weeks. Once the disease has progressed to its chronic phase, resolution can be slow, and approximately 5% of patients develop respiratory failure and die. Table 23.2 summarizes the myriad diseases that represent forms of hypersensitivity pneumonitis.
Table 23.2Typical presentations of hypersensitivity pneumonitis ||Download (.pdf) Table 23.2 Typical presentations of hypersensitivity pneumonitis
|Syndrome ||Exposure ||Antigens |
|Fungal/Bacterial Antigens || || |
|Farmer's lung ||Moldy hay ||Micropolyspora faeni |
|Bagassosis ||Moldy sugar cane ||Thermoactinomyces sacchari |
|Maple bark disease ||Moldy maple tree bark ||Cryptostroma corticale |
|Humidifier lung ||Cool-mist humidifier ||Thermophilic Actinomycetes, Aureobasidium pullulans |
|Malt worker's lung ||Moldy barley grain ||Aspergillus clavatus |
|Cheese washer's lung ||Moldy cheeses ||Penicillium casei |
|Insect Products || || |
|Miller's lung ||Dust-contaminated grain ||Sitophilus granarius (wheat weevil) |
|Animal Products || || |
|Bird fancier's lung ||Pigeon, parakeet, chicken ||Serum proteins in droppings |
|Chemicals || || |
|Chemical worker's lung ||Chemical industries ||Trimellitic anhydride, isocyanates |
CLINICAL CORRELATION 23.2
A 13-year-old boy with a history of congenital heart disease presents with interstitial lung disease of unknown etiology. A wedge biopsy of lung is procured and shows interstitial non-necrotizing granulomatous inflammation with multinucleated giant cells (Fig. 23.8). Special stains for acid-fast microorganisms and fungi are negative. Histologic findings are nonspecific but suggestive of hypersensitivity pneumonitis. Subsequently, additional history is obtained: the patient lives in a home with 17 birds. Combining the clinical scenario with histologic findings, a diagnosis of hypersensitivity pneumonitis (bird fancier's disease) is made, establishing the etiology for the patient's interstitial lung disease.
Pulmonary eosinophilia is a collection of diseases with similar morphologies of eosinophilic infiltration of the pulmonary interstitium and/or alveolar spaces (Fig. 23.9) and similar clinical scenarios of corticosteroid-responsive fever, night sweats, and dyspnea. Acute eosinophilic pneumonia with respiratory failure is an idiopathic illness with rapid onset of fever, dyspnea, and potentially fatal hypoxemic respiratory failure. Simple pulmonary eosinophilia (Löffler syndrome) is characterized by transient pulmonary eosinophilic infiltrates and peripheral blood eosinophilia. Tropical eosinophilia represents a microfilarial infection. Secondary chronic pulmonary eosinophilia occurs in a number of settings, including certain infections (parasitic, fungal, bacterial), drug allergies, asthma, allergic bronchopulmonary aspergillosis (Chap. 20), and polyarteritis nodosa. Idiopathic chronic eosinophilic pneumonia is characterized by interstitial and intra-alveolar lymphocytic and eosinophilic infiltrates in peripheral lung fields. From the morphologic perspective, many of these diseases are indistinguishable, thus giving rise to the morphologic term pulmonary eosinophilia.
Pulmonary eosinophilia. (a) Intra-alveolar eosinophil-rich exudates dominate this example of idiopathic chronic eosinophilic pneumonia. (b) In this example of acute eosinophilic pneumonia, eosinophils are in the interstitium. From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002.
Though smoking-related lung disease is frequently obstructive (see Chap. 20 for discussions of emphysema and chronic bronchitis), there are several smoking-related restrictive lung diseases. Desquamative interstitial pneumonitis (DIP) and respiratory bronchiolitis-associated interstitial lung disease are thought of as opposite ends of a spectrum of interstitial lung disease that may develop in smokers; the pathogenesis of both is unknown. In DIP [Fig 23.10(a), (b)], there is mononuclear interstitial inflammation, an abundance of airspace macrophages with dusty brown cytoplasmic pigment, and type 2 pneumocyte hyperplasia. The airspace macrophages in DIP typically clump together, resulting in an appearance that was historically (and erroneously) interpreted as desquamated alveolar epithelium. In respiratory bronchiolitis-associated interstitial lung disease, there is patchy bronchiolocentric distribution of pigmented macrophages [Fig. 23.10(c)], and there can be histologic overlap with DIP. Both DIP and respiratory bronchiolitis-associated interstitial lung disease present in the fourth to fifth decade, show a male gender bias (male:female ratio of about 2:1), may occur with insidious onset of dyspnea and cough, and improve with cessation of smoking and steroid therapy.
Smoking-related restrictive lung disease. (a) DIP at low magnification. Airspaces are difficult to discern due to accumulated clumps of intra-alveolar macrophages. (b) DIP at high magnification. Clumping of faintly pigmented intra-alveolar macrophages resembles the cohesion of epithelial cells. (c) In respiratory bronchiolitis, there is patchy distribution of macrophages in the bronchiolar lumen and adjacent airspaces. From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002.
Pulmonary amyloidosis can show diffuse deposition of amyloid in alveolar septa, a pattern typically associated with disseminated primary amyloidosis or multiple myeloma, or there may be nodular deposition of amyloid. Pulmonary symptoms are usually not severe. Morphologically, amyloid is hyaline and stains with Congo red stain [Fig. 23.11(a), (b)]. Amyloid shows apple-green birefringence when stained with Congo red and viewed through a polarized light source [Fig. 23.11(c)].
Pulmonary amyloidosis. (a) By routine H&E staining, amyloid appears as eosinophilic amorphous material, shown here (arrow) surrounding two blood vessels. (b) Amyloid stains deep red with Congo red stain. (c) When stained with Congo red stain and viewed with polarized light, amyloid shows "apple-green" birefringence. (b) and (c): From Travis et al. Atlas of Nontumor Pathology: Volume 2: Non-Neoplastic Disorders of the Lower Respiratory Tract, American Registry of Pathology; 2002.
Cryptogenic organizing pneumonia (COP) is a nonspecific pattern of lung injury characterized by polypoid plugs of loose fibrous tissue. In contrast to the majority of diseases discussed in this chapter, in COP the fibrous tissue is not in the interstitium but rather within lumina of alveolar ducts, alveoli, and often bronchioles (Fig. 23.12). The distribution of lesions is typically more peripheral than distal. There are many etiologies of COP including infection (viral, bacterial), collagen vascular diseases, drug toxicity, toxic inhalants, and bronchial obstruction. Most patients show gradual improvement with steroid therapy.
Cryptogenic organizing pneumonia. Fibrous plugs (*), representing organizing exudate, occlude the lumina of distal airways. From Klatt. Robbins & Cotran Atlas of Pathology, 2nd ed. 2010.
Pulmonary alveolar proteinosis (PAP) is a rare disease with bilateral, patchy, and asymmetric lung involvement manifesting as opacification on chest radiograph. PAP can be acquired (being most common with ~90% of cases), congenital, or secondary. Acquired PAP appears to result from an autoantibody that inhibits the activity of GM-CSF, thereby impairing macrophage clearance of pulmonary surfactant. Congenital PAP is genetically heterogeneous, with the genetic lesion unknown in most cases; alternatively, congenital PAP can arise in the setting of mutations in the genes for ATP-binding cassette protein member A3 (ABCA3), surfactant protein B, GM-CSF, or the GM-CSF receptor β chain. Secondary PAP can arise in the setting of hematopoietic disease, malignancy, immunodeficiency, lysinuric protein intolerance, or acute silicosis (and other pneumoconioses, see below). Morphologically, whether acquired, congenital, or secondary, PAP is characterized by enlarged and abnormally heavy lungs which exude turbid fluid on sectioning. Microscopically (Fig. 23.13), there is intra-alveolar accumulation of dense, granular, eosinophilic material containing lipid and PAS-positive material. Clinically, PAP presents with insidious respiratory difficulty and a cough productive of abundant gelatinous chunks. With disease progression, dyspnea, cyanosis, and respiratory insufficiency can develop. Therapy for adult PAP involves lung lavage, and approximately one-half of adults benefit from recombinant GM-CSF therapy. Congenital PAP is fatal in 3-6 months without lung transplantation.
Pulmonary alveolar proteinosis. Alveolar septa are normal, but airspaces are filled with granular eosinophilic material. Pulmonary edema fluid (Chap. 26) is less granular than PAP material and typically does not contain PAS-positive debris that is present in PAP. From Klatt. Robbins & Cotran Atlas of Pathology, 2nd ed. 2010.
Collagen vascular diseases can be complicated by pulmonary involvement. In progressive systemic sclerosis (scleroderma), pulmonary injury is typified by diffuse interstitial fibrosis. In systemic lupus erythematosus (SLE), pulmonary histopathology typically consists of patchy, transient parenchymal infiltrates. In rheumatoid arthritis, pulmonary involvement can manifest as chronic pleuritis (with or without a pleural effusion), diffuse interstitial pneumonitis and fibrosis, pulmonary hypertension (Chap. 26), or intrapulmonary rheumatoid nodules. The presence of rheumatoid nodules in the setting of pneumoconiosis (see below) is known as Caplan syndrome.