Mattia Barbareschi, MD, and Alberto Cavazza, MD
Large Airways: Trachea and Bronchi
Nonneoplastic diseases affecting the trachea and bronchi are commonly related to inhalation exposure or, more rarely, to developmental anomalies and systemic diseases; they may also involve the larynx (Box 9.1). The effect of these diseases is usually luminal obstruction or collapse, whereas they rarely present as circumscribed nodular lesions or marked dilation of the tracheal and bronchial lumen.
Trachea
Nonneoplastic pathology of the trachea can be divided broadly into extrinsic and intrinsic diseases. Among extrinsic diseases are certain infections, such as rhinoscleroma (caused by Klebsiella rhinoscle- romatis1,2) (Fig. 9.1), and systemic autoimmune diseases that affect cartilage (e.g., granulomatosis with polyangiitis, so-called Wegener granulomatosis3,4). These diseases may cause tracheal obstruction or collapse and may also involve the larynx, bronchi, or both. Diseases intrinsic and unique to the trachea are few; they usually involve also the large bronchi and are mainly of congenital and/or metabolic origin. The following section describes three of these entities: tracheobronchial amyloidosis, tracheobronchomalacia, and tracheo- bronchopathia osteochondroplastica. The last of these may be rare but deserves mention because it can be encountered incidentally during bronchoscopy.
Tracheobronchial Amyloidosis
Tracheobronchial amyloidosis is a rare idiopathic disease characterized by amyloid deposition, often throughout the tracheobronchial tree5,6 but sometimes restricted to the larynx and trachea.7 It typically presents after the fifth decade of life with dyspnea, cough, wheezing (sometimes misdiagnosed as asthma), and occasionally hemoptysis and determines narrowing of the airways, which may cause recurrent pneumonias and parenchymal atelectasis. Pulmonary function tests usually show fixed obstruction. Tracheobronchial amyloidosis can be associated with tracheobronchomegaly, a rare disorder characterized by marked dilation of the trachea and bronchi. On histopathologic examination, amyloid deposits are usually seen in the submucosa and may involve the entire tracheal or bronchial wall, occurring in irregular masses or sheets (Fig. 9.2). Amyloid may be accompanied by multinucleated giant cells; calcification and ossification are frequent (Fig. 9.3).5,6,8,9 When amyloid is identified in bronchoscopic biopsy specimens, this is typically an organ-limited manifestation, similar to nodular lung parenchymal amyloid.10 Of the three major types of amyloid, AL, AA, and transthyretin, the AL type is the most common in tracheobronchial amyloid deposits. The prognosis is poor: nearly one-third of patients die within 7 to 12 years of diagnosis.6 Therapy is limited to debulking procedures and stent placement for localized lesions, although some evidence suggests that radiation therapy may provide more definitive treatment.11-14
Tracheobronchomalacia
Tracheobronchomalacia (TBM) is a term used to encompass a number of conditions characterized by a decrease in the structural rigidity of the trachea and conducting airways. Such changes are manifested clinically by excessive expiratory collapse of the central airways owing to increased flaccidity or redundancy of the posterior membranous airway wall or to weakness of the supporting cartilage.15 Although typically a disease process of the central airways, TBM has been shown to frequently have associated air trapping on computed tomography (CT) scan, an indicator of small airway disease.16,17
Both children and adults may be affected.18 In children, the disease is most often related to prematurity and the requirement for prolonged mechanical ventilation. In these patients, TBM appears to be self- limited.19,20 In adults, TBM is seen in the middle-aged and elderly and is a progressive condition, commonly seen in association with chronic obstructive pulmonary disease (COPD).16 Other reported associations in adults include prolonged intubation, vascular anomalies, and exposure to mustard gas.21 TBM may complicate tracheobronchial amyloidosis and rheumatoid arthritis22 and may be related to relapsing polychondritis, a systemic disease affecting the cartilaginous tissue in several organs including the airways.18,23-25 Pathologically, the tracheal wall is soft as a result of inflammatory destruction of the cartilage (Fig. 9.4). Over time, the cartilage is replaced by fibrous tissue, accompanied by inflammatory infiltration and reparative vascular proliferation.
Treatment is variable and depends on symptom severity, with conservative therapy appropriate for mildly symptomatic cases and more invasive therapy, including tracheoplasty, indicated for severely symptomatic cases for reduction of expiratory tracheal collapse and symptomatic improvement.26 In the absence of treatment, severely symptomatic TBM can lead to significant respiratory morbidity and may rarely be fatal.
Figure 9.1 Tracheal rhinoscleroma. (A) Low-power view showing the tracheal wall and mucosa infiltrated and expanded by inflammatory cells and histiocytes with clear cytoplasm, seen more clearly at higher magnification, as shown in part B. (C) Warthin-Starry silver impregnation highlights (in black) the bacterial pathogen Klebsiella rhinoscleromatis in the cytoplasm of the histiocytes.
Figure 9.2 Tracheal amyloid. (A) Low-power view showing the tracheal wall with diffuse amyloid deposition. (B) At higher magnification, the amyloid is seen to be present just below the respiratory epithelium.
Figure 9.3 Tracheal amyloid. (A) In this tracheal biopsy specimen, the amyloid is diffusely calcified. (B) Osseous metaplasia can occur in tracheal amyloid.
Figure 9.4 Tracheal chondritis. (A) the cartilage of the tracheal wall is surrounded and replaced by inflammatory, vascular, and fibrous tissue. (B) At higher magnification (upper center of part A), cartilage is seen to be disrupted and replaced by inflammatory cells.
Tracheobronchomegaly
Tracheobronchomegaly, also known as Mounier-Kuhn syndrome, is a rare disorder characterized by marked dilation of the trachea and central bronchi with thinning of the wall. It is associated with impaired dynamic function, in particular dynamic collapse, and patients may present with varying degrees of recurrent infection, breathlessness, hemoptysis, and dyspnea. The disease is related to congenital connective tissue diseases such as Ehler-Danlos syndrome, cutis laxa, Marfan syndrome, and Kenny-Caffey syndrome27,28.
Tracheobronchopathia Osteochondroplastica
Tracheobronchopathia osteochondroplastica is a rare disease characterized by the presence of cartilaginous or osseous submucosal nodules that bulge into the lumen of the trachea and bronchi (Fig. 9.5) with sparing of the posterior membranous portion.29-32 the etiology and pathogenesis are unknown. The disease affects adults more commonly than children, with a predilection for males. Most cases are asymptomatic and are most often diagnosed incidentally during intubation or bronchoscopy. A minority of patients may experience cough, dyspnea, and hemoptysis.
The bronchoscopic appearance alone is usually diagnostic, and biopsy is seldom if ever required.33 In the rare bronchoscopic biopsy showing the cartilaginous or ossified lesions of tracheobronchopathia osteochondroplastica (Fig. 9.6), the differential diagnosis includes ossified amyloid deposits.
Figure 9.5 Tracheobronchopathia osteochondroplastica. Gross specimen of trachea showing prominent nodularity (arrows). This condition presents a striking bronchoscopic image (not shown).
Bronchi
The conducting airways begin at the carina and extend distally in the lung to the level of the noncartilaginous bronchioles. Although many diffuse lung diseases involve the large airways secondarily, some diseases may affect primarily the bronchi and are presented here. Asthma- associated diseases, typically observed in the large airways, are discussed later in the final section of this chapter. Cystic fibrosis and ciliary disorders are not discussed here because detailed expositions can be found in other sources.34,35
Bronchitis
Inflammatory conditions of the large airways are frequently seen in small biopsies and cytologic specimens but are rarely specific: in practice, the presence of acute or chronic inflammation in endobronchial biopsies demands a descriptive diagnosis (Fig. 9.7). It is best to avoid the use of the term chronic bronchitis in reference to such inflammatory changes involving respiratory mucosa because it carries a clinical implication regarding the diffuse nature of the disease and specific clinical manifestations. When bronchitis occurs as a direct result of respiratory infection, necrosis of the mucosa may be present (acute necrotizing bronchitis). In the postinfection period, residual chronic inflammatory changes may be the dominant findings. Unfortunately the list of possible etiologic disorders associated with chronic inflammation in bronchial mucosa is quite long (Box 9.2) and sufficiently diverse as to not be useful in narrowing the clinical differential diagnosis. For this reason, a careful search for other, more specific findings is always in order (e.g., vasculitis, granulomas, necrosis, tumor).
Bronchiectasis
Bronchiectasis is defined as a permanent dilation of the bronchi, often attended by acute and chronic inflammation. Conceptually, bronchiectasis can be considered the end result of any number of conditions that damage the airway wall and result in weakening over time and dilation.36
Figure 9.6 Tracheobronchopathia osteochondroplastica. (A) the panoramic view shows a nodular protrusion into the tracheal lumen, composed of fibrous tissue and mature bone. (B) A preparation from a different patient showing osseous metaplasia. (C) An area from the same nodule as in (A), seen at higher magnification.
Figure 9.7 Bronchitis. The bronchial wall shows a chronic inflammatory infiltrate in the subepithelial connective tissue and surrounding cartilage.
In a significant percentage of cases no specific cause can be identified.37,38 Among recognizable causes of bronchiectasis are infections, primary ciliary dyskinesia, immunodeficiency, cystic fibrosis, rheumatoid arthritis, inflammatory bowel disease,39 and graft-versus-host disease.40 An intriguing implication of Helicobacter pylori in the pathogenesis of bronchiectasis has been raised in some studies.41-43 In specific conditions such as cystic fibrosis, bronchiectasis may dominate the pulmonary pathology. Bronchiectasis outside the setting of cystic fibrosis is often perceived to be rare in developed nations, but it remains an important cause of chronic suppurative lung disease in the developing world. The decline in hospital admissions for pediatric bronchiectasis in the developed nations has been noted since the 1950s and has been attributed to improvements in sanitation and nutrition, introduction of childhood immunization (particularly against pertussis and measles), and the early and frequent use of antibiotics.
Bronchiectasis is a radiologic diagnosis in the living patient but has distinctive features in resected lungs (Fig. 9.8) and lobes and sometimes in surgical biopsies. The historical classification of bronchiectasis divided the process into three types: saccular (progressive dilation of the bronchi from central to peripheral), varicose (combined dilation and constriction), and cylindrical (uniform dilation). Today most cases of bronchiectasis are diagnosed with great sensitivity by high-resolution computed tomography (HRCT).44-47 the HRCT findings in bronchiectasis are summarized in Box 9.3.
Figure 9.8 Bronchiectasis. Gross specimen showing classic saccular enlargement of the bronchi.
Presenting signs and symptoms include cough with production of purulent sputum, fever, shortness of breath, and occasionally hemoptysis. No age or sex predilection has been noted, and the disease tends to run a course of recurrent exacerbation, sometimes with superimposed infection. The gross findings in bronchiectasis have been well described in autopsy series.48 For the histopathologist, acute and chronic inflammatory changes dominate the bronchoscopic biopsy picture (Fig. 9.9). These findings are not specific; however, bioptic specimens may be useful for ancillary laboratory studies (such as microbiologic investigations or ultrastructural studies in search of ciliary abnormalities). In most instances, even surgical lung biopsy findings reflect only downstream secondary manifestations of obstruction or infection occurring more proximally. Lymphoid hyperplasia surrounding the large airways may occur in bronchiectasis and bronchoscopically derived biopsies may sample such hyperplastic lymphoid tissue, raising concern for lymphoproliferative disease.
Middle Lobe Syndrome
Middle lobe syndrome is included in this disease category because the disorder is fundamentally one of chronic large airway obstruction with secondary bronchiectasis, bronchitis, and bronchiolitis-associated parenchymal changes that arise as additional downstream effects of these airway abnormalities.
The concept of right middle lobe syndrome was highlighted in studies of children with chronic failure to thrive and right middle lobe abnormalities on chest radiographs. The proposed hypothesis was based on the notion that lymphoid hyperplasia occurring around the right middle lobe bronchus produced compression and narrowing of the bronchial lumen. Also, the position of the middle lobe (and the lingula of the left lung) relative to the remainder of the tracheobronchial tree makes it susceptible to obstruction and secondary chronic inflammatory changes (long narrow bronchus). In clinical practice, the disease occurs more frequently in adults and often without an identifiable obstructing lesion.49 the affected population consists predominantly of middle-aged or elderly women, and the condition has been referred to as the Lady Windermere syndrome.50-52 A role for Mycobacterium avium complex infection has been postulated in the pathogenesis of middle lobe syndrome, although it remains unclear whether this is an epiphenomenon related to the common occurrence of bronchiectasis in this condition. Consolidation of the right middle lobe, or lingula, attended by bronchiectasis is typical.36’49
Figure 9.9 Bronchiectasis. The lumen of the bronchus is dilated, and There is prominent chronic inflammation in the bronchial wall.
Figure 9.11 Normal lobule. A near-normal pulmonary lobule whose outlines are enhanced in this preparation by a slight degree of septal edema. In the middle of the lobule is the bronchiole along with the adjacent pulmonary artery. Note that the diameter of the terminal bronchiole, seen here in cross section, is very similar to that of the nearby arteries.
Figure 9.10 Middle lobe syndrome. The bronchial wall shows prominent lymphoid infiltration, with many germinal centers. The inflammatory infiltrate extends in the surrounding lung parenchyma, where it is associated with several small granulomas (a feature suggesting atypical mycobacterial infection).
In surgical lung biopsies of the right middle lobe or lingula, advanced remodeling, extensive bronchiolocentric inflammatory infiltrates, and mucostasis, when present together, should always suggest the possibility of middle lobe syndrome (Fig. 9.10). The presence of granulomas in the context of middle lobe syndrome should raise suspicion for colonization by atypical mycobacterial species, and acid-fast organisms may be identified in granulomas.50 A number of inflammatory changes are observed in middle lobe syndrome; these are listed in Box 9.4.49’53 Removal of any obstructing lesions, whether neoplasm or other, in early stages of the disease process may avoid the need for lobectomy.54
Small Airways
he small airways of the lung include the small bronchi, with a diameter less than 2 to 3 mm, and the membranous bronchioles (terminal and respiratory bronchioles). Terminal bronchioles have a diameter of less than 1 mm and are just proximal to the respiratory bronchioles, the first airways that have alveoli budding from their walls. The terminal bronchioles are located in the center of the pulmonary lobule and, like all conducting airways, are always accompanied by a pulmonary artery branch (Fig. 9.11). The morphology of bronchioles in surgical specimens is modified by smooth muscle contraction, which causes prominent narrowing of the lumen with epithelial folding; this may give a false impression of constrictive bronchiolitis or other small airway diseases, including asthma.55 A useful criterion to evaluate bronchiolar morphology in cross-sectional views is that the respective diameters of the bronchiole and artery are normally approximately equal (Fig. 9.12A). The lumen of the terminal bronchiole is uniform in longitudinal histologic sections with minor variations in size (Fig. 9.12B). From a radiologic standpoint, the anatomy of the small airways is straightforward: simply, they are not visible even in a CT scan. Whereas the large airways are distinctly seen as black, roundish or linear elements alongside their companion arteries, the small airways are not.
Figure 9.12 Terminal bronchiole. (A) A cross section of a terminal bronchiole and adjacent artery. The normal terminal bronchiole has a thin wall and an open lumen. The wall is composed of a variably enfolded mucosa, showing a columnar to cuboidal epithelium with ciliated columnar cells and Clara cells. The folding of the epithelium and basement membrane is thought to be due to ex vivo smooth muscle contraction of the bronchiolar wall. (B) This bronchiole is cut lengthwise; its major axis is relatively straight, and the lumen has a relatively constant diameter.
The small airways play an important role in air distribution and flow but lack the rigid structure of the bronchi to protect them from collapse during exhalation, especially when affected by disease. This anatomic condition is at the base of the main functional manifestation of small airway disease, which is obstruction due to collapse, especially during expiration.
The small airways can be affected secondarily by inflammatory diseases that involve primarily the bronchi, alveoli, or both or by primary diseases that selectively involve these delicate anatomic structures. No single classification of bronchiolar disorders has been widely accepted, and many classification schemes have been proposed based on cause and underlying diseases, radiologic features, histopathologic findings, or some combination of these parameters.56-59 Ryu and colleagues have suggested a classification of bronchiolar disorders in three groups: primary bronchiolar disorders, bronchiolar involvement in interstitial lung diseases, and bronchiolar involvement in large airway disease.60,61 More recently Rice and Nicholson proposed an integrated classification, which, though similarly distinguishing between disorders where bronchioles are primarily or secondarily affected, also includes a distinction between diseases with nonspecific/suggestive/specific histologic changes, and whether the secondary involvement is associated with proximal airway disease or diffuse interstitial lung disease (Box 9.5).62
From a clinicopathologic point of view, it should be pointed out that clinically significant diseases of the small airways may be associated with quite subtle histologic lesions, which may even be overlooked at first glance.63,64 Conversely, some degree of histopathologic alteration in the small airways is a frequent incidental finding in lung biopsies and is related to cigare The smoking. ’Hierefore for the evaluation of small airway changes it is critical to know the clinical manifestations, the radiologic distribution of disease (whether localized or bilateral and diffuse), and the patient’s cigare The smoking history. The most frequent setting in which the pathologist must evaluate small airways with special attention is when a patient has significant respiratory dysfunction clinically but few obvious histologic findings in the lung biopsy to explain it. Attempts to predict clinical disease based on isolated abnormalities of the small airways as viewed through the microscope are often unrewarding. The HRCT scan may provide valuable information regarding the possible pathologic pattern of disease, as shown in Table 9.1.
What follows is a compilation of the elementary pathologic changes in the small airways that can be identified on histopathologic examination, along with the lists of conditions that should be considered when each such change is encountered.65 It is important to recognize that the elementary lesions rarely occur in isolation and that they are frequently combined. Also presented is a brief review of some general histopathologic patterns of lesions (or specific diseases) that may involve the small airways.
Table 9.1 High-Resolution Computed Tomography Abnormalities of the Small Airways
|
Radiologic Finding |
Pathologic Pattern |
|
Centrilobular nodularity |
Cellular bronchiolitis |
|
— |
Follicular bronchiolitis |
|
— |
Respiratory bronchiolitis |
|
Peribronchial nodules |
Follicular bronchiolitis |
|
“Tree in bud” pattern |
Cellular bronchiolitis |
|
Panbronchiolitis |
|
|
Diffuse or “geographic” air trapping |
— |
|
Mosaic pattern |
Constrictive bronchiolitis |
|
Bronchioloectasis, bronchiectasis |
Panbronchiolitis |
|
Patchy ground-glass attenuation |
Respiratory bronchiolitis |
|
Ground-glass opacity |
Follicular bronchiolitis |
Modified from Lynch DA. Imaging of small airways diseases. Clin Chest Med. 1993;14(4): 623-634.
Conceptually, the elementary histopathologic lesions of the small airways can be subdivided into inflammatory (acute, chronic, granulomatous, with or without necrosis) and proliferative (epithelial or mesenchymal, concentric within the lumen or eccentric in peribronchiolar tissue). The foregoing reactions may lead to a number of distortions of the normal bronchiolar architecture, including occlusion, constriction, dilation (with or without mucostasis), tortuosity, and nodularity. The lesion may be exquisitely bronchiolar or may extend to involve the surrounding parenchyma; in the latter case it is important to distinguish between lesions that extend from the bronchiole to the parenchyma and those with the reverse orientation (as with organizing pneumonia patterns, in which the main lesion is in the parenchyma). All of these features must be considered in analyzing the histology of the small airways. An important point is that most of the described lesions are typically part of a dynamic process, whereby one single causative agent may produce distinct pathologic features at different times in the natural history of the disease. In addition, the same clinical disease manifestations may result in a variety of pathologic lesions. In practice, it is best not to assume an unequivocal relationship between the histopathologic lesions observed on biopsy and a specific clinical disease. The diagnosis of small airway diseases is rarely possible in traditional transbronchial biopsies but may be appreciated in cryobiopsies and66-68 surgical lung sections, often as a “minimal changes” pattern (see introductory section PatternBased Approach to Diagnosis).
Inflammatory Bronchiolitis
Inflammatory bronchiolitis, also known as cellular bronchiolitis, is a generic term that includes acute bronchiolitis, chronic bronchiolitis, and combined forms with variable amounts of both types of processes. All forms may be associated with bronchiolar fibrosis.64 An important point is that both acute and chronic forms of bronchiolitis may have significant overlap, with one form typically being dominant. Inflammatory diseases of the airways rarely have histopathologic features sufficiently specific to point to a single etiologic disorder or a specific disease in the absence of some characteristic finding (e.g., viral inclusions, aspirated foreign material). When the surgical pathologist is confronted with isolated inflammatory changes in the small airways, it is important to invoke a differential diagnosis to stimulate clinicopathologic correlation and There by help to narrow considerations in the clinical differential diagnosis.
Acute Bronchiolitis
Florid acute bronchiolitis is characterized by predominantly acute inflammation of the small airways, with variable epithelial sloughing. Extension of acute inflammation into surrounding peribronchiolar parenchyma is typical (Fig. 9.13). Very often, acute bronchiolitis is associated with some degree of chronic inflammatory infiltration, as described further on. Conditions associated with relatively pure acute bronchiolitis include the early phase of certain infections (most of which also produce epithelial necrosis), acute fume or toxic gas inhalation, and acute aspiration.69,70 Acute bronchiolitis can be an uncommon manifestation of granulomatosis with polyangiitis, formerly called Wegener granulomatosis.71 A careful search for viral inclusions or food particles is especially relevant. Pure acute bronchiolitis due to gas inhalation or aspiration is most commonly seen at autopsy, where aspiration may have been part of the terminal event. Following the very acute phase of the disease, loose connective tissue polyps may develop as a consequence of basement membrane disruption with fibroblastic migration into the airway lumens from subepithelial regions (so-called Masson polyps).
Occasionally the predominant inflammatory infiltrate seen in bronchial biopsies is a dense eosinophilic infiltrate, a condition sometimes referred as eosinophilic bronchiolitis. In these cases a careful correlation with clinical features is mandatory, as this finding could be associated with asthma or could be part of an established condition of either unknown (e.g., eosinophilic granulomatosis with polyangiitis/Churg- Strauss syndrome or clonal hypereosinophilic syndrome) or determined cause (e.g., allergic bronchopulmonary fungal disease or drug reaction). In some cases, where no cause can be identified, the eosinophilic infiltrate is idiopathic. Eosinophilic bronchiolitis may be the histologic substrate of a clinical syndrome known as hypereosinophilic obliterative bronchiolitis.72
Acute and Chronic Bronchiolitis
Acute and chronic inflammation of the small airways (Fig. 9.14) is one of the most common manifestations of cellular bronchiolitis.73 This inflammatory process is frequently associated with other bronchiolocentric manifestations, including intraluminal polyp formation, constriction and obliteration, and the presence of lymphoid follicles within the peribronchiolar sheath (follicular bronchiolitis).
When acute or chronic bronchiolitis is the primary manifestation in the lung biopsy, clinical manifestations may be accompanied by completely obstructive, completely restrictive, or a mixture of obstructive and restrictive pulmonary physiology. HRCT scans may show a predominantly nodular pattern, although reticulonodular infiltrates are more commonly observed. Box 9.6 lists the most frequent diseases associated with acute and chronic bronchiolitis.
Figure 9.13 Acute bronchiolitis. (A) A bronchovascular bundle with the small artery and the respiratory bronchiole. Increased cellularity of the bronchiolar wall is evident, and many neutrophils are present within its lumen, accompanied by some acellular exudate. The surrounding lung parenchyma is uninvolved by the disease. (B) At higher magnification, the bronchiolar wall shows a cellular infiltrate composed of neutrophils, which expand the adventitial connective tissue and the subepithelial tissue.
Figure 9.14 Acute and chronic bronchitis/bronchiolitis. (A) At low magnification, a definite peribronchiolar lesion is seen that also involves the adjacent lung parenchyma. (B) the cellular infiltrate is composed of neutrophils and lymphocytes; epithelial cells show some degree of reactive changes. This preparation is from a patient with bronchiolocentric granulomatosis with polyangiitis.
Chronic Bronchiolitis
Chronic inflammation within and surrounding the walls of small airways (Figs. 9.15 and 9.16) can be seen in several conditions (Box 9.7). Chronic bronchiolitis can occur with or without lymphoid follicles or some degree of fibrosis. Follicular bronchiolitis is a specific subtype of chronic bronchiolitis, characterized by the presence of lymphoid follicles with well-formed germinal centers surrounding the bronchiolar walls, sometimes with lymphocytes migrating in the respiratory epithelium, either singly or in small clusters (Figs. 9.179.19). Follicular bronchiolitis may be seen in several connective tissue diseases.74-78 In cases with dense and extensive lymphoid infiltrates, especially if lymphoepithelial lesions are prominent, one should always consider the possibility of a lung lymphoma. Most such lymphomas are low-grade B-cell lymphomas of the extranodal marginal zone type arising from the bronchus-associated lymphoid tissue (Fig. 9.20).79-81 Follicular bronchiolitis may also be seen in some occupational exposure settings, as among nylon flocking workers82-86 and in immunodeficiency syndromes including the acquired immunodeficiency syndrome (AIDS), related to human immunodeficiency virus (HIV) infection.87
Figure 9.15 Chronic bronchiolitis. (A) the bronchiole shows an inflammatory reaction that expands the subepithelial connective tissue, whereas the actual diameter of the airway is similar to that of the adjacent artery. (B) At higher magnification, the chronic inflammatory infiltrate can be seen to fill the subepithelial area and also extends across the muscular wall to involve the bronchovascular sheath. The patient had a severe obstructive ventilatory defect.
Figure 9.16 Chronic bronchiolitis. Effects on the structure of the terminal bronchioles are seen, as well as a longitudinal section of a terminal bronchiole along with the adjacent artery in a preparation from a patient with a severe obstructive ventilatory defect. The airway is surrounded by a prominent lymphocytic infiltrate and shows distortion of the lumen, with variable stricture and dilation.
Figure 9.17 Follicular bronchiolitis. Biopsy specimen from a patient with Sjogren syndrome. (A) At low magnification the characteristic bronchiolocentric lymphoid infiltrate of follicular bronchiolitis can be seen. (B) Lymphoid follicles with germinal centers are readily apparent and associated with bronchiolar distortion. Follicular bronchiolitis may have a number of causes, including collagen vascular disease (as in this case), cystic fibrosis, ciliary defects, or immunodeficiency syndromes, or it may be secondary to bronchiectasis, previous infection, or aspiration.
Granulomatous Bronchiolitis
Granulomatous bronchiolitis, a relatively frequent finding for the histopathologist, can be seen on endoscopic biopsies; it constitutes an important clue that opens a well-defined differential diagnosis.88,89 the most frequent conditions associated with granulomatous bronchiolitis are summarized in Table 9.2. The most important diagnostic features of the granulomas to be evaluated by the pathologist are the presence of necrosis, their distribution in relation to the bronchioles and lung parenchyma, their intrinsic character (loose or well formed, number and features of the giant cells), their relation to the surrounding stroma (circumscription, perigranulomatous fibrosis, coalescence), the presence of foreign material, and the degree of perigranulomatous inflammation. In the presence of granulomas, special stains and molecular studies for mycobacteria and fungi are always mandatory, since infection should always be high in the differential diagnosis. In the absence of necrosis, sarcoidosis is the leading consideration (Fig. 9.21). Granulomas of sarcoidosis are usually distributed along lymphatic routes in the lung and There fore are frequently bronchi- olocentric, allowing bronchoscopic and transbronchial biopsies to provide excellent diagnostic material. Sarcoid granulomas are usually well defined; they look pink in hematoxylin and eosin-stained slides owing to peribronchiolar fibrosis without a prominent lymphocytic infiltrate. On the other hand, in the presence of necrosis, the possibility of infection (especially caused by mycobacteria and fungi)90 is high (Fig. 9.22). In contrast to sarcoid granulomas, infectious granulomas have less clearly defined borders, are frequently associated with a more prominent lymphocytic infiltrate, and are usually present both around bronchioles and in the surrounding lung parenchyma (i.e., their distribution is random in lung parenchyma, in contrast to the lymphangitic distribution seen in sarcoidosis). Peribronchiolar granulomas are also seen in a majority of patients with hypersensitivity pneumonitis (Fig. 9.23). Granulomas in hypersensitivity do not show necrosis and are generally less well delimited and well formed than in infectious diseases; they may even take the form of loose aggregations of histiocytic epithelioid cells with or without giant cells. In selected cases immunostains for cathepsin K, a potent cysteine protease expressed at high levels in activated macrophages, may be of help in the detection of epithelioid cells.91
Figure 9.18 Follicular bronchiolitis. The patient presented with bronchiectasis in the setting of a middle lobe syndrome. (A) the terminal bronchiole is surrounded by a prominent inflammatory infiltrate, with lymphoid follicles having well-formed germinal centers. The inflammatory process involves both the subepithelial layer and the adventitial tissue. (B) the subepithelial layer has a diffuse lymphoid infiltrate composed of mature small lymphocytes, which may show a tendency toward intraepithelial migration, simulating the lymphoepithelial lesions seen in low-grade lymphomas of the bronchus-associated lymphoid tissue (BALT).
Figure 9.19 Follicular bronchiolitis. The patient had IgA deficiency. (A) A respiratory bronchiole surrounded by several lymphoid follicles. (B) the lymphoid tissue expands the bronchiolar wall, and many mononuclear cells are seen between the epithelial cell layer and the muscularis propria.
Figure 9.20 A low-grade lymphoma of the bronchus-associated lymphoid tissue (BALT). This lymphoma, the bronchial counterpart of gastric MALToma, is a marginal-zone lymphoma that originates from the BALT lymphoid tissue. (A) the present case shows a dense homogeneous cellular infiltrate composed predominantly of small lymphocytes that extends along the bronchiolar wall and involves adjacent lung parenchyma. (B) A CD20 immunostain highlights the diffuse and monomorphous spread of small B lymphocytes.
Another frequent cause of granulomatous bronchiolitis is aspiration pneumonia,73 which may be clinically occult and manifest as diffuse bronchiolar disease with bronchiolocentric granulomatous inflammation.92,93 Granulomas of aspiration may have variable aspects, ranging from a very active process associated with prominent acute inflammation and possibly food particles to very chronic phase with few giant cells and hyaline foreign material (Figs. 9.25 and 9.26). It is worth noting that aspirated food particles are not usually birefringent under polarized light; exceptions include talc and microcrystalline cellulose, both of which may be used as inert components of oral pharmaceutical tablets and are susceptible to accidental aspiration, and starch particles, which show a typical Maltese cross birefringence. Talc aspiration has also been rarely reported in children related to the liberal use of baby powder on the skin.93
Figure 9.21 Granulomatous bronchiolitis in sarcoidosis. (A) At scanning magnification, the serpiginous outline of the bronchovascular bundle is accentuated by pale pink granulomas, collagen, and scant chronic inflammation. (B) the bronchiole shows the typical granulomas and sclerotic background matrix of sarcoidosis, which involves the airway wall and impinges on the adjacent arterial wall. The granulomas are well formed, with a definite fibrous demarcation, and show a tendency to coalesce. Inflammatory cells are scant, and the whole process has an eosinophilic appearance, which is clearly different from that of the lesions seen in granulomatous bronchiolitis due to infection (compare Fig. 9.22).
Figure 9.22 Granulomatous bronchiolitis due to infection. (A) A granulomatous bronchiolitis in Mycobacterium tuberculosis infection: granulomas are abundant and have distinct giant cells. (B) A case of Mycobacterium avium complex (MAC) infection, with nonnecrotizing granulomas centered on the bronchioles (note the dilated bronchiole in the left upper corner). The small granulomas are usually solitary, with a cuff of lymphocytes, and involve respiratory and terminal bronchioles. These lesions are frequently seen in association with a predisposing factor (e.g., bronchiectasis) or in healthy patients exposed to a contaminated environment (such as that associated with hot tub use). The inflammatory process surrounding the granulomas is more pronounced than that associated with sarcoidosis. On the other hand, MAC granulomas are much better organized than those seen in hypersensitivity pneumonitis, where granulomas tend to be nothing more than loose clusters of interstitial epithelioid histiocytes and giant cells (compare Fig. 9.23).
Figure 9.23 Granulomatous bronchiolitis in hypersensitivity pneumonitis (HP). Granulomas in HP are associated with a bronchiolocentric cellular infiltrate (A) and may lie in the interstitium of lung parenchyma or within the bronchiolar wall. They are typically ill-defined, as they may be constituted only by a loose aggregate of epithelioid histiocytes and giant cells (B). Granulomas of sarcoid or infection are usually much more clearly defined and organized (compare Fig. 9.21 and 9.22). In this case, the patient had a hypersensitivity reaction after using a polyurethane spray indoors.
Granulomatous bronchiolitis may also be seen in the setting of middle lobe syndrome,49 chronic necrotizing forms of pulmonary aspergillosis,94 and in association with inflammatory bowel disease, such as Crohn disease, sometimes accompanied by microabscesses.95
When isolated peribronchiolar multinucleated giant cells are the major finding, one should consider granulomatosis with polyangiitis (Fig. 9.24), aspiration pneumonia (Figs. 9.25 and 9.26), and hard metal (cobalt) pneumoconiosis (so-called giant cell interstitial pneumonia of Liebow).
Bronchiolar Necrosis
Complete mucosal necrosis with epithelial sloughing and variable acute inflammation is typical of a limited number of lung diseases, mainly those of infectious origin (Box 9.8). In the presence of bronchiolar necrosis, a careful search for viropathic changes or microorganisms (bacterial and fungal) should be undertaken (Fig. 9.27-9.29). When the process is intensely suppurative with large nodular foci of necrosis, consideration should be given to the rare possibility of pyoderma gangrenosum lesions in the lung, occurring de novo or associated with inflammatory bowel disease (e.g., ulcerative colitis).96-103
Figure 9.24 Granulomatous bronchiolitis in granulomatosis with polyangiitis (formerly called Wegener granulomatosis). This lung biopsy specimen shows a granulomatous reaction, with central necrosis, involving a small airway. Note the basophilic appearance of the necrosis, which is a typical feature of this disease.
Figure 9.25 Aspiration bronchiolitis. This biopsy is from a patient who suffered from gastroesophageal reflux disease (GERD). He underwent lung biopsy 4 weeks after the sudden onset of pneumonia that failed to resolve. (A) the pattern is one of nonnecrotizing granulomatous bronchiolitis with many giant cells, some of which can be seen surrounding typical aspirated starch grains (B).
Figure 9.26 Aspiration bronchiolitis. Typical starch grains surrounded by foreign body-type giant cells.
Respiratory (Smoker’s) Bronchiolitis
Respiratory bronchiolitis is a very special marker for smoking-related lung injury and is extremely common in lung biopsies and surgical specimens (cigare The smoking being a cause of, or associated with, many lung diseases).104-110 the histopathologic lesion of respiratory bronchiolitis is characterized by the accumulation of lightly pigmented macrophages (smoker’s macrophages) within the lumens of the respiratory bronchioles as well as in the surrounding peribronchiolar alveoli. This macrophage accumulation is associated with mild distortions of the overall architecture of the bronchiole, slight inflammation, fibrosis, and smooth muscle hyperplasia of the bronchiole wall. Minimal inflammation and interstitial fibrosis variably extend to the surrounding alveolar walls (Figs. 9.30 and 9.31). Sometimes respiratory bronchiolitis can be sufficiently extensive to produce clinical and radiologic manifestations of diffuse interstitial lung disease, so-called respiratory bronchiolitis-associated interstitial lung disease (RBILD) (see Chapter 8).108,111,112 Histologically, RBILD is indistinguishable from respiratory bronchiolitis. A diagnosis of RBILD, as opposed to respiratory bronchiolitis, should be rendered only (1) in the presence of clinically significant diffuse lung disease (shortness of breath, cough, mixed restrictive and obstructive physiology), (2) if HRCT findings are compatible with the diagnosis (centrilobular micronodules, ground-glass opacities, and peribronchiolar thickening), and (3) if other causes of lung disease can be excluded with reasonable confidence.108 RBILD can also be associated with significant panlobular and subpleural alveolar septal fibrosis, which may simulate fibrotic nonspecific interstitial pneumonia (NSIP).113 Respiratory bronchiolitis is very commonly seen in association with Langerhans cell histiocytosis (pulmonary eosinophilic granuloma) because both have the same relationship to cigare The smoking.104,114,115
When respiratory bronchiolitis is the sole pathologic finding in a smoker, a careful search for another disease process is in order because mild respiratory bronchiolitis alone is probably an innocent bystander, unlikely to produce sufficient clinical and radiographic findings to warrant lung biopsy. Conversely, in a lifelong nonsmoker, changes resembling respiratory bronchiolitis usually indicate significant smallairway pathology, and some of these patients may have profound clinical symptoms with significant hypoxia and manifestations on CT, suggesting interstitial lung disease (particularly mosaic perfusion). Trichrome and elastic tissue stains may be useful in this setting to highlight the occasionally subtle small airway pathology in the biopsy, such as excessive peribronchiolar fibrosis and obliterative scars. In this situation, high- resolution inspiratory and expiratory CT scans may provide additional radiologic evidence to support the small airways as the primary focus of the lung disease (see discussion of constrictive bronchiolitis later in this chapter).
Figure 9.27 Herpetic necrotizing bronchiolitis. (A) An acute necrotizing inflammatory process involves the entire bronchiolar wall as well as surrounding alveolar septa. (B) the lumen of the bronchiole contains exudate, red blood cells, and single epithelial cells.
Figure 9.28 Adenovirus necrotizing acute bronchiolitis. This biopsy is from a renal transplant recipient undergoing immunosuppressive therapy. The lung tissue shows a bronchiolocentric acute inflammatory process characterized by prominent epithelial necrosis. (A) the lumen of the bronchiole has been obliterated. (B) At higher magnification, the presence of the muscular layer can be appreciated, whereas the epithelial layer is almost completely destroyed. Adenovirus was cultured from the biopsy specimen.
Peribronchiolar Metaplasia (Lambertosis)
Peribronchiolar metaplasia is a pathologic process in which bronchiolar epithelial cells extend beyond the respiratory bronchioles along alveolar septa, replacing the normal alveolar lining cells, usually accompanied by some degree of stromal fibrosis (Fig. 9.32). This lesion is often referred to as Lambertosis because it is hypothesized that the metaplastic epithelium derives from the canals of Lambert that connect nonrespiratory bronchioles directly to adjacent alveoli. Peribronchiolar metaplasia can be seen in a number of pathologic conditions, including COPD and constrictive bronchiolitis, among others. In most cases the lesion is felt to be postinflammatory in origin; There fore it could potentially be seen as a consequence of any number of inflammatory diseases involving the small airways. No specific cause is identified in some patients, and the disease may be an idiopathic manifestation of an unidentified remote injury to the small airways. When this is the case, the disease may manifest clinically as an interstitial lung disease with restrictive physiology. The histopathology of peribronchiolar metaplasia is characterized by variable extension of columnar and sometimes ciliated epithelium beyond the alveolar ducts to involve the alveolar walls. When the lesions are exuberant, they may appear as nodules 2 to 5 mm in diameter. These lesions must be distinguished from microscopic honeycombing, atypical adenomatous hyperplasia,116-120 and the micronodular pneumocyte hyperplasia of tuberous sclerosis complex.121-123
Figure 9.29 Cytomegalovirus bronchiolitis. (A) the bronchiole shows an acute inflammatory necrotizing process. (B) Viral inclusions are seen at higher magnification.
Figure 9.30 Respiratory bronchiolitis. Two different histopathologic patterns of distortion and inflammation in so-called smoker's bronchiolitis. (A) the bronchiole is dilated and mildly distorted, and There is prominent filling of the alveolar spaces by macrophages containing finely granular golden brown pigment (so-called smoker's macrophages). (B) the bronchiolar wall shows mild thickening with chronic interstitial inflammation, along with smoker's macrophages in the lumen.
Figure 9.31 Smoker's macrophages versus hemosiderin-laden macrophages seen in hemorrhagic syndromes. (A) Smoker's macrophages have finely granular golden brown cytoplasmic pigment and accumulate in the respiratory bronchiole, alveolar ducts, and peribronchiolar alveoli. (B) Macrophages seen in hemorrhagic syndromes show more abundant and coarser hemosiderin pigment granules. In some cases (e.g., in heavy smokers) the distinction can be difficult to make on purely morphologic grounds and clinical information is necessary.
Figure 9.32 Peribronchiolar metaplasia (so-called Lambertosis). (A) A proliferation of cuboidal epithelial cells extending from alveolar ducts into proximal lobular acini along the alveolar septa is a common finding in smokers and may be considered to represent a reactive or reparative process involving chronic injury to the terminal and respiratory bronchioles. (B) At higher magnification, the bronchiolocentric nature is readily appreciated. This image is of a preparation from a patient who was a heavy smoker.
Figure 9.33 Mucostasis in respiratory bronchiolitis. (A) the respiratory bronchioles and alveolar ducts are filled with mucinous material. (B) Extension of free mucus into peribronchiolar alveoli is seen along with many smoker’s-type macrophages with dusty brown pigment (center right).
When prominent peribronchiolar metaplasia is identified along with some other significant pathology (e.g., in association with a lobectomy for carcinoma), the exact significance of this process relative to the patient’s clinical manifestations is unclear. Peribronchiolar metaplasia in the setting of smoking-related lung disease may or may not have a clinical or radiologic correlation. Conversely, such changes in a nonsmoker are always significant. Diseases associated with prominent peribronchiolar metaplasia are listed in Box 9.9.
Mucostasis
Mucostasis is the effect of impaired drainage of mucin and defined as the accumulation of amphophilic mucin within dilated terminal airways or in surrounding alveolar ducts and alveolar spaces (Fig. 9.33).73,124 Mucostasis is a common finding in cigare The smokers and can occur in a number of other settings, as detailed in Box 9.10. When mucostasis is accompanied by extensive mucus extrusion into alveolar spaces, a careful search for mucinous adenocarcinoma, either primary or metastatic, is in order, especially in the absence of another specific pathologic entity in the biopsy.
Bronchiolar Smooth Muscle Hyperplasia
Generalized thickening of the smooth muscle around conducting airways and alveolar ducts (Fig. 9.34A) can be seen in a number of inflammatory lung diseases, which are listed in Box 9.11. Sometimes smooth muscle nodules formed of haphazard fascicles can be seen in smokers and are of unknown clinical significance (Fig. 9.34B).
Fibrous Proliferations in and Around Bronchioles
Increase of fibrous tissue in the lumen or wall of bronchioles and the immediately surrounding tissue may be seen in several clinicopathologic conditions, particularly those associated with acute inhalational injury (Figs. 9.35 and 9.36). The fibrous proliferation seen at the microscopic level may be of different ages, ranging from recently developed loose fibromyxoid myofibroblastic intraluminal polypoid proliferation—so-called Masson bodies125—to more advanced fibrosis with fewer fibrocytes, more abundant extracellular collagen, and usually more prominent distortion of bronchiolar morphology. More advanced fibrotic processes may have a predominant concentric growth pattern in and around the airway, resulting in narrowing or obliteration of the lumen. In other cases, fibrosis may have a predominant peribronchiolar-radiating pattern, involving the adventitia of the airway with variable extension into the adjacent lung parenchyma.
Figure 9.34 Smooth muscle hyperplasia. (A) This terminal bronchiole is from a patient with a previous history of radiation therapy; it exhibits an irregular lumen with an excessively thick smooth muscle layer. (B) A typical smoker’s nodule, characterized by radial fascicles of smooth muscle in a centrilobular distribution.
Figure 9.35 Bronchiolar intraluminar Masson polyps and fibrin. These images are from the lung biopsy of a patient who worked as a silo filler. He developed an acute illness and died 3 days after biopsy despite steroid therapy. (A) the bronchioles are filled with polypoid formations. (B) Some of these formations are partially fibroblastic and partially fibrinous, whereas others are purely fibroblastic and show an investing epithelial layer.
Affected bronchioles may show lesions of different ages, and the injury-related changes may not be uniform throughout the biopsy (and presumably the lung as a whole). They may be seen in conjunction with aspects of bronchioloectasia and mucostasis, which can be consequences of the same pathogenetic event, as the possible effect of air trapping, and defects in mucus clearance. Indeed, the bronchioles, seen in longitudinal sections, may exhibit an irregular distribution of constricted and dilated tracts, with a somewhat varicose aspect. The fibrotic process may also be accompanied by variable amounts of bronchiolar and peribronchiolar inflammation, which may extend to involve the alveolar walls of the adjacent lung parenchyma, and by smooth muscle hyperplasia and proliferation of respiratory epithelium, sometimes leading to peribronchiolar metaplasia.
Figure 9.36 Bronchiolar intraluminar Masson polyps and fibrin. (A) A polyp extending along the terminal airway in a patient with granulomatosis with polyangiitis (previously called Wegener granulomatosis). (B) A bronchiole in a patient with rheumatoid arthritis shows luminal polypoid myofibroblastic proliferation accompanied by a peribronchiolar lymphoid infiltrate.
Intraluminar fibroblastic Masson bodies (Fig. 9.36A) are only rarely observed and may be the predominant finding in lung biopsies in cases of very acute fume inhalation. More frequently intraluminar fibroblastic Masson bodies are concurrently and more conspicuously located in the surrounding distal airspaces, representing a generalized parenchymal repair reaction. In these cases they are almost always associated with significant inflammatory changes in the airway wall and surrounding lung parenchyma, a feature now referred to as organizing pneumonia pattern, or simply airspace organization.126 When this type of fibroinflam- matory reaction has no apparent etiology, the condition is referred to clinically as cryptogenic organizing pneumonia,127 formerly known as idiopathic bronchiolitis obliterans organizing pneumonia.1228 Intraluminal fibroblastic Masson bodies can be seen in many lung disorders, as detailed in Box 9.12.
Bronchiolitis Obliterans Syndrome
Fibrous proliferation at the bronchiolar level resulting in luminal constriction and ultimately complete obliteration of the small airways can be seen in two different clinical settings, depending whether it manifests in transplant settings or not.129 In the setting of chronic lung transplant rejection (see Chapter 13) or graft versus host disease in bone marrow transplants, the fibrotic process is referred to as obliterative bronchiolitis (OB)130,131 and corresponds to the clinical entity referred to as bronchiolitis obliterans syndrome (BOS).132-134 OB/BOS is a complex multifactorial process involving immune-mediated-dependent tissue injuries and aberrant reparative responses or remodeling.135 Histopathologically, the earliest stage is characterized by eccentric subepithelial fibrosis with scattered admixed chronic inflammatory cells. Concentric fibrosis then progresses over time until the lumen becomes markedly narrowed or entirely obliterated. In other instances, the lumen may be initially occluded by loose fibrous Masson bodies, presumably as a manifestation of active repair following an injury to the airway epithelium and basal lamina.
In the non-lung transplant patient, the small airway disease characterized by variable narrowing or obliteration of the small airways is referred as constrictive bronchiolitis and may be a consequence of injuries resulting from infection, toxic fume inhalation, drug reaction, chemical toxins, hematopoietic stem cell transplantation, or connective tissue disease (Table 9.3). In some cases no etiology is identified.64,73,77,136-146 It is worth noting that the pathologic findings in constrictive bronchiolitis may be quite subtle (see the introductory section Pattern-Based Approach to Diagnosis, Pattern 6, Minimal Changes). When no explanation for a patient’s significant hypoxia is identifiable in lung biopsy sections, trichrome and elastic tissue stains may be helpful in highlighting the changes in small airways. Nevertheless it is important to remember that some degree of subepithelial fibrosis in the small airways is an almost universal finding in heavy cigare The smokers. Without clinical manifestations of lung disease, such findings are most often irrelevant. Examples of the spectrum of constrictive airway injury are presented in Figs. 9.37 to 9.39.
Table 9.3 Known Causes of Constrictive Bronchiolitis
|
Category |
Specific Agents |
|
Infections |
Mycoplasma, viruses (cytomegalovirus, adenovirus, influenza virus, parainfluenza virus, varicella virus) |
|
Fumes |
Nitrogen dioxide, sulfur dioxide, ammonia, phosgene, chlorine, fly ash, styrene, fire fumes, possibly volatile chemicals used as flavoring ingredients in food industry |
|
Toxins |
Ingested toxins from juice of the plant Sauropus androgynu145 |
|
Massive dust exposure140 |
— |
|
Drugs |
Penicillamine, cocaine, gold, chemotherapeutic agents (lomustine, 5-fluorouracil)147 |
|
Paraneoplastic syndromes139,148 |
Paraneoplastic pemphigus in cases of malignant lymphomas and Castleman disease |
|
Stevens-Johnson syndrome143 |
— |
|
Systemic connective tissue disease |
Rheumatoid arthritis, mixed connective tissue disease |
|
Idiopathic |
— |
Data from Colby TV, Leslie KO. Small airway lesions. In: Cagle PT, ed. Diagnostic Pulmonary Pathology. New York: Marcel Dekker; 2000:231-249; King TE Jr. Bronchiolitis. In: Schwartz MI, King TE, eds. Interstitial Lung Disease. London: BC Decker; 1998:654-684; and Ryu JH. Classification and approach to bronchiolar diseases. Curr Opin Pulm Med. 2006;12(2):145-151.
Given the limited repertoire of airway repair after injury, it is probably best to think of constrictive and obliterative forms of bronchiolitis simply as a representation of a later evolution of the repair process, whereas organizing intraluminal polyps are a more subacute manifestation of injury.134 Why some injuries resolve with little permanent structural abnormalities while others result in persistent damage is unknown.
Fibrosis centered on the small airway, involving the wall of the bronchiole and surrounding lung parenchyma with or without any degree of inflammation and peribronchiolar metaplasia, may be descriptively termed airway-centered interstitial fibrosis (ACIF, Fig. 9.40). ACIF may be seen as a late manifestation of several conditions, most notoriously hypersensitivity pneumonitis. In some cases the process appears to be idiopathic.149-153
Terminal Airway Fibrosis With Dust Deposition (Pneumoconiosis-Associated Small Airway Disease)
Variable dust deposition around airways accompanied by an increase of fibrous and sometimes muscle tissue can commonly be seen in smokers and in people exposed to high concentrations of ambient particulate matter, as can occur in some highly polluted urban areas.154 Under polarized light, small refractile silicate particles (typically aluminum and magnesium silicates) may be identified within areas of pigment deposition, either as a consequence of lifelong dust exposure in the older patient or as a common finding in cigare The smokers.
When peribronchiolar dust deposition around airways is prominent and associated with numerous and large (typically larger than 1 cm in diameter) “dust nodules,” sometimes accompanied by fibrosis, a pneumoconiosis due to occupational exposure enters into the differential diagnosis. Small airway disease associated with exposure to a specific mineral dust—as from asbestos, aluminum oxide, iron oxide, silicates, or coal—is referred to as pneumoconiosis-associated small airway disease.131 In this case the bronchiolar and alveolar duct walls are thickened by fibrous tissue, and dust deposition occurs along the small airways with only minimally inflammatory changes (Figs. 9.41 and 9.42). Clinical and radiographic correlation is essential before a pathologic diagnosis of clinically significant pneumoconiosis is made. When hemosiderin is present along with alveolar duct fibrosis and other pigment deposition, a careful search for asbestos bodies is in order. In this setting, iron stains (Prussian blue) may be helpful for identifying foci of iron deposition, there by attracting the pathologist’s attention to areas where asbestos bodies (ferruginous bodies) are more likely to be identified (Fig. 9.42B). Not all ferruginous bodies are asbestos-related, so it is important to establish the presence of a delicate translucent core fiber, the characteristic feature of asbestos bodies.
Figure 9.37 Constrictive bronchiolitis. (A) the wall of this bronchiole is thick and fibrotic without much associated inflammatory change. (B) the luminal profiles may be highly variable; here they appear slightly dilated and tortuous despite abundant mural fibrosis. No cause could be identified in this patient; the case has There fore been defined as idiopathic.
Figure 9.38 Constrictive bronchiolitis. (A) Lung tissue from a child after a viral infection. The lumen of the bronchiole is small, the walls are fibrotic, and the epithelial cells are sloughed into the lumen. (B) Lung preparation from a patient who developed obstructive lung disease after an acute pneumonia due to Mycoplasma infection. The bronchiole is almost completely obliterated by fibrous tissue. The epithelial cells are lost, although the muscularis propria is still preserved. (C) Lung preparation from a bone marrow transplant recipient. Note the entire segmental obliteration by fibrous tissue.
Figure 9.39 Constrictive bronchiolitis associated with inflammatory bowel disease. (A) Low-magnification image showing bronchiolocentric lesions characterized by fibrosis and a chronic inflammatory infiltrate with almost complete destruction of the terminal bronchioles. (B) A higher-magnification image from another patient shows changes that are quite subtle. There is no inflammation in the bronchiolar wall, but the diameter of the airway is smaller than that of the artery and the subepithelial connective tissue is dense and fibrotic.
Figure 9.40 Airway-centered interstitial fibrosis (ACIF). An example of ACIF in a patient with chronic hypersensitivity pneumonitis.
Figure 9.41 Silicatosis. Biopsy from a pottery factory worker showing a thickened and distorted bronchiolar wall. Most cells in the wall are histiocytes; under polarized light, they show many needle-shaped birefringent silicate crystals.
Figure 9.42 Mixed dust pneumoconiosis. (A) At low magnification, the bronchiole and accompanying artery are surrounded by densely pigmented fibrous tissue that distorts the normal architecture of the bundle. (B) At higher magnification, the histiocytic cells within the fibrous tissue contain abundant black pigment; the lumen of the bronchiole contains densely pigmented cells, most of which contain hemosiderin and occasionally ferruginous bodies.
Dilated and Irregular Bronchiolar Shapes
Variation in the shape and other distortions of the terminal airways can be seen as a secondary phenomenon in many inflammatory airway diseases and is a common finding in smokers. A useful method for assessing such changes is to search for terminal airways that are visible in cross section, so that the diameter of the airway and of the adjacent artery can be compared. In this setting, their diameters should be equal under normal conditions. When considerable bronchiolar distortion is present, thin-walled dilated airways may greatly exceed the pulmonary artery in diameter or, alternatively, may be significantly smaller when constricted. Such variable saccular or varicose dilation and constriction is common in chronic small airway diseases that result in fibrosis.
Bronchiolocentric Nodules
Bronchiolocentric nodules are nodular lesions centered on the small airways and may be caused by a number of different diseases,64 including primarily inflammatory lesions (e.g., panbronchiolitis), inflammatory and fibrotic lesions (e.g., pulmonary Langerhans cell histiocytosis) (Figs. 9.43 and 9.44), and miscellaneous disease processes (e.g., multiple carcinoid tumorlets with or without constrictive bronchiolitis or lymphangitic tumor, including malignant lymphoma).
Figure 9.43 Pulmonary Langerhans cell histiocytosis (PLCH). Three different phases of the disease, with nodular cellular lesions (A and B) undergoing transition to characteristic stellate scar morphology (C). The nodules involve the bronchioles, which may cavitate, contain variable numbers of eosinophils and Langerhans cells; these can even be absent in late fibrotic lesions. The diagnosis of PLCH can frequently be made at scanning magnification, which allows one to easily appreciate the typical discrete, roughly symmetrical nodules, some of which have a stellate shape, a dense fibrotic core, and frequently a more cellular peripheral zone.
Figure 9.44 Pulmonary Langerhans cell histiocytosis (PLCH). Explanted lung from a patient with advanced airway-centered fibrosis due to PLCH.
Clinicopathologic Entities With Prominent Airway Manifestations
Defined clinical diseases with distinctive inflammatory reaction patterns in the airways are few. In this section, we examine two frequent diseases, asthma and COPD, and two additional rare but well-defined diseases, panbronchiolitis and neuroendocrine cell hyperplasia with occlusive bronchiolar fibrosis (Aguayo-Miller disease). Emphysema is also covered in this section because it features a structural remodeling of the lung parenchyma that involves the small airways.
Figure 9.45 Asthmatic changes in a bronchus. The lumen is filled with mucus, the epithelium shows prominent goblet cell hyperplasia, the basal membrane is thick, smooth muscle is prominent, and There is a chronic inflammatory infiltrate extending through the bronchial wall.
Asthma-Associated Airway Diseases
Asthma is a chronic inflammatory disease of the airways accompanied by bronchial hyperresponsiveness (The primary clinical manifestation). Affected individuals develop a number of well-characterized inflammatory changes in the large airways, including epithelial fragility, intraepithelial goblet cell hyperplasia, mural infiltration by eosinophils, smooth muscle hyperplasia, and enlargement of subepithelial mucous glands (Fig. 9.45 and Box 9.13).155 A subset of asthmatic individuals will also develop chronic disease of the small airways.64,155-160 the large airway pathology is seen mainly in lobectomy specimens removed for other causes and autopsy lungs from patients who die in status asthmaticus. The small airway changes are more often observed in surgical biopsy specimens and include chronic bronchiolitis, eosinophilic bronchiolitis, varicosity of bronchiolar lumens, peribronchiolar metaplasia, constrictive bronchiolitis, and even features of bronchocentric granulomatosis (Figs. 9.46-9.49). In addition to these bronchial and bronchiolar histologic alterations, four distinctive albeit partially overlapping asthma-associated lung diseases are recognized: eosinophilic pneumonia, allergic bronchial pulmonary fungal disease, mucoid impaction of bronchi, and bronchocentric granulomatosis. Eosinophilic pneumonia is discussed in Chapters 6 and 8; the other three asthma-associated diseases are described next.
Figure 9.46 Constrictive bronchiolitis in asthma. A lung biopsy specimen shows some of the usual features of asthma as well as some scarring of the small airways. The patient suffered from severe obstructive disease with a concurrent restrictive component. (A) the bronchiole on the left is somewhat dilated and demonstrates mucostasis. (B) the bronchiole on the right is smaller, with subepithelial and adventitial fibrosis and inflammation with a prominent eosinophilic component.
Figure 9.47 Constrictive bronchiolitis in asthma. This bronchiole shows a very corrugated mucosa, with collagen fibers in the subepithelial connective tissue and also between the muscle fibers (trichrome stain).
Allergic Bronchopulmonary Fungal Disease
In certain predisposed individuals, Aspergillus and other fungi may colonize the mucus of the respiratory tract, resulting in a form of chronic inflammatory disease termed allergic bronchopulmonary fungal disease (ABFD).161-163 Other fungi implicated in the pathogenesis of this disorder include Pseudallescheria boydii, Bipolaris species, Torulopsis glabrata, Curvularia, and Lunata. The hallmark of ABFD is the presence of so- called allergic mucin,164 which is characterized by a lamellar structure with alternating layers of mucin and large amounts of eosinophils and their cytoplasmic granular debris (Fig. 9.50). Calcium oxalate, presenting as polarizable crystals, may be seen in the granular debris of allergic mucin, similar to that seen with sinus hypersensitivity to Aspergillus and other fungi in asthmatic patients. When allergic mucin is present, silver stains for fungal organisms are helpful in confirming the diagnostic impression of ABFD; however, the fungi are often focal and fragmented and can easily be overlooked. ABFD may also present with other clinical manifestations such as mucoid impaction of bronchi, bronchocentric granulomatosis, and eosinophilic pneumonia. Because ABFD is considered an allergic manifestation rather than a true infection, a course of oral corticosteroids is often the treatment of choice.
Figure 9.48 Bronchiolitis in asthma. This bronchiole shows prominent goblet cell metaplasia and basement membrane thickening: the mucus in the lumen shows eosinophils, and There are also increased numbers of eosinophils in the epithelium and the subepithelial connective tissue.
Figure 9.49 Small airway changes in a case of fatal asthma. In a small bronchiole, a very prominent goblet cell metaplasia with mucostasis is evident, and the basement membrane is thick and intensely eosinophilic. The smooth muscle layer is prominent.
Mucoid Impaction of Bronchi
Mucoid impaction of bronchi is a distinctive clinicopathologic syndrome considered to be one of the major manifestations of ABFD and characterized by the presence of extensive allergic mucin plugging of the airways accompanied by airway dilation.165-168 Patients may be asymptomatic or may have obstructive pneumonia distal to the impaction. Radiologically, bandlike or branching densities involving the upper lobes are characteristic findings (“gloved finger sign”)165 and bronchoscopy may identify clues to the disease, showing airways impacted by dense mucus. Branching strands of inspissated mucus may be coughed up by the patient (so-called plastic bronchitis) (Fig. 9.51) or captured by the endoscopist.
Microscopically, the affected bronchi are dilated and contain brownish to green mucus of tenacious consistency. The mucus has the laminated appearance of allergic mucin (Fig. 9.52) with eosinophilic debris, Charcot-Leyden crystals (hexagonal brightly eosinophilic crystals), Curshmann spirals (curled mucoid filament), and Creola bodies (detached epithelial cells with degenerative atypia). Asthma-type changes may be present in bronchoscopic biopsies from more central airways. Fungal stains may demonstrate hyphae, and the use of such stains is highly recommended whenever allergic mucin is found. Polarizable calcium oxalate crystals may also be present. Because mucous plugging can occur in a number of airway diseases, a distinctive laminated appearance should be present before the diagnosis is invoked.
Figure 9.50 Allergic bronchopulmonary fungal disease. The lumen of this distended bronchiole is filled with so-called allergic mucin (mucus containing eosinophils and Charcot-Leyden crystals).
Figure 9.51 Plastic bronchitis. Solid mucous casts of the airways may be expectorated or extracted at bronchoscopy.
Bronchocentric Granulomatosis
Bronchocentric granulomatosis is a distinctive form of granulomatous inflammation that surrounds the larger airways, replacing bronchial walls and mucosa.163,169-171 In bronchocentric granulomatosis, the lumen of the airway contains necrotic debris, and palisaded histiocytes surround the lumen. Bronchocentric granulomatosis is not only confined to the larger bronchi but may also involve more distal bronchioles. Both infectious and noninfectious causes are described; these are presented in Box 9.14. A useful distinguishing clinical feature for separating infectious and noninfectious bronchocentric granulomatosis is the presence or absence of asthma in the affected individual. In asthmatic patients, the disease may manifest as an exacerbation of the underlying airway disease, accompanied by wheezing, cough, and fever, or it can be related to hypersensitivity and may be associated with mucoid impaction and ABFD. In nonasthmatic patients, infection should be the main consideration in the differential diagnosis even when special stains are negative in tissue sections.
Figure 9.52 Mucoid impaction of bronchi in a case of allergic bronchopulmonary fungal disease. (A) Mucin plugs are characteristically laminated owing to the accumulation of mucus, eosinophils, and Charcot-Leyden crystals. (B) the nature of the laminated appearance of the plugs is easily recognized at higher magnification, showing many eosinophils and Charcot-Leyden crystals (inset).
In the asthmatic patient, the radiographic findings are often accompanied by the changes of mucoid impaction (branching opacities in a bronchial distribution). In the nonasthmatic patient, given the propensity for infection as the etiology, the radiologic manifestations may be quite variable, ranging from localized consolidation to nodular parenchymal lesions on chest radiographs. Also, in the nonasthmatic patient, cavitation may be present in the nodules, attesting to the likelihood of an infectious etiology.172
The most prominent histologic manifestation of bronchocentric granulomatosis is the destruction of the airway wall (Fig. 9.53). This feature is helpful in distinguishing peribronchial granulomas that occur in a number of infectious and noninfectious conditions (e.g., sarcoidosis). As in all cases of necrotizing granulomatosis inflammation, special stains for organisms should always be performed, even in the asthmatic patient in whom a hypersensitivity disease process is suspected. Rarely, granulomatosis with polyangiitis, formerly called Wegener disease, may be present in an exclusively airway-centered distribution, so clinical correlation and serologic studies may be useful. A feature helpful in excluding granulomatosis with polyangiitis is the presence of well-formed granulomas in the surrounding parenchyma (see Chapter 11, on vasculitis). When well-formed granulomas are present, granulomatosis with polyangiitis is an unlikely etiology. If the biopsy is obtained from the middle lobe or lingula, middle lobe syndrome should be considered as an alternative diagnosis. Aspiration pneumonia is also in the differential diagnosis, and a careful search for foreign material or foreign body giant cells is always advisable. Vegetable material with thick cellular walls or meat (skeletal muscle fragments) implicates aspiration when present.93 the presence of conchoid calcifications or calcium oxalate crystals in isolation is a nonspecific finding that can occur in any granulomatous inflammatory reaction and is not a sign of aspiration.
Chronic Obstructive Pulmonary Disease
COPD is a common disease characterized by chronic airflow obstruction and small airway abnormalities.173-175 the disease is usually related to cigare The smoking. The small airways in COPD are often subtly abnormal; this is the most common situation in which minor abnormalities of the bronchioles are seen, reflecting the high prevalence of smoking in affected patients. Histologically, there is a minor degree of inflammation in the walls of bronchioles, including respiratory bronchioles, with variable occurrence of fibrosis, mucus stasis, loss of radial attachments, and bronchiolectasis (with dilation and distortion). Emphysema and chronic bronchiolitis both occur in COPD but vary in proportion and severity from patient to patient.
Emphysema
Emphysema may be classified according to the part of the lung acinus that is primarily affected.176 Proximal (centrilobular, centriacinar) emphysema (Fig. 9.54A) involves the proximal part of the lung acinus. This form of emphysema is strongly associated with smoking. The respiratory bronchioles are enlarged and destroyed, and the enlarged airspaces are seen at the center of the secondary acinus; respiratory bronchiolitis of variable degree may be present. Panacinar emphysema (Fig. 9.54B) affects the whole acinus and is characteristic of a1-antitrypsin deficiency; the airspaces of the whole acinus are diffusely enlarged. Distal (septal, pleural, localized) emphysema affects the periphery of the acinus, most often beneath the pleura; it may be a cause of spontaneous pneumothorax in the young adult. Irregular emphysema may be seen in association with a lung scar, such as those due to healed Langerhans cell histiocytosis, granulomatous inflammation, dust deposits, or pulmonary infarcts. Although gross examination of the lungs allows distinction between centriacinar and panacinar emphysema,173 the surgical biopsy is not a reliable method for diagnosing pulmonary emphysema. Noting the presence of emphysema on surgical wedge biopsies is reasonable, but attempts to grade its severity are not advisable (Fig. 9.55). The associated small airway and vascular changes may be prominent and include tortuosity.
Figure 9.53 Bronchocentric granulomatosis. (A) the disease is characterized by obliteration of the airway lumen by granulomatous inflammation and complete effacement of the airway epithelium. (B) Note the prominent histiocytic reaction at higher magnification.
Figure 9.54 Emphysema. Paper-thin Gough-Wentworth sections prepared from whole lungs. (A) Centriacinar emphysema in a smoker. (B) Panacinar emphysema in arantitrypsin deficiency. (Original Gough sections courtesy T.V Colby and the Charles B. Carrington Memorial Lung Pathology Library.)
Neuroendocrine Cell Hyperplasia With Occlusive Bronchiolar Fibrosis (Aguayo-Miller Disease)
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a primary proliferation of bronchiolar neuroendocrine cells that can be associated with partial or total occlusion of airway lumens by fibrous tissue.177 DIPNECH is more frequent in women and is not related to cigare The smoke. DIPNECH may be an incidental finding or may present as a symptomatic disease, typically comprising a nonproductive cough, dyspnea (which is usually not progressive), and an obstructive lung function profile.178,179 HRCT180 scans may reveal evidence of small airway obstruction (mosaic attenuation with air trapping) and the coexistence of minute bronchiolocentric pulmonary nodules. Rare cases have been found in association with multiple endocrine neoplasia (MEN) type 1 syndrome or other endocrine disorders.163 Pathologically, the mildest lesions consist of linear zones of neuroendocrine cell hyperplasia along the basal membrane with very focal subepithelial fibrosis. More obvious lesions consist of a plaque of eccentric fibrous tissue, occasionally intermingled with neuroendocrine cell nests, partially occluding the airway lumen. Sometimes the occlusion can be caused directly by the proliferation of neuroendocrine cells (Figs. 9.56 and 9.57) within the airway epithelium. The most severely involved bronchioles show total occlusion of their lumens by fibrous tissue, with few visible neuroendocrine cells.
Figure 9.55 Emphysema. The type and severity of emphysema may be difficult or impossible to determine on histopathologic grounds. (A) Here, centriacinar emphysema is seen with dilation of the airspaces surrounding the bronchiole. (B) By contrast, panacinar emphysema features a more diffuse airspace dilation.
Figure 9.56 Aguayo-Miller disease. These lung preparations are from a 74-year-old woman who presented with dyspnea of recent onset. Multiple pulmonary nodules are easily identified in the low-magnification view of a lung biopsy. (A) One of the nodules shows fibrosis encasing the bronchiole and pulmonary artery, with several neuroendocrine cell aggregations (arrows)and tortuous bronchiolar profiles (br). These neuroendocrine cell aggregations are demonstrable by their immunoreactivity for chromogranin A and synaptophysin. The entrapped airways in the nodule show a narrowed lumen, with neuroendocrine cell aggregates that may bulge into the bronchiolar lumen. (B) Neuroendocrine cell hyperplasia in Aguayo-Miller disease is not limited to airways associated with the nodules but can also be found in isolated airways.
Figure 9.57 Aguayo-Miller disease: constrictive bronchiolitis. In Aguayo-Miller disease the clinical picture is dominated by obstructive physiology. In this case, besides the neuroendocrine hyperplasia, other bronchioles demonstrated prominent fibrosis with luminal narrowing.
Figure 9.58 Diffuse panbronchiolitis. (A) Low-magnification view shows a centrilobular nodule composed of distinctive foamy macrophages distending the peribronchiolar septa, alveolar duct walls, and some alveolar septa. (B) This infiltration by pale foamy macrophages is more evident at higher magnification; an associated chronic inflammatory infiltrate can also be appreciated. This biopsy was taken from a Japanese man with a long history of chronic cough, sputum production, and dyspnea. A plain film of the chest showed diffuse disseminated nodular shadows with hyperinflation. Pulmonary function testing indicated an obstructive pattern with hypoxemia.
Diffuse Panbronchiolitis
Diffuse panbronchiolitis (DPB)181 is a distinctive inflammatory condition characterized by chronic bronchiolitis associated with prominent interstitial vacuolated or “foamy” histiocytes in a peribronchiolar distribution (Fig. 9.58). DPB is seen more commonly in natives of Japan, Korea, and China; only rare cases have been described in non-Asian individuals.182,183 the age range for affected patients is 20 to 60 years. Men are twice as commonly affected as women. Chronic productive cough and dyspnea are the typical presenting complaints, and most patients have sinusitis.182,184-190 A genetic susceptibility191 has been well documented over the years and recently has been identified as a human leukocyte antigen (HLA)-associated major susceptibility gene, probably residing within the HLA-B locus on the short arm of chromosome 6 (6p21.3). HLA-B54 is the haplotype reported in Japanese patients, and HLA-A11 is identified in those of Korean ancestry, suggesting that the DPB susceptibility locus is located between the HLA-B and HLA-A
Table 9.4 Key Morphologic Findings in Diseases of the Large and Small Airways and Adjacent Lung Parenchyma: When You See One of These Elements, You Think of DIPNECH, Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.
|
When You See ... |
Think of ... |
|
Nonnecrotizing granulomas in bronchial/ bronchiolar mucosa |
Frequent: sarcoidosis (with eosinophilic fibrous peripheral layers, few surrounding lymphocytes, coalescent granulomas), infection (with lymphoid cuff and usually associated with randomly distributed granulomas around bronchioles and in lung parenchyma), aspiration (especially with foreign body-type giant cells). Rare: berylliosis (indistinguishable from sarcoidosis), tracheobronchial amyloidosis (look for associated typical eosinophilic material) |
|
Nonnecrotizing granulomas around bronchioles |
Frequent: hypersensitivity pneumonitis (especially if loose and associated with interstitial lymphoid infiltrate and alveolar foamy macrophages), infection (usually associated with randomly distributed granulomas in lung parenchyma), aspiration(especially with foreign body giant cells), sarcoidosis Rare: atypical mycobacterial infection (including hot tub lung), granulomatosis with polyangiitis, Crohn disease, Sjogren syndrome, primary biliary cirrhosis |
|
Well-formed necrotizing granulomas in bronchiolar wall or surrounding lung parenchyma |
Infection (usually randomly distributed), aspiration |
|
Necrosis of bronchiolar mucosa and bronchiolar wall |
Frequent: infection, granulomatosis with polyangiitis Rare: bronchocentric granulomatosis, relapsing polychondritis, pyoderma gangrenosum, fume exposure |
|
Lymphoid follicles in the bronchiolar wall |
Frequent: collagen vascular diseases, bronchiectasis in more proximal airways, lymphoproliferative diseases Rare: immune deficiency, inflammatory bowel diseases |
|
Peribronchiolar metaplasia |
Healed bronchiolitis (of any cause), chronic hypersensitivity pneumonitis, bronchiectasis, constrictive bronchiolitis, incidental finding |
|
Mucostasis |
Bronchiolitis (of any cause), distal to bronchiolar constriction, occlusion (of any cause), bronchiectasis, allergic bronchopulmonary aspergillosis, as part of a localized inflammation, incidental finding (especially in the smoker, associated with smoker's macrophages) |
|
Intraalveolar foamy macrophages in peribronchiolar parenchyma |
Frequent: distal to bronchiolar constriction/obstruction (of any cause), hypersensitivity pneumonitis, cryptogenic organizing pneumonia, as a reaction to some drugs (e.g., amiodarone) Rare: Niemann-Pick disease |
|
Interstitial foamy macrophages |
Diffuse panbronchiolitis, inflammatory bowel diseases, distal to bronchiectasis |
|
Lightly pigmented alveolar macrophages |
Respiratory bronchiolitis (in smokers) |
|
Densely pigmented alveolar macrophages |
If hemosiderin/pearls positive: chronic hemorrhage, asbestosis, welder’s pneumoconiosis If anthracotic with or without refractile material: dust exposure |
|
Conchoidal calcifications in giant cells |
Aspecific finding: may be seen in any granulomatous disease |
|
Neuroendocrine cell proliferation |
Incidental finding frequently associated with bronchiectasis, DIPNECH (with or without airway occlusion) |
|
Reduction in airway lumen diameter (sometimes associated with bronchioloectasia) |
Infection, toxic fume inhalation, drug reaction, chemical toxins, connective tissue disease, transplantation |
|
Mucous cell hyperplasia |
Asthma (frequently associated with basal membrane thickening and eosinophilic infiltrate) |
|
Eosinophils |
Asthma, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), allergic bronchopulmonary fungal disease |
|
Smooth muscle hyperplasia |
Asthma, constrictive bronchiolitis, fibrosing lung disease, localized inflammatory process, bronchiolar scarring/peribronchiolar metaplasia, incidental finding (especially in smokers), DIPNECH with occlusive bronchiolar fibrosis |
A summary of the key morphologic findings related to diseases of the large and small airways is presented in Table 9.4.
Self-assessment questions related to this chapter can be found online at ExpertConsult.com.
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1. The presence of a rich lymphoplasmacytic infiltrate with germinal centers within and around the bronchiolar wall suggests the following diagnosis:
A. Follicular bronchiolitis
B. Acute and chronic bronchiolitis
C. Obliterative bronchiolitis
D. Mycobacterial infection
ANSWER: A
2. The presence of prominent mucostasis should alert the pathologist to:
A. Constrictive bronchiolitis
B. Mucinous adenocarcinoma
C. Acute bronchiolitis
D. Hypersensitivity pneumonitis
ANSWERS: A and B
3. Mucoid impaction of the bronchi with allergic mucin can be found:
A. Only in cases of aspergillosis
B. In any fungal infections
C. Only in children
D. In association with drug abuse
ANSWER: B
4. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is associated with:
A. Increased incidence of small cell lung carcinoma
B. Bronchiolar constriction and obstructive lung disease
C. MEN-1
D. Asthma
ANSWER: B
5. Which of the following conditions is not associated with bronchiolar necrosis?
A. Toxic fume exposure
B. Infections (especially viral infections and certain bronchocentric fungal infections)
C. Aspiration
D. Mixed dust exposure
E. Granulomatosis with polyangiitis
ANSWER: D
6. Smoking is related to:
A. DIPNECH
B. Bronchiolar distortion with pigmented macrophage accumulation within bronchiolar lumen and adjacent airspaces (respiratory bronchiolitis)
C. Acute bronchiolitis
D. Hypersensitivity pneumonitis
ANSWER: B
7. Which of the following pathologic findings in not typically seen in asthma?
A. Mucous plugs with eosinophils and distinctive inclusions in airway mucus (Charcot-Leyden crystals, Creola bodies, Cur- schmann spirals)
B. Mucosal eosinophils and basement membrane thickening
C. Goblet cell metaplasia/hyperplasia
D. Fibrotic constriction of bronchioli with neuroendocrine cell hyperplasia
ANSWER: D
8. Which of the following diseases is not associated with peribronchiolar metaplasia (Lambertosis)?
A. Healed bronchiolitis (from any cause)
B. Chronic hypersensitivity pneumonitis
C. Cigarettes smoking
D. Cryptogenic organizing pneumonia
ANSWER: D
9. Well-formed nonnecrotizing granulomas with prominent fibrosis and scant lymphoplasmacytic infiltrate of the bronchiolar wall are usually associated with:
A. Sarcoidosis
B. Mycobacterial infection
C. Granulomatosis with angiitis
D. Hypersensitivity pneumonitis
ANSWER: A
10. Hemosidern-laden macrophages in bronchioli and surrounding airspaces are not a typical feature of
A. Smoking-related respiratory bronchiolitis
B. Hypersensitivity pneumonitis
C. Chronic passive congestion
D. Chronic alveolar hemorrhage
ANSWER: B
11. Small airway alterations can present with significant clinical dysfunction, and histologic findings can be:
A. Very subtle and easily overlooked
B. Always associated with diffuse fibrosis
C. Always associated with acute lung injury
D. Seen only in transplant patients
ANSWER: A
12. Aspiration bronchiolitis is usually associated with:
A. Granulomatous reaction with foreign body-type giant cells
B. Pigmented macrophages and bronchiolar wall remodeling (respiratory bronchiolitis)
C. Bronchiolar smooth muscle hyperplasia
D. Mucoid impaction
ANSWER: A
13. Constrictive bronchiolitis can be associated with:
A. Infections
B. Fume exposure, toxins, drugs
C. Systemic connective tissue disease
D. All of the above
ANSWER: D
14. Tracheobronchial amyloidosis:
A. Is typically limited to the tracheobronchial tract
B. Is typically a manifestation of systemic amyloidosis
C. Generally has a benign clinical behavior
D. Typically affects children
ANSWER: A
15. Middle lobe syndrome:
1. Is part of the spectrum of chronic large airway obstruction
2. Can affect not only the right middle lobe but also the lingula
3. Can be associated with granulomas, and in these cases the suspicion of atypical mycobacterial colonization should be raised
4. All of the above
ANSWER: D
16. Respiratory bronchiolitis:
A. Is frequently an incidental finding in smokers
B. Is frequently a cause of interstitial lung disease
C. Is never associated with fibrosis
D. Is easily distinguished from chronic hemorrhage
ANSWER: A
17. Bronchocentric granulomatosis can be due to:
A. Allergic bronchopulmonary aspergillosis and infections
B. Smoking
C. Connective tissue diseases
D. All of the above
ANSWER: A
18. The histologic hallmark of diffuse panbronchiolitis is:
A. Intraalveolar foamy macrophages
B. Interstitial foamy macrophages
C. Bronchiolocentric inflammation
D. Peribronchiolar metaplasia
ANSWER: B
19. Poorly formed peribronchiolar interstitial granulomas are typical of:
A. Sarcoidosis
B. Infection
C. Hypersensitivity pneumonitis
D. Berilliosis
ANSWER: C
20. Bronchiolar necrosis can be seen in:
A. Infections
B. Granulomatosis with polyangiitis (Wegener granulomatosis)
C. Aspiration
D. All of the above
ANSWER: D
Case 1
eSlide 9.1
Clinical History
A 71-year-old man experienced an episode of meningitis in December 2015; since then he had recurrent episodes of pneumonia. A high resolution computed tomography (HRCT) scan showed an interstitial lung
disease (ILD) pattern with crazy paving and tree-in-bud features. The patient underwent bronchial arterial lavage (BAL), which showed the presence of numerous granulocytes and fungal hyphae consistent with Candida albicans infection. After treatment with antibiotics and steroids, the patient underwent transbronchial biopsy in March 2016. The four tissue fragments are shown in eFig. 9.1 and eSlide 9.1. The tissue fragments are representative of the bronchiolar wall and lumen (eFigs. 9.2 and 9.3) and of surrounding lung parenchyma (eFigs. 9.4 to 9.9).
Microscopic Pathology
The tissue fragments of bronchiolar wall and lumen show the presence of an inflammatory infiltrate characterized by histiocytes and granulocytes surrounding and destroying the bronchiolar wall (eFigs. 9.2 and 9.3). The surrounding lung parenchyma is characterized by two different features: a giant cell granulomatous reaction with some foreign material (eFigs. 9.4 and 9.5) and an interstitial infiltrate of cells with vacuoles in the cytoplasm (eFigs. 9.4 to 9.9).
eFigure 9.1
eFigure 9.2
eFigure 9.3
eFigure 9.4
eFigure 9.5
eFigure 9.6
eFigure 9.7
eFigure 9.8
eFigure 9.9
Diagnosis
This case represents an example of full-blown bronchiolar and parenchymal damage due to aspiration. The bronchiole shows an acute and chronic inflammatory reaction with many histiocytes and the surrounding lung parenchyma shows a granulomatous foreign body reaction with many giant cells and an infiltrate of vacuolated histiocytes, which is characteristic of the chronic aspiration of lipoid material.
Comment
Aspiration is a frequent, albeit sometimes underestimated, cause of bronchiolitis and pneumonia; the presence of giant cell granulomas, especially if associated with acute inflammation, or the presence of foamy cells in the interstitium with irregular cytoplasmic vacuoles should raise the suspicion of aspiration. Multiple sections may be useful to search for foreign bodies, which can sometimes be a very subtle finding.
Bibliography
1. Cheung OY, Muhm JR, Helmers RA, et al. Surgical pathology of granulomatous interstitial pneumonia. Ann Diagn Pathol. 2003;7(2):127-138.
2. Mukhopadhyay S, Katzenstein AL. Pulmonary disease due to aspiration of food and other particulate matter: a clinicopathologic study of 59 cases diagnosed on biopsy or resection specimens. Am
J Surg Pathol. 2007;31(5):752-759.
3. El-Zammar OA, Katzenstein AL. Pathologic diagnosis of granulomatous lung disease: a review. Histopathology. 2007;50(3):289-310.
4. Hutton Klein JR, Tazelaar HD, Leslie KO, Colby TV. One hundred consecutive granulomas in a pulmonary pathology consultation practice. Am J Surg Pathol. 2010;34(10):1456-1464.
Case 2
eSlide 9.2
Clinical History
A 48-year-old woman with dyspnea, cough, mild fever, and a slight elevation of rheumatoid factor (RF) underwent HRCT, which showed bilateral reticular and ground-glass opacities. A video-assisted thoracic surgery (VATS) biopsy was performed (eSlide 9.2).
Microscopic Pathology
The biopsy showed a lymphoplasmacytic interstitial infiltrate associated with lymphoid follicles with germinal centers, which was more pronounced around bronchioles (eFigs. 9.10 to 9.12). The infiltrate extended to the wall of some centrilobular arterioles (eFigs. 9.13 and
9.14) and to the pleura (eFigs. 9.15 and 9.16). At immunohistochemical analysis, the infiltrate was found to be composed of a mixture of B and T lymphocytes without clonal restriction. IgG4-positive plasma cells were unremarkable.
Diagnosis
The pattern of lung involvement can be descriptively classified as a cellular nonspecific interstitial pneumonia (NSIP) associated with follicular bronchiolitis and pleuritis.
Comment
This combination of histologic findings suggests the possibility of an underlying connective tissue disease (CTD). The present patient showed only a slight elevation of RF without any other serologic or clinical symptoms of CTD at the time of diagnosis. This is not an uncommon situation, and in some cases a full-blown CTD may develop during the follow-up period.
eFigure 9.10
eFigure 9.11
eFigure 9.12
eFigure 9.13
eFigure 9.14
Bibliography
1. Romagnoli M, Nannini C, Piciucchi S, et al. Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders? Eur Respir J. 2011;38(2):384-391.
2. Schneider F, Gruden J, Tazelaar HD, Leslie KO. Pleuropulmonary pathology in patients with rheumatic disease. Arch Pathol Lab Med 2012;136(10):1242-1252.
3. Leslie KO, Trahan S, Gruden J. Pulmonary pathology of the rheumatic diseases. Semin Respir Crit Care Med. 2007;28(4):369-378.
eFigure 9.15
Case 3
eSlide 9.3
Clinical History
A 35-year-old woman, nonsmoker, presented with subacute onset of dyspnea, fever, and mild cough. Pulmonary function tests showed a mild restrictive defect; on HRCT, bilateral centrilobular ground-glass opacities were present. The patient underwent bronchoscopy with BAL and transbronchial biopsy (eSlide 9.3).
Microscopic Pathology
BAL showed a marked lymphocytosis. The transbronchial biopsy (eFig. 9.17) showed a lymphoplasmacytic interstitial infiltrate (eFig. 9.18) with rare giant cells and cholesterol crystals (eFig. 9.19). Focally, foamy histiocytes were seen within alveolar lumina (eFig. 9.20).
Diagnosis
The pattern of lung involvement can be descriptively classified as cellular nonspecific interstitial pneumonia (NSIP) with isolated giant cells.
eFigure 9.18
eFigure 9.19
eFigure 9.20
Comment
The combination of cellular NSIP, isolated interstitialgiant cells, and intraalveolar foamy histiocytes (an indirect sign of bronchiolar obstruction) suggests the possibility of hypersensitivity pneumonitis (HP). A more detailed clinical history revealed that the patient used to clean an attic where pigeons frequently entered and built their nests. Of note, our patient was a nonsmoker and it is well known that smoking reduces the risk of HP.
Bibliography
1. Cheung OY, Muhm JR, Helmers RA, et al. Surgical pathology of granulomatous interstitial pneumonia. Ann Diagn Pathol. 2003;7(2):127-138.
2. Coleman A, Colby TV Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol. 1988;12(7):514-518.
3. Spagnolo R Rossi G, Cavazza A, et al. Hypersensitivity pneumonitis: a comprehensive review. J Investig Allergol Clin Immunol. 2015;25(4):237-250.
Case 4
eSlide 9.4
Clinical History
The patient was a 60-year-old woman, a nonsmoker, with a long history of dry cough clinically interpreted as asthma, mild shortness of breath, and obstruction at lung function testing. HRCT showed a mosaic attenuation pattern with small bronchiolocentric nodules. A VATS biopsy was performed (eSlide 9.4).
Microscopic Pathology
The biopsy specimen showed a preserved lung architecture with tiny bronchiolocentric cellular proliferations as well as distortion of the bronchiolar lumen and wall (eFig. 9.21). At higher magnification the cellular proliferation consisted of small nests of bland-appearing elements with no mitotic activity separated by fibrous stroma (eFigs. 9.22 to 9.24), which were strongly immunoreactive for chromogranin A and synaptophysin. The same immunostainings highlighted foci of linear hyperplasia of neuroendocrine cells. Bronchioles were occasionally ecstatic and more frequently distorted or obliterated (eFig. 9.25). Beside the bronchiolocentric neuroendocrine cell micronodules, this biopsy shows the presence of several additional micronodules composed of small nests of epithelial-looking bland cells, which are not immunoreactive for neuroendocrine markers (eFigs. 9.26 and 9.27).
eFigure 9.21
eFigure 9.22
eFigure 9.23
eFigure 9.24
eFigure 9.25
eFigure 9.26
eFigure 9.27
Diagnosis
The case shows a diffuse neuroendocrine proliferation with tumorlets and neuroendocrine cell hyperplasia associated with mild bronchiolar distortion. This finding is defined as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). In association with this neuroendocrine lesion the biopsy shows several minute meningothelial nodules (once called minute pulmonary chemodectomas, illustrated in eFig. 9.29), which can be considered incidental findings.
Comment
DIPNECH is a rare condition that is probably underrecognized, and its frequency is apparently increasing owing to more awareness of the disease. DIPNECH is more frequent in nonsmoking women and may be associated with peripheral lung carcinoids and a variable clinical obstructive syndrome.
Bibliography
1. Rossi G, Cavazza A, Spagnolo P, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Eur Respir J. 2016;47(6):1829-1841.
2. Gosney JR, Williams IJ, Dodson AR, Foster CS. Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathology. 2011;59(4):751-762.
3. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62(3):248-252.
Case 5
eSlide 9.5
Clinical History
A 36-year-old asthmatic woman presented with fever, peripheral eosinophilia, and bilateral pulmonary ground-glass opacities. At bronchoscopy, a tenacious endoluminal plug was removed (eSlide 9.5).
Microscopic Pathology
The plug consisted of mucoid material with a laminated appearance (eFigs. 9.28 and 9.29). At higher magnification the layers consisted of acellular material alternating with densely cellulated layers rich in degenerating eosinophils with Charcot-Leyden crystals (eFigs. 9.30 and 9.31). This finding is referred to as allergic mucus. Grocott silver impregnation revealed rare fragmented fungal hyphae.
eFigure 9.28
eFigure 9.29
eFigure 9.30
eFigure 9.31
Diagnosis
The case is diagnostic of allergic bronchopulmonary fungal disease (ABFD).
Comment
ABFD is a clinical syndrome that manifests histologically with a variable combination of mucoid impaction, bronchocentric granulomatosis, and eosinophilic pneumonia. ABFD is considered to be an allergic manifestation rather than a true infection, and a course of oral corticosteroids
is often the treatment of choice. The more frequent fungus identified in these cases is Aspergillus, but occasionally other fungi may be involved. The finding of allergic mucus should always prompt a careful search of fungal hyphae, which may be very few and inconspicuous.
Bibliography
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2. Aubry MC, Fraser R. The role of bronchial biopsy and washing in the diagnosis of allergic bronchopulmonary aspergillosis. Mod Pathol. 1998;11(7):607-611.