The concept of small airways disease varies

Transcription

1 SMALL AIRWAYS DISEASE Timothy Craig Allen, MD, JD KEYWORDS Constrictive bronchiolitis Hypersensitivity pneumonitis Bronchiolitis Organizing pneumonia with intraluminal polyps Idiopathic bronchiolocentric pneumonia ABSTRACT The concept of small airways disease varies among specialties, with clinicians generally considering them in terms of terminal airway changes causing airflow obstruction, radiologists considering them in the context of direct signs and indirect signs identified on high-resolution computed tomography scans, and pathologists evaluating them based entirely or almost entirely on the histologic changes present in the bronchioles, with or without associated changes involving bronchi and alveoli. Small airways diseases are best defined pathologically as a diverse group of conditions that primarily involve bronchioles and acartilagenous airways 2 mm or less in diameter, which include membranous bronchioles, respiratory bronchioles, and alveolar ducts. Small airways can be involved with disease primarily or secondarily. The histologic features of small airways diseases may be confusing because they overlap. There may be incomplete assessment of the histologic process with limited biopsy. Other disease processes may occur along with a small airways disease, and may obscure or confound its histologic features. This article focuses on the histologic changes diagnostic of a variety of primary and secondary small airways diseases. Because the histologic features involve bronchioles, gross findings are often minimal and/or nonspecific. The article provides a nonexhaustive examination of conditions and diseases involving the small airways, focusing on the microscopic features, with emphasis on the limitations of histologic diagnosis and differential diagnosis. Although small airways diseases occur relatively frequently, there is no universal agreement on their classification, and pathologists generally have a poor understanding of them. Indeed, the Key Features SMALL AIRWAYS DISEASES 1. Small airways diseases are a group of diseases that by definition involve bronchioles acartilagenous airways that are 2 mm or less in diameter, including membranous bronchioles, respiratory bronchioles, and alveolar ducts. 2. Small airways diseases may be classified as diseases that involve small airways primarily, or as lesions involving small airways primarily or secondarily. 3. The different specialties evaluate small airways diseases differently, with clinicians generally evaluating the terminal airway changes causing airflow obstruction, radiologists examining them in the context of direct signs and indirect signs identified on high-resolution CT scans, and pathologists evaluating them based almost entirely on the histologic changes within the bronchioles. 4. Small airways disease patients often exhibit straightforward clinical and radiographic changes, and do not require biopsy. 5. Transbronchial biopsy is more commonly performed than wedge biopsy, and is less invasive; however, it generally yields limited information and is of less utility than wedge biopsy. 6. The histologic features of the small airways diseases may cause considerable confusion due to overlapping features among the various small airways diseases, incomplete histologic assessment due to a limited biopsy, and the occurrence of other diseases processes along with a small airways disease. Department of Pathology, The University of Texas Health Science Center at Tyler, US Highway 271, Tyler, TX 75708, USA address: timothy.allen@uthct.edu Surgical Pathology 3 (2010) doi: /j.path /10/$ see front matter ª 2010 Elsevier Inc. All rights reserved. surgpath.theclinics.com

2 172 Allen concept of small airways disease varies among specialties, with clinicians generally considering them in terms of terminal airway changes causing airflow obstruction, radiologists considering them in the context of direct signs and indirect signs identified on high-resolution computed tomography (CT) scans, and pathologists evaluating them based entirely or almost entirely on the histologic changes present in the bronchioles, with or without associated changes involving bronchi and alveoli Small airways diseases are best defined pathologically as a diverse group of conditions that primarily involve bronchioles and acartilagenous airways 2 mm or less in diameter, which include membranous bronchioles, respiratory bronchioles, and alveolar ducts Small airways can be involved with disease primarily or secondarily. Many patients have straightforward clinical and radiographic changes and do not require biopsy. When performed, transbronchial biopsy is more common and less invasive than wedge biopsy, but typically yields limited information and results in a relatively less utile descriptive diagnosis than does wedge biopsy. Various classification systems for small airways diseases have been proposed. 11,18 Some are limited to diseases arising within the small airways, which may then spread to proximal bronchioles or distal alveoli. Others include diseases that may arise elsewhere and go on to involve small airways secondarily. Box 1 is a nonexhaustive list of conditions that are primary to the small airways. Box 2 is a list of some of the conditions for which there may be secondary involvement of the small airways. The histologic features of small airways diseases may be confusing because they overlap. Also, there may be incomplete assessment of the histologic Box 1 Conditions primarily involving small airways Peribronchiolar metaplasia Acute bronchiolitis Acute and chronic bronchiolitis Chronic bronchiolitis Constrictive bronchiolitis Eosinophilic bronchiolitis Granulomatous bronchiolitis Follicular bronchiolitis Diffuse panbronchiolitis Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) Mineral dust small airways diseases Box 2 Conditions that may exhibit secondary small airways involvement Respiratory bronchiolitis/respiratory bronchiolitis-associated interstitial lung disease (RBILD) Desquamative interstitial pneumonia (DIP) Pulmonary Langerhans cell histiocytosis Sarcoidosis Wegener granulomatosis Hypersensitivity pneumonitis Bronchiectasis Chronic bronchitis/chronic obstructive pulmonary disease (COPD) Asthma process with limited biopsy. Other disease processes may occur along with a small airways disease, and may obscure or confound its histologic features. This article focuses on the histologic changes diagnostic of a variety of primary and secondary small airways diseases. Because the histologic features involve bronchioles, gross findings are often minimal and/or nonspecific. The article provides a nonexhaustive examination of conditions and diseases involving the small airways, focusing on the microscopic features, with emphasis on the limitations of histologic diagnosis and differential diagnosis. PERIBRONCHIOLAR METAPLASIA Along alveolar septal surfaces adjacent to bronchioles, bronchiolar-type epithelium may proliferate. This proliferation has also been termed bronchiolarization, and has also been called Lambertosis, as it was once believed that bronchiolar epithelium traversed the canals of Lambert to involve alveolar septa. 19,20 This pathologic process may arise in association with various small airways diseases, including bronchiectasis, constrictive bronchiolitis, and hypersensitivity pneumonitis, among other diseases. 20,21 The process most likely represents a postinflammatory change. Peribronchiolar metaplasia is frequently identified surrounding the scarring of constrictive bronchiolitis. 21 Surrounding bronchioles, which may contain variable degrees of inflammation and fibrosis, show metaplastic bronchiolar epithelium lining variably fibrotic first-tier alveolar septa (Figs. 1 and 2).

3 Small Airways Disease 173 Fig.1. Peribronchiolar metaplasia showing mildly thickened peribronchiolar alveolar septa lined by bronchiolar metaplastic epithelium (H & E, original magnification 10). Goblet cell metaplasia and squamous metaplasia may occasionally occur. 21 Diagnosis may occasionally be less than straightforward, particularly with limited biopsy tissue. Peribronchiolar metaplasia may occasionally mimic atypical adenomatous hyperplasia; however, the bland and uniform cytologic features of peribronchiolar metaplastic cells lining alveolar septa are in contrast to the cells lining atypical adenomatous hyperplasia, which are characterized by an interrupted lining of variably sized Fig. 2. Higher power image of peribronchiolar metaplasia showing low cuboidal bronchiolar metaplastic epithelial cells lining thickened first-tier peribronchiolar alveolar septa (H & E, original magnification 20).

4 174 Allen cuboidal cells, occasional apical snouts, and occasional nuclear inclusions and double nuclei. 22 ACUTE BRONCHIOLITIS The primary cause of respiratory disease in the first year of life, acute bronchiolitis is generally a condition of infants and very young children. Acute bronchiolitis is predominantly caused by respiratory syncytial virus infection Infants with acute bronchiolitis clinically exhibit tachypnea and wheezing, and may exhibit chest retraction and nasal flaring if symptoms worsen. In obvious cases of disease radiology may be unnecessary, but where radiology is performed patients often show lung hyperinflation, and may show small centrilobular nodules and ground-glass opacities. 25,29 31 Adults may also acquire acute bronchiolitis, generally caused by viral or bacterial infections, or acute exposure to fumes and toxins. Biopsy from patients with acute bronchopneumonia and Wegener granulomatosis may occasionally show histologic features of acute pneumonia. 14 As most cases are diagnostically straightforward, biopsy is rarely performed. In cases that are not straightforward and biopsy may be performed, acute bronchiolitis is characterized histologically by bronchioles filled with purulent exudative and necrotic material and sloughed bronchiolar mucosa, with a neutrophilic infiltrate involving associated bronchiolar mucosa and bronchiolar wall. Although the majority of infant cases of acute bronchiolitis are caused by respiratory syncytial virus, infection by other viruses that may cause acute bronchiolitis, including influenza and parainfluenza, adenovirus, and measles, must be considered. Moreover, infections with fungi, mycoplasma, and Bordetella pertussis may cause acute bronchiolitis. 25,28 Diagnosis of acute bronchiolitis, occurring in infants and young children, is typically rendered clinically and radiologically. In less straightforward cases, biopsy may be of benefit. Although the majority of cases are caused by respiratory syncytial virus, other viral and nonviral origins must be considered. Prognosis is excellent in infants and young children with symptomatic treatment. Oxygen is of benefit in patients with significant hypoxia. Drug treatments have not shown significant therapeutic benefit; however, corticosteroids have shown some benefit in patients with croup ACUTE AND CHRONIC BRONCHIOLITIS Generally a condition found in adults, acute and chronic bronchiolitis is frequently caused by infections, including viral infections such as respiratory syncytial virus; however, noninfectious cases, including idiopathic cases, occur. Patients usually present clinically with mild respiratory symptoms such as cough and dyspnea, and show an obstructive pattern with pulmonary function testing. 11,12,36,38 40 The histologic findings with acute and chronic bronchiolitis include bronchiolar filling with mucus and purulent exudative and necrotic material, sloughed bronchiolar mucosa, and acute and chronic inflammatory cells, as well as an acute and chronic inflammatory cell infiltrate involving the bronchiolar mucosa and wall, extending into surrounding peribronchiolar tissue. The inflammatory cell infiltrate is predominantly composed of neutrophils, plasma cells, and lymphocytes. Acute and chronic bronchiolitis is often caused by viral infection, including respiratory syncytial virus; however, there are several potential causes (Box 3). 11,12,36,38,39 Diagnosis is often straightforward and is made clinically and/or radiologically. Biopsy is generally not required. In cases with a more confusing or complex clinical course or radiologic pattern, biopsy may assist in limiting the differential diagnosis or rendering a definitive diagnosis. Patients typically have a good prognosis with recovery after symptomatic treatment. Cases of

5 Small Airways Disease 175 Box 3 Causes of acute and chronic bronchiolitis Infections (bacterial, viral, mycobacterial) Aspiration pneumonia Asthma Hypersensitivity pneumonitis Fume/toxin inhalation Collagen vascular diseases Post lung transplantation Wegener granulomatosis Idiopathic idiopathic acute and chronic bronchiolitis may benefit from antibiotic and immunosuppressive therapy. 36 CHRONIC BRONCHIOLITIS The term chronic bronchiolitis describes a characteristic histologic pattern that is a feature of a variety of diseases. Infections, including viral infections, may frequently cause the histologic changes of chronic bronchiolitis; however, there are many other potential origins, including idiopathic ones. 11,12,14,36,40 Chronic bronchiolitis is characterized histologically by bronchioles that contain an infiltrate of chronic inflammatory cells within bronchiolar mucosa and walls. The inflammatory cell infiltrate often extends into surrounding peribronchiolar tissue. Germinal centers may or not be present. The histologic features may overlap with acute and chronic bronchiolitis (Fig. 3). 12,14,36,40 There are many causes for the findings of chronic bronchiolitis on biopsy. Box 4 lists various diseases for which chronic bronchiolitis may be a feature. In cases where germinal centers and constriction of the airway lumen are present, follicular bronchiolitis must be considered in the differential diagnosis. There are many potential causes for the histologic features of chronic bronchiolitis in a biopsy. When the histologic features of chronic bronchiolitis are identified on biopsy, clinical and radiologic correlation may assist in limiting the differential diagnosis or rendering a specific diagnosis. Fig. 3. Chronic bronchiolitis involving a respiratory bronchiole, with a predominantly lymphocytic infiltrate within the bronchiolar wall (H & E, original magnification 40).

6 176 Allen Box 4 Causes of chronic bronchiolitis Infections (bacterial, viral, mycobacterial) Aspiration pneumonia Asthma Graft versus host disease, post transplantation Collagen vascular disease Hypersensitivity pneumonitis COPD Lymphoproliferative diseases Pulmonary Langerhans cell histiocytosis Lung involvement with inflammatory bowel disease Idiopathic Prognosis with chronic bronchiolitis is dependent on the underlying disease process. FOLLICULAR BRONCHIOLITIS The term follicular bronchiolitis denotes hyperplasia of the bronchus-associated lymphoid tissue (BALT), a condition caused by altered immune stimulus or immune response of the BALT. Follicular bronchiolitis occurs in a variety of immuneassociated diseases that involve the pulmonary system, including collagen vascular disease, especially rheumatoid arthritis and Sjögren syndrome. Follicular bronchiolitis may also be found in patients with congenital immunodeficiency disorders, immune deficiency states such as AIDS, bronchiectasis and middle lobe syndrome, and hypersensitivity reactions. Idiopathic cases occur. Radiologic studies may exhibit peribronchiolar and peribronchial nodules, with or without associated patchy ground-glass opacification. 36,41 45 Follicular bronchiolitis is characterized histologically by peribronchiolar hyperplasia of lymphoid tissue, with reactive germinal centers, which extends to a varying degree into surrounding peribronchiolar tissue (Fig. 4). 36,41 Follicular bronchiolitis must be distinguished from primary or secondary pulmonary lymphoma. Clinical and radiologic correlation, as well as immunohistochemical studies, is of benefit if making the correct diagnosis. Reactive changes within bronchioles may be seen adjacent to other disease Fig. 4. Low-power image of follicular bronchiolitis showing peribronchiolar lymphoid hyperplasia with a centrally placed reactive lymphoid follicle (H & E, original magnification 4).

7 Small Airways Disease 177 processes, including infections and tumors both benign and malignant. The diagnosis of follicular bronchiolitis must be rendered with caution, and additional biopsy, including open biopsy, may be required in some cases to make an accurate diagnosis. 43,46 In patients for whom clinical and radiologic correlation support the diagnosis of follicular bronchiolitis, and for whom histology shows diagnostic features, the diagnosis is relatively straightforward. In less clear cases, immunostains will assist in making an accurate diagnosis. Prognosis is generally good in patients with follicular bronchiolitis; however, prognosis and therapy depend on the underlying causative disease. Corticosteroids and bronchodilators have shown therapeutic benefit in patients with idiopathic follicular bronchiolitis. 43,46 CONSTRICTIVE BRONCHIOLITIS An obstructive airway disease that is also termed bronchiolitis obliterans and obliterative bronchiolitis, constrictive bronchiolitis may be associated with a variety of diseases, including, importantly, chronic lung allograft rejection. Among never-smoking middle-aged and older women, constrictive bronchiolitis may occur idiopathically Constrictive bronchiolitis histologically features concentric narrowing of the bronchiolar lumen, ultimately resulting in complete obliteration of the lumen with only a remaining scar. The histologic features may be subtle, especially with early disease. Chronic inflammation within the bronchiolar wall is a variable feature. Patients with idiopathic disease often exhibit little bronchiolar or peribronchiolar chronic inflammation. Within membranous bronchiolar walls, smooth muscle hyperplasia and adventitial fibrosis may occur (Figs. 5 and 6). 13,48,50,51 There are several causes for the histologic finding of constrictive bronchiolitis on biopsy. Clinical and radiologic correlation is often helpful in determining the underlying etiology of constrictive bronchiolitis (Box 5). Plugs of granulation tissue, termed intraluminal polyps, are a characteristic of Fig. 5. Constrictive bronchiolitis showing concentric narrowing of the bronchiolar lumen (H & E, original magnification 20).

8 178 Allen Fig. 6. Constrictive bronchiolitis with almost complete occlusion of the bronchiolar lumen. Only athinslitlikemucosa-lined central space remains (H & E, original magnification 10). organizing pneumonia with intraluminal polyps, but are not found with constrictive bronchiolitis. Diagnosis of well-developed or later-stage constrictive bronchiolitis is often straightforward. Clinical and radiologic correlation is especially beneficial in cases where the histologic findings are more subtle. Prognosis in patients with the histologic features of constrictive bronchiolitis is based on the Box 5 Causes of constrictive bronchiolitis Post lung transplantation and bone marrow transplantation Drug reactions Fume/toxin exposure Healed infection (particularly adenovirus) Collagen vascular diseases (particularly rheumatoid arthritis) Lung involvement with inflammatory bowel disease Complicating or advanced component of cystic fibrosis, bronchiectasis, asthma, or chronic bronchitis Idiopathic underlying etiology. Among never-smoking older women with constrictive bronchiolitis, there are variable disease courses from slowly progressive disease to rapidly progressive deteriorating disease. 49 ORGANIZING PNEUMONIA WITH INTRALUMINAL POLYPS Known for many years as bronchiolitis obliterans organizing pneumonia (BOOP)/organizing pneumonia pattern, organizing pneumonia with intraluminal polyps is a histologic pattern that has been identified in numerous lung diseases Organizing pneumonia with intraluminal polyps is characterized histologically with plugs of granulation tissue that fill alveoli, alveolar ducts, and bronchiolar lumens. The plugs of granulation tissue may become rounded and nodular, and these are termed Masson bodies. The plugs of granulation tissue are made up of edematous or myxoid stroma within which lie variable numbers of fibroblasts and lymphocytes. Foamy macrophages may accompany the plugs of granulation tissue if bronchiolar obstruction is present (Figs. 7 and 8). 62,63

9 Small Airways Disease Fig. 7. Organizing pneumonia with intraluminal polyps, with polypoid granulation tissue lying within airspaces centrally, adjacent to necrotizing granulomas (H & E, original magnification 20). The histologic pattern of organizing pneumonia with intraluminal polyps may be found in a wide variety of pulmonary diseases (Box 6). Clinical and radiologic correlation is frequently necessary to determine specific etiology, unless within the Fig. 8. Higher power image of organizing pneumonia with intraluminal polyps showing a plug of granulation tissue, containing fibroblasts and lymphocytes, within a bronchiolar lumen (H & E, original magnification 40). biopsy there are histologic features indicating an etiologic factor such as viral inclusions suggestive of viral infectious origin. Idiopathic disease is termed cryptogenic organizing pneumonia (COP), previously termed idiopathic BOOP. COP generally occurs in middle-aged to older women who 179

10 180 Allen Box 6 Causes of organizing pneumonia with intraluminal polyps Resolving diffuse alveolar damage, aspiration pneumonia, or infections Acute pulmonary allograft rejection Adjacent to necrotic tumor, abscess, or infarct Hypersensitivity pneumonitis Fume/toxin exposure Drug reactions Post bone marrow or other nonpulmonary organ transplantation Post radiation or chemotherapy Lung involvement with inflammatory bowel disease Collagen vascular diseases Wegener granulomatosis Underlying hematologic disorder Idiopathic present with dyspnea, cough, and flu-type symptoms. Diagnosis of the histologic features of organizing pneumonia with intraluminal polyps is generally straightforward and is based on the finding of polypoid granulation tissue within bronchiolar lumens, as well as within alveolar ducts and alveolar spaces. Prognosis is dependent on the type and severity of the underlying disease process that produces on biopsy the histologic features of organizing pneumonia with intraluminal polyps. The majority of patients with COP show improvement with steroid therapy and have a good prognosis. 57,64 SMOKING-RELATED BRONCHIOLAR DISEASES Smoking-related bronchiolar diseases include membranous bronchiolitis, respiratory bronchiolitis, and respiratory bronchiolitis associated interstitial lung disease (RBILD). Membranous bronchiolitis is a smoking-related bronchiolar disease that involves membranous bronchioles, and respiratory bronchiolitis involves respiratory bronchioles. Membranous bronchiolitis and respiratory bronchiolitis are typically asymptomatic, often identified as an incidental finding when the patient undergoes lung biopsy for another condition RBILD is a more severe disease on a continuum with respiratory bronchiolitis. Patients with RBILD typically exhibit mild cough and dyspnea, and also have variable radiologic changes including ground-glass opacities, interstitial thickening with an upper lobe predominance, and centrilobular nodules. 71,72 The histologic features of membranous bronchiolitis and respiratory bronchiolitis include a predominantly lymphocytic and histiocytic bronchiolar and peribronchiolar infiltrate within membranous bronchioles and respiratory bronchioles, respectively, of smokers. Macrophages with finely granular brown pigment are variably present within surrounding alveolar spaces and within the bronchiolar wall. Bronchiolar metaplasia may be present; however, there is only minimal to mild peribronchiolar fibrosis, which may extend into first-tier alveolar septa (Figs. 9 and 10). Smooth muscle hyperplasia and adventitial fibrosis may also be present. Emphysema, as well as other tobacco smoking related histologic changes such as chronic bronchitis and desquamative interstitial pneumonia, may be present in the biopsy tissue. 65,68 Although RBILD is histologically similar to respiratory bronchiolitis and the diseases exist along a continuum, RBILD has generally more pronounced bronchiolar and peribronchiolar changes, such as more numerous pigmented macrophages within surrounding alveolar spaces and within the bronchiolar wall (Fig. 11). More severe RBILD itself merges with the histologic features of desquamative interstitial pneumonia. 65,69 Differential diagnosis includes chronic bronchiolitis and hypersensitivity pneumonitis, among others. Chronic bronchiolitis generally does not have obvious peribronchiolar infiltrates of finely granular pigmented macrophages, as are found in patients with membranous bronchiolitis and respiratory bronchiolitis, who are smokers. Under-sampled hypersensitivity pneumonitis may show similar histologic features to respiratory bronchiolitis and RBILD; however, again pigmented macrophages are not a characteristic of the disease. Clinical and radiologic correlation is beneficial in differentiating between these lesions. The histologic features of RBILD and

11 Small Airways Disease 181 Fig. 9. Respiratory bronchiolitis showing a mild predominantly lymphocytic bronchiolar infiltrate. Macrophages with finely granular brown pigment are identified within surrounding alveolar spaces (H & E, original magnification 20). desquamative interstitial pneumonia are similar, and the diagnosis generally depends on the severity of disease. Here also, clinical and radiologic correlation is helpful in making an accurate diagnosis. The diagnoses of membranous bronchiolitis and respiratory bronchiolitis are often made incidentally. The diagnosis of respiratory bronchiolitis proceeds along a continuum of increasing Fig. 10. RBILD showing pigmented macrophages and lymphocytes within a mildly thickened bronchiolar wall, and pigmented macrophages within surrounding peribronchiolar airspaces (H & E, original magnification 20).

12 182 Allen Fig. 11. RBILD with abundant pigmented macrophages within alveolar spaces which, while not diagnostic, is histologically suggestive of desquamative interstitial pneumonia (H & E, original magnification 10). histologic severity until the histologic changes meet the criteria for the diagnosis of RBILD. 65 Patients with respiratory bronchiolitis typically have a very good prognosis with smoking cessation alone. Corticosteroid therapy is of no or limited benefit. Patients with membranous bronchiolitis generally exhibit a good prognosis, as do the majority of patients with RBILD. Smoking cessation is usually the only therapy necessary for these patients. Patients with more severe RBILD, bordering on desquamative interstitial pneumonia, may exhibit a worse prognosis, and corticosteroid therapy may be of benefit in these patients. DIFFUSE PANBRONCHIOLITIS Diffuse panbronchiolitis is an uncommon disease in the United States, and occurs predominantly in Japan. Diffuse panbronchiolitis is being identified increasingly in other Asian countries. There is thought to be a genetic predisposition to diffuse panbronchiolitis, and associations with HLA- Bw54 and HLA-A11 have been shown. Diffuse panbronchiolitis is an idiopathic small airways disease characterized by bilateral progressive, obstructive, suppurative lesions. Patients average approximately 40 years of age and are predominantly men. Presenting symptoms include cough, dyspnea, and chronic sinusitis. No association has been shown between diffuse panbronchiolitis and smoking or fume/toxin exposures. Patients radiographically have small centrilobular nodules in a bilateral distribution. With wedge biopsy, yellow nodules approximately 1 to 3 mm in size may be identified in a bronchiolocentric distribution Diffuse panbronchiolitis is characterized histologically by an infiltrate of foamy macrophages, lymphocytes, and plasma cells in a transmural bronchiolar distribution, predominantly involving respiratory bronchioles. Occasional neutrophils may also be identified. While foamy macrophages and other inflammatory cells may be identified within peribronchiolar tissue, surrounding alveoli are relatively uninvolved in the process. Patients often have infections; associated organizing pneumonia and acute pneumonia may be present and may cause a more complex histologic pattern. In advancing disease, terminal bronchioles may become ectatic. 73,76,80,81

13 Small Airways Disease 183 The involvement of predominantly respiratory bronchioles by diffuse panbronchiolitis is a distinctive feature that helps distinguish it from other differential diagnoses, such as constrictive bronchiolitis, that generally involve membranous bronchioles. Bronchiolitis due to rheumatoid arthritis and other collagen vascular diseases or due to autoimmune diseases must be considered. Xanthomatous bronchiolitis may present with a similar histologic pattern; however, clinical and radiologic correlation is helpful in rendering the correct diagnosis. 76,80,82 Diagnosis of diffuse panbronchiolitis generally requires clinical and radiologic correlation. Without treatment, patients often progress to bronchiectasis, respiratory failure, and ultimately, death. Pseudomonas infection has been related to poorer prognosis. Low-dose macrolide antibiotic therapy may improve prognosis due to its anti-inflammatory effect. 76,80,83 AIRWAY-CENTERED INTERSTITIAL FIBROSIS/ PERIBRONCHIOLAR METAPLASIA AND FIBROSIS/IDIOPATHIC BRONCHIOLOCENTRIC INTERSTITIAL PNEUMONIA There are 3 recently described airway-centered entities that may represent different points of progression or similar manifestations of the same disease or group of diseases: airway-centered interstitial fibrosis, idiopathic bronchiolocentric idiopathic pneumonia, and peribronchiolar metaplasia related interstitial lung disease Churg and colleagues 84 described airway-centered interstitial fibrosis, arising predominantly in middleaged women with dyspnea and chronic cough who exhibit radiologic changes of peribronchiolar, peribronchial, and perivascular fibrosis. Yousem and Dacic 85 described idiopathic bronchiolocentric interstitial pneumonia in a group of patients, predominantly middle-aged women, with bronchiolocentric fibrosis. Fukuoka and colleagues 86 described peribronchiolar metaplasia related interstitial lung disease in a group of patients with peribronchiolar metaplasia who clinically exhibited interstitial lung disease. Churg and colleagues 84 characterized airwaycentered interstitial fibrosis histologically by interstitial fibrosis that is bronchiolocentric, with associated peribronchiolar fibrosis, bronchiolar metaplasia, hyperplastic bronchiolar smooth muscle, and minimal to mild interstitial inflammatory cell infiltrate. Features of usual interstitial pneumonia, including honeycombing, are not present. There is also no increased infiltrate of alveolar macrophages. Yousem and Dacic 85 described idiopathic bronchiolocentric interstitial pneumonia, characterized by centrilobular and bronchiolocentric fibrosis with associated patchy areas of interstitial inflammation, which increased in comparison to patients with airway-centered interstitial fibrosis. Granulomas, suggestive of hypersensitivity pneumonitis, are not a characteristic feature. Fukuoka and colleagues 86 described peribronchiolar metaplasia related interstitial lung disease, characterized by predominantly peribronchiolar metaplasia, without features of fibrosis or inflammation described by Churg and colleagues or Yousem and Dacic in their patients. It is not currently known whether airway-centered interstitial fibrosis is a distinct entity or whether it represents other disease processes such as hypersensitivity pneumonitis, RBILD, nonspecific interstitial pneumonia, or usual interstitial pneumonia. 84 It is not known whether idiopathic bronchiolocentric interstitial pneumonia represents a distinct entity or hypersensitivity pneumonitis, RBILD, or usual interstitial pneumonia. 85 Peribronchiolar metaplasia related interstitial lung disease may represent a variant of airway-centered interstitial fibrosis or idiopathic bronchiolocentric interstitial pneumonia, or other common interstitial lung diseases such as hypersensitivity pneumonitis. 86 Diagnosis of these rare and controversial entities should be made with caution. Clinical and radiologic correlation is essential to make these diagnoses with reasonable certainty. Patients diagnosed with airway-centered interstitial fibrosis generally have shown no improvement with bronchodilators and corticosteroid therapy, and have a generally poor prognosis, with 40% dead of disease within a 10-year follow-up period. 84

14 184 Allen REFERENCES Pitfalls SMALL AIRWAYS DISEASE! Small biopsies with limited material must be evaluated with caution, as not all criteria for the diagnosis of a disease or condition may be present in the limited tissue. Wedge biopsies are more diagnostically helpful, but are less frequently available as they require an open lung procedure.! Associated infections or other conditions may present additional histologic patterns that may make diagnosis more complex or confusing; this is especially problematic with the limited tissue obtained from small biopsies.! The histologic features identified in the small airways may be diagnostic, such as with diffuse panbronchiolitis, or merely supportive of a histologic diagnosis for which there are multiple potential causes. Clinical and radiologic correlation may be extremely helpful, and in some cases absolutely necessary, to render as accurate a diagnosis as possible in each case. 1. Chen CZ, Lin CC, Lee CH, et al. Small airways obstruction syndrome in clinical practice. Respirology 2009;14: Vilchez RA, Dauber J, Kusne S. Infectious etiology of bronchiolitis obliterans: the respiratory viruses connection myth or reality? Am J Transplant 2003; 3: Izumi T, Kitaichi M, Nishimura K, et al. Bronchiolitis obliterans organizing pneumonia. Clinical features and differential diagnosis. Chest 1992;102: Valentine VG, Gupta MR, Walker JE Jr, et al. Effect of etiology and timing of respiratory tract infections on development of bronchiolitis obliterans syndrome. J Heart Lung Transplant 2009;28: Muller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology 1995;196: Hwang JH, Kim TS, Lee KS, et al. Bronchiolitis in adults: pathology and imaging. J Comput Assist Tomogr 1997;21: Hansell DM, Rubens MB, Padley SP, et al. Obliterative bronchiolitis: individual CT signs of small airways disease and functional correlation. Radiology 1997; 203: Nakanishi M, Demura Y, Mizuno S, et al. Changes in HRCT findings in patients with respiratory bronchiolitis-associated interstitial lung disease after smoking cessation. Eur Respir J 2007;29: Visscher DW, Myers JL. Bronchiolitis: the pathologist s perspective. Proc Am Thorac Soc 2006;3: Stern EJ, Frank MS. Small-airway diseases of the lungs: findings at expiratory CT. AJR Am J Roentgenol 1994;163: Myers JL, Colby TV. Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med 1993;14: Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998;109: Yousem SA. Small airways disease. Pathol Annu 1991;26(Pt 2): Wang CW, Muhm JR, Colby TV, et al. Small airway lesions. In: Cagle PT, Allen TC, Beasley MB, editors. Diagnostic pulmonary pathology. 2nd edition. New York: Informa; p Lynch DA. Imaging of small airways disease and chronic obstructive pulmonary disease. Clin Chest Med 2008;29:165 79, vii. 16. Sturton G, Persson C, Barnes PJ. Small airways: an important but neglected target in the treatment of obstructive airway diseases. Trends Pharmacol Sci 2008;29: Vikgren J, Bake B, Ekberg-Jansson A, et al. Value of air trapping in detection of small airways disease in smokers. Acta Radiol 2003;44: Katzenstein ALA. Miscellaneous II. Nonspecific Inflammatory and destructive diseases. In: Katzenstein ALA, editor. Katzenstein and Askin s surgical pathology of non-neoplastic lung disease. 4th edition. Philadelphia: Elsevier; p Stanescu D. Small airways obstruction syndrome. Chest 1999;116: Ryu JH, Colby TV, Hartman TE, et al. Smokingrelated interstitial lung diseases: a concise review. Eur Respir J 2001;17: Cagle PT. Bronchiolar and peribronchiolar inflammation, fibrosis and metaplasia. In: Cagle PT, Allen TC, Barrios R, et al, editors. Color atlas and text of pulmonary pathology. Philadelphia: Lippincott, Williams & Wilkins; p Kerr KM, Fraire AE. Atypical adenomatous hyperplasia. In: Cagle PT, Allen TC, Barrios R, et al, editors. Color atlas and text of pulmonary pathology. 2nd edition. Philadelphia: Lippincott, Williams & Wilkins; p Bush A, Thomson AH. Acute bronchiolitis. BMJ 2007;335: Panitch HB. Respiratory syncytial virus bronchiolitis: supportive care and therapies designed to overcome airway obstruction. Pediatr Infect Dis J 2003; 22:S83 7 [discussion: S87 8]. 25. Everard ML. Acute bronchiolitis and croup. Pediatr Clin North Am 2009;56:

15 Small Airways Disease Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med 2001;344: McNamara PS, Smyth RL. The pathogenesis of respiratory syncytial virus disease in childhood. Br Med Bull 2002;61: Stempel HE, Martin ET, Kuypers J, et al. Multiple viral respiratory pathogens in children with bronchiolitis. Acta Paediatr 2009;98: Fjaerli HO, Farstad T, Rod G, et al. Acute bronchiolitis in infancy as risk factor for wheezing and reduced pulmonary function by seven years in Akershus County, Norway. BMC Pediatr 2005;5: Schuh S, Lalani A, Allen U, et al. Evaluation of the utility of radiography in acute bronchiolitis. J Pediatr 2007;150: Barben J, Kuehni CE, Trachsel D, et al. Management of acute bronchiolitis: can evidence based guidelines alter clinical practice? Thorax 2008;63: Andersen P. Pathogenesis of lower respiratory tract infections due to Chlamydia, Mycoplasma, Legionella and viruses. Thorax 1998;53: Joseph L, Goldberg S, Picard E. A randomized trial of home oxygen therapy from the emergency department for acute bronchiolitis. Pediatrics 2006; 118: [author reply: ]. 34. Unger S, Cunningham S. Effect of oxygen supplementation on length of stay for infants hospitalized with acute viral bronchiolitis. Pediatrics 2008;121: Amirav I, Luder AS, Kruger N, et al. A double-blind, placebo-controlled, randomized trial of montelukast for acute bronchiolitis. Pediatrics 2008;122: e Ryu JH. Classification and approach to bronchiolar diseases. Curr Opin Pulm Med 2006;12: Smith J, Salinas R. Do systemic corticosteroids improve acute outcomes in infants with RSV bronchiolitis? J Okla State Med Assoc 2008;101: Wright JL, Cagle P, Churg A, et al. Diseases of the small airways. Am Rev Respir Dis 1992;146: King TE Jr. Overview of bronchiolitis. Clin Chest Med 1993;14: Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med 2003;168: Allen TC, Cagle PT. Follicular bronchiolitis. In: Cagle PT, Allen TC, Barrios R, et al, editors. Color text and atlas of pulmonary pathology. 2nd edition. Philadelphia: Lippiincott, Williams & Wilkins; p Exley CM, Suvarna SK, Matthews S. Follicular bronchiolitis as a presentation of HIV. Clin Radiol 2006; 61: Aerni MR, Vassallo R, Myers JL, et al. Follicular bronchiolitis in surgical lung biopsies: clinical implications in 12 patients. Respir Med 2008;102: Theron S, Goussard P. Follicular bronchiolitis in an HIV-positive child. Pediatr Radiol 2008;38: Howling SJ, Hansell DM, Wells AU, et al. Follicular bronchiolitis: thin-section CT and histologic findings. Radiology 1999;212: Vos R, Vanaudenaerde BM, De Vleeschauwer SI, et al. Follicular bronchiolitis: a rare cause of bronchiolitis obliterans syndrome after Lung transplantation: a case report. Am J Transplant 2009;9(3): Hansell DM. HRCT of obliterative bronchiolitis and other small airways diseases. Semin Roentgenol 2001;36: Cagle PT, Truong LD, Holland VA, et al. Lung biopsy evaluation of acute rejection versus opportunistic infection in lung transplant patients. Transplantation 1989;47: Kraft M, Mortenson RL, Colby TV, et al. Cryptogenic constrictive bronchiolitis. A clinicopathologic study. Am Rev Respir Dis 1993;148: Cagle PT, Brown RW, Frost A, et al. Diagnosis of chronic lung transplant rejection by transbronchial biopsy. Mod Pathol 1995;8: Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 1996;15: Maldonado F, Pittelkow MR, Ryu JH. Constrictive bronchiolitis associated with paraneoplastic autoimmune multi-organ syndrome. Respirology 2009;14: Verleden GM. Chronic allograft rejection (obliterative bronchiolitis). Semin Respir Crit Care Med 2001;22: Galbraith D, Weill D. Popcorn lung and bronchiolitis obliterans: a critical appraisal. Int Arch Occup Environ Health 2009;82: Cagle PT. Organizing pneumonia (bronchiolitis obliterans organizing pneumonia). In: Cagle PT, Allen TC, Barrios R, et al, editors. Color text and atlas of pulmonary pathology. 2nd edition. Philadelphia: Lippincott, Williams & Wilkins; p Cagle PT, Allen TC. Organizing pneumonia. In: Cagle PT, Allen TC, Kerr KM, editors. Transbronchial and endobronchial biopsies. Philadelphia: Lippincott Williams & Wilkins; p Cordier JF. Organizing pneumonia: cryptogenic and disease associated. Semin Respir Crit Care Med 2003;24: Ko KH, Hsu HH, Kao WY, et al. An unusual radiologic pattern of cryptogenic organizing pneumonia: diffuse pulmonary nodules in a leukemia patient. Korean J Radiol 2009;10: Okada F, Ando Y, Honda K, et al. Comparison of pulmonary CT findings and serum KL-6 levels in patients with cryptogenic organizing pneumonia. Br J Radiol 2009;82: Mori S, Cho I, Koga Y, et al. A simultaneous onset of organizing pneumonia and rheumatoid arthritis,

16 186 Allen along with a review of the literature. Mod Rheumatol 2008;18: Epler GR. Drug-induced bronchiolitis obliterans organizing pneumonia. Clin Chest Med 2004;25: Uner AH, Rozum-Slota B, Katzenstein AL. Bronchiolitis obliterans-organizing pneumonia (BOOP)-like variant of Wegener s granulomatosis. A clinicopathologic study of 16 cases. Am J Surg Pathol 1996;20: Popper HH. Bronchiolitis obliterans. Organizing pneumonia. Verh Dtsch Ges Pathol 2002;86: Oymak FS, Demirbas HM, Mavili E, et al. Bronchiolitis obliterans organizing pneumonia. Clinical and roentgenological features in 26 cases. Respiration 2005;72: Woo OH, Yong HS, Oh YW, et al. Respiratory bronchiolitis-associated interstitial lung disease in a nonsmoker: radiologic and pathologic findings. AJR Am J Roentgenol 2007;188:W Allen TC, Cagle PT. Langerhans cell histiocytosis. In: Cagle PT, Allen TC, Kerr KM, editors. Transbronchial and endobronchial biopsies. Philadelphia: Lippincott, Williams & Wilkins; p Allen TC, Ostrowski ML, Kerr KM. Pulmonary Langerhans-cell histiocytosis. In: Cagle PT, Allen TC, Barrios R, et al, editors. Color text and atlas of pulmonary pathology. 2nd edition. Philadelphia: Lippincott, Williams & Wilkins; p Cagle PT. Respiratory bronchiolitis. In: Cagle PT, Allen TC, Barrios R, et al, editors. Color text and atlas of pulmonary pathology. 2nd edition. Philadelphia: Lippincott, Williams & Wilkins; p Cagle PT. Respiratory bronchiolitis-associated interstitial lung disease/desquamative interstitial pneumonia. In: Cagle PT, Allen TC, Barrios R, et al, editors. Color text and atlas of pulmonary pathology. 2nd edition. Philadelphia: Lippincott, Williams & Wilkins; p Allen TC. Pulmonary Langerhans cell histiocytosis and other pulmonary histiocytic diseases: a review. Arch Pathol Lab Med 2008;132: Park JS, Brown KK, Tuder RM, et al. Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation. J Comput Assist Tomogr 2002;26: Heyneman LE, Ward S, Lynch DA, et al. Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process? AJR Am J Roentgenol 1999;173: Cagle PT. Diffuse panbronchiolitis. In: Cagle PT, Allen TC, Barrios R, et al, editors. Color text and atlas of pulmonary pathology. 2nd edition. Philadelphia: Lippincott, Williams & Wilkins; p Adams NP, Congelton J. Diffuse panbronchiolitis. Eur Respir J 2008;32: McGrath EE, McLaughlin AM, Fitzgerald MX. Diffuse panbronchiolitis: east meets west. Eur Respir J 2007;29: Poletti V, Casoni G, Chilosi M, et al. Diffuse panbronchiolitis. Eur Respir J 2006;28: Kudoh S, Keicho N. Diffuse panbronchiolitis. Semin Respir Crit Care Med 2003;24: Keicho N, Ohashi J, Tamiya G, et al. Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis. Am J Hum Genet 2000;66: She J, Sun Q, Fan L, et al. Association of HLA genes with diffuse panbronchiolitis in Chinese patients. Respir Physiolo Neurobiol 2007;157: Homma S, Sakamoto S, Kawabata M, et al. Comparative clinicopathology of obliterative bronchiolitis and diffuse panbronchiolitis. Respiration 2006;73: Sugiyama Y. Diffuse panbronchiolitis. Clin Chest Med 1993;14: Poletti V, Chilosi M, Trisolini R, et al. Idiopathic bronchiolitis mimicking diffuse panbronchiolitis. Sarcoidosis Vasc Diffuse Lung Dis 2003;20: Kadota J, Mukae H, Mizunoe S, et al. Long-term macrolide antibiotic therapy in the treatment of chronic small airway disease clinically mimicking diffuse panbronchiolitis. Intern Med 2005;44: Churg A, Myers J, Suarez T, et al. Airway-centered interstitial fibrosis: a distinct form of aggressive diffuse lung disease. Am J Surg Pathol 2004;28: Yousem SA, Dacic S. Idiopathic bronchiolocentric interstitial pneumonia. Mod Pathol 2002;15: Fukuoka J, Franks TJ, Colby TV, et al. Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases. Am J Surg Pathol 2005;29: