Small Airways Disease

SMALL AIRWAYSDISEASE
Timothy Craig Allen, MD, JD
KEYWORDS

� Constrictive bronchiolitis � Hypersensitivity pneumonitis � Bronchiolitis� Organizing pneumonia with intraluminal polyps � Idiopathic bronchiolocentric pneumonia

Key Features
ABSTRACT
SMALL AIRWAYS DISEASES

1. Small airways diseases are a group ofdiseases that by definition involve bronchi-oles—acartilagenous airways that are 2 mmor less in diameter, including membranousbronchioles, respiratory bronchioles, andalveolar ducts.

2. Small airways diseases may be classified asdiseases that involve small airways primarily,or as lesions involving small airwaysprimarily or secondarily.

3. The different specialties evaluate smallairways diseases differently, with cliniciansgenerally evaluating the terminal airwaychanges causing airflow obstruction, radiol-ogists examining them in the context ofdirect signs and indirect signs identified onhigh-resolution CT scans, and pathologistsevaluating them based almost entirely onthe histologic changes within thebronchioles.

4. Small airways disease patients often exhibitstraightforward clinical and radiographicchanges, and do not require biopsy.

5. Transbronchial biopsy is more commonlyperformed than wedge biopsy, and is lessinvasive; however, it generally yields limitedinformation and is of less utility than wedgebiopsy.

6. The histologic features of the small airwaysdiseases may cause considerable confusiondue to overlapping features among thevarious small airways diseases, incompletehistologic assessment due to a limitedbiopsy, and the occurrence of other diseasesprocesses along with a small airways disease. s.

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T he concept of small airways disease variesamong specialties, with clinicians generallyconsidering them in terms of terminal airway

changes causing airflow obstruction, radiologistsconsidering them in the context of direct signsand indirect signs identified on high-resolutioncomputed tomography scans, and pathologistsevaluating them based entirely or almost entirelyon the histologic changes present in the bronchi-oles, with or without associated changes involvingbronchi and alveoli. Small airways diseases arebest defined pathologically as a diverse group ofconditions that primarily involve bronchioles andacartilagenous airways 2 mm or less in diameter,which include membranous bronchioles, respira-tory bronchioles, and alveolar ducts. Small airwayscan be involved with disease primarily or second-arily. The histologic features of small airwaysdiseases may be confusing because they overlap.There may be incomplete assessment of the histo-logic process with limited biopsy. Other diseaseprocesses may occur along with a small airwaysdisease, and may obscure or confound its histo-logic features. This article focuses on the histo-logic changes diagnostic of a variety of primaryand secondary small airways diseases. Becausethe histologic features involve bronchioles, grossfindings are often minimal and/or nonspecific.The article provides a nonexhaustive examinationof conditions and diseases involving the smallairways, focusing on the microscopic features,with emphasis on the limitations of histologic diag-nosis and differential diagnosis.

Although small airways diseases occur relativelyfrequently, there is no universal agreement on theirclassification, and pathologists generally havea poor understanding of them. Indeed, the

Department of Pathology, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler,TX 75708, USAE-mail address: [email protected]

Surgical Pathology 3 (2010) 171–186doi:10.1016/j.path.2010.04.0021875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved. su

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Box 2Conditions that may exhibit secondary smallairways involvement

Respiratory bronchiolitis/respiratory bronchio-litis-associated interstitial lung disease (RBILD)

Desquamative interstitial pneumonia (DIP)

Pulmonary Langerhans cell histiocytosis

Sarcoidosis

Wegener granulomatosis

Hypersensitivity pneumonitis

Bronchiectasis

Chronic bronchitis/chronic obstructive pulmo-nary disease (COPD)

Asthma

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concept of ‘‘small airways disease’’ varies amongspecialties, with clinicians generally consideringthem in terms of terminal airway changes causingairflow obstruction, radiologists considering themin the context of direct signs and indirect signsidentified on high-resolution computed tomog-raphy (CT) scans, and pathologists evaluatingthem based entirely or almost entirely on the histo-logic changes present in the bronchioles, with orwithout associated changes involving bronchiand alveoli.1–14 Small airways diseases are bestdefined pathologically as a diverse group of condi-tions that primarily involve bronchioles and acarti-lagenous airways 2 mm or less in diameter, whichinclude membranous bronchioles, respiratorybronchioles, and alveolar ducts.15–17 Smallairways can be involved with disease primarily orsecondarily. Many patients have straightforwardclinical and radiographic changes and do notrequire biopsy. When performed, transbronchialbiopsy is more common and less invasive thanwedge biopsy, but typically yields limited informa-tion and results in a relatively less utile descriptivediagnosis than does wedge biopsy. Various classi-fication systems for small airways diseases havebeen proposed.11,18 Some are limited to diseasesarising within the small airways, which may thenspread to proximal bronchioles or distal alveoli.Others include diseases that may arise elsewhereand go on to involve small airways secondarily.Box 1 is a nonexhaustive list of conditions thatare primary to the small airways. Box 2 is a list ofsome of the conditions for which there may besecondary involvement of the small airways. Thehistologic features of small airways diseases maybe confusing because they overlap. Also, theremay be incomplete assessment of the histologic

Box 1Conditions 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 hyper-plasia (DIPNECH)

Mineral dust small airways diseases

process with limited biopsy. Other diseaseprocesses may occur along with a small airwaysdisease, and may obscure or confound its histo-logic features. This article focuses on the histo-logic changes diagnostic of a variety of primaryand secondary small airways diseases. Becausethe histologic features involve bronchioles, grossfindings are often minimal and/or nonspecific.The article provides a nonexhaustive examinationof conditions and diseases involving the smallairways, focusing on the microscopic features,with emphasis on the limitations of histologic diag-nosis and differential diagnosis.

PERIBRONCHIOLAR METAPLASIA

OVERVIEW

Along alveolar septal surfaces adjacent to bronchi-oles, bronchiolar-type epithelium may proliferate.This proliferation has also been termed bronchio-larization, and has also been called Lambertosis,as it was once believed that bronchiolar epitheliumtraversed the canals of Lambert to involve alveolarsepta.19,20 This pathologic process may arise inassociation with various small airways diseases,including bronchiectasis, constrictive bronchioli-tis, and hypersensitivity pneumonitis, among otherdiseases.20,21 The process most likely representsa postinflammatory change. Peribronchiolar meta-plasia is frequently identified surrounding the scar-ring of constrictive bronchiolitis.21

MICROSCOPIC FEATURES

Surrounding bronchioles, which may contain vari-able degrees of inflammation and fibrosis, showmetaplastic bronchiolar epithelium lining variablyfibrotic first-tier alveolar septa (Figs. 1 and 2).

Fig.1. Peribronchiolarmeta-plasia showing mildlythickened peribronchio-lar alveolar septa linedby bronchiolar meta-plastic epithelium (H &E, original magnification�10).

Small Airways Disease 173

Goblet cell metaplasia and squamous metaplasiamay occasionally occur.21

DIFFERENTIAL DIAGNOSIS

Diagnosis may occasionally be less than straight-forward, particularly with limited biopsy tissue.

Fig.2. Higherpower imageof peribronchiolar meta-plasia showing lowcuboidal bronchiolar meta-plastic epithelial cells liningthickened first-tier peri-bronchiolar alveolar septa(H & E, original magnifica-tion�20).

Peribronchiolar metaplasia may occasionallymimic atypical adenomatous hyperplasia;however, the bland and uniform cytologic featuresof peribronchiolar metaplastic cells lining alveolarsepta are in contrast to the cells lining atypicaladenomatous hyperplasia, which are character-ized by an interrupted lining of variably sized

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cuboidal cells, occasional apical snouts, andoccasional nuclear inclusions and double nuclei.22

ACUTE BRONCHIOLITIS

OVERVIEW

The primary cause of respiratory disease in thefirst year of life, acute bronchiolitis is generallya condition of infants and very young children.Acute bronchiolitis is predominantly caused byrespiratory syncytial virus infection.23–28 Infantswith acute bronchiolitis clinically exhibit tachypneaand wheezing, and may exhibit chest retractionand nasal flaring if symptoms worsen. In obviouscases of disease radiology may be unnecessary,but where radiology is performed patients oftenshow lung hyperinflation, and may show smallcentrilobular nodules and ground-glass opaci-ties.25,29–31 Adults may also acquire acute bron-chiolitis, generally caused by viral or bacterialinfections, or acute exposure to fumes and toxins.Biopsy from patients with acute bronchopneu-monia and Wegener granulomatosis may occa-sionally show histologic features of acutepneumonia.14


As most cases are diagnostically straightforward,biopsy is rarely performed. In cases that are notstraightforward and biopsy may be performed,acute bronchiolitis is characterized histologicallyby bronchioles filled with purulent exudative andnecrotic material and sloughed bronchiolarmucosa, with a neutrophilic infiltrate involvingassociated bronchiolar mucosa and bronchiolarwall.


Although the majority of infant cases of acutebronchiolitis are caused by respiratory syncytialvirus, infection by other viruses that may causeacute bronchiolitis, including influenza and parain-fluenza, adenovirus, and measles, must beconsidered. Moreover, infections with fungi,mycoplasma, and Bordetella pertussis may causeacute bronchiolitis.25,28

DIAGNOSIS

Diagnosis of acute bronchiolitis, occurring ininfants and young children, is typically renderedclinically and radiologically. In less straightforwardcases, biopsy may be of benefit. Although themajority of cases are caused by respiratory

syncytial virus, other viral and nonviral originsmust be considered.

PROGNOSIS

Prognosis is excellent in infants and young chil-dren with symptomatic treatment. Oxygen is ofbenefit in patients with significant hypoxia. Drugtreatments have not shown significant therapeuticbenefit; however, corticosteroids have shownsome benefit in patients with croup.32–37

ACUTE AND CHRONIC BRONCHIOLITIS

OVERVIEW

Generally a condition found in adults, acute andchronic bronchiolitis is frequently caused by infec-tions, including viral infections such as respiratorysyncytial virus; however, noninfectious cases,including idiopathic cases, occur. Patients usuallypresent clinically with mild respiratory symptomssuch as cough and dyspnea, and show anobstructive pattern with pulmonary functiontesting.11,12,36,38–40


The histologic findings with acute and chronicbronchiolitis include bronchiolar filling with mucusand purulent exudative and necrotic material,sloughed bronchiolar mucosa, and acute andchronic inflammatory cells, as well as an acuteand chronic inflammatory cell infiltrate involvingthe bronchiolar mucosa and wall, extending intosurrounding peribronchiolar tissue. The inflamma-tory cell infiltrate is predominantly composed ofneutrophils, plasma cells, and lymphocytes.


Acute and chronic bronchiolitis is often caused byviral infection, including respiratory syncytial virus;however, there are several potential causes(Box 3).11,12,36,38,39

DIAGNOSIS

Diagnosis is often straightforward and is madeclinically and/or radiologically. Biopsy is generallynot required. In cases with a more confusing orcomplex clinical course or radiologic pattern,biopsy may assist in limiting the differential diag-nosis or rendering a definitive diagnosis.

PROGNOSIS

Patients typically have a good prognosis withrecovery after symptomatic treatment. Cases of

Box 3Causes of acute and chronic bronchiolitis

Infections (bacterial, viral, mycobacterial)

Aspiration pneumonia

Asthma


Fume/toxin inhalation

Collagen vascular diseases

Post lung transplantation


Idiopathic


idiopathic acute and chronic bronchiolitis maybenefit from antibiotic and immunosuppressivetherapy.36

CHRONIC BRONCHIOLITIS

OVERVIEW

The term ‘‘chronic bronchiolitis’’ describes a char-acteristic histologic pattern that is a feature ofa variety of diseases. Infections, including viralinfections, may frequently cause the histologicchanges of chronic bronchiolitis; however, there

Fig. 3. Chronic bronchio-litis involving a respira-tory bronchiole, witha predominantly lympho-cytic infiltrate within thebronchiolar wall (H & E,original magnification�40).

are many other potential origins, including idio-pathic ones.11,12,14,36,40


Chronic bronchiolitis is characterized histologi-cally by bronchioles that contain an infiltrate ofchronic inflammatory cells within bronchiolarmucosa and walls. The inflammatory cell infiltrateoften extends into surrounding peribronchiolartissue. Germinal centers may or not be present.The histologic features may overlap with acuteand chronic bronchiolitis (Fig. 3).12,14,36,40


There are many causes for the findings of chronicbronchiolitis on biopsy. Box 4 lists variousdiseases for which chronic bronchiolitis may bea feature. In cases where germinal centers andconstriction of the airway lumen are present, follic-ular bronchiolitis must be considered in the differ-ential diagnosis.

DIAGNOSIS

There are many potential causes for the histologicfeatures of chronic bronchiolitis in a biopsy. Whenthe histologic features of chronic bronchiolitis areidentified on biopsy, clinical and radiologic corre-lation may assist in limiting the differential diag-nosis or rendering a specific diagnosis.

Box 4Causes of chronic bronchiolitis

Infections (bacterial, viral, mycobacterial)

Aspiration pneumonia

Asthma

Graft versus host disease, post transplantation

Collagen vascular disease


COPD

Lymphoproliferative diseases

Pulmonary Langerhans cell histiocytosis

Lung involvement with inflammatory boweldisease

Idiopathic

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PROGNOSIS

Prognosis with chronic bronchiolitis is dependenton the underlying disease process.

FOLLICULAR BRONCHIOLITIS

OVERVIEW

The term ‘‘follicular bronchiolitis’’ denotes hyper-plasia of the bronchus-associated lymphoid tissue

(BALT), a condition caused by altered immunestimulus or immune response of the BALT. Follic-ular bronchiolitis occurs in a variety of immune-associated diseases that involve the pulmonarysystem, including collagen vascular disease,especially rheumatoid arthritis and Sjogrensyndrome. Follicular bronchiolitis may also befound in patients with congenital immunodefi-ciency disorders, immune deficiency states suchas AIDS, bronchiectasis and middle lobesyndrome, and hypersensitivity reactions. Idio-pathic cases occur. Radiologic studies may exhibitperibronchiolar and peribronchial nodules, with orwithout associated patchy ground-glass opacifi-cation.36,41–45


Follicular bronchiolitis is characterized histologi-cally by peribronchiolar hyperplasia of lymphoidtissue, with reactive germinal centers, whichextends to a varying degree into surrounding peri-bronchiolar tissue (Fig. 4).36,41


Follicular bronchiolitis must be distinguished fromprimary or secondary pulmonary lymphoma. Clin-ical and radiologic correlation, as well as immuno-histochemical studies, is of benefit if making thecorrect diagnosis. Reactive changes within bron-chioles may be seen adjacent to other disease

Fig. 4. Low-power imageof follicular bronchiolitisshowing peribronchiolarlymphoid hyperplasiawith a centrally placedreactive lymphoid follicle(H & E, original magnifi-cation �4).


processes, including infections and tumors bothbenign and malignant. The diagnosis of follicularbronchiolitis must be rendered with caution, andadditional biopsy, including open biopsy, may berequired in some cases to make an accuratediagnosis.43,46

DIAGNOSIS

In patients for whom clinical and radiologic corre-lation support the diagnosis of follicular bronchio-litis, and for whom histology shows diagnosticfeatures, the diagnosis is relatively straightfor-ward. In less clear cases, immunostains will assistin making an accurate diagnosis.

PROGNOSIS

Prognosis is generally good in patients with follic-ular bronchiolitis; however, prognosis and therapydepend on the underlying causative disease.Corticosteroids and bronchodilators have showntherapeutic benefit in patients with idiopathicfollicular bronchiolitis.43,46

CONSTRICTIVE BRONCHIOLITIS

OVERVIEW

An obstructive airway disease that is also termed‘‘bronchiolitis obliterans’’ and ‘‘obliterative

Fig. 5. Constrictive bron-chiolitis showing concen-tric narrowing of thebronchiolar lumen (H & E,original magnification�20).

bronchiolitis,’’ constrictive bronchiolitis may beassociated with a variety of diseases, including,importantly, chronic lung allograft rejection.Among never-smoking middle-aged and olderwomen, constrictive bronchiolitis may occur idio-pathically.47–54


Constrictive bronchiolitis histologically featuresconcentric narrowing of the bronchiolar lumen,ultimately resulting in complete obliteration of thelumen with only a remaining scar. The histologicfeatures may be subtle, especially with earlydisease. Chronic inflammation within the bronchi-olar wall is a variable feature. Patients with idio-pathic disease often exhibit little bronchiolar orperibronchiolar chronic inflammation. Withinmembranous bronchiolar walls, smooth musclehyperplasia and adventitial fibrosis may occur(Figs. 5 and 6).13,48,50,51


There are several causes for the histologic findingof constrictive bronchiolitis on biopsy. Clinical andradiologic correlation is often helpful in deter-mining the underlying etiology of constrictive bron-chiolitis (Box 5). Plugs of granulation tissue,termed intraluminal polyps, are a characteristic of

Fig. 6. Constrictive bron-chiolitis with almost com-plete occlusion of thebronchiolar lumen. Onlya thin slitlike mucosa-linedcentral space remains(H & E, original magnifica-tion �10).

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organizing pneumonia with intraluminal polyps,but are not found with constrictive bronchiolitis.

DIAGNOSIS

Diagnosis of well-developed or later-stageconstrictive bronchiolitis is often straightforward.Clinical and radiologic correlation is especiallybeneficial in cases where the histologic findingsare more subtle.

PROGNOSIS

Prognosis in patients with the histologic features ofconstrictive bronchiolitis is based on the

Box 5Causes of constrictive bronchiolitis

Post lung transplantation and bone marrowtransplantation

Drug reactions

Fume/toxin exposure

Healed infection (particularly adenovirus)

Collagen vascular diseases (particularly rheu-matoid arthritis)


Complicating or advanced component of cysticfibrosis, bronchiectasis, asthma, or chronicbronchitis

Idiopathic

underlying etiology. Among never-smoking olderwomen with constrictive bronchiolitis, there arevariable disease courses from slowly progressivedisease to rapidly progressive deterioratingdisease.49

ORGANIZING PNEUMONIA WITH

INTRALUMINAL POLYPS

OVERVIEW

Known for many years as bronchiolitis obliteransorganizing pneumonia (BOOP)/organizing pneu-monia pattern, organizing pneumonia with intralu-minal polyps is a histologic pattern that has beenidentified in numerous lung diseases.55–63


Organizing pneumonia with intraluminal polyps ischaracterized histologically with plugs of granu-lation tissue that fill alveoli, alveolar ducts, andbronchiolar lumens. The plugs of granulationtissue may become rounded and nodular, andthese are termed Masson bodies. The plugs ofgranulation tissue are made up of edematousor myxoid stroma within which lie variablenumbers of fibroblasts and lymphocytes. Foamymacrophages may accompany the plugs ofgranulation tissue if bronchiolar obstruction ispresent (Figs. 7 and 8).62,63

Fig. 7. Organizing pneu-monia with intraluminalpolyps, with polypoidgranulation tissue lyingwithin airspaces centrally,adjacent to necrotizinggranulomas (H & E, orig-inal magnification �20).



The histologic pattern of organizing pneumoniawith intraluminal polyps may be found in a widevariety of pulmonary diseases (Box 6). Clinicaland radiologic correlation is frequently necessaryto determine specific etiology, unless within the

Fig. 8. Higher powerimage of organizing pneu-monia with intraluminalpolyps showing a plug ofgranulationtissue,contain-ingfibroblastsandlympho-cytes, within a bronchiolarlumen (H & E, originalmagnification�40).

biopsy there are histologic features indicating anetiologic factor such as viral inclusions suggestiveof viral infectious origin. Idiopathic disease istermed cryptogenic organizing pneumonia (COP),previously termed idiopathic BOOP. COP gener-ally occurs in middle-aged to older women who

Box 6Causes of organizing pneumonia withintraluminal polyps

Resolving diffuse alveolar damage, aspirationpneumonia, or infections

Acute pulmonary allograft rejection

Adjacent to necrotic tumor, abscess, or infarct


Fume/toxin exposure

Drug reactions

Post bone marrow or other nonpulmonaryorgan transplantation

Post radiation or chemotherapy


Collagen vascular diseases


Underlying hematologic disorder

Idiopathic

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present with dyspnea, cough, and flu-typesymptoms.

DIAGNOSIS

Diagnosis of the histologic features of organizingpneumonia with intraluminal polyps is generallystraightforward and is based on the finding ofpolypoid granulation tissue within bronchiolarlumens, as well as within alveolar ducts and alve-olar spaces.

PROGNOSIS

Prognosis is dependent on the type and severity ofthe underlying disease process that produces onbiopsy the histologic features of organizing pneu-monia with intraluminal polyps. The majority ofpatients with COP show improvement with steroidtherapy and have a good prognosis.57,64

SMOKING-RELATED BRONCHIOLAR DISEASES

OVERVIEW

Smoking-related bronchiolar diseases includemembranous bronchiolitis, respiratory bronchioli-tis, and respiratory bronchiolitis–associated inter-stitial lung disease (RBILD). Membranousbronchiolitis is a smoking-related bronchiolardisease that involves membranous bronchioles,and respiratory bronchiolitis involves respiratory

bronchioles. Membranous bronchiolitis and respi-ratory bronchiolitis are typically asymptomatic,often identified as an incidental finding when thepatient undergoes lung biopsy for another condi-tion.65–70 RBILD is a more severe disease ona continuum with respiratory bronchiolitis. Patientswith RBILD typically exhibit mild cough and dysp-nea, and also have variable radiologic changesincluding ground-glass opacities, interstitial thick-ening with an upper lobe predominance, andcentrilobular nodules.71,72


The histologic features of membranous bronchioli-tis and respiratory bronchiolitis include a predomi-nantly lymphocytic and histiocytic bronchiolar andperibronchiolar infiltrate within membranous bron-chioles and respiratory bronchioles, respectively,of smokers. Macrophages with finely granularbrown pigment are variably present withinsurrounding alveolar spaces and within the bron-chiolar wall. Bronchiolar metaplasia may bepresent; however, there is only minimal to mildperibronchiolar fibrosis, which may extend intofirst-tier alveolar septa (Figs. 9 and 10). Smoothmuscle hyperplasia and adventitial fibrosis mayalso be present. Emphysema, as well as othertobacco smoking–related histologic changessuch as chronic bronchitis and desquamativeinterstitial pneumonia, may be present in thebiopsy tissue.65,68 Although RBILD is histologicallysimilar to respiratory bronchiolitis and the diseasesexist along a continuum, RBILD has generally morepronounced bronchiolar and peribronchiolar changes,such as more numerous pigmented macro-phages within surrounding alveolar spaces and withinthe bronchiolar wall (Fig. 11). More severe RBILDitself merges with the histologic features of desqua-mative interstitial pneumonia.65,69


Differential diagnosis includes chronic bronchioli-tis and hypersensitivity pneumonitis, amongothers. Chronic bronchiolitis generally does nothave obvious peribronchiolar infiltrates of finelygranular pigmented macrophages, as are foundin patients with membranous bronchiolitis andrespiratory bronchiolitis, who are smokers.Under-sampled hypersensitivity pneumonitismay show similar histologic features to respira-tory bronchiolitis and RBILD; however, againpigmented macrophages are not a characteristicof the disease. Clinical and radiologic correlationis beneficial in differentiating between theselesions. The histologic features of RBILD and

Fig. 9. Respiratory bron-chiolitis showing a mildpredominantly lympho-cytic bronchiolar infil-trate. Macrophages withfinely granular brownpigment are identifiedwithin surrounding alve-olar spaces (H & E, orig-inal magnification �20).


desquamative interstitial pneumonia are similar,and the diagnosis generally depends on theseverity of disease. Here also, clinical and radio-logic correlation is helpful in making an accuratediagnosis.

Fig. 10. RBILD showingpigmented macrophagesand lymphocytes within amildly thickened bronchi-olar wall, and pigmentedmacrophages within sur-rounding peribronchiolarairspaces (H & E, originalmagnification �20).

DIAGNOSIS

The diagnoses of membranous bronchiolitis andrespiratory bronchiolitis are often made inciden-tally. The diagnosis of respiratory bronchiolitisproceeds along a continuum of increasing

Fig. 11. RBILD with abun-dant pigmented macro-phages within alveolarspaces which, while notdiagnostic, is histologi-cally suggestive of des-quamative interstitialpneumonia (H & E, orig-inal magnification �10).

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histologic severity until the histologic changesmeet the criteria for the diagnosis of RBILD.65

PROGNOSIS

Patients with respiratory bronchiolitis typicallyhave a very good prognosis with smoking cessa-tion alone. Corticosteroid therapy is of no orlimited benefit. Patients with membranous bron-chiolitis generally exhibit a good prognosis, as dothe majority of patients with RBILD. Smokingcessation is usually the only therapy necessaryfor these patients. Patients with more severeRBILD, bordering on desquamative interstitialpneumonia, may exhibit a worse prognosis, andcorticosteroid therapy may be of benefit in thesepatients.

DIFFUSE PANBRONCHIOLITIS

OVERVIEW

Diffuse panbronchiolitis is an uncommon diseasein the United States, and occurs predominantly inJapan. Diffuse panbronchiolitis is being identifiedincreasingly in other Asian countries. There isthought to be a genetic predisposition to diffusepanbronchiolitis, and associations with HLA-Bw54 and HLA-A11 have been shown. Diffusepanbronchiolitis is an idiopathic small airwaysdisease characterized by bilateral progressive,

obstructive, suppurative lesions. Patients averageapproximately 40 years of age and are predomi-nantly men. Presenting symptoms include cough,dyspnea, and chronic sinusitis. No associationhas been shown between diffuse panbronchiolitisand smoking or fume/toxin exposures. Patientsradiographically have small centrilobular nodulesin a bilateral distribution. With wedge biopsy,yellow nodules approximately 1 to 3 mm insize may be identified in a bronchiolocentricdistribution.73–80


Diffuse panbronchiolitis is characterized histolog-ically by an infiltrate of foamy macrophages,lymphocytes, and plasma cells in a transmuralbronchiolar distribution, predominantly involvingrespiratory bronchioles. Occasional neutrophilsmay also be identified. While foamy macro-phages and other inflammatory cells may beidentified within peribronchiolar tissue,surrounding alveoli are relatively uninvolved inthe process. Patients often have infections;associated organizing pneumonia and acutepneumonia may be present and may causea more complex histologic pattern. In advancingdisease, terminal bronchioles may becomeectatic.73,76,80,81



The involvement of predominantly respiratorybronchioles by diffuse panbronchiolitis is a distinc-tive feature that helps distinguish it from otherdifferential diagnoses, such as constrictive bron-chiolitis, that generally involve membranous bron-chioles. Bronchiolitis due to rheumatoid arthritisand other collagen vascular diseases or due toautoimmune diseases must be considered. Xan-thomatous bronchiolitis may present with a similarhistologic pattern; however, clinical and radiologiccorrelation is helpful in rendering the correctdiagnosis.76,80,82

DIAGNOSIS

Diagnosis of diffuse panbronchiolitis generallyrequires clinical and radiologic correlation.

PROGNOSIS

Without treatment, patients often progress tobronchiectasis, respiratory failure, and ultimately,death. Pseudomonas infection has been relatedto poorer prognosis. Low-dose macrolide antibi-otic therapy may improve prognosis due to itsanti-inflammatory effect.76,80,83

AIRWAY-CENTERED INTERSTITIAL FIBROSIS/

PERIBRONCHIOLAR METAPLASIA AND

FIBROSIS/IDIOPATHIC BRONCHIOLOCENTRIC

INTERSTITIAL PNEUMONIA

OVERVIEW

There are 3 recently described airway-centeredentities that may represent different points ofprogression or similar manifestations of the samedisease or group of diseases: airway-centeredinterstitial fibrosis, idiopathic bronchiolocentricidiopathic pneumonia, and peribronchiolar meta-plasia–related interstitial lung disease.84–86 Churgand colleagues84 described airway-centered inter-stitial fibrosis, arising predominantly in middle-aged women with dyspnea and chronic coughwho exhibit radiologic changes of peribronchiolar,peribronchial, and perivascular fibrosis. Yousemand Dacic85 described idiopathic bronchiolocen-tric interstitial pneumonia in a group of patients,predominantly middle-aged women, with bron-chiolocentric fibrosis. Fukuoka and colleagues86

described peribronchiolar metaplasia–relatedinterstitial lung disease in a group of patientswith peribronchiolar metaplasia who clinicallyexhibited interstitial lung disease.


Churg and colleagues84 characterized airway-centered interstitial fibrosis histologically byinterstitial fibrosis that is bronchiolocentric, withassociated peribronchiolar fibrosis, bronchiolarmetaplasia, hyperplastic bronchiolar smoothmuscle, and minimal to mild interstitial inflamma-tory cell infiltrate. Features of usual interstitialpneumonia, including honeycombing, are notpresent. There is also no increased infiltrate ofalveolar macrophages. Yousem and Dacic85

described idiopathic bronchiolocentric interstitialpneumonia, characterized by centrilobular andbronchiolocentric fibrosis with associated patchyareas of interstitial inflammation, which increasedin comparison to patients with airway-centeredinterstitial fibrosis. Granulomas, suggestive ofhypersensitivity pneumonitis, are not a character-istic feature. Fukuoka and colleagues86 describedperibronchiolar metaplasia–related interstitial lungdisease, characterized by predominantly peribron-chiolar metaplasia, without features of fibrosis orinflammation described by Churg and colleaguesor Yousem and Dacic in their patients.


It is not currently known whether airway-centeredinterstitial fibrosis is a distinct entity or whether itrepresents other disease processes such ashypersensitivity pneumonitis, RBILD, nonspecificinterstitial pneumonia, or usual interstitial pneu-monia.84 It is not known whether idiopathic bron-chiolocentric interstitial pneumonia representsa distinct entity or hypersensitivity pneumonitis,RBILD, or usual interstitial pneumonia.85 Peribron-chiolar metaplasia–related interstitial lung diseasemay represent a variant of airway-centered inter-stitial fibrosis or idiopathic bronchiolocentric inter-stitial pneumonia, or other common interstitial lungdiseases such as hypersensitivity pneumonitis.86

DIAGNOSIS

Diagnosis of these rare and controversial entitiesshould be made with caution. Clinical and radio-logic correlation is essential to make these diag-noses with reasonable certainty.

PROGNOSIS

Patients diagnosed with airway-centered intersti-tial fibrosis generally have shown no improvementwith bronchodilators and corticosteroid therapy,and have a generally poor prognosis, with 40%dead of disease within a 10-year follow-upperiod.84

PitfallsSMALL AIRWAYS DISEASE

! Small biopsies with limited material must beevaluated with caution, as not all criteria forthe diagnosis of a disease or condition maybe present in the limited tissue. Wedge biop-sies are more diagnostically helpful, but areless frequently available as they require anopen lung procedure.

! Associated infections or other conditions maypresent additional histologic patterns thatmay make diagnosis more complex orconfusing; this is especially problematic withthe limited tissue obtained from smallbiopsies.

! The histologic features identified in the smallairways may be diagnostic, such as withdiffuse panbronchiolitis, or merely supportiveof a histologic diagnosis for which there aremultiple potential causes. Clinical and radio-logic correlation may be extremely helpful,and in some cases absolutely necessary, torender as accurate a diagnosis as possible ineach case.

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