Pathologic Aspects of Bronchiolitis Obliterans Organlzfng Pneumonia* 'Ihomas v. Colby, M.D., F.C.C.P.
f"J"'be term "bronchiolitis obliterans organizing pneumonia .I. (BOOP)" is a relatively recent term for a clinicopatho-
logic entity that has been recognized for some time. ' The name derives from a series of cases collected in the 19705 and 1980s by Charles Carrington. These represented examples of idiopathic diffuse (or at least multifocal) interstitial pneumonia clinically that showed histologic features of bronchiolitis obliterans with patchy organizing pneumonia, as well as other features as discussed below. This series was collected and collated by Epler et all and published in the New EnglandjournalofMedicine as "bronchiolitis obliterans organizing pneumonia:' The eponym BOOP derives from hiatologic presence of bronchiolitis obliterans and organizing pneumonia. BOOP is not a new lesion and similar cases have been previously reported under a number of different synonyms (1hble 1)..... Some of the previous synonyms for BOOP have emphasized the presence of bronchiolitis obliterans because of its identification histologically'" and not on the basis of clinical evidence of airflow obstruction. Lange" is credited with the first histologic description of bronchiolitis obliterans in an autopsy study of 2 patients, 1 of whom died of an acute illness in 8 days, and the other who died after 6 months of progressive lung disease. Microscopically, polypoid granulation tissue was found in airways and the terms ''bronchitis and bronchiolitis obliterans" were applied," Subsequent to this report, bronchiolitis obliterans is mentioned as a histologic finding in a number of other studies, notably those ofWmternitz" in 1920 on war gas inhalation and the 1918 influenza pandemic," Blumgart and MacMahon'O in 1929, McAdams" in 1955, and Gosink et aJ3 in 1973. In these studies, the term ''bronchiolitis obliterans" is again used in a histologic sense to refer to a specific histologic finding under the microscope. The terms ''bronchiolitis fibrosa obliterans" and "obliterative bronchiolitis" are considered synonymous with bronchiolitis obliterans in this discussion. The large series by Gosink et al3 used bronchiolitis obliterans for 2 distinct histologic lesions: the classic intraluminal polyps as described by Lange," as well as a spectrum of bronchiolar constriction, narrowing, submucosal fibrosis, or complete obliteration by fibrous tissue (as distinct from intraluminal polyps), which they termed "constrictive bronchiolitis." A considerable amount of confusion has surrounded "BOOP" because of the connotations of the term "bronchilitis obliteranS:' For morphologists, bronchiolitis obliterans refers to the 2 lesions noted by Gosink et al,3 namely -From the Department of Pathology and Laboratory Medicine, Mayo Clinic, l\ochester, Minn. ReprInt t'8qUUtB: Dr. Colby, DloUion of Surgicallbthology, Mayo Clinic, Rochuter; MN 55905 .
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intraluminal polyps of granulation tissue and constrictive bronchiolitis. Clinicians often use the term "bronchiolitis obliterans" to refer to a clinical syndrome of airflow obstruction thought to be due to lesions of the small airways, classically postinfectious or following toxic fume exposure. IS Unfortunately, there is nota one-to-one relationship between what the morphologist sees under the microscope and what the clinician sees as a clinical syndrome. Thus, clinical bronchiolitis obliterans is distinctfrom histologic bronchiolitis obliterans. As it turns out, the histologic form of bronchiolitis obliterans with endobronchiolar polyps is only rarely associated with the clinical evidence of airflow 0bstruction, whereas (the much less common) constrictive bronchiolitis is the lesion that is usually seen in patients who have the clinical syndrome of bronchiolitis obliterans. 13 BOOP has been recognized as an interstitial lung disease clinically rather than an airflow obstructive disease,1."".''''0 and the term ''bronchiolitis obliterans" is used solely in a histologic descriptive sense. Because of the confusion around bronchiolitis obliterans (BO) in the term "BOOP" some have recommended the term "cryptogenic organizing pneumonitis" as a descriptive alternative that avoids the term ''bronchiolitis obliterans" altogether. 13 The concept of organizing pneumonia has been wellknown to autopsy pathologists for decades and its origins may go back as far as Laennec." Pathologists familiar with the features of infectious pneumonias at autopsy have long recognized the pattern of organizing pneumonia as one of the reparative reactions that may be seen following infectious pneumontas.P" Its presence was originally emphasized in bacterial pneumonias, but it has been recognized subsequently in a variety of other infectious, as well as noninfectious, pneumonias. As histologic findings, bronchiolitis obliterans and organizing pneumonia frequently coexist and indeed appear to be part of the same reparative reaction pattern in the lung." In tissue sections with airways cut longitudinally, one can sometimes see an endobronchial polyp of connective tissue extending all the way from the bronchiole to the distal alveolar duct with only focal attachments to walls of the airway. In routine practice, involvement of alveolar ducts is usually most prominent and easily appreciated by pathologists. The presence of bronchiolitis obliterans with organizTable I-PreoiotMlg Vied SfI'IOIIfI"IIfor BOOP Synonym Bronchiolitis obliterans with organizing interstitial pneumonia or organizing diffuse alveolar damage (BIP)! Bronchiolitis obliteransOrganizing pneumonia-like lesion" Cryptogenic organizing pneumonia" Unresolved/chronic pneumonia PathologIc Aspects 01 BOOP (11Iotnes V. Colby)
Table 2-Major Hiatologic &Jturea ojBOOP* Features Patchy bronchiolitis obliterans with organizing pneumonia Interstitial mononuclear cell inliltrate, variable in density Alveolar spacefoam cells Absence of honeycombing or extensive interstitiallibrosis ·From references I, 3, 4, 6, 14-16.
ing pneumonia by itself is quite nonspecific. BOOP is a clinicopathologic syndrome that requires the identification of the histologic pattern of bronchiolitis obliterans and organizing pneumonia in the clinical setting of an idiopathic interstitial pneumonia. 1 In the original report by
Epler et al,' a number of cases that showed this pattern
were excluded when a putative cause or association could be identified, primarily infections and collagen vascular diseases. HISTOLOGIC FEATURES OF
BOOP
The major histologic changes that comprise BooP are summarized in Table 2 and illustrated in Figures 1 through 5. The key histologic finding in BooP is the presence of patchy bronchiolitis obliterans and organizing pneumonia. The "patchiness" may manifest as involvement of 1 lobule adjacent to an uninvolved lobule or as a nodular pattern at scanning power microscopy in which the nodules appear to center on bronchioles. Occasional cases showing this nodular pattern also show a micronodular pattern roentgenographically. The intensity of the interstitial infiltrate varies from inconspicuous to quite dense and generally comprises lymphocytes and/or plasma cells. Cellular infiltration of bronchioles (cellular bronchiolitis), sometimes with some associated peribronchiolar scarring, may be seen in a portion of cases. A few germinal centers may be found . Airspace accumulation offoamy macrophages is probably a manifestation of obstruction at the microscopic level. A nonspecific increase in alveolar macrophages that are not foamy may also be seen, particularly in smokers in whom the macrophages may contain small flecks of debris. An isolated or rare granuloma does not entirely exclude the diagnosis of Boop, but should lead to exclusion of extrinsic allergic a1veolitisand granulomatous infection. A characteristic feature of uninflated biopsy specimens in cases ofBooP is the tendency for the tissue to be atelectatic in the zones of organization. This probably reflects the fact that relatively little permanent scarring (which would lend rigidity) is present. The lung collapses around the intraluminal polyps of connective tissue and can simulate severe interstitial fibrosis. While the intraluminal polyps are connected focally to the interstitium, in bronchioles, alveolar ducts, or both (and from these points derive their cellular
FIGURE 1. Bronchiolitis obliterans organizing pneumonia (BOOP). A, In this well-inHated biopsy specimen, one can see all the pathologic aspects of BOOP. Bronchiolitis obliterans with intraluminal polyps is seen (long arrows), as well as foci of organizing pneumonia (short arrows) with intraluminal organization in alveolar ducts. The lung architecture is maintained and the alveolar septa
are modestly thickened by chronic inHammatory infiltrates. B, There is some loss of bronchiolar epithelium where the intraluminal polyp of connective tissue is attached (arrow). C, In some lields, the intraluminal organization in the respiratory bronchioles and alveolar ducts (arrows) is surrounded by abundant aerated lumen pictorially showing why clinical evidence of airflow obstruction is unusual in BOOP. D, Nevertheless, evidence of obstruction at a microscopic level is common as manifested by intra-alveolar accumulations of foam cells. The surrounding alveolar septa are thickened with a mild chronic inHammatory inliltrate, and they are covered by a prominent type 2 alveolar lining cells. CHEST I 102 I 1 I JULY. 1992 I Supplement
318
FIGURE 2. Bronchiolitis obliterans organizing pneumonia (BOOP). A well-inflated biopsy specimen showing tufts of organization within the alveolar ducts and alveoli (arrows). The intervening alveolar wa1ls show mild thickening and inflammatory infiltrates, but the lung architecture is otherwise maintained.
FIGURE 3. Bronchiolitis obliterans organizing pneumonia (BOOP). Commonly in BOOP there is atelectasis, particularly around the zones of organization, and that is well seen in this biopsy specimen where zones of organization with pale polyps of intraluminal organization are surrounded by atelectatic parenchyma (curved arrows). A nearby bronchiole also shows bronchiolitis obliterans (straight arrow).
and vascular elements). they are primarily intraluminal and ootinre~tiruu . , The intraluminal polyps frequently have a central collection of inflammatory cells, including histiocytes, lymphocytes, and plasma cells. In cross-sections of intraluminal polyps, these cellular elements and fibroblasts may appear almost granulomatous ; however, giant cells are lacking and metachromasia of the young fibroblastic stroma is prominent. The metachromasia can be brought out by connective tissue stains such as alcian blue and colloidal iron. The intraluminal polyps can sometimes be seen to arise as organization of airspace fibrinous exudate. In the majority of cases ofBoop, a fibrinous exudate represents a focal finding. Away from the involved lung tissue in BooP, the alveoli appear normal or nearly SQ, although they may show slight thickening of septa with mild inflammatory infiltrate and slight prominence of type 2 cells. Some open lung biopsy specimens, particularly those from lobar tips, may include foci of old fibrosiS. In such cases, one must be careful not to equate the old scarring with the parenchymal lesion of BooP and the 2 usually appear as distinct and separate lesions. The presence of honeycombing as part of the interstitial pneumonia (and not an incidental finding) is evidence against the diagnosis of BooP. The majority of cases of BooP respond to steroids and pathologists are not often afforded the opportunity to study the natural history of the process. Anecdotally, in the small number offatal cases that I have reviewed, the morphologic changes at autopsy are primarily those of massive fibroblastic proliferation identical to that seen in massive organizing diffuse alveolar damage. The histologic changes associated with successfully treated BooP are not well-characterized. In the occasional case I have personally observed, the lung tissue appears to revert entirely to normal histologic features. Nevertheless, it is well-mown that organization of the type seen in BooP may occasionally lead to Interstitial fibrosis, so that its identification in a case of treated BooP would not be entirely surprising. HISTOLOGIC DIFFERENTIAL DIAGNOSIS OF
BOOP
The histologic differenruu diagnosis of BooP can be Table 3-Conditiona that mtJfI Show BronchioUti. Obliteraru1Dit1a Organizing Pneumonia· Conditions
FIGURE 4. Bronchiolitis obliterans organizing pneumonia (BOOP). In this case. there is a nodule zone of organization in the region around a small bronchiole which itself is relatively unaffected
(arrow).
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Organizing infections (bacterial, fungal,viral, protozoan) Organizing diffuse alveolar damage Drug, toxic, and fume exposures Allergic reactions (especially extrinsic allergic alveolitis) Organizing chronic eosinophilic pneumonia Collagen vascular diseases Organizing pneumonias associated with chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, and others Organizing pneumonias distal to obstruction Organizing pneumonias following aspiration Vasculitides (especially Wegener's granulomatosis) As a reaction around other processes (eg, abscess, infarct, tumors, and others) or a focal nodule (Ie, focal organizing pneumonia) Idiopathic (Ie, BOOP) -From references 13, 20.
•
.
..
< ~ ~ ~
:.
'
FIGURE 5. Bronchiolitis obliterans organizing pneumonia (BooP). Detail of a small bronchiole (A, left) shows a large polyp of myxomatous connective and their remnant of bronchiolar smooth muscle (arrows). In a nearby alveolar duct (right), a cluster of mononuclear cells (arrows)is seen with the tuft of organization. The surrounding alveolar walls show a moderate and chronic inHammatory cell infiltrate and foam cells can be seen within some of the alveoli.
divided into 2 broad groups. The first group is comprised of those lesions that may show a BooP pattern. Since bronchiolitis obliterans and organizing pneumonia are common reparative reactions in the lung, it is not surprising that this list of lesions is quite extensive. Lesions that may have a BooP pattern as part of their histologic features are shown in Table 3. The second group of cases that enter into the histologic differential diagnosis do so in part because of the clinical presentation and in part because they represent idiopathic fibrosing interstitial pneumonias. These include idiopathic organizing diffuse alveolar damage (acute interstitial pneumonia) and idiopathic pulmonary fibrosis (usual interstitial pneumonia or UIP). When the pathologist is faced with a case that may represent Boop, he must first consider and exclude possibilities listed in Table 3. Many organizing infections may show a pattern similar to that of Boop, and clinical correlation, special stains, and cultures are generally necessary for a specific diagnosis in individual cases. A clinical lesion that is identical to that of BooP may follow influenza (A or B) pneumonia and be recognized only after serologic studies. Other organizing infections that may resemble BooP include Nocardia, Legionnaire's disease, Pneumocystis carinii pneumonia, and others. 13.... Organizing diffuse alveolar damage shows some overlap with BOOP histologically,although in the former the changes tend to be more extensive, uniform, and confluent, and hyaline membranes are often present. There are some cases of idiopathic organizing diffuse alveolar damage that show both clinical and histologic overlap with BooP and the distinction may be somewhat arbitrary. Some drug reactions have histologic features identical to BooP. In general, only clinical history and follow-up allow recognition of a drug reaction. Bronchiolitis obliterans and organizing pneumonia are frequent histologic features seen in cases of extrinsic allergic alveolitis (hypersensitivity pneumonitis) and organizing chronic eosinophilic pneumonia.... A BOOP reaction is a common histologic component in cases of Wegener's granulomatosis and occasionally may
dominate the histologic findings (Fig 6). In some cases, bronchiolitis obliterans with organizing pneumonia comprises many contiguous low-power fields and the vasculitis and necrosis diagnostic of Wegener's granulomatosis are relatively inconspicuous. Similarly, a BooF-Jike reaction is a common finding surrounding lung abscesses, regardless of cause, and some organizing infarcts. Isolated masses resected from the lung may show the features of bronchiolitis obliterans and organizing pneumonia. Rather than a term like localized Boop, I prefer the term "focal organizing pneumonia" to avoid any confusion. These patients lack any signs and symptoms of interstitial lung disease, and the mass is resected to exclude the possibility of a neoplasm. The distinction of BOOP from other idiopathic fibrosing interstitial lung diseases, particularly idiopathic organizing diffuse alveolar damage and idiopathic pulmonary fibrosis, is summarized in Table 4......3 .......... In considering both the histologic changes that characterize BooP and lesions listed in the differential diagnosis, Table 5 summarizes the histologic findings that when present suggest a diagnosis other than BOOP. The presence of numerous hyaline membranes should
FIGURE 6. VVegener's granulomatosis with large zones showing a BooP pattern indistinguishable from idiopathic BOOP.
CHEST I 102 I 1 I JULY, 1992 I Supplemenl
418
Idiopathic Organizing
Diffuse Alveolar Damage
Generally uniform diffuse involvement of lung parenchyma; honeycombing rare in biopsy tissue
Idiopathic Pulmonary Fibrosis (IPF)
BOOP
(Acute Interstitial Pneumonia)
Patchy intraluminal organlzation (bronchiolitis obliterans and organizing pneumonia) with zones of relatively unaffected lung; honeycombing absent
Variegated histologic features with zones ofhoneycombing, zones of normal lung, zones of active interstitial widening
thiclceniog
Interstitial in6ltrate may be prominent
Reaction often most prominent in the paraseptal and subpleural regions
Residual hyaline membranes
Cellular bronchiolitis may be present
Foam cells inconspicuous
Microatelectasis with collapse of alveolar
Alveolar foam cells often conspicuous
Intraluminal organization and edematous interstitial fibroblastic thickening may be present focally, but are not a dominant finding
Edematous interstitial fibroblastic
walls Paucity of chronic inHammation, foam cells
Edematous fibroblastic interstitial thickening generally inconspicuous
Absence of cellular bronchiolitis -From references I, 4, 13, 15, 20-23.
Table 5-HUtologic &mira againBt the DiagnoIia of BOO,.. Features Hyaline membranes (fibrinous exudate may be seen focally in BOOP) Marked fibrinous alveolar exudates Necrosis Acute inHammation Microabscess formation Vasculitis Prominent eosinophils Granulomas Marked alveolar lining cell and bronchiolar metaplasia Honeycombing (except as an incklentalfinding) -From references 13, 20-23.
lead to consideration of organizing diffuse alveolar damage. The presence of necrosis, acute inflammation, microabscess formation, and vasculitis are strong evidence against the diagnosis of BooP and should lead to rigorous exclusion of infection and vasculitis, particularly Wegeners granulomatosis. A few eosinophils are occasionally seen in Boop, but numerous eosinophils raise the possibility of organizing chronic eosinophilic pneumonia or an organizing allergic reaction such as a drug reaction. Likewise, the presence of more than a rare or isolated granuloma should lead to exclusion of granulomatous infection and, more commonly, extrinsic allergic alveolitis. Honeycombing may be a.focal incidental finding in Boop, but when present as part of the interstitial pneumonia is strong evidence against the diagnosis.
FIGURE 7. Bronchiolitis obliterans organizing pneumonia (BOOP); transbronchial and open lung biopsy specimens from the same case . A (left). Transbroochial biopsy specimen shows sigomcant crush artifact and distortion of architecture, although the presence of an alveolar in6ltrate can be made out in addition to edematous intraluminal organization (center). B (right). Open lung biopsy specimen shows identical features in a better inDated specimen. There are fuci of organization (large arrows) with surrounding intact lung architecture with mild chronic in6ammatory thickening of alveolar walls. This case showed relatively prominent airspace accumulations of fibrin (small arrows).
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PalhologIc Aspeds 01 BOOP (7homu V. CoIt1y)
The presence of occasional granulomas or clusters of eosinophils in some otherwise typical cases ofBOOP suggest the possibility that some cases of BooP may be closely related to chronic eosinophilic pneumonia or hypersensitivity pneumonitis. Some cases appear to be true hybrid cases between either BOOP and chronic eosinophilic pneumonia or BOOP and hypersensitivity pneumonitis. HISTOLOGIC DIAGNOSIS OF
BOOP
BooP is not a lesion that can be diagnosed solely on the basis of histologic features or solely on the basis of the clinical findings. BooP is a clinicopathologic diagnosis in which the appropriate histologic findings (as outlined above) occur in a compatible clinical context, ie, an idiopathic interstitial pneumonia clinically The question often arises as to whether a transbronchial biopsy specimen of lung tissue is sufficient for a diagnosis of BOOE The histologic findings seen in BOOE including both bronchiolitis obliterans and organizing pneumonia, but particularly the latter, may be seen in transbronchia1 lung biopsy specimens (Fig 7). As seen from the differential diagnosis in Table 3, there are many conditions that may be associated with these Bndings, and their presence on a small transbronchia1 biopsy specimen is quite nonspecific. Nevertheless, in the appropriate clinical setting and with full cognizance of the limitations of transbronchiallung biopsy; a clinicopathologic diagnosis of BooP is possible with a transbronchia1 biopsy specimen alone. For purposes of clinical research and publication, however, an open biopsy specimen is recommended for a confirmed diagnosis of BOO]?
REFERENCES
1 Epler GR, Colby ~ McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152-58 2 Liebow AA, Carrington CB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, eds. Frontiers of pulmonary radiolo~ New York: Grone & Stratton, 1969:102-41 3 Gosink BB, Friedman PJ, Liebow M. Bronchiolitis obliterans. AJR 1973; 117:816-31 4 Katzenstein ALA, Myers JL, Prophet WD, Corley LS III, Shin MS. Bronchiolitis obliterans and usual interstitial pneumonia: a comparative clinicopathologic study Am J Surg Pathol 1986; 10:373-81 5 Grinblat J, Mechlis S, Lewitus Z. Organizing pneumonia-like process: an unusual observation in steroid responsive cases with
6
7
8 9 10
11
features of chronic interstitial pneumonia. Chest 1981; 80:25963 Davison AG, Heard BE, McAllister WAC, Turner-Warwick MEH. Cryptogenic organizing pneumonitis. Q J Moo 1983; 52:382-93 Lange W. Uber eine eigenthiimliche Erkrankung der kleinen Bronchien und Bronchiolen (Bronchitis et Bronchiolitis obliterans). Dtsch Arch Klin Moo 1901; 70:342-64 Wintemitz MC. Collected studies on the pathology of war gas poisoning. New Haven, Conn: YaleUniversity Press, 1920 Winternitz MC, Wason lA, McNamara FB. The pathology of influenza. New Haven, Conn: YaleUniversity Press, 1920 Blumgart HI, MacMahon HE. Bronchiolitis fibrosa obliterans: clinical and pathologic study Med Coo North Am 1929; 13:197214 McAdams AJ. Bronchiolitis obliterans. Am J Med 1955; 19:314-
22
12 King TE. Bronchiolitis obliterans. In: Schwarz MI, King TE, eds. Interstitial lung disease. Philadelphia: BC Decker, 1988:325-42 13 Colby ~ Myers JL. The clinical and histologic spectrum of bronchiolitis obliterans including bronchiolitis obliterans organizing pneumonia (BOOP). Semin Respir Dis 1992; 13:119-33 14 Case Records of Massachusetts General Hospital (case 24-1986). N Engl J Med 1986; 314:1627-36 15 Guerry-Force ML, MiiUer NL, Wright JL, et al. A comparison of bronchiolitis obliterans with organizing pneumonia, usual interstitial pneumonia, and small airways disease. Am Rev Respir Dis 1986; 135:705-12 16 Cordier J, Loire R, Brune J. Idiopathic bronchiolitis obliterans organizing pneumonia: definition of characteristic clinical profiles in a series of 16 patients. Chest 1989; 96:999-1004 17 Floyd R. Organization of pneumonic exudates. Am J Med Sci 1922; 163:527-48 18 Auerbach SH, Mims OM, Goodpasture EW. Pulmonary fibrosis secondary to pneumonia. Am J Patholl952; 28:69-87 19 Spencer H. Pathology of the lung. London: Pergamon Press, 1985:174-75 20 Colby ~ Churg AC. Patterns of pulmonary fibrosis. Pathol Annu 1986; 21:277-310 21 Kitaichi M. Alveolar septal inflammation: a comparative pathologic study of IPF and BOOE In: Harasawa M, Fukuchi Y, Morimari H, eds. Interstitial pneumonia of unknown etiology Tokyo: University of Tokyo Press, 1989:189-99 22 Katzenstein ALA, Myers JL, Mazur Ml: Acute interstitial pneumonia: a clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Patholl986; 10:256-67 23 Kitaichi M. Pathologic features and the classification of interstitial pneumonia of unknown etiology. Bull Chest Dis Res Inst Kyoto Univ 1990; 23:1-18
CHEST I 102 I 1 I JULY; 1992 I Supplement
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f"J"'be term "bronchiolitis obliterans organizing pneumonia .I. (BOOP)" is a relatively recent term for a clinicopatho-
logic entity that has been recognized for some time. ' The name derives from a series of cases collected in the 19705 and 1980s by Charles Carrington. These represented examples of idiopathic diffuse (or at least multifocal) interstitial pneumonia clinically that showed histologic features of bronchiolitis obliterans with patchy organizing pneumonia, as well as other features as discussed below. This series was collected and collated by Epler et all and published in the New EnglandjournalofMedicine as "bronchiolitis obliterans organizing pneumonia:' The eponym BOOP derives from hiatologic presence of bronchiolitis obliterans and organizing pneumonia. BOOP is not a new lesion and similar cases have been previously reported under a number of different synonyms (1hble 1)..... Some of the previous synonyms for BOOP have emphasized the presence of bronchiolitis obliterans because of its identification histologically'" and not on the basis of clinical evidence of airflow obstruction. Lange" is credited with the first histologic description of bronchiolitis obliterans in an autopsy study of 2 patients, 1 of whom died of an acute illness in 8 days, and the other who died after 6 months of progressive lung disease. Microscopically, polypoid granulation tissue was found in airways and the terms ''bronchitis and bronchiolitis obliterans" were applied," Subsequent to this report, bronchiolitis obliterans is mentioned as a histologic finding in a number of other studies, notably those ofWmternitz" in 1920 on war gas inhalation and the 1918 influenza pandemic," Blumgart and MacMahon'O in 1929, McAdams" in 1955, and Gosink et aJ3 in 1973. In these studies, the term ''bronchiolitis obliterans" is again used in a histologic sense to refer to a specific histologic finding under the microscope. The terms ''bronchiolitis fibrosa obliterans" and "obliterative bronchiolitis" are considered synonymous with bronchiolitis obliterans in this discussion. The large series by Gosink et al3 used bronchiolitis obliterans for 2 distinct histologic lesions: the classic intraluminal polyps as described by Lange," as well as a spectrum of bronchiolar constriction, narrowing, submucosal fibrosis, or complete obliteration by fibrous tissue (as distinct from intraluminal polyps), which they termed "constrictive bronchiolitis." A considerable amount of confusion has surrounded "BOOP" because of the connotations of the term "bronchilitis obliteranS:' For morphologists, bronchiolitis obliterans refers to the 2 lesions noted by Gosink et al,3 namely -From the Department of Pathology and Laboratory Medicine, Mayo Clinic, l\ochester, Minn. ReprInt t'8qUUtB: Dr. Colby, DloUion of Surgicallbthology, Mayo Clinic, Rochuter; MN 55905 .
38S
intraluminal polyps of granulation tissue and constrictive bronchiolitis. Clinicians often use the term "bronchiolitis obliterans" to refer to a clinical syndrome of airflow obstruction thought to be due to lesions of the small airways, classically postinfectious or following toxic fume exposure. IS Unfortunately, there is nota one-to-one relationship between what the morphologist sees under the microscope and what the clinician sees as a clinical syndrome. Thus, clinical bronchiolitis obliterans is distinctfrom histologic bronchiolitis obliterans. As it turns out, the histologic form of bronchiolitis obliterans with endobronchiolar polyps is only rarely associated with the clinical evidence of airflow 0bstruction, whereas (the much less common) constrictive bronchiolitis is the lesion that is usually seen in patients who have the clinical syndrome of bronchiolitis obliterans. 13 BOOP has been recognized as an interstitial lung disease clinically rather than an airflow obstructive disease,1."".''''0 and the term ''bronchiolitis obliterans" is used solely in a histologic descriptive sense. Because of the confusion around bronchiolitis obliterans (BO) in the term "BOOP" some have recommended the term "cryptogenic organizing pneumonitis" as a descriptive alternative that avoids the term ''bronchiolitis obliterans" altogether. 13 The concept of organizing pneumonia has been wellknown to autopsy pathologists for decades and its origins may go back as far as Laennec." Pathologists familiar with the features of infectious pneumonias at autopsy have long recognized the pattern of organizing pneumonia as one of the reparative reactions that may be seen following infectious pneumontas.P" Its presence was originally emphasized in bacterial pneumonias, but it has been recognized subsequently in a variety of other infectious, as well as noninfectious, pneumonias. As histologic findings, bronchiolitis obliterans and organizing pneumonia frequently coexist and indeed appear to be part of the same reparative reaction pattern in the lung." In tissue sections with airways cut longitudinally, one can sometimes see an endobronchial polyp of connective tissue extending all the way from the bronchiole to the distal alveolar duct with only focal attachments to walls of the airway. In routine practice, involvement of alveolar ducts is usually most prominent and easily appreciated by pathologists. The presence of bronchiolitis obliterans with organizTable I-PreoiotMlg Vied SfI'IOIIfI"IIfor BOOP Synonym Bronchiolitis obliterans with organizing interstitial pneumonia or organizing diffuse alveolar damage (BIP)! Bronchiolitis obliteransOrganizing pneumonia-like lesion" Cryptogenic organizing pneumonia" Unresolved/chronic pneumonia PathologIc Aspects 01 BOOP (11Iotnes V. Colby)
Table 2-Major Hiatologic &Jturea ojBOOP* Features Patchy bronchiolitis obliterans with organizing pneumonia Interstitial mononuclear cell inliltrate, variable in density Alveolar spacefoam cells Absence of honeycombing or extensive interstitiallibrosis ·From references I, 3, 4, 6, 14-16.
ing pneumonia by itself is quite nonspecific. BOOP is a clinicopathologic syndrome that requires the identification of the histologic pattern of bronchiolitis obliterans and organizing pneumonia in the clinical setting of an idiopathic interstitial pneumonia. 1 In the original report by
Epler et al,' a number of cases that showed this pattern
were excluded when a putative cause or association could be identified, primarily infections and collagen vascular diseases. HISTOLOGIC FEATURES OF
BOOP
The major histologic changes that comprise BooP are summarized in Table 2 and illustrated in Figures 1 through 5. The key histologic finding in BooP is the presence of patchy bronchiolitis obliterans and organizing pneumonia. The "patchiness" may manifest as involvement of 1 lobule adjacent to an uninvolved lobule or as a nodular pattern at scanning power microscopy in which the nodules appear to center on bronchioles. Occasional cases showing this nodular pattern also show a micronodular pattern roentgenographically. The intensity of the interstitial infiltrate varies from inconspicuous to quite dense and generally comprises lymphocytes and/or plasma cells. Cellular infiltration of bronchioles (cellular bronchiolitis), sometimes with some associated peribronchiolar scarring, may be seen in a portion of cases. A few germinal centers may be found . Airspace accumulation offoamy macrophages is probably a manifestation of obstruction at the microscopic level. A nonspecific increase in alveolar macrophages that are not foamy may also be seen, particularly in smokers in whom the macrophages may contain small flecks of debris. An isolated or rare granuloma does not entirely exclude the diagnosis of Boop, but should lead to exclusion of extrinsic allergic a1veolitisand granulomatous infection. A characteristic feature of uninflated biopsy specimens in cases ofBooP is the tendency for the tissue to be atelectatic in the zones of organization. This probably reflects the fact that relatively little permanent scarring (which would lend rigidity) is present. The lung collapses around the intraluminal polyps of connective tissue and can simulate severe interstitial fibrosis. While the intraluminal polyps are connected focally to the interstitium, in bronchioles, alveolar ducts, or both (and from these points derive their cellular
FIGURE 1. Bronchiolitis obliterans organizing pneumonia (BOOP). A, In this well-inHated biopsy specimen, one can see all the pathologic aspects of BOOP. Bronchiolitis obliterans with intraluminal polyps is seen (long arrows), as well as foci of organizing pneumonia (short arrows) with intraluminal organization in alveolar ducts. The lung architecture is maintained and the alveolar septa
are modestly thickened by chronic inHammatory infiltrates. B, There is some loss of bronchiolar epithelium where the intraluminal polyp of connective tissue is attached (arrow). C, In some lields, the intraluminal organization in the respiratory bronchioles and alveolar ducts (arrows) is surrounded by abundant aerated lumen pictorially showing why clinical evidence of airflow obstruction is unusual in BOOP. D, Nevertheless, evidence of obstruction at a microscopic level is common as manifested by intra-alveolar accumulations of foam cells. The surrounding alveolar septa are thickened with a mild chronic inHammatory inliltrate, and they are covered by a prominent type 2 alveolar lining cells. CHEST I 102 I 1 I JULY. 1992 I Supplement
318
FIGURE 2. Bronchiolitis obliterans organizing pneumonia (BOOP). A well-inflated biopsy specimen showing tufts of organization within the alveolar ducts and alveoli (arrows). The intervening alveolar wa1ls show mild thickening and inflammatory infiltrates, but the lung architecture is otherwise maintained.
FIGURE 3. Bronchiolitis obliterans organizing pneumonia (BOOP). Commonly in BOOP there is atelectasis, particularly around the zones of organization, and that is well seen in this biopsy specimen where zones of organization with pale polyps of intraluminal organization are surrounded by atelectatic parenchyma (curved arrows). A nearby bronchiole also shows bronchiolitis obliterans (straight arrow).
and vascular elements). they are primarily intraluminal and ootinre~tiruu . , The intraluminal polyps frequently have a central collection of inflammatory cells, including histiocytes, lymphocytes, and plasma cells. In cross-sections of intraluminal polyps, these cellular elements and fibroblasts may appear almost granulomatous ; however, giant cells are lacking and metachromasia of the young fibroblastic stroma is prominent. The metachromasia can be brought out by connective tissue stains such as alcian blue and colloidal iron. The intraluminal polyps can sometimes be seen to arise as organization of airspace fibrinous exudate. In the majority of cases ofBoop, a fibrinous exudate represents a focal finding. Away from the involved lung tissue in BooP, the alveoli appear normal or nearly SQ, although they may show slight thickening of septa with mild inflammatory infiltrate and slight prominence of type 2 cells. Some open lung biopsy specimens, particularly those from lobar tips, may include foci of old fibrosiS. In such cases, one must be careful not to equate the old scarring with the parenchymal lesion of BooP and the 2 usually appear as distinct and separate lesions. The presence of honeycombing as part of the interstitial pneumonia (and not an incidental finding) is evidence against the diagnosis of BooP. The majority of cases of BooP respond to steroids and pathologists are not often afforded the opportunity to study the natural history of the process. Anecdotally, in the small number offatal cases that I have reviewed, the morphologic changes at autopsy are primarily those of massive fibroblastic proliferation identical to that seen in massive organizing diffuse alveolar damage. The histologic changes associated with successfully treated BooP are not well-characterized. In the occasional case I have personally observed, the lung tissue appears to revert entirely to normal histologic features. Nevertheless, it is well-mown that organization of the type seen in BooP may occasionally lead to Interstitial fibrosis, so that its identification in a case of treated BooP would not be entirely surprising. HISTOLOGIC DIFFERENTIAL DIAGNOSIS OF
BOOP
The histologic differenruu diagnosis of BooP can be Table 3-Conditiona that mtJfI Show BronchioUti. Obliteraru1Dit1a Organizing Pneumonia· Conditions
FIGURE 4. Bronchiolitis obliterans organizing pneumonia (BOOP). In this case. there is a nodule zone of organization in the region around a small bronchiole which itself is relatively unaffected
(arrow).
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Organizing infections (bacterial, fungal,viral, protozoan) Organizing diffuse alveolar damage Drug, toxic, and fume exposures Allergic reactions (especially extrinsic allergic alveolitis) Organizing chronic eosinophilic pneumonia Collagen vascular diseases Organizing pneumonias associated with chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, and others Organizing pneumonias distal to obstruction Organizing pneumonias following aspiration Vasculitides (especially Wegener's granulomatosis) As a reaction around other processes (eg, abscess, infarct, tumors, and others) or a focal nodule (Ie, focal organizing pneumonia) Idiopathic (Ie, BOOP) -From references 13, 20.
•
.
..
< ~ ~ ~
:.
'
FIGURE 5. Bronchiolitis obliterans organizing pneumonia (BooP). Detail of a small bronchiole (A, left) shows a large polyp of myxomatous connective and their remnant of bronchiolar smooth muscle (arrows). In a nearby alveolar duct (right), a cluster of mononuclear cells (arrows)is seen with the tuft of organization. The surrounding alveolar walls show a moderate and chronic inHammatory cell infiltrate and foam cells can be seen within some of the alveoli.
divided into 2 broad groups. The first group is comprised of those lesions that may show a BooP pattern. Since bronchiolitis obliterans and organizing pneumonia are common reparative reactions in the lung, it is not surprising that this list of lesions is quite extensive. Lesions that may have a BooP pattern as part of their histologic features are shown in Table 3. The second group of cases that enter into the histologic differential diagnosis do so in part because of the clinical presentation and in part because they represent idiopathic fibrosing interstitial pneumonias. These include idiopathic organizing diffuse alveolar damage (acute interstitial pneumonia) and idiopathic pulmonary fibrosis (usual interstitial pneumonia or UIP). When the pathologist is faced with a case that may represent Boop, he must first consider and exclude possibilities listed in Table 3. Many organizing infections may show a pattern similar to that of Boop, and clinical correlation, special stains, and cultures are generally necessary for a specific diagnosis in individual cases. A clinical lesion that is identical to that of BooP may follow influenza (A or B) pneumonia and be recognized only after serologic studies. Other organizing infections that may resemble BooP include Nocardia, Legionnaire's disease, Pneumocystis carinii pneumonia, and others. 13.... Organizing diffuse alveolar damage shows some overlap with BOOP histologically,although in the former the changes tend to be more extensive, uniform, and confluent, and hyaline membranes are often present. There are some cases of idiopathic organizing diffuse alveolar damage that show both clinical and histologic overlap with BooP and the distinction may be somewhat arbitrary. Some drug reactions have histologic features identical to BooP. In general, only clinical history and follow-up allow recognition of a drug reaction. Bronchiolitis obliterans and organizing pneumonia are frequent histologic features seen in cases of extrinsic allergic alveolitis (hypersensitivity pneumonitis) and organizing chronic eosinophilic pneumonia.... A BOOP reaction is a common histologic component in cases of Wegener's granulomatosis and occasionally may
dominate the histologic findings (Fig 6). In some cases, bronchiolitis obliterans with organizing pneumonia comprises many contiguous low-power fields and the vasculitis and necrosis diagnostic of Wegener's granulomatosis are relatively inconspicuous. Similarly, a BooF-Jike reaction is a common finding surrounding lung abscesses, regardless of cause, and some organizing infarcts. Isolated masses resected from the lung may show the features of bronchiolitis obliterans and organizing pneumonia. Rather than a term like localized Boop, I prefer the term "focal organizing pneumonia" to avoid any confusion. These patients lack any signs and symptoms of interstitial lung disease, and the mass is resected to exclude the possibility of a neoplasm. The distinction of BOOP from other idiopathic fibrosing interstitial lung diseases, particularly idiopathic organizing diffuse alveolar damage and idiopathic pulmonary fibrosis, is summarized in Table 4......3 .......... In considering both the histologic changes that characterize BooP and lesions listed in the differential diagnosis, Table 5 summarizes the histologic findings that when present suggest a diagnosis other than BOOP. The presence of numerous hyaline membranes should
FIGURE 6. VVegener's granulomatosis with large zones showing a BooP pattern indistinguishable from idiopathic BOOP.
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Idiopathic Organizing
Diffuse Alveolar Damage
Generally uniform diffuse involvement of lung parenchyma; honeycombing rare in biopsy tissue
Idiopathic Pulmonary Fibrosis (IPF)
BOOP
(Acute Interstitial Pneumonia)
Patchy intraluminal organlzation (bronchiolitis obliterans and organizing pneumonia) with zones of relatively unaffected lung; honeycombing absent
Variegated histologic features with zones ofhoneycombing, zones of normal lung, zones of active interstitial widening
thiclceniog
Interstitial in6ltrate may be prominent
Reaction often most prominent in the paraseptal and subpleural regions
Residual hyaline membranes
Cellular bronchiolitis may be present
Foam cells inconspicuous
Microatelectasis with collapse of alveolar
Alveolar foam cells often conspicuous
Intraluminal organization and edematous interstitial fibroblastic thickening may be present focally, but are not a dominant finding
Edematous interstitial fibroblastic
walls Paucity of chronic inHammation, foam cells
Edematous fibroblastic interstitial thickening generally inconspicuous
Absence of cellular bronchiolitis -From references I, 4, 13, 15, 20-23.
Table 5-HUtologic &mira againBt the DiagnoIia of BOO,.. Features Hyaline membranes (fibrinous exudate may be seen focally in BOOP) Marked fibrinous alveolar exudates Necrosis Acute inHammation Microabscess formation Vasculitis Prominent eosinophils Granulomas Marked alveolar lining cell and bronchiolar metaplasia Honeycombing (except as an incklentalfinding) -From references 13, 20-23.
lead to consideration of organizing diffuse alveolar damage. The presence of necrosis, acute inflammation, microabscess formation, and vasculitis are strong evidence against the diagnosis of BooP and should lead to rigorous exclusion of infection and vasculitis, particularly Wegeners granulomatosis. A few eosinophils are occasionally seen in Boop, but numerous eosinophils raise the possibility of organizing chronic eosinophilic pneumonia or an organizing allergic reaction such as a drug reaction. Likewise, the presence of more than a rare or isolated granuloma should lead to exclusion of granulomatous infection and, more commonly, extrinsic allergic alveolitis. Honeycombing may be a.focal incidental finding in Boop, but when present as part of the interstitial pneumonia is strong evidence against the diagnosis.
FIGURE 7. Bronchiolitis obliterans organizing pneumonia (BOOP); transbronchial and open lung biopsy specimens from the same case . A (left). Transbroochial biopsy specimen shows sigomcant crush artifact and distortion of architecture, although the presence of an alveolar in6ltrate can be made out in addition to edematous intraluminal organization (center). B (right). Open lung biopsy specimen shows identical features in a better inDated specimen. There are fuci of organization (large arrows) with surrounding intact lung architecture with mild chronic in6ammatory thickening of alveolar walls. This case showed relatively prominent airspace accumulations of fibrin (small arrows).
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PalhologIc Aspeds 01 BOOP (7homu V. CoIt1y)
The presence of occasional granulomas or clusters of eosinophils in some otherwise typical cases ofBOOP suggest the possibility that some cases of BooP may be closely related to chronic eosinophilic pneumonia or hypersensitivity pneumonitis. Some cases appear to be true hybrid cases between either BOOP and chronic eosinophilic pneumonia or BOOP and hypersensitivity pneumonitis. HISTOLOGIC DIAGNOSIS OF
BOOP
BooP is not a lesion that can be diagnosed solely on the basis of histologic features or solely on the basis of the clinical findings. BooP is a clinicopathologic diagnosis in which the appropriate histologic findings (as outlined above) occur in a compatible clinical context, ie, an idiopathic interstitial pneumonia clinically The question often arises as to whether a transbronchial biopsy specimen of lung tissue is sufficient for a diagnosis of BOOE The histologic findings seen in BOOE including both bronchiolitis obliterans and organizing pneumonia, but particularly the latter, may be seen in transbronchia1 lung biopsy specimens (Fig 7). As seen from the differential diagnosis in Table 3, there are many conditions that may be associated with these Bndings, and their presence on a small transbronchia1 biopsy specimen is quite nonspecific. Nevertheless, in the appropriate clinical setting and with full cognizance of the limitations of transbronchiallung biopsy; a clinicopathologic diagnosis of BooP is possible with a transbronchia1 biopsy specimen alone. For purposes of clinical research and publication, however, an open biopsy specimen is recommended for a confirmed diagnosis of BOO]?
REFERENCES
1 Epler GR, Colby ~ McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152-58 2 Liebow AA, Carrington CB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, eds. Frontiers of pulmonary radiolo~ New York: Grone & Stratton, 1969:102-41 3 Gosink BB, Friedman PJ, Liebow M. Bronchiolitis obliterans. AJR 1973; 117:816-31 4 Katzenstein ALA, Myers JL, Prophet WD, Corley LS III, Shin MS. Bronchiolitis obliterans and usual interstitial pneumonia: a comparative clinicopathologic study Am J Surg Pathol 1986; 10:373-81 5 Grinblat J, Mechlis S, Lewitus Z. Organizing pneumonia-like process: an unusual observation in steroid responsive cases with
6
7
8 9 10
11
features of chronic interstitial pneumonia. Chest 1981; 80:25963 Davison AG, Heard BE, McAllister WAC, Turner-Warwick MEH. Cryptogenic organizing pneumonitis. Q J Moo 1983; 52:382-93 Lange W. Uber eine eigenthiimliche Erkrankung der kleinen Bronchien und Bronchiolen (Bronchitis et Bronchiolitis obliterans). Dtsch Arch Klin Moo 1901; 70:342-64 Wintemitz MC. Collected studies on the pathology of war gas poisoning. New Haven, Conn: YaleUniversity Press, 1920 Winternitz MC, Wason lA, McNamara FB. The pathology of influenza. New Haven, Conn: YaleUniversity Press, 1920 Blumgart HI, MacMahon HE. Bronchiolitis fibrosa obliterans: clinical and pathologic study Med Coo North Am 1929; 13:197214 McAdams AJ. Bronchiolitis obliterans. Am J Med 1955; 19:314-
22
12 King TE. Bronchiolitis obliterans. In: Schwarz MI, King TE, eds. Interstitial lung disease. Philadelphia: BC Decker, 1988:325-42 13 Colby ~ Myers JL. The clinical and histologic spectrum of bronchiolitis obliterans including bronchiolitis obliterans organizing pneumonia (BOOP). Semin Respir Dis 1992; 13:119-33 14 Case Records of Massachusetts General Hospital (case 24-1986). N Engl J Med 1986; 314:1627-36 15 Guerry-Force ML, MiiUer NL, Wright JL, et al. A comparison of bronchiolitis obliterans with organizing pneumonia, usual interstitial pneumonia, and small airways disease. Am Rev Respir Dis 1986; 135:705-12 16 Cordier J, Loire R, Brune J. Idiopathic bronchiolitis obliterans organizing pneumonia: definition of characteristic clinical profiles in a series of 16 patients. Chest 1989; 96:999-1004 17 Floyd R. Organization of pneumonic exudates. Am J Med Sci 1922; 163:527-48 18 Auerbach SH, Mims OM, Goodpasture EW. Pulmonary fibrosis secondary to pneumonia. Am J Patholl952; 28:69-87 19 Spencer H. Pathology of the lung. London: Pergamon Press, 1985:174-75 20 Colby ~ Churg AC. Patterns of pulmonary fibrosis. Pathol Annu 1986; 21:277-310 21 Kitaichi M. Alveolar septal inflammation: a comparative pathologic study of IPF and BOOE In: Harasawa M, Fukuchi Y, Morimari H, eds. Interstitial pneumonia of unknown etiology Tokyo: University of Tokyo Press, 1989:189-99 22 Katzenstein ALA, Myers JL, Mazur Ml: Acute interstitial pneumonia: a clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Patholl986; 10:256-67 23 Kitaichi M. Pathologic features and the classification of interstitial pneumonia of unknown etiology. Bull Chest Dis Res Inst Kyoto Univ 1990; 23:1-18
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