Differential Diagnosis of Bronchiolitis Obliterans Organizing Pneumonla* Masanori Kitaichi, M.D., D.Med. Sc.
B
ronchiolitis obliterans organizing pneumonia (BOOP) is a distinct entity among the spectrum ofinfiltrative lung diseases without apparent causes or associated diseases. I While the disease concept of BOOP is based on the combination of clinical setting and pathologic findings, histopathologic features ofBOOP (ie, bronchiolitis obliterans and organizing pneumonia) are not speciDc and are seen in various pulmonary diseases, including infectious and noninfectious diseases." Because of this, the term BOOP bas caused some confusion and, to avoid this, the term idiopathic BOOP will be used. Idiopathic BOOP is an infiltrative lung disease with a subacute clinical course, and therefore, both acute and chronic pulmonary diseases must be considered in the differential diagnosis before a diagnosis of BOOP can be established. This review is based on the Kyotosymposium on BOOP between November 29 and December 1, 1990, personal study, and a review of the literature.
virus may cause obliterative changes of bronchioles but with airllowobstruction, and therefore, they differ clinically from BOOP.··· Legionella pneumophila is reported to cause a BOOP pattern. I. Localized Organizing Pneumonia
Localized organizing pneumonia is a focal lesion roentgenographically that shows organization in the bronchioles and distal air spaces."·" Besides differing clinically from idiopathic BOOp, localized organizing pneumonia may show loss of background alveolar architecture with fibrosis and marked fibrotic and inflammatory lesions in the wall of bronchioles causing luminal stenosis (Fig 3).
. f. ..
" l1'
~ ,
-c
' D~ .. ,.. .. ....
~
'
.
PATHOLOGIC DIFFERENTIAL DIAGNOSIS OF BOOP IN THE SPECTRUM OF INFILTRATIVE LUNG DISEASES
The major histopathologic findings in BOOP are as follows: polypoid masses of granulation tissues in the lumen of small airways, alveolar ducts, and some alveoli, a variable degree of interstitial infiltration of mononuclear cells and accumulation of foamy macrophages in alveolar spaces in a patchy distribution, and preservation of background architecture of the lung (Figs 1 and 2). I Pulmonary disorders that have been encountered in the pathologic differential diagnosis ofBOOP are shown in Table 13·' and are discussed in detail . Infectious P1dmonary Disease8
An infectious lung disease is important to exclude in the differential diagnosis, particularly for treatment. 3-5 After clinical examinations, an open lung biopsy specimen may be necessary for diagnosis of the pulmonary disease and lung tissues submitted for both microbiologic and histopathologic examinations. Findings such as a marked infiltration of polymorphonuclear leukocytes, granulomatous changes, and necrosis are suggestive of an infectious cause . Mycoplasma pneumoniae infection may present an acute or subacute clinical course with diffuse bilateral small nodular shadows on chest roentgenograms and may also cause histopathologic changes similar to those in idiopathic BOOp, including bronchiolitis obliterans and reparative metaplastic epithelial changes.5-7 Viruses such as the adena*From the Chest Disease Research Institute, Kyoto University, Kyoto, Japan. Reprint requests: Dr. Iatalchi, Chen Disease Research Institute , Kyoto UnlversUy, 53 Kawahara-cho , Shogoin, Salqp-ku, Kyoto ,
japan 606
44S
I FIGURE 1. A biopsy specimen of bronchiolitis obliterans organizing pneumonia (BOOP). Granulation tissues are formed in a respiratory bronchiole (asterisk) and a few alveolar ducts . These granulation tissues are continued into the wall of the bronchiole and alveolar ducts in a few places. Bronchiolar and alveolar walls show mild infiltration of lymphocytes and plasma cells (bematoxylin-eosin, original magnification 4X8),
FIGURE 2. Another biopsy specimen of BOOP. A respiratory bronchiole (asterisk) is filled with a granulation tissue that is continued into a portion of the bronchiolar wall. Many distal air spaces are filled with foamy cells (bematoxylin-eosin, original magnification 4X8). DtllenlnliaI DIagnosIs of BOOP (Masanorl KJtaichI)
Table I-Pathologic Di.ffenmtial DitJgnosia ofBOOP in the Spectrum oflnjiltratice Lung DilIea3e* Findings Negative for BOOP Honeycombing in the process of the diffuse infiltrative disease Fibrotic lesions with loss of background alveolar architecture Heterogeneous fibrotic lesions in distribution and in progress Necrosis or infarction Marked cellular infiltration in pleura or interlobular septa Solid nodular proliferation oflymphocytic cells Marked hyalinous exudates Granulomatous lesion Marked infiltration of eosinophils Marked reparative metaplastic changes of bronchiolar epithelial cells Marked infiltration of polymorphonuclear leukocyte (PMN) neutrophils
Vasculitis
Localized lesion
Suspected Pulmonary Diseases Usual interstitial pneumonia (UIP), other types of interstitial pneumonias UIp, organizing diffuse alveolar damage (organizing DAD), unclassified interstitial pneumonia (unclass IP), late fibrotic lesion of pulmonary eosinophilic granuloma, others VIp, fibrotic stage of pulmonary eosinophilic granuloma Infection including TB bacillus and virus, abscess, pulmonary infarction, lymphoproliferative disorder, Wegener's granulomatosis (WG) Lymphoproliferative disorder, eosinophilic pneumonia, WG Lymphoproliferative disorder DAD including infectious cause, acute interstitial pneumonia (AlP), eosinophilic pneumonia, WG, lymphoproliferative disorder Infection including TB bacilli and fungi, hypersensitivity pneumonitis, lymphoproliferative disorder, eosinophilic pneumonia, WG Eosinophilic pneumonia, WG Infection (mycoplasma) Infection, pulmonary abscess, acute bronchiolopneumonia, WG Infection, WG, eosinophilic pneumonia, lymphoproliferative disorder Localized organizing pneumonia, organizing pneumonia distal to endobronchial tumor, organizing pneumonia adjacent to bronchiectasis
*The histologic evaluation of biopsy specimens is usually made for those taken from the most involved areas of the lung for the diagnosis of BOOP. Apparent causes or associated diseases such as a collagen vascular disease should be excluded considering the clinical and follow-up information before the final diagnosis of BOOP (idiopathic BOOP).
UBtUJllnterBtitial Pneumoni6
Usual interstitial pneumonia (UIP) or idiopathic pulmonary fibrosis (IPF) has a chronic progressive course that is usually not altered by treatment.v'" Histologically, UIP shows a highly variegated structure often including the entire spectrum from normal alveolar walls to fibrotic, end-stage (honeycombing) lesions in the same tissue sample;" UIP may show several fibroblastic lesions protruding into the terminal air spaces-.... reminiscent of those in idiopathic BooP and may be difficult to differentiate if the biopsy sample is very small (Fig 4). However, in contrast to BOOp, UIP shows heterogeneous fibrotic lesions in spatial distribution and in progression, variable degrees of smooth muscle proliferation in fibrotic lesions and often honeycombing with or without mucin stasis being lined with mature epithelial cells. A pattern of peripheral acinar distribution is often identified in less fibrotic areas.3.' In contrast, BooP is more uniform in appearance with more prominent polypoid intraluminal lesions and architectural preservation. DiffuseAlveolarDamage
Diffuse alveolar damage (DAD) is a common histologic reaction in severe acute lung injury and shows a relatively broad spectrum...... I •• I • In the organizing stage, DAD may show granulation tissue polyps in bronchioles and alveolar ducts. In contrast to Boop, DAD usually also shows hyaline membranes and prominent hyalinous exudates with or without organization (Fig 5) but when these features are dissipating, in the later phase of DAD, differential diagnosis
on histologic features alone may be difficult. Clinical correlation is helpful. Unclas&ified InterBtitial Pneumoni6
Some cases of interstitial pneumonia of unknown etiology cannot be put into any of the well-described categories and may be termed as unclassified interstitial pneumonia (unclass IP).3.• Some of those show organization in the bronchioles and distal air spaces, as well as interstitial fibrosis causing loss of background alveolar architecture (Fig 6). ChronicEomnophilic Pneumoni6
Chronic eosinophilic pneumonia has significant infiltrations of eosinophils in the peripheral air spaces and/or the pulmonary interstitium. I... U Eosinophilic infiltrations are also seen in other types of pulmonary eosinophilia, I. including infectious etiologies." Chronic eosinophilic pneumonia is included in the differential diagnosis of Boop'13 because some cases of chronic eosinophilic pneumonia may not show marked eosinophilia either in examinations of blood or bronchoalveolar lavage fluid and there are true overlap cases of chronic eosinophilic pneumonia and idiopathic BooP clinically, roentgenographically, and histologically. In addition, few foca] tissue eosinophilia may be seen in cases of chronic eosinophilic pneumonia. In chronic eosinophilic pneumonia, intra-alveolar exudates of fibrin, bronchiolitis obliterans, eosinophilic microabscesses with intra-alveolar necrosis, sarcoid-like granulomas, and organizing pneumonia are observed with considerable frequency'•. (Figs 7 and 8). Eosinophils are numerous. In contrast, in idiopathic BooP eosinophils are sparse.
I.......
CHEST 1102 1 1 1 JULY, 1992 1 Supplement
45S
I
t
FIGURE 4. A biopsy specimen of usual interstitial pneumonia (UIP~ A(upper). Pulmonary lobules show patchy and periaclnar distribution of fibrotic lesions with loss of background alveolar structure being intermingled with normal alveolar walls. Interlobular septae (8) are not involved essentially (hematoxylin-eosin, original magnification lXS). B(lower). An elastic tissue stain of the specimen shown in Fig 4A. The periacinar dense fibrotic lesion shows aggregation and distortion of alveolar elastic frameworks. Fibroblastic lesions protrude into the distal air space (arrows), which is covered with epithelial lining cells. Some alveolar walls show fibrous thickening (Weigert's elastic van Ciesons method, original magnification 4.X8).
FIGURE 3. A surgical specimen of localized organizing pneumonia. A(top). A nodular pulmonary lesion shows marked chronic inflammatory and fibrotic changes with loss of background alveolar architecture (hematoxylin-eosin, original magnification lX8). B(center~ A higher magnification of Fig 3A. Bronchioles in the nodular pulmonary lesion show marked obliterative changes with subepithelial chronic inOammatory and fibrotic lesions (hematoxylin-eosin, original magnification 4.X8). C(bottom). A higher magnification of Fig 3A. Lung parenchyma adjacent to the nodular lesion shows granulation tissues formed in a respiratory bronchiole (asterisk) and alveolar ducts. The focal findings are similar to those in BooP (hematoxylin-eosin, original magnification 4X8). Hyperaemltioity Pneumonitis
Cases of hypersensitivity pneumonitis (extrinsic allergic alveolitis) show a granulomatous interstitial pneumonitis. In open lung biopsy specimens, the features include a cellular bronchiolitis (infiltration of lymphocytes and plasma cells along bronchioles), interstitial infiltrates (diffuse interstitial in61trates of chronic inflammatory cells), and granulomas
(scattered, small nonnecrotizing granulomas)""·· (Fig 9). In contrast to hypersensitivity pneumonitis, cases of BooP do not show granuloma formation and the process is more patchy in distribution. Idiopathic BooP is not related to particular seasons or environments as seen in farmer's lung disease" and summer-type hypersensitivity pneumonitis" when developing the pulmonary disorder (unpublished observation by the author). Wegeners Granulomatosis
Wegeners granulomatosis is a pulmonary necrotizing granulomatosis and angiitis of unknown etiology.· This disease includes a broad spectrum of pathologic manifestations, including pulmonary hemorrhage, marked tissue eosinophilia, and a BooP patternllll (Fig 10). In contrast, cases of idiopathic BooP do not show necrotizing granulomatous lesions or marked vasculitic features and do not have the systemic manifestations of Wegener's granulomatosis. ColUJgen \fucular Disease
Collagen vascular diseases are associated with a variety of noninfectious pulmonary lesions, including a BooP pattern.3.5·14..u.30 ,31 By definition, these cases are excluded DlfferentlaI DlagIlOllis 01 BOOP (Muanorl Kl/8lchf)
FIGURE 6. A biopsy specimen of unclassifled interstitial pneumonia. A(upper). An elastic tissue stain shows granulation tissues formed in a respiratory bronchiole (large arrow) and an alveolar duct (small arrow) with diffuse fibrous thickening of alveolar walls (Weigert's elastic van Gieson's method, original magnification 4X8). B(lower). Another histologic view of the same case . The histologic view shows extensive interstitial fibrotic lesions (asterisks) in the lobule with loss of background alveolar structure, a flndlng against a diagnosis of BooP (hematoxylln-eosin , original magnification lX8).
lblmonary lJpnphoproliferative Disorders
Pulmonary lymphoma may show organizing exudates in the bronchioles and distal air spaces in adjacent areas to the main pulmonary lesion." In contrast to BOOp, pulmonary FIGURE 5. A biopsy specimen of acute interstitial pneumonia (AlP) (idiopathic organizing diffuse alveolar damage). A(top). The biopsy specimen shows diffuse in1Iammatory and fibrotic lesions with multlfocalloss of background alveolar structure (hematoxylln-eosin, original magnification lX8). B(center). A higher magnification of Fig SA. Hyaline membranes are formed along peripheral airways while alveolar walls show fibrous thickening (hematoxylln-eosin, original magnification 10XS). C(bottcnn). A higher magnification of Fig SA. An organizing hyalinous exudate (arrow) is formed in a respiratory bronchiole. Adjacent alveolar areas show fibrous thicJcenlng of alveolar walls and extensive fibrotic lesions with loss of alveolar structures (hematoxylln-eosin, original magnification 4X8).
from idiopathic BOOP. lblmonary Lerlons due to Drugs
Some drugs may cause a BOOP pattern. lUll When the clinical history or lymphocyte stimulation tests suggest a drug to be the causative agent of the pulmonary disorder, the case is excluded by definition from being idiopathic BOOP.
FIGURE 7. A biopsy specimen of chronic eosinophilic pneumonia. Granulation tissues are formed in a respiratory bronchiole (arrow) and alveolar ducts . Many eosinophils are inflltrated in the granulation tissues, alveolar air spaces, and interstitium (hematoxylin-eosin, original magnification 4X8). CHEST' 102 , 1 , JULY, 1992 , SUpplement
478
FIGURE 10. A biopsy specimen of Wegeners granulomatosis. The field of view shows a granulation tissue formed in a respiratory bronchiole. The interstitium shows moderate infiltration oflymphoeytes and plasma cells and a germinal center in the bronchiolar wall (hematoxylin-eosin, original magnification 4X8).
_-'::''''040 -;('::-
FIGURE 8. Another biopsy specimen of chronic eosinophilic pneumonia. A(upper). Lung parenchyma shows eosinophilic microabscesses with focal intraalveolar necrosis and a rim of histiocytes, byalinous exudates, and a granulation tissue (asterisk) in an alveolar duct. Many eosinophils are infiltrated in these lesions (hematoxylineosin, original magnification IOX8). B(lower). Another view of the same biopsy specimen of Fig 8A. Granulation tissues are formed in a respiratory bronchiole (arrow) and alveolar ducts. Lymphocytes and plasma cells are infiltrated in the interstitium . The focal area shows a BooP pattern (hematoxylin-eosin, original magnification 4X8).
lymphomas usually also show necrotizing lesions and/or marked hyallnous exudates, as well as the obvious infiltration of atypical lymphoid cells, usually along interlobular septae, bronchiolovascular bundles, and visceral pleura (Fig 11).
Others
Alveolar tissues surrounding carcinomas, bronchiectasis, and histiocytosis X lesions may show a BOOP pattern." PATHOLOGIC DIFFERENTIAL DIAGNOSIS OF BOOP IN THE SPECTRUM OF BRONCHIOLITIS OBLITERANS
~ FIGURE 9. A biopsy specimen of hypersensitivity pneumonitis. Granulation tissues are formed in a respiratory bronchiole (large arrow) and alveolar ducts. Lymphoid cells are infiltrated in the wall ofthe bronchiole and alveoli. Twogranulomas having multinucleated giant cells are formed in the interstitium (small arrows) (hematoxylin-eosm, original magnification 4X8). 48S
Two types of bronchiolitis obliterans can be identified:"'," proliferative bronchiolitis obliterans and constrictive bronchiolitis. In the former type . bronchiolar lumens have polypoid masses of organizing exudates or granulation tissues. In constrictive bronchiolitis, bronchioles are obstructed or stenosed by peribronchiolar, mural, or subepithelial fibrosis, sometimes with complete occlusion. Constrictive bronchiolitis is usually associated with airflow obstruction. BOOP shows proliferative bronchiolitis obliterans. The spectrum of pulmonary lesions showing either proliferative bronchiolitis obliterans or constrictive bronchiolitis are reviewed in the literature.v- sa,.. SUMMARY
The disease concept of idiopathic BooP has emerged from a study of many open lung biopsy cases of diffuse Dlfferential Diagnosis 0/ BOOP (Masanorl KJtaIc:hI)
infiltrative lung disease. 1 The histopathologic features of idiopathic BOOP have several components: bronchiolitis obliterans, organizing pneumonia, accumulation of foamy
MllllH lk@ ~PlBk~N1
alP IlWAl, uA b\t~~lIHa1Idl~()ft
of mononuclear ceDs. These pathologic findings are nonspecific and many conditions show such a BOOP pattern. Idiopathic BOOP has been discussed in the context of bronchiolitis obliterans, organizing pneumonia, and interstitial pneumonia.H.1.1l.lS.14.:W While clinically idiopathic BOOP has a relatively broad spectrum of manifestation, BOOP stands as a clinicopathologic disease entity among diffuse infiltrative lung diseases of unknown etiology. REFERENCES 1 Epler GR, Colby ~ McLoud TC, Carrington CD, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152-58 2 Colby ~ Churg AC. Patterns of pulmonary fibrosis. Pathol Annu 1986; 21:277-309 3 Colby ~ Lombard C, Yousem SA, Kitaichi M. Atlas of pulmonary surgical pathol~ Philadelphia: WB Saunders Co, 1991 4 Kitaichi M. Pathologic features and the classification of interstitial pneumonia of unknown etiol~ Bull Chest Dis Res Inst Kyoto Univ 1990; 23:1-18 5 Flint A, Colby ~ Surgical pathology of diftUse infiltrative lung disease. Orlando: Grone ~ Stratton, 1987 6 Rollins S, Colby ~ Clayton F. Open lung biopsy in Mycoplasma pneumoniae pneumonia. Arch Pathol Lab Med 1986; 110:34-41 7 Kitaichi M, Nishimura K, Izumi T. Diffuse panbronchiolitis. In: Sharma O~ edt Lung disease in the tropics. New York: Marcel Dekker Inc, 1991:479-509 8 Becroft D MO. Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children. J Clin PathoII971; 24:72-82 9 Wohl MEB, Chernick Bronchiolitis. Am Rev Respir Dis 1978; 118:759-81 10 Sato ~ Madtes DK, Thorning D, Albert RIC. Bronchiolitis obliterans caused by l£gIonelia pneumophlla. Chest 1985; 87: 840-42 11 Epler GR, Colby ~ The spectrum of bronchiolitis obliterans. Chest 1983; 83:161-62 12 SulavilcSB. The concept ofuorganizing pneumonia:' Chest 1989; 96:967-69 13 Carrington CB, Gaensler EA, Coutu BE, FitzGerald MX, Gupta RG. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298:
v
801-09
14 Katzenstein A-LA, Askin FB. Surgical pathology of non-neoplastic lung disease. Philadelphia: WB Saunders Co, 1990 15 Olson], Colby ~ Elliott CG. Hamman-Rich syndrome revis-
i~1
MIYO Goo fIOO I.!M!IM
16 Bayley EC, Lindberg DON, Baggestoss AH. Loeftler's syndrome. Arch Pathol Lab Med 1945; 40:376-81 17 Christoforidis AJ. Eosinophilic pneumonia. JAMA 1960; 173: 157-61 18 Liebow AA, Carrington CB. The eosiniophilic pneumonias. Medicine 1969; 48:251-85 19 Carrington CB, Addington ww, Goff AM, Madoff 1M, Marks A, Schwaber JR, et ale Chronic eosiniophilic pneumonia. N Engl J Med 1969; 280:787-98 20 Bedrossian CM, Greenberg SD, Wtlliams LJ. Ultrastructure of the lung in Loe8ler's pneumonia. Am ] Med 1975; 58:438-43 21 Dail DH. Hammar S (eds). Pulmonary pathol~ New York: Springer-Verlag, 1988 22 Wright JL, Pare PD, Hammond M, Donevan RE. Eosinophilic pneumonia and atypical mycobacterial infection. Am Rev Respir Dis 1983; 127:497-99 23 Jederinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia. Medicine 1988; 67:154-62 24 Cooney TE Interrelationship of chronic eosinophilic pneumonia, bronchiolitis obliterans, and rheumatoid disease: a hypothesis. J Clin PathoII981; 34:129-37 25 Reyes CN, Wenzel FJ, Lawton DR, Emanuel DA. The pulmonary pathology of farmer's lung disease. Chest 1982; 81:142-46 26 Coleman A, Colby ~ Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Patholl988; 2:514-18 27 Ando M. Summer-type hypersensitivity pneumonitis. In: Sharma O~ edt Lung disease in the tropics. New York: Marcel Dekker, 1991:449-78 28 Churg A. Pulmonary angiitis and granulomatosis revisited. Hum Patholl983; 14:868-83 29 Yousem SA, LombardCM. The eosinophilic variant of Wegener's granulomatosis. Hum Patholl988; 19:682-88 30 Yousem SA, Colby ~ Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis 1985; 131:770-77 31 Tazelaar HD, Viggiano ~ Pikersgill J, Colby ~ Interstitial lung disease in polymyositis and dermatomyositis. Am Rev Respir Dis 1990; 141:727-33 32 Camus ~ Lombard J, Perrichon M, Piard F, Guerin J, Thivolet FB, et ale Bronchiolitis obliterans organizing pneumonia in patients taking acebutolol or amiodarone. Thorax 1989; 44:71115 33 Gosink B, Friedman PJ, Liebow M. Bronchiolitis obliterans. AJR 1973; 117:816-32 34 ICingTE Jr. Bronchiolitis obliterans. Schwartz MI, ICingTE Jr, eds. In: Interstitial lung disease. Toronto: BC Decker Inc, 1988: 325-42
CHEST I 102 I 1 I JUL~
1992 I Supplement
48S
B
ronchiolitis obliterans organizing pneumonia (BOOP) is a distinct entity among the spectrum ofinfiltrative lung diseases without apparent causes or associated diseases. I While the disease concept of BOOP is based on the combination of clinical setting and pathologic findings, histopathologic features ofBOOP (ie, bronchiolitis obliterans and organizing pneumonia) are not speciDc and are seen in various pulmonary diseases, including infectious and noninfectious diseases." Because of this, the term BOOP bas caused some confusion and, to avoid this, the term idiopathic BOOP will be used. Idiopathic BOOP is an infiltrative lung disease with a subacute clinical course, and therefore, both acute and chronic pulmonary diseases must be considered in the differential diagnosis before a diagnosis of BOOP can be established. This review is based on the Kyotosymposium on BOOP between November 29 and December 1, 1990, personal study, and a review of the literature.
virus may cause obliterative changes of bronchioles but with airllowobstruction, and therefore, they differ clinically from BOOP.··· Legionella pneumophila is reported to cause a BOOP pattern. I. Localized Organizing Pneumonia
Localized organizing pneumonia is a focal lesion roentgenographically that shows organization in the bronchioles and distal air spaces."·" Besides differing clinically from idiopathic BOOp, localized organizing pneumonia may show loss of background alveolar architecture with fibrosis and marked fibrotic and inflammatory lesions in the wall of bronchioles causing luminal stenosis (Fig 3).
. f. ..
" l1'
~ ,
-c
' D~ .. ,.. .. ....
~
'
.
PATHOLOGIC DIFFERENTIAL DIAGNOSIS OF BOOP IN THE SPECTRUM OF INFILTRATIVE LUNG DISEASES
The major histopathologic findings in BOOP are as follows: polypoid masses of granulation tissues in the lumen of small airways, alveolar ducts, and some alveoli, a variable degree of interstitial infiltration of mononuclear cells and accumulation of foamy macrophages in alveolar spaces in a patchy distribution, and preservation of background architecture of the lung (Figs 1 and 2). I Pulmonary disorders that have been encountered in the pathologic differential diagnosis ofBOOP are shown in Table 13·' and are discussed in detail . Infectious P1dmonary Disease8
An infectious lung disease is important to exclude in the differential diagnosis, particularly for treatment. 3-5 After clinical examinations, an open lung biopsy specimen may be necessary for diagnosis of the pulmonary disease and lung tissues submitted for both microbiologic and histopathologic examinations. Findings such as a marked infiltration of polymorphonuclear leukocytes, granulomatous changes, and necrosis are suggestive of an infectious cause . Mycoplasma pneumoniae infection may present an acute or subacute clinical course with diffuse bilateral small nodular shadows on chest roentgenograms and may also cause histopathologic changes similar to those in idiopathic BOOp, including bronchiolitis obliterans and reparative metaplastic epithelial changes.5-7 Viruses such as the adena*From the Chest Disease Research Institute, Kyoto University, Kyoto, Japan. Reprint requests: Dr. Iatalchi, Chen Disease Research Institute , Kyoto UnlversUy, 53 Kawahara-cho , Shogoin, Salqp-ku, Kyoto ,
japan 606
44S
I FIGURE 1. A biopsy specimen of bronchiolitis obliterans organizing pneumonia (BOOP). Granulation tissues are formed in a respiratory bronchiole (asterisk) and a few alveolar ducts . These granulation tissues are continued into the wall of the bronchiole and alveolar ducts in a few places. Bronchiolar and alveolar walls show mild infiltration of lymphocytes and plasma cells (bematoxylin-eosin, original magnification 4X8),
FIGURE 2. Another biopsy specimen of BOOP. A respiratory bronchiole (asterisk) is filled with a granulation tissue that is continued into a portion of the bronchiolar wall. Many distal air spaces are filled with foamy cells (bematoxylin-eosin, original magnification 4X8). DtllenlnliaI DIagnosIs of BOOP (Masanorl KJtaichI)
Table I-Pathologic Di.ffenmtial DitJgnosia ofBOOP in the Spectrum oflnjiltratice Lung DilIea3e* Findings Negative for BOOP Honeycombing in the process of the diffuse infiltrative disease Fibrotic lesions with loss of background alveolar architecture Heterogeneous fibrotic lesions in distribution and in progress Necrosis or infarction Marked cellular infiltration in pleura or interlobular septa Solid nodular proliferation oflymphocytic cells Marked hyalinous exudates Granulomatous lesion Marked infiltration of eosinophils Marked reparative metaplastic changes of bronchiolar epithelial cells Marked infiltration of polymorphonuclear leukocyte (PMN) neutrophils
Vasculitis
Localized lesion
Suspected Pulmonary Diseases Usual interstitial pneumonia (UIP), other types of interstitial pneumonias UIp, organizing diffuse alveolar damage (organizing DAD), unclassified interstitial pneumonia (unclass IP), late fibrotic lesion of pulmonary eosinophilic granuloma, others VIp, fibrotic stage of pulmonary eosinophilic granuloma Infection including TB bacillus and virus, abscess, pulmonary infarction, lymphoproliferative disorder, Wegener's granulomatosis (WG) Lymphoproliferative disorder, eosinophilic pneumonia, WG Lymphoproliferative disorder DAD including infectious cause, acute interstitial pneumonia (AlP), eosinophilic pneumonia, WG, lymphoproliferative disorder Infection including TB bacilli and fungi, hypersensitivity pneumonitis, lymphoproliferative disorder, eosinophilic pneumonia, WG Eosinophilic pneumonia, WG Infection (mycoplasma) Infection, pulmonary abscess, acute bronchiolopneumonia, WG Infection, WG, eosinophilic pneumonia, lymphoproliferative disorder Localized organizing pneumonia, organizing pneumonia distal to endobronchial tumor, organizing pneumonia adjacent to bronchiectasis
*The histologic evaluation of biopsy specimens is usually made for those taken from the most involved areas of the lung for the diagnosis of BOOP. Apparent causes or associated diseases such as a collagen vascular disease should be excluded considering the clinical and follow-up information before the final diagnosis of BOOP (idiopathic BOOP).
UBtUJllnterBtitial Pneumoni6
Usual interstitial pneumonia (UIP) or idiopathic pulmonary fibrosis (IPF) has a chronic progressive course that is usually not altered by treatment.v'" Histologically, UIP shows a highly variegated structure often including the entire spectrum from normal alveolar walls to fibrotic, end-stage (honeycombing) lesions in the same tissue sample;" UIP may show several fibroblastic lesions protruding into the terminal air spaces-.... reminiscent of those in idiopathic BooP and may be difficult to differentiate if the biopsy sample is very small (Fig 4). However, in contrast to BOOp, UIP shows heterogeneous fibrotic lesions in spatial distribution and in progression, variable degrees of smooth muscle proliferation in fibrotic lesions and often honeycombing with or without mucin stasis being lined with mature epithelial cells. A pattern of peripheral acinar distribution is often identified in less fibrotic areas.3.' In contrast, BooP is more uniform in appearance with more prominent polypoid intraluminal lesions and architectural preservation. DiffuseAlveolarDamage
Diffuse alveolar damage (DAD) is a common histologic reaction in severe acute lung injury and shows a relatively broad spectrum...... I •• I • In the organizing stage, DAD may show granulation tissue polyps in bronchioles and alveolar ducts. In contrast to Boop, DAD usually also shows hyaline membranes and prominent hyalinous exudates with or without organization (Fig 5) but when these features are dissipating, in the later phase of DAD, differential diagnosis
on histologic features alone may be difficult. Clinical correlation is helpful. Unclas&ified InterBtitial Pneumoni6
Some cases of interstitial pneumonia of unknown etiology cannot be put into any of the well-described categories and may be termed as unclassified interstitial pneumonia (unclass IP).3.• Some of those show organization in the bronchioles and distal air spaces, as well as interstitial fibrosis causing loss of background alveolar architecture (Fig 6). ChronicEomnophilic Pneumoni6
Chronic eosinophilic pneumonia has significant infiltrations of eosinophils in the peripheral air spaces and/or the pulmonary interstitium. I... U Eosinophilic infiltrations are also seen in other types of pulmonary eosinophilia, I. including infectious etiologies." Chronic eosinophilic pneumonia is included in the differential diagnosis of Boop'13 because some cases of chronic eosinophilic pneumonia may not show marked eosinophilia either in examinations of blood or bronchoalveolar lavage fluid and there are true overlap cases of chronic eosinophilic pneumonia and idiopathic BooP clinically, roentgenographically, and histologically. In addition, few foca] tissue eosinophilia may be seen in cases of chronic eosinophilic pneumonia. In chronic eosinophilic pneumonia, intra-alveolar exudates of fibrin, bronchiolitis obliterans, eosinophilic microabscesses with intra-alveolar necrosis, sarcoid-like granulomas, and organizing pneumonia are observed with considerable frequency'•. (Figs 7 and 8). Eosinophils are numerous. In contrast, in idiopathic BooP eosinophils are sparse.
I.......
CHEST 1102 1 1 1 JULY, 1992 1 Supplement
45S
I
t
FIGURE 4. A biopsy specimen of usual interstitial pneumonia (UIP~ A(upper). Pulmonary lobules show patchy and periaclnar distribution of fibrotic lesions with loss of background alveolar structure being intermingled with normal alveolar walls. Interlobular septae (8) are not involved essentially (hematoxylin-eosin, original magnification lXS). B(lower). An elastic tissue stain of the specimen shown in Fig 4A. The periacinar dense fibrotic lesion shows aggregation and distortion of alveolar elastic frameworks. Fibroblastic lesions protrude into the distal air space (arrows), which is covered with epithelial lining cells. Some alveolar walls show fibrous thickening (Weigert's elastic van Ciesons method, original magnification 4.X8).
FIGURE 3. A surgical specimen of localized organizing pneumonia. A(top). A nodular pulmonary lesion shows marked chronic inflammatory and fibrotic changes with loss of background alveolar architecture (hematoxylin-eosin, original magnification lX8). B(center~ A higher magnification of Fig 3A. Bronchioles in the nodular pulmonary lesion show marked obliterative changes with subepithelial chronic inOammatory and fibrotic lesions (hematoxylin-eosin, original magnification 4.X8). C(bottom). A higher magnification of Fig 3A. Lung parenchyma adjacent to the nodular lesion shows granulation tissues formed in a respiratory bronchiole (asterisk) and alveolar ducts. The focal findings are similar to those in BooP (hematoxylin-eosin, original magnification 4X8). Hyperaemltioity Pneumonitis
Cases of hypersensitivity pneumonitis (extrinsic allergic alveolitis) show a granulomatous interstitial pneumonitis. In open lung biopsy specimens, the features include a cellular bronchiolitis (infiltration of lymphocytes and plasma cells along bronchioles), interstitial infiltrates (diffuse interstitial in61trates of chronic inflammatory cells), and granulomas
(scattered, small nonnecrotizing granulomas)""·· (Fig 9). In contrast to hypersensitivity pneumonitis, cases of BooP do not show granuloma formation and the process is more patchy in distribution. Idiopathic BooP is not related to particular seasons or environments as seen in farmer's lung disease" and summer-type hypersensitivity pneumonitis" when developing the pulmonary disorder (unpublished observation by the author). Wegeners Granulomatosis
Wegeners granulomatosis is a pulmonary necrotizing granulomatosis and angiitis of unknown etiology.· This disease includes a broad spectrum of pathologic manifestations, including pulmonary hemorrhage, marked tissue eosinophilia, and a BooP patternllll (Fig 10). In contrast, cases of idiopathic BooP do not show necrotizing granulomatous lesions or marked vasculitic features and do not have the systemic manifestations of Wegener's granulomatosis. ColUJgen \fucular Disease
Collagen vascular diseases are associated with a variety of noninfectious pulmonary lesions, including a BooP pattern.3.5·14..u.30 ,31 By definition, these cases are excluded DlfferentlaI DlagIlOllis 01 BOOP (Muanorl Kl/8lchf)
FIGURE 6. A biopsy specimen of unclassifled interstitial pneumonia. A(upper). An elastic tissue stain shows granulation tissues formed in a respiratory bronchiole (large arrow) and an alveolar duct (small arrow) with diffuse fibrous thickening of alveolar walls (Weigert's elastic van Gieson's method, original magnification 4X8). B(lower). Another histologic view of the same case . The histologic view shows extensive interstitial fibrotic lesions (asterisks) in the lobule with loss of background alveolar structure, a flndlng against a diagnosis of BooP (hematoxylln-eosin , original magnification lX8).
lblmonary lJpnphoproliferative Disorders
Pulmonary lymphoma may show organizing exudates in the bronchioles and distal air spaces in adjacent areas to the main pulmonary lesion." In contrast to BOOp, pulmonary FIGURE 5. A biopsy specimen of acute interstitial pneumonia (AlP) (idiopathic organizing diffuse alveolar damage). A(top). The biopsy specimen shows diffuse in1Iammatory and fibrotic lesions with multlfocalloss of background alveolar structure (hematoxylln-eosin, original magnification lX8). B(center). A higher magnification of Fig SA. Hyaline membranes are formed along peripheral airways while alveolar walls show fibrous thickening (hematoxylln-eosin, original magnification 10XS). C(bottcnn). A higher magnification of Fig SA. An organizing hyalinous exudate (arrow) is formed in a respiratory bronchiole. Adjacent alveolar areas show fibrous thicJcenlng of alveolar walls and extensive fibrotic lesions with loss of alveolar structures (hematoxylln-eosin, original magnification 4X8).
from idiopathic BOOP. lblmonary Lerlons due to Drugs
Some drugs may cause a BOOP pattern. lUll When the clinical history or lymphocyte stimulation tests suggest a drug to be the causative agent of the pulmonary disorder, the case is excluded by definition from being idiopathic BOOP.
FIGURE 7. A biopsy specimen of chronic eosinophilic pneumonia. Granulation tissues are formed in a respiratory bronchiole (arrow) and alveolar ducts . Many eosinophils are inflltrated in the granulation tissues, alveolar air spaces, and interstitium (hematoxylin-eosin, original magnification 4X8). CHEST' 102 , 1 , JULY, 1992 , SUpplement
478
FIGURE 10. A biopsy specimen of Wegeners granulomatosis. The field of view shows a granulation tissue formed in a respiratory bronchiole. The interstitium shows moderate infiltration oflymphoeytes and plasma cells and a germinal center in the bronchiolar wall (hematoxylin-eosin, original magnification 4X8).
_-'::''''040 -;('::-
FIGURE 8. Another biopsy specimen of chronic eosinophilic pneumonia. A(upper). Lung parenchyma shows eosinophilic microabscesses with focal intraalveolar necrosis and a rim of histiocytes, byalinous exudates, and a granulation tissue (asterisk) in an alveolar duct. Many eosinophils are infiltrated in these lesions (hematoxylineosin, original magnification IOX8). B(lower). Another view of the same biopsy specimen of Fig 8A. Granulation tissues are formed in a respiratory bronchiole (arrow) and alveolar ducts. Lymphocytes and plasma cells are infiltrated in the interstitium . The focal area shows a BooP pattern (hematoxylin-eosin, original magnification 4X8).
lymphomas usually also show necrotizing lesions and/or marked hyallnous exudates, as well as the obvious infiltration of atypical lymphoid cells, usually along interlobular septae, bronchiolovascular bundles, and visceral pleura (Fig 11).
Others
Alveolar tissues surrounding carcinomas, bronchiectasis, and histiocytosis X lesions may show a BOOP pattern." PATHOLOGIC DIFFERENTIAL DIAGNOSIS OF BOOP IN THE SPECTRUM OF BRONCHIOLITIS OBLITERANS
~ FIGURE 9. A biopsy specimen of hypersensitivity pneumonitis. Granulation tissues are formed in a respiratory bronchiole (large arrow) and alveolar ducts. Lymphoid cells are infiltrated in the wall ofthe bronchiole and alveoli. Twogranulomas having multinucleated giant cells are formed in the interstitium (small arrows) (hematoxylin-eosm, original magnification 4X8). 48S
Two types of bronchiolitis obliterans can be identified:"'," proliferative bronchiolitis obliterans and constrictive bronchiolitis. In the former type . bronchiolar lumens have polypoid masses of organizing exudates or granulation tissues. In constrictive bronchiolitis, bronchioles are obstructed or stenosed by peribronchiolar, mural, or subepithelial fibrosis, sometimes with complete occlusion. Constrictive bronchiolitis is usually associated with airflow obstruction. BOOP shows proliferative bronchiolitis obliterans. The spectrum of pulmonary lesions showing either proliferative bronchiolitis obliterans or constrictive bronchiolitis are reviewed in the literature.v- sa,.. SUMMARY
The disease concept of idiopathic BooP has emerged from a study of many open lung biopsy cases of diffuse Dlfferential Diagnosis 0/ BOOP (Masanorl KJtaIc:hI)
infiltrative lung disease. 1 The histopathologic features of idiopathic BOOP have several components: bronchiolitis obliterans, organizing pneumonia, accumulation of foamy
MllllH lk@ ~PlBk~N1
alP IlWAl, uA b\t~~lIHa1Idl~()ft
of mononuclear ceDs. These pathologic findings are nonspecific and many conditions show such a BOOP pattern. Idiopathic BOOP has been discussed in the context of bronchiolitis obliterans, organizing pneumonia, and interstitial pneumonia.H.1.1l.lS.14.:W While clinically idiopathic BOOP has a relatively broad spectrum of manifestation, BOOP stands as a clinicopathologic disease entity among diffuse infiltrative lung diseases of unknown etiology. REFERENCES 1 Epler GR, Colby ~ McLoud TC, Carrington CD, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312:152-58 2 Colby ~ Churg AC. Patterns of pulmonary fibrosis. Pathol Annu 1986; 21:277-309 3 Colby ~ Lombard C, Yousem SA, Kitaichi M. Atlas of pulmonary surgical pathol~ Philadelphia: WB Saunders Co, 1991 4 Kitaichi M. Pathologic features and the classification of interstitial pneumonia of unknown etiol~ Bull Chest Dis Res Inst Kyoto Univ 1990; 23:1-18 5 Flint A, Colby ~ Surgical pathology of diftUse infiltrative lung disease. Orlando: Grone ~ Stratton, 1987 6 Rollins S, Colby ~ Clayton F. Open lung biopsy in Mycoplasma pneumoniae pneumonia. Arch Pathol Lab Med 1986; 110:34-41 7 Kitaichi M, Nishimura K, Izumi T. Diffuse panbronchiolitis. In: Sharma O~ edt Lung disease in the tropics. New York: Marcel Dekker Inc, 1991:479-509 8 Becroft D MO. Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children. J Clin PathoII971; 24:72-82 9 Wohl MEB, Chernick Bronchiolitis. Am Rev Respir Dis 1978; 118:759-81 10 Sato ~ Madtes DK, Thorning D, Albert RIC. Bronchiolitis obliterans caused by l£gIonelia pneumophlla. Chest 1985; 87: 840-42 11 Epler GR, Colby ~ The spectrum of bronchiolitis obliterans. Chest 1983; 83:161-62 12 SulavilcSB. The concept ofuorganizing pneumonia:' Chest 1989; 96:967-69 13 Carrington CB, Gaensler EA, Coutu BE, FitzGerald MX, Gupta RG. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298:
v
801-09
14 Katzenstein A-LA, Askin FB. Surgical pathology of non-neoplastic lung disease. Philadelphia: WB Saunders Co, 1990 15 Olson], Colby ~ Elliott CG. Hamman-Rich syndrome revis-
i~1
MIYO Goo fIOO I.!M!IM
16 Bayley EC, Lindberg DON, Baggestoss AH. Loeftler's syndrome. Arch Pathol Lab Med 1945; 40:376-81 17 Christoforidis AJ. Eosinophilic pneumonia. JAMA 1960; 173: 157-61 18 Liebow AA, Carrington CB. The eosiniophilic pneumonias. Medicine 1969; 48:251-85 19 Carrington CB, Addington ww, Goff AM, Madoff 1M, Marks A, Schwaber JR, et ale Chronic eosiniophilic pneumonia. N Engl J Med 1969; 280:787-98 20 Bedrossian CM, Greenberg SD, Wtlliams LJ. Ultrastructure of the lung in Loe8ler's pneumonia. Am ] Med 1975; 58:438-43 21 Dail DH. Hammar S (eds). Pulmonary pathol~ New York: Springer-Verlag, 1988 22 Wright JL, Pare PD, Hammond M, Donevan RE. Eosinophilic pneumonia and atypical mycobacterial infection. Am Rev Respir Dis 1983; 127:497-99 23 Jederinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia. Medicine 1988; 67:154-62 24 Cooney TE Interrelationship of chronic eosinophilic pneumonia, bronchiolitis obliterans, and rheumatoid disease: a hypothesis. J Clin PathoII981; 34:129-37 25 Reyes CN, Wenzel FJ, Lawton DR, Emanuel DA. The pulmonary pathology of farmer's lung disease. Chest 1982; 81:142-46 26 Coleman A, Colby ~ Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Patholl988; 2:514-18 27 Ando M. Summer-type hypersensitivity pneumonitis. In: Sharma O~ edt Lung disease in the tropics. New York: Marcel Dekker, 1991:449-78 28 Churg A. Pulmonary angiitis and granulomatosis revisited. Hum Patholl983; 14:868-83 29 Yousem SA, LombardCM. The eosinophilic variant of Wegener's granulomatosis. Hum Patholl988; 19:682-88 30 Yousem SA, Colby ~ Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis 1985; 131:770-77 31 Tazelaar HD, Viggiano ~ Pikersgill J, Colby ~ Interstitial lung disease in polymyositis and dermatomyositis. Am Rev Respir Dis 1990; 141:727-33 32 Camus ~ Lombard J, Perrichon M, Piard F, Guerin J, Thivolet FB, et ale Bronchiolitis obliterans organizing pneumonia in patients taking acebutolol or amiodarone. Thorax 1989; 44:71115 33 Gosink B, Friedman PJ, Liebow M. Bronchiolitis obliterans. AJR 1973; 117:816-32 34 ICingTE Jr. Bronchiolitis obliterans. Schwartz MI, ICingTE Jr, eds. In: Interstitial lung disease. Toronto: BC Decker Inc, 1988: 325-42
CHEST I 102 I 1 I JUL~
1992 I Supplement
48S
