Abstract. American Society for Clinical Pathology. Am J Clin Pathol 2009;131: DOI: /AJCPNWX4SLZRP9SW 405

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1 Anatomic Pathology / Chronic Hypersensitivity Pneumonitis Histopathologic Analysis of Sixteen Autopsy Cases of Chronic Hypersensitivity Pneumonitis and Comparison With Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia Takumi Akashi, MD, PhD, 1 Tamiko Takemura, MD, PhD, 2 Noboru Ando, MT, 1 Yoshinobu Eishi, MD, PhD, 1 Masanobu Kitagawa, MD, PhD, 1 Touichirou Takizawa, MD, PhD, 1 Morio Koike, MD, PhD, 1 Yoshio Ohtani, MD, PhD, 3 Yasunari Miyazaki, MD, PhD, 3 Naohiko Inase, MD, PhD, 3 and Yasuyuki Yoshizawa, MD, PhD 3 Key Words: Chronic hypersensitivity pneumonitis; Idiopathic pulmonary fibrosis; Usual interstitial pneumonia; Centrilobular fibrosis; Threedimensional reconstruction; Autopsy Abstract Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by the inhalation of organic substances and certain inorganic chemicals. The histopathologic features of chronic HP (CHP) have not been studied extensively. We examined the pathologic characteristics of 16 autopsy cases of clinically confirmed CHP and compared them with 11 cases of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). To clarify the exact intralobular location of the fibrotic lesions, we conducted 3-dimensional reconstruction of fibrosis of CHP and IPF/UIP. Granuloma was not detected in any CHP case. Similar to IPF/UIP, honeycombing lesions were found dominantly in the lower lobes in most CHP cases; upper lobe dominance and asymmetrical distribution of honeycomb lesions were more frequent in CHP than in IPF/UIP. In all lungs affected by CHP, centrilobular fibrosis was outstanding, often connecting to the perilobular areas in the appearance of bridging fibrosis, which was clearly demonstrated by 3-dimensional imaging. Centrilobular and bridging fibrosis were significantly more conspicuous in CHP than IPF/UIP; however, considerable overlap was found. It is important to thoroughly explore the possibility of antigen exposure in cases of lungs with UIP with centrilobular fibrosis to discriminate CHP from IPF/UIP. Hypersensitivity pneumonitis (HP) is one of the interstitial lung diseases caused by the inhalation of organic substances and certain inorganic chemicals. HP is clinically classified into 3 forms: acute, subacute, and chronic. 1 Acute HP is characterized by systemic symptoms after exposure to high doses of causative antigens. The subacute and chronic forms of HP are considered to be induced by low antigen doses, and they are distinguished based on the presence of fibrosis in radiographic examinations. 2,3 The histopathologic characteristics of acute HP, ie, lymphocytic alveolitis with bronchiolocentric accentuation, nonnecrotizing epithelioid cell granulomas, intra-alveolar fibrosis, and cellular bronchiolitis, are well established. 4,5 The precise autopsy findings of acute HP, such as farmer s lung (including its later stage) were documented previously; they were characterized by interstitial fibrosis with upper lobe dominance and peribronchial accentuation. 6 In contrast with acute HP, the histopathologic features of chronic HP (CHP) have not been studied extensively. Recently, several reports presented the histopathologic findings of surgical specimens of CHP, and its features became clear; usual interstitial pneumonia (UIP)-like or nonspecific interstitial pneumonia (NSIP)-like interstitial fibrosis with characteristic peribronchiolar distribution, mild alveolitis/ bronchiolitis, and limited granuloma formation. 3,7-9 Herein, we describe 16 autopsy cases of clinically confirmed CHP, a topic that has rarely been addressed previously. Pathologic examination of autopsy lungs gives valuable information such as various stages of fibrosis, including early patchy fibrosis and honeycombing lesions, and their distribution and progression in the lungs. In previous reports, early fibrotic lesions showing centrilobular distribution were considered one of the histologic Am J Clin Pathol 2009;131:

2 Akashi et al / Chronic Hypersensitivity Pneumonitis characteristics of CHP. 3,7,8 Silva et al 10 also described that the best computed tomographic (CT) features for differentiating CHP from idiopathic pulmonary fibrosis (IPF)/UIP were centrilobular nodules. Accordingly, we compared the autopsy findings in CHP, particularly the pattern of fibrosis, with those of IPF/UIP, which was often difficult in differential diagnosis, both clinically and histopathologically. To clarify the exact intralobular location of the fibrotic lesions, we created 3-dimensional (3-D) images of the early fibrotic lesions of CHP, particularly in correlation with respiratory bronchioles, and compared them with those of IPF/UIP. Materials and Methods We examined 16 cases of CHP autopsied in the Tokyo Medical and Dental University Hospital, Tokyo, Japan, between 1999 and Among them, 7 cases had surgical lung biopsies. The diagnostic criteria for CHP comprised 3 or more of the following conditions 2,8,11 : (1) recurrence of HP symptoms triggered by an environmental stimulus or laboratory-controlled inhalation of the antigen; (2) antibodies and/or lymphocyte proliferation to the antigen; (3) evidence of pulmonary fibrosis with or without granulomas; (4) honeycombing evident on CT scans; (5) progressive deterioration of a restrictive impairment in pulmonary function during 1 year; and (6) persistence of respiratory symptoms associated with HP for more than 6 months. All cases fulfilled the diagnostic criteria for CHP. After the diagnosis of CHP, the patients avoided antigen exposure. All cases were treated with corticosteroids, and 11 cases were treated with additional immunosuppressants. We also evaluated the terminal events, such as acute exacerbation 12,13 and infection. We also examined 11 cases of IPF/UIP from the Tokyo Medical and Dental University Hospital and the Japanese Red Cross Medical Center, Tokyo, for clinical and pathologic comparison. IPF and UIP were diagnosed according to the American Thoracic Society/European Respiratory Society consensus statement, and all cases fulfilled the following diagnostic criteria: (1) careful exclusion of other known causes of interstitial lung disease such as toxic effects of drugs, environmental exposure, and connective tissue diseases; (2) restrictive pulmonary function abnormalities; and (3) bibasilar reticular abnormalities with minimal ground-glass opacities evident on chest radiographs and high-resolution CT scan. 14 This study was approved by the internal review boards of our institutions. Informed consent was obtained from the family members of each patient. Macroscopic features of the autopsied lungs were assessed and included contraction of the lobes, subpleural fibrosis, intralobar fibrosis, honeycombing lesions, emphysematous change, bullae, and exudation suggesting diffuse alveolar damage (DAD) or infectious pneumonia. The cases were graded for these distinct lesions as negative (no lesions), occasional lesions, and marked lesions. The degree of honeycombing lesions was graded according to the portion of the lobe occupied, as follows: none, one third of the lobe, one third to two thirds of the lobe, two thirds or more of the lobe. Microscopic features assessed included smooth muscle hyperplasia, lymphoid aggregation, and fibroblastic foci in the honeycombing areas of the UIP-like area. Fibrotic patterns resembling NSIP, 15 centrilobular fibrosis, bridging fibrosis between respiratory bronchioles and adjacent subpleural or intralobular septa, atelectatic fibrosis, cholesterol clefts, multinucleated giant cells, and granuloma were also assessed in the areas not involved by UIP-like fibrosis. The cases were graded for these distinct lesions as negative, occasional, or marked. Lymphoid aggregation and fibroblastic foci were graded according to the number or amount per square centimeter as follows: none, less than 5/cm 2, 5 to 10/cm 2, and 10/ cm 2 or more. A patchy fibrotic lesion about 1 mm in size was regarded as centrilobular when it involved a respiratory or terminal bronchiole. The frequency of centrilobular fibrosis was graded as follows: 0 when any patchy fibrotic lesions did not involve a respiratory or terminal bronchiole, 1 lesion per slide, 2 to 4 lesions per slide, and 5 or more lesions per slide. Reconstruction of early fibrotic lesions was performed based on 50 sheets of semiserial sections stained with elastic van Gieson at 40-µm intervals. Digital images of 10 8 mm were printed to cm, and fibrotic lesions, bronchioles, arteries, and veins were traced on transparent films. The film sheets were then converted to digital images again via scanning in the appropriate position. The reconstructed digital images were visualized by using VoxBlast software (VayTek, Fairfield, IA). Results Clinical Findings ztable 1z summarizes the clinical features of CHP cases. The patient group comprised 11 men and 5 women with an average age of 69.1 years; of the patients, 7 did not have a history of smoking. The average of the total duration of illness was 63 months. Three patients had acute episodes, including low-grade fever, mild exertional dyspnea, and cough, corresponding to recurrent CHP, and the remaining 13 did not, corresponding to insidious cases. 2 The IPF/UIP patient group consisted of 9 men and 2 women, with an average age of 76.1 years, among which 3 patients did not have a history of smoking. Of the 11 patients, 6 patients had a history of lung cancer or presently had lung cancer, and 1 patient had a history of thymic cancer. The average of the total duration of illness was 57 months. The average age in the CHP group was significantly younger than that in the IPF/UIP group (P = 406 Am J Clin Pathol 2009;131: Downloaded 406 from

3 Anatomic Pathology / Original Article ztable 1z Clinical Findings in 16 Cases of Chronic Hypersensitivity Pneumonitis Case No./ Anti- Provocation BAL Lympho- Observation Last Hospital- Sex/Age (y) Smoking Diagnosis Onset body * LST Test * cyte (%) Treatment Period (mo) ized Period (d) Complication 1/F/78 NS BFL Recurrent CS Bronchopneumonia 2/F/66 NS BFL Insidious CS DAD 3/M/55 S BFL Insidious CS, IS DAD 4/M/72 S BFL Insidious CS, IS Aspergillosis 5/F/69 NS BFL Insidious CS, IS Aspergillosis 6/M/75 Ex BFL Insidious CS, IS DAD 7/M/76 NS BFL Insidious CS, IS /M/59 Ex BFL Insidious CS, IS DAD 9/F/81 NS BFL Insidious CS Tuberculosis 10/M/67 S BFL Insidious + + ND CS, IS DAD 11/M/70 S BFL Insidious CS DAD, lung cancer 12/M/54 Ex BFL Insidious CS, IS DAD 13/M/78 S SHP Recurrent + NA CS DAD 14/M/69 NS SHP Recurrent + NA + ND CS, IS DAD 15/F/71 NS SHP Insidious + NA + ND CS, IS 76 7 Bronchopneumonia 16/M/65 Ex SHP Insidious + NA + ND CS, IS Pulmonary embolism BAL, bronchoalveolar lavage; BFL, bird fancier s lung; CS, corticosteroid; DAD, diffuse alveolar damage; Ex, ex-smoker; IS, immunosuppressant; LST, lymphocyte stimulation test to the avian antigen; NA, not available; ND, not done; NS, nonsmoker; S, current smoker; SHP, summer-type hypersensitivity pneumonitis; +, positive;, negative. * Antibody is the serum antibody to the avian or Trichosporon antigen, and the provocation test is an environmental or laboratory-controlled antigen inhalation test..02; Welch test). There were no significant differences in sex or smoking habits between the 2 groups. Macroscopic Features All cases showed honeycombing lesions that were 2 to 4 mm in diameter, with enlargement of air spaces of various sizes. Honeycombing lesions were found dominantly in the lower lobes in most cases zimage 1Az and zimage 1Bz and resulted in contraction of the lobes in the advanced cases. In only 1 case were they more prominent in the upper lobes zimage 1Cz; equal progression in both lobes was noted in 3 cases. In 6 cases, the honeycombing lesions advanced asymmetrically zimage 1Dz. Subpleural sparing in the diaphragm face could not be found in any case. Even in rather well-preserved lobes, subpleural fibrosis was found in 7 cases and intralobar fibrosis along the interlobular septum and bronchovascular bundles in 10 cases zimage 1Ez. Centrilobular emphysema was complicated in 2 cases and bullae, up to 3.5 cm, were noted in 1 case. The macroscopic features are summarized in ztable 2z. The incidence of atypical dominance of honeycombing lesions, including upper lobe dominance, and asymmetry was significantly higher in CHP than in IPF/UIP. The incidence of the complication of bullae was significantly lower in CHP. Intralobar fibrosis was more prominent in CHP, and emphysema was more frequent in IPF/UIP; however, the differences were not statistically significant ztable 3z. Microscopic Features Granuloma, one of the hallmarks of acute and subacute HP, was not apparent in any of the cases. Cholesterol crystals and giant cells in the alveolar spaces or fibrous interstitium were observed in 8 and 5 cases, respectively. Lymphoid aggregates were frequently observed, mainly in the honeycombing areas. Lymphocytic bronchiolitis and alveolitis were difficult to assess because of the complicated infectious disease or DAD at the terminal stage. The honeycombing lesions were present in the UIP-like pattern. The dilated airspaces were mostly covered with metaplastic bronchiolar epithelium, and smooth muscle hyperplasia was commonly observed in the interstitium. Fibroblastic foci were found in 6 of 8 cases zimage 2Az. In 8 other cases, fibroblastic foci could not be identified because of extensive organizing DAD or organizing pneumonia. Diffuse thickening of the alveolar wall with minimal distortion and no bronchiolar metaplasia resembling a fibrosing NSIP-like pattern could be found in 9 cases zimage 2Bz. Massive atelectatic fibrosis composed of collapsed alveoli with dense accumulation of elastic fibers but minimal collagen deposition was found in 6 cases zimage 2Cz. In the areas where the alveolar structures were relatively well preserved, centrilobular fibrosis involving the respiratory or terminal bronchioles with frequent luminal occlusion and smooth muscle hyperplasia were found in all the CHP cases. They were prominent in 4 cases zimage 2Dz. Centrilobular fibrotic lesions were scattered in the upper and lower lobes but were barely identified in the developed honeycombing areas of the lower lobes. Occasionally, centrilobular fibrotic lesions were connected with adjacent bronchioles, interlobular septa, or pleural connective tissue and mimicked the appearance of bridging fibrosis zimage 2Ez and zimage 2Fz. Am J Clin Pathol 2009;131:

4 Akashi et al / Chronic Hypersensitivity Pneumonitis A B C D E zimage 1z Macroscopic findings of lungs affected by chronic hypersensitivity pneumonitis. A and B (Case 6), Honeycombing lesions were mainly distributed in both lower lobes and were composed of rather small airspaces of < 5 mm. C (Case 5), Fibrosis is more marked in the upper lobes. D (Case 12), Fibrosis is more distinct in the upper and lower lobes of the left lung than the right lung. E (Case 6), Close-up view of the right upper lobe. Subpleural fibrosis (arrows) and intralobar fibrosis (arrowheads) were observed in the upper lobes with minimal honeycombing lesions. 408 Am J Clin Pathol 2009;131: Downloaded 408 from

5 Anatomic Pathology / Original Article ztable 2z Macroscopic Features of 16 Cases of Chronic Hypersensitivity Pneumonitis Subpleural Intralobar Contraction Fibrosis Fibrosis Honeycombing Upper Lobe Emphysema Bullae Exudation Case No./ Dominance Clinical Diagnosis U L U L U L U * L * or Asymmetry U L U L U L 1/BFL None <⅓ 2/BFL ⅓-⅔ ⅓-⅔ + + 3/BFL ⅓-⅔ ⅔ LD /BFL <⅓ ⅓-⅔ /BFL ⅓-⅔ <⅓ UD + + 6/BFL + 2+ ND + ND <⅓ ⅔ ND 7/BFL + + <⅓ <⅓ 8/BFL + + ND + ND ⅓-⅔ ⅔ LD ND + 9/BFL + + ⅓-⅔ ⅓-⅔ LD 10/BFL + + ND + ND <⅓ ⅔ ND + ND 11/BFL None <⅓ /BFL <⅓ ⅓-⅔ LD /SHP + ND <⅓ ⅓-⅔ RD /SHP + None <⅓ /SHP <⅓ ⅓-⅔ /SHP <⅓ ⅓-⅔ RD + + BFL, bird fancier s lung; L, lower lobe; LD, left lung dominant; ND, could not be determined owing to advanced honeycombing; RD, right lung dominant; SHP, summer-type hypersensitivity pneumonitis; U, upper lobe; UD, upper lobe dominant;, none; +, occasional; 2+, marked. * Portion of the lobe occupied by honeycombing. ztable 3z Comparison of Macroscopic Features Between CHP and IPF/UIP CHP IPF/UIP P * CHP IPF/UIP P * Contraction Upper lobe.26 None 10 9 Occasional 5 2 Lower lobe.59 None 7 6 Occasional 7 4 Marked 2 1 Subpleural fibrosis Upper lobe.65 None 9 4 Occasional 4 7 Marked 3 0 Lower lobe.70 None 9 5 Occasional 3 1 Marked 0 0 Intralobar fibrosis Upper lobe.05 None 6 7 Occasional 9 3 Lower lobe.20 None 8 7 Occasional 4 1 Honeycombing Upper lobe.22 None 3 1 <1/ /3-2/ /3 0 0 Lower lobe.85 None 0 0 <1/ /3-2/ /3 4 4 Upper lobe dominance or asymmetry <.01 Absent 9 11 Present 7 0 Emphysema Upper lobe.08 None 14 6 Occasional 1 4 Marked 1 1 Lower lobe.68 None 13 7 Occasional 1 1 Marked 0 0 Bullae Upper lobe <.01 None 15 5 Occasional 0 1 Marked 1 5 Lower lobe.07 None 15 5 Occasional 0 2 Marked 1 1 Exudation Upper lobe.09 None 5 7 Occasional 10 4 Lower lobe.49 None 5 5 Occasional 9 5 Marked 0 0 CHP, chronic hypersensitivity pneumonitis; IPF/UIP, idiopathic pulmonary fibrosis/usual interstitial pneumonia. * Mann-Whitney test. Indicates the portion of the lobe occupied by honeycombing. Am J Clin Pathol 2009;131:

6 Akashi et al / Chronic Hypersensitivity Pneumonitis A B C D zimage 2z Microscopic findings in the fibrotic areas of chronic hypersensitivity pneumonitis. A (Case 6), Fibroblastic focus (H&E, 70). Fibroblasts (arrows) overlie the densely fibrotic lesion. B (Case 1), Fibrotic nonspecific interstitial pneumonia like lesion (H&E, 20). C (Case 5), Atelectatic fibrosis located in the subpleura (elastic van Gieson [EVG], 7). The fibrotic lesion was mainly composed of densely accumulated alveolar elastic fibers with minimal collagen fibers. A few dilated air spaces were left in the scar. D (Case 14), Centrilobular fibrosis. Many patchy fibrotic lesions were noted around the terminal and respiratory bronchioles (*). Patchy fibrotic lesions without a distinct connection with the respiratory bronchioles were also noted (arrows) (EVG, 10). Surgical lung biopsy specimens were obtained from 7 cases, 16 to 126 months before autopsy. Of these specimens, 6 showed a UIP-like pattern, and a coexistent fibrosing NSIP pattern was found in 3 of them. One case showed a fibrosing NSIP pattern without a UIP-like pattern. All cases revealed a dominant UIP-like pattern with honeycomb change at autopsy, but a fibrosing NSIP-like pattern was also focally present in 4 cases that were not complicated by DAD or organizing pneumonia. Lymphoid aggregation and fibroblastic foci were prominent in the UIP-like areas in surgical biopsy specimens. Centrilobular fibrosis and bridging fibrosis were common and were observed in 5 of 7 cases. The microscopic features of CHP are summarized in ztable 4z. Centrilobular and bridging fibrosis were found in the lungs affected by IPF/UIP as well, but the degree was significantly greater in the lungs with CHP. Cholesterol clefts and a fibrosing NSIP-like pattern were more frequent in CHP than in IPF/UIP; however, the differences were not statistically significant ztable 5z. 3-D Reconstruction of Fibrotic Lesions To clarify the exact distribution of patchy fibrotic lesions in the lobules, particularly in regard to the stereoscopic 410 Am J Clin Pathol 2009;131: Downloaded 410 from

7 Anatomic Pathology / Original Article E F E and F (Case 11), Centrilobular fibrosis with a bridging appearance. Fibrosis was mainly distributed around the respiratory bronchiole (arrowheads) and connected with the interlobular septum, mimicking bridging fibrosis (*). The arrow denotes a terminal bronchiole (E, H&E, 15; F, H&E, 35). ztable 4z Microscopic Features of Chronic Hypersensitivity Pneumonitis Cases UIP-like Area Characteristics of Fibrosis Case No./Clini- Cholesterol Giant Smooth Muscle Lymphoid Fibroblastic f-nsip-like Complications cal Diagnosis Cleft Cells Hyperplasia Aggregation (/cm 2 ) Foci (/cm 2 ) Area Centrilobular * Bridging Atelectatic of DAD 1/BFL P (U, L) 5 (U) + (U) 2/BFL ND ND 5 (L) + (U) Ex-org 3/BFL <5 ND ND 2-4 (L, U) Ex-org 4/BFL P (U, M) 2-4 (U) + (U) 5/BFL + + <5 ND P (L) 2-4 (L) + (L) + 6/BFL + < P (U) 5 (U) + (U) Ex 7/BFL <5 <5 A 2-4 (U) + 8/BFL + <5 ND ND 1 (U) Ex-org 9/BFL <5 A 5 (L) 2+ (U, L) 10/BFL + + <5 ND A 2-4 (U) Ex-org 11/BFL + 0 <5 P (U, L) 2-4 (L) + (U) + Ex 12/BFL 10 ND ND 1 (M) + (M) 2+ Ex-org 13/SHP ND P (U) 1 (L) Ex-org 14/SHP ND P (U) 2-4 (U) Ex-org 15/SHP P (M) 1 (U, L) + 16/SHP + <5 0 P (U) 2-4 (U) + A, absent; BFL, bird fancier s lung; DAD, diffuse alveolar damage; Ex, exudative; f-nsip, fibrosing nonspecific interstitial pneumonia; L, in lower lobe; M, in middle lobe; ND, could not be determined owing to superimposed organizing DAD or organizing pneumonia; org, organizing; P, present; SHP, summer-type hypersensitivity pneumonitis; U, in upper lobe; UIP, usual interstitial pneumonia;, none; +, occasional; 2+, marked. * The number of lesions per slide is given. relationship with respiratory bronchioles, we created 3-D images of early fibrotic lesions of 2 CHP cases and 1 IPF/ UIP case. In CHP case 6, most of the fibrotic lesions showed a nodular or cord-like shape involving the respiratory bronchioles and occasionally extended to the periphery of the lobules around the large membranous bronchioles and showed bridging fibrosis zimage 3z. In CHP case 5, fine fibrosis spread from the respiratory bronchioles toward the periphery of the lobules zimage 4Az and zimage 4Bz. In contrast, in an IPF/UIP case, the fibrotic lesions were mainly distributed in the periphery of the lobules along the interlobular septum. A small amount of fine fibrosis around the respiratory bronchioles was also observed zimage 4Cz and zimage 4Dz. Complications Regarding the associated complications, emphysematous change was found in 2 patients who were both smokers. Multiple cysts, up to 3.5 cm, were found in 1 case. In 9 cases, there was terminal DAD in both exudative and organizing stages. Bacterial pneumonia (2 cases), tuberculosis (1 case), Am J Clin Pathol 2009;131:

8 Akashi et al / Chronic Hypersensitivity Pneumonitis ztable 5z Comparison of Microscopic Features Between CHP and IPF/UIP and invasive aspergillosis (2 cases) were complications. In 11 IPF/UIP cases, 2 cases showed acute exacerbation, histologically showing DAD. Bacterial pneumonia (5 cases) and invasive aspergillosis (1 case) were terminal complications. Recurrence of cancer was found in 3 patients with lung cancer and 1 patient with thymic carcinoma. Discussion CHP IPF/UIP P * Cholesterol cleft.15 None 8 9 Occasional 7 1 Marked 1 1 Giant cells.56 None 11 9 Occasional 5 1 Marked 0 1 UIP-like area Smooth muscle hyperplasia.19 None 3 5 Occasional 11 5 Marked 2 1 Lymphoid aggregation (/cm 2 ) < Fibroblastic foci (/cm 2 ) < Fibrosis f-nsip-like area.07 Absent 3 7 Present 9 4 Centrilobular (No. of lesions per slide) Bridging.03 None 8 10 Occasional 7 1 Atelectatic.50 None 10 5 Occasional 5 6 Complications of DAD.49 Absent 7 7 Present 9 4 CHP, chronic hypersensitivity pneumonitis; DAD, diffuse alveolar damage; f-nsip, fibrosing nonspecific interstitial pneumonia; IPF/UIP, idiopathic pulmonary fibrosis/usual interstitial pneumonia. * Mann-Whitney test. Autopsy revealed that honeycombing lesions in lungs with CHP were mainly distributed in the lower lobes. This distribution pattern is rather different from that in farmer s lung cases discussed in a previous report, in which 3 of 4 cases showed fibrosis distributed mainly in the upper lobes. 6 The lower lobe dominance of fibrosis and honeycombing lesions in lungs with CHP has been described previously in a radiologic study. 10,16 In this aspect, the honeycombing lesions of CHP appear to closely resemble those of IPF/UIP. However, the frequent asymmetry of honeycombing lesions, which has not been well documented thus far, except with regard to the asymmetrical or random distribution of radiologic abnormalities in CHP, 10,17 seems to be one of the characteristics of CHP. The factor that determines the vertical or horizontal distribution of honeycombing lesions is difficult to be presumed, although it might be attributed to the unequal distribution of inhaled antigens in the lung. Although a previous study described that UIP-like fibrosis and NSIP-like fibrosis never coexisted in the biopsied specimens of CHP, 3 the NSIP pattern was occasionally present in the IPF/UIP specimens Our study revealed that UIP-like fibrosis coexistent with NSIP-like fibrosis was common in the biopsied and autopsied CHP cases. In most of the autopsied lungs, UIP-like fibrosis was more conspicuous than NSIP-like fibrosis. Follow-up CT study demonstrated that initial CT findings suggestive of NSIP often progressed to findings suggestive of IPF/UIP. 21 Thus, it is considered that UIP-like fibrosis becomes more evident in the progression of the disease. In fact, 1 case of CHP showing NSIP-like fibrosis at surgical biopsy showed NSIP-like and UIP-like fibrosis at autopsy in this study. Loose granuloma is one of the histologic characteristics of acute HP. The incidence of loose epithelioid cell granuloma in the biopsied specimens of CHP is reported as 20% to 59%. 3,7-9,22 However, granuloma was not observed in the autopsy lungs. Granuloma is considered to disappear over 6 months. 6,23 In addition, the incidence of granuloma in CHP with UIP-like fibrosis was apparently rare or absent, 7,8 while Churg et al reported it in 5 of 9 cases. 3 Thus, it is likely that granuloma is rarely formed in lungs of patients having CHP with UIP-like fibrosis who showed an insidious onset and were affected by low doses of antigens. This study clearly demonstrated that centrilobular fibrosis is one of the characteristic histologic features of CHP. In previous reports, centrilobular fibrosis was found in 20% to 54% of surgical biopsy specimens of lungs with CHP. 3,7,9 One explanation for the higher incidence of centrilobular fibrosis in this autopsy study is the larger areas searched to detect early fibrotic lesions. Centrilobular fibrosis involved peribronchiolar alveolar ducts and extended to the perilobular areas in the appearance of bridging fibrosis. 22 This pattern of fibrosis was demonstrated apparently by the 3-D reconstruction of early fibrotic lesions. Bridging fibrosis may develop from intraluminal and interstitial fibrosis along the peribronchiolar areas, which were considered the most susceptible areas in cases of airborne insults. 24 Later, continuous inflammation and organization probably affect more diffuse areas toward the alveolar duct and alveoli and finally involve the entire lobule. 25 Subsequently, the area of organization became atelectatic. These pathologic processes 412 Am J Clin Pathol 2009;131: Downloaded 412 from

9 Anatomic Pathology / Original Article A B C D zimage 3z Intralobular distribution of fibrosis in chronic hypersensitivity pneumonitis. A, Low-magnification microscopy showing many small fibrotic lesions (elastic van Gieson [EVG] staining, 5). Each fibrotic lesion is identified using a number from 1 to 10. B, Higher magnification of fibrotic lesion No. 4 around the respiratory bronchiole (EVG, 25). Orange arrowheads, fibrosis; orange arrow, pulmonary artery; black arrows, terminal bronchiole; black arrowheads, smooth muscle bundles of the respiratory bronchiole. C and D, Reconstruction of fibrotic lesions ( 5). Green, bronchus and bronchioles; red, pulmonary artery; light blue, fibrosis; MB, membranous bronchiole; RB, respiratory bronchiole; TB, terminal bronchiole. C and D show 3-dimensional reconstructions of the same area of A. C shows only the bronchus and bronchioles. The identification number of each fibrotic area in D is identical to that in A. Most of the fibrotic lesions are connected to the respiratory bronchioles (arrows) and occasionally extend to the periphery of the lobules around adjacent bronchioles and assume a bridge-like appearance (arrowheads). can explain the characteristic patterns of centrilobular and bridging fibrosis in lungs with CHP. Centrilobular fibrosis is one of the characteristics of CHP; however, it is also observed in other diffuse lung diseases, such as respiratory bronchiolitis associated with interstitial lung disease, collagen vascular disease, pneumoconiosis, Langerhans cell histiocytosis, ancient infectious pneumonia, and idiopathic bronchiolocentric interstitial pneumonia. 26,27 These diseases, as well as CHP, might be masked in IPF/ UIP because centrilobular fibrosis was found in about 30% of the lungs with IPF/UIP examined in this study. Accordingly, clinical examination, including obtaining precise details of exposure history, radiographic findings, and histologic findings, are indispensable for the accurate diagnosis of CHP. Am J Clin Pathol 2009;131:

10 Akashi et al / Chronic Hypersensitivity Pneumonitis A B C D zimage 4z Reconstruction of fibrotic lesions of chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis/ usual interstitial pneumonia (IPF/UIP). A and B (Case 5, 5), CHP. C and D, IPF/UIP ( 6.5). A and C show only the bronchus (Br) and bronchioles in the same areas of B and D. Green, bronchus and bronchioles; red, pulmonary artery; yellow, interlobular septum; light blue, fibrosis; MB, membranous bronchiole; RB, respiratory bronchiole; TB, terminal bronchiole. Fibrotic lesions connected to the respiratory bronchioles or terminal bronchioles are indicated by arrows. In CHP (case 5), fine fibrotic lesions are connected to the respiratory bronchioles and extend to the adjacent bronchioles. In IPF/UIP, fibrosis along the interlobular septum is prominent. A small amount of fibrosis was also found around the respiratory bronchioles. A terminal bronchiole was buried in the advanced fibrotic lesion (arrows). Previous studies have suggested a significantly higher incidence of emphysema in lungs with HP. 10,28 In our study, both patients with CHP with emphysema were smokers, and the effect of smoking on the pathogenesis of emphysematous change was considered. Complication of the cysts in 13% to 39% of lungs with HP was also reported, and partial bronchiolar obstruction with air trapping due to peribronchiolar inflammation was considered. 10,29 However, the complication of bullae was seen only in 1 case of CHP in this study and was less frequent in CHP than in IPF/UIP. The main causes of mortality were complications of DAD and infectious pneumonia. The incidence of DAD in our study was compatible with a previous report stating that 60% of patients with UIP died of DAD. 30 However, the underlying causes were not discussed in the previous report. Reexposure or unrecognized antigen exposure might be the cause of acute exacerbation in cases of CHP. 31,32 The fibrotic pattern in lungs with CHP closely resembled that in lungs with IPF/UIP; however, centrilobular fibrosis and bridging fibrosis extending to the perilobular areas are 414 Am J Clin Pathol 2009;131: Downloaded 414 from

11 Anatomic Pathology / Original Article considered the most characteristic findings of CHP. It is important to thoroughly explore the possibility of antigen exposure, even in cases of UIP with centrilobular fibrosis, to discriminate insidious CHP from IPF/UIP because avoidance of antigen exposure may improve the patient s condition or stop disease progression. From the Departments of 1 Pathology and 3 Integrated Pulmonology, Tokyo Medical and Dental University; and 2 Pathology, Japanese Red Cross Medical Center, Tokyo, Japan. Address reprint requests to Dr Takemura: Dept of Pathology, Japanese Red Cross Medical Center, , Hiroo, Shibuya-ku, Tokyo , Japan. 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