Histopathologic Variability in Usual and Nonspecific Interstitial Pneumonias

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1 Histopathologic Variability in Usual and Nonspecific Interstitial Pneumonias KEVIN R. FLAHERTY, WILLIAM D. TRAVIS, THOMAS V. COLBY, GALEN B. TOEWS, ELLA A. KAZEROONI, BARRY H. GROSS, ARVIND JAIN, ROBERT L. STRAWDERMAN III, ANDREW FLINT, JOSEPH P. LYNCH III, and FERNANDO J. MARTINEZ Division of Pulmonary and Critical Care Medicine, and Departments of Radiology and Pathology, University of Michigan Health System, and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan; Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, D.C.; Department of Pathology, Mayo Clinic, Scottsdale, Arizona Findings of surgical lung biopsy (SLB) are important in categorizing patients with idiopathic interstitial pneumonia (IIP). We investigated whether histologic variability would be evident in SLB specimens from multiple lobes in patients with IIP. SLBs from 168 patients, 109 of whom had multiple lobes biopsied, were reviewed by three pathologists. A diagnosis was assigned to each lobe. A different diagnosis was found between lobes in 26% of the patients. Patients with usual interstitial pneumonia (UIP) in all lobes were categorized as concordant for UIP (n 51) and those with UIP in at least one lobe were categorized as discordant for UIP (n 28). Patients with nonspecific interstitial pneumonia () in all lobes were categorized as having fibrotic (n 25) or cellular (n 5). No consistent distribution of lobar histology was noted. Patients concordant for UIP were older (63 9 [mean SD] yr; p 0.05 as compared with all other groups) than those discordant for UIP (57 12 yr) or with fibrotic (56 11 yr) or cellular (50 9 yr). Semiquantitative high-resolution computed tomography demonstrated a varied profusion of fibrosis (p 0.05 for all group comparisons), with more fibrosis in concordant UIP ( ) than in discordant UIP ( ), fibrotic ( ), or cellular ( ). Survival was better for patients with than for those in both UIP groups (p 0.001), although survival in the two UIP groups was comparable (p 0.16). Lobar histologic variability is frequent in patients with IIP, patients with a histologic pattern of UIP in any lobe should be classified as having UIP. Keywords: pulmonary fibrosis; usual interstitial pneumonia; nonspecific interstitial pneumonia; idiopathic interstitial pneumonia; idiopathic pulmonary fibrosis Patients with nonspecific interstitial pneumonia () have better survival than those with usual interstitial pneumonia (UIP) (1 5). In addition, patients with a predominantly cellular pattern of appear to have a better prognosis than those with either UIP or a fibrotic pattern of (3 6). The ability of histopathology to predict prognosis has generated renewed interest in categorizing patients with idiopathic interstitial pneumonia (IIP) according to histology (6, 7). Recently, an American Thoracic Society (ATS) statement concluded that idiopathic pulmonary fibrosis (IPF) should reflect only the histologic picture of UIP, thus making patients with IPF a more homogeneous group with a worse prognosis than previously described (8). However, the current literature (Received in original form March 15, 2001; accepted in final form June 17, 2001) Supported by NHLBI Grants P50HL46487, and 1 K24 HL from the National Heart, Lung and Blood Institute NIH/NCRR 3 MO1 RR S3, NIH/ NIA P60 AG , from the National Institutes of Health. Correspondence and requests for reprints should be addressed to Fernando J. Martinez, M.D., 1500 E. Medical Center Dr., 3916 TC, Ann Arbor, MI fmartine@umich.edu Am J Respir Crit Care Med Vol 164. pp , 2001 DOI: /rccm Internet address: indicates some differences in survival of patients with (and especially fibrotic ) among several series (3 5, 9), suggesting that diagnostic criteria for may not be uniformly applied. This is not surprising, since includes a spectrum of inflammatory and fibrosing lesions that do not fall within the histologic criteria for UIP, and as such, it represents somewhat of a wastebasket condition (3). A consensus on diagnostic criteria for remains to be established, and the relationship between the cellular and fibrosing patterns of and UIP needs further study. High-resolution computed tomography (HRCT) scans in patients with IIP are heterogeneous; the typical changes in UIP are first noted at the bases of the lungs (10). We hypothesized that there would also be significant histologic variability in the surgical lung biopsies (SLB) of patients with IIP when they were examined at the lobar level. The purpose of this study was to evaluate intrapatient lobar variability in patients with IIP and to determine how to classify patients when lobar variability was present. METHODS Patient Recruitment and Therapy The study utilized patients in the data base of the University of Michigan Specialized Center of Research (SCOR) in the Pathobiology of Fibrotic Lung Disease. Patients in this data base were referred for enrollment in study protocols for suspected interstitial pulmonary fibrosis (IPF) and underwent SLB between October 1989 and February In these patients, a suspicion of IPF was based on symptoms, physiologic abnormalities, and radiographic findings. None of the patients had undergone previous SLB or received therapy for IPF. Patients without a histopathologic pattern of or UIP were excluded from this analysis (respiratory bronchiolitis interstitial lung disease/desquamative interstitial pneumonitis, n 22; bronchiolitis obliterans organizing pneumonia, n 1; hypersensitivity pneumonia, n 5; and unclassified, n 1). We also excluded 27 patients with UIP and three patients with who did not have a biopsy specimen from more than one lobe. Patients were additionally excluded if they were found to have a disease other than IPF during the enrollment evaluation. Diseases that were exclusionary included pneumoconiosis, sarcoidosis, cancer, lymphoma, Langerhan s histiocytosis, and lymphangioleiomyomatosis. Similarly, patients with underlying collagen vascular disease were excluded from analysis. Patients were treated with a variety of regimens (Table 1). Clinical information has been reported (11, 12) on a subgroup (n 26) of these patients categorized as having IPF according to previously published criteria (13). Five of these patients (19%) were reclassified using criteria described in the section on pathologic assessment. Biopsy Technique All patients in the study underwent SLB by formal thoracotomy or video-assisted thoracoscopy. Similar sized biopsy specimens were obtained by either technique. All patients had an SLB involving more than one lobe. Surgeons were asked to obtain biopsy specimens from all three lobes on the right side or from the upper and lower lobes on the left side, with exclusion of the lingula.

2 Flaherty, Travis, Colby, et al.: Histopathologic Variability 1723 TABLE 1. TREATMENT ADMINISTERED TO 109 PATIENTS WITH USUAL INTERSTITIAL PNEUMONIA OR NONSPECIFIC INTERSTITIAL PNEUMONIA Treatment Concordant UIP Discordant UIP Pathologic Assessment Fibrotic Cellular None Prednisone alone Prednisone azathioprine or cyclophosphamide Zileuton* Azathioprine alone Miscellaneous Definition of abbreviations: nonspecific interstitial pneumonia; UIP usual interstitial pneumonia. * Patients received zileuton as part of a Phase I clinical trial. In concordant UIP, all lobes showed usual interstitial pneumonia; in discordant UIP, lung lobes showed a mixture of UIP and. All biopsy slides available for review were obtained, and each lobe was assigned a random number and reviewed by three pathologists (T.V.C., A.F., W.D.T.). Initial readings were done individually without knowledge of other pathologists interpretations or any clinical or radiographic information. Cases without a uniform diagnostic consensus among the three examining pathologists were reviewed by all three together to reach a consensus during three review sessions between March 1999 and February The pathologists assigned a diagnosis of UIP,, or other to each lobe. Patients with were further classified as having predominantly cellular or fibrosing patterns according to established criteria (3, 9). The definition of was still evolving at the beginning of the study; all specimens classified as representing were re-reviewed at the end of the study period (February 2000) for consistency and to confirm the accuracy of the initial diagnosis. UIP was defined by patchy dense interstitial fibrosis, often with a subpleural and paraseptal distribution and associated with loss of lung architecture, frequent honeycomb changes, and fibroblastic foci (9). Interstitial inflammation was usually minimal. Fibrotic was defined by dense or loose interstitial fibrosis lacking the temporal heterogeneity of UIP and usually showing diffuse uniform involvement of the lung tissue (spatial uniformity). Fibroblastic foci were inconspicuous or absent, and inflammation was mild to moderate. Cellular was characterized by mild to moderate chronic interstitial inflammation without interstitial fibrosis. Type II pneumocyte hyperplasia was often present in areas of inflammation. Foci of organizing pneumonia could be seen in both groups, but these were focal and not the predominant feature. Cellular corresponded to group 1 of Katzenstein and Fiorelli, whereas fibrotic corresponded to Katzenstein and Fiorelli groups 2 and 3 (6). Cases were classified in the following manner to allow comparison of demographic data, pulmonary physiology, radiographic data, and survival: 1. Concordant UIP: UIP pattern in all lobes. 2. Discordant UIP: UIP pattern in at least one lobe but a non-uip pattern in at least one lobe (intrapatient lobar variability). 3. Fibrotic : Fibrotic pattern in all lobes or a combination of a fibrotic and cellular pattern. 4. Cellular : Cellular pattern in all lobes. Physiologic Assessment Physiologic assessment was performed before SLB and before the initiation of therapy. Pulmonary function tests including spirometry, lung volume measurements, and diffusion capacity for carbon monoxide (DL CO ) were done on the same day and before a cardiopulmonary exercise test (CPET) as previously described (12). HRCT Protocol HRCT examinations were performed with 1.0- or 1.5-mm-thick sections taken at 1-cm intervals throughout the lungs during inspiration with the patient in the supine position, and through the caudal 10 cm of the lungs at 2- to 3-cm increments with the patient in the prone position. All HRCT scans were done from 1 to 4 wk before SLB. Two thoracic radiologists (E.A.K., B.H.G.) prospectively and independently scored all lobes on HRCT for ground-glass opacity (CT-alv) and interstitial opacity (CT-fib) on a scale of 0 to 5 as described previously (14). The radiologists were unaware of the histologic diagnosis at the time of interpretation. Statistical Analysis Categorical data for the various histopathologic groups were compared through the use of Fisher s exact test, and continuous data were compared through analysis of variance (ANOVA). When ANOVA results indicated that histopathologic groups differed, post hoc comparisons were performed on the relevant continuous measures with unpaired, two-tailed t tests. All t tests assumed unequal variances, and a value of p 0.05 was considered statistically significant. Survival experiences for histopathologic groups were illustrated via Kaplan Meier curves. Cox regression analysis was used to examine the relationship between histopathologic group and mortality, with control for demographic characteristics such as age, sex, and smoking status, and baseline physiologic and radiographic variables. patients were grouped together for survival analysis, since there were no deaths among the patients with cellular. RESULTS Patient Population One hundred and sixty-eight patients had an SLB during the study period. One hundred and nine had biopsies in multiple lobes and were included in the study. The baseline characteristics for these patients are shown in Table 2. Lobar Histologic Variability Significant intrapatient variability was noted. The lobar distribution of UIP and is shown in Figure 1. Fifty-one patients exhibited a histologic picture of UIP in all lobes evaluated (concordant UIP); 28 patients had in at least one lobe and UIP in at least one lobe (discordant UIP). The pattern was fibrotic in 92% of the lobes and cellular in 8%. Twenty-eight patients had in all lobes sampled. There was no predilection for the distribution of UIP or by location of lobe when this was examined both for all patients (Figure 1a; chi-square p 0.14) and for patients with discordant UIP (Figure 1b; chi-square p 0.20). In 11 patients, two or more biopsies were taken from the same lobe; discordant histology was noted in eight of these patients. The pathologists individual histologic interpretations agreed in 66.9% of the lobes biopsied. Baseline Characteristics Patients baseline demographic, physiologic, and HRCT characteristics are shown in Table 2. Age differed among the study groups and tended to increase as the number of lobes with UIP increased. No significant differences were noted in the gender distribution, duration of symptoms, or smoking status of the groups. Differences in TLC % predicted were present, although a uniform trend for these differences did not exist across histologic categories. Differences were also noted in HRCT features (Table 2). Although patients concordant for UIP demonstrated greater ground glass opacity than patients with fibrotic, the greatest differences were noted in interstitial abnormality as shown by HRCT. Patients concordant for UIP demonstrated a greater profusion of abnormality than all other groups. Patients discordant for UIP were of intermediate status, with greater abnormality than both groups, and patients with fibrotic had higher scores than patients with cellular.

3 1724 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 2. BASELINE CHARACTERISTICS IN 109 PATIENTS WITH IDIOPATHIC INTERSTITIAL PNEUMONIA WHO UNDERWENT MULTIPLE-LOBE BIOPSIES Characteristic Cellular Fibrotic Discordant UIP Concordant UIP ANOVA p Value Sex 3 F, 2 M 14 F, 11 M 16 F, 12 M 22 F, 29 M 0.63 (Fisher s exact test) Age, yr * Onset, yr Weight, kg Nonsmokers, % (Fisher s exact test) Pack-years Physiologic FVC, L FVC, % pred FEV 1, L FEV 1, % pred TLC, L TLC, % pred * DL CO DL CO, % pred HRCT Alveolar * Interstitial * Definition of abbreviations: ANOVA analysis of variance; HRCT high-resolution computed tomography; nonspecific interstitial pneumonia; UIP usual interstitial pneumonia. * Post hoc comparisons, listed comparisons are significant at the p 0.05 level. In concordant UIP, all lobes showed usual interstitial pneumonia; in discordant UIP, lung lobes showed a mixture of UIP and. Age: concordant UIP versus discordant UIP, concordant UIP versus fibrotic, concordant UIP versus cellular ; TLCppd: concordant UIP versus discordant UIP, concordant UIP versus fibrotic ; CT Alveolar: concordant UIP versus fibrotic, discordant UIP versus concordant UIP; CT Interstitial: concordant UIP versus discordant UIP, concordant UIP versus fibrotic, concordant UIP versus cellular, discordant UIP versus fibrotic, discordant UIP versus cellular, fibrotic versus cellular. Survival Marked differences in survival were noted among the different histologic groups (Figure 2). Patients with had better survival than did either UIP group. This advantage persisted even after age, gender, smoking history, physiologic variables, and onset of symptoms were controlled. The risk of mortality was 24.3 times greater (95% confidence interval [CI]: 3.3 to 177; p ) for patients concordant for UIP than for those with. The risk of mortality was 16.8 times greater (95% CI: 2.8 to 98.9; p ) for patients discordant for UIP than for patients. Survival of patients concordant for UIP as compared with that of patients discordant for UIP was similar when either the early portion of the survival curve was weighted (Wilcoxon s test p value 0.16) or when equal statistical weight was given to each time point (log rank test, p 0.16). The survival experience of the groups was statistically similar (log rank test, p 0.33); the sample size yielded a 79.7% power in this analysis. DISCUSSION Radiographic findings in patients with IIP demonstrated lobar heterogeneity. We hypothesized that heterogeneity of histologic diagnosis might exist from lobe to lobe in SLB specimens from patients with suspected IIP. Our findings showed that: (1) interlobar and intralobar histologic variability is present in IIP; and (2) the presence of a UIP pattern in any sample confers a poor prognosis. These data quantify the frequency of histologic variability in IIP and suggest a paradigm for assigning a histologic diagnosis if histologic heterogeneity is identified. Interlobar histologic variability is common in IIP. This complicates the histologic classification of the disease. The histologic classification in 26% of the patients in our study could have differed between UIP and if only one biopsy had been obtained. Histologic heterogeneity has received little attention in the literature (13, 15, 16). No previous studies have analyzed the frequency of coexistence of histologic patterns suggestive of and UIP in the same patient. Heterogeneity of histologic patterns among lobes documents that significant sampling errors may result from protocols that obtain only one biopsy specimen for IIP. Our findings emphasize the value of obtaining a biopsy specimen from multiple lobes during a diagnostic evaluation for IIP. A histologic pattern of UIP in any lobe, even if a pattern of is seen in other lobes, is associated with a poor prognosis. We propose that these patients be classified as having UIP. This proposal is based largely on our finding that UIP-concordant and UIP-discordant patients had similar relative risks of mortality, and that the mortality of each of these groups was poor as compared with that for patients with. Differences in baseline demographic and physiologic characteristics were small and not of sufficient magnitude to allow the clinical separation of groups. Conversely, the amount of fibrosis seen on HRCT differed in all groups, being greatest in the group with concordant UIP and successively less so in the groups with discordant UIP, fibrotic, and cellular, in that order. Further investigation is needed to see if the degree of fibrosis seen on HRCT can serve as a surrogate marker for the presence of UIP in patients unable to undergo SLB. The finding of patterns of UIP and within the same patient raises questions about the pathogenesis and nosology of these disorders. Several pathogenic sequences are possible. may be an early lesion that progresses with time to UIP. Our patients with were younger than our patients with discordant UIP, who in turn were younger than our patients with concordant UIP. Similar differences were observed for the degree of fibrosis seen on HRCT. Interestingly, patients with cellular and those concordant for UIP had less ex-

4 Flaherty, Travis, Colby, et al.: Histopathologic Variability 1725 Figure 2. Kaplan Meier survival curves for patients with concordant UIP (n 51), discordant UIP (n 28), and (n 30), grouped by histologic classification (p ). (dotted line: ; solid line: discordant UIP; dashed line: concordant UIP; : last follow up visit; o: death). Figure 1. (A) Lobar histologic diagnosis in 109 patients with UIP or. (B) Lobar histologic diagnosis in 28 patients with a UIP pattern in at least one lobe but an pattern in at least one lobe (discordant UIP). tensive ground glass infiltrates on HRCT than did patients with fibrotic and those discordant for UIP. Some have speculated that ground glass infiltrates may represent areas of inflammation or fine fibrosis (10). If this is true, our data could support the hypothesis that inflammation/fine fibrosis is early and mild in cellular and increases with fibrotic and discordant UIP, only to be burnt out with concordant UIP. These data could be interpreted to support the concept of an evolving disease process from to UIP, with gradually increasing physiologic derangement and fibrosis, and eventual death. Our data do not address whether this continuum should include all or only fibrotic. Our data and those of others suggest that cellular and fibrotic may not necessarily be related (3, 5). However, these cross-sectional data are not conclusive, particularly since the histologic pattern of is predominantly diffuse, whereas that of UIP is patchier. Because the characterization of remains a work in progress, further prospective evaluation of the change in pulmonary function, as well as sequential quantitative and qualitative HRCT studies with the passage of time, are required. The current prevailing concept is that fibrotic can lead to fibrosis and death (17) while representing a different disease process than UIP (personal communication from W. Travis, co-chair of ATS/European Respiratory Society [ERS] International Multidisciplinary Consensus Classification of Idiopathic Interstitial Pneumonias committee). This important issue can best be addressed by a longitudinal study design. Studies of patients that compare biopsy findings on SLB at the time of initial diagnosis of IIP with findings subsequently obtained from lung tissue removed at lung transplantation or autopsy could be instructive. Serial HRCT scanning may offer an alternative method to serial biopsy for monitoring changes in the degree of fibrosis over time. Although previous studies suggested specific HRCT findings in patients with (18, 19), more recent data highlight the limitation of these radiographic findings in accurate diagnosis (20, 21). Interestingly, short-term studies of serial HRCT scans have suggested improvement in patients (22, 23), in contrast to those with UIP (24). Further prospective data collection is required to answer this important question. Our data provide valuable evidence on which to base recommendations for diagnostic SLB in patients suspected of having IIP. The biopsy technique should maximize the likelihood of identifying the histologic pattern of UIP. Adoption of this practice would result in more accurate segregation of patients into those with UIP and those with. Given the poor prognosis associated with a UIP pattern on any biopsy, the most important goal of the biopsy is finding UIP. Biopsy specimens should be obtained from areas that reflect the entire gamut of gross disease patterns as guided by intraoperative inspection of the lung surface or correlation with HRCT abnormality. This may be achieved by HRCT-guided biopsies or biopsies of multiple lung zones. Areas of gross honeycombing should be avoided, since they show end stage disease, and areas that show intermediate or relatively preserved lung should specifically be selected for biopsy, since the lung specimen must have fibrotic lung adjacent to normal lung for the pathologist to identify the UIP pattern. Our data support the concept that biopsy should be performed in a fashion that minimizes the chance of failing to sample areas most likely to demonstrate the histologic picture of UIP. Missing an area of when UIP is present will have less clinical impact (in terms of an accurate prognosis) than will missing UIP when UIP is actually present. The results of this study emphasize the importance of the pathologic findings obtained on SLB. The distinctions between pathologic diagnoses and clinical diagnoses were addressed by an international multidisciplinary ATS/ERS panel for the classification of IIPs (personal communication, W. Travis, co-chair of the ATS/ERS International Multidisciplinary Consensus Classification of Idiopathic Interstitial Pneumonias committee). In our series, the appropriate histopathologic diagnosis was straightforward for those patients with a pathologic pattern of or UIP in all multiple biopsy specimens. However, there was some question about how patients should be

5 1726 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL classified if multiple biopsies showed different patterns. Our data suggest that presence of the UIP pattern is the most important factor in predicting clinical outcome, and that patients should be classified as having UIP even if their lung histology is discordant. Nevertheless, the clinical differences we observed suggest that patients discordant for UIP have some intermediate features that fall between concordant UIP and. The long-term, prospective follow-up of patients with is required to determine whether their survival declines with time, as recently suggested (5). A decrease in survival with time would suggest that patients with have disease that is evolving into UIP, and that their improved survival reflects lead-time bias. This information, however, will not be definitive. Clearly, further prospective data collection and consensus on the histologic pattern of are required to address these important questions. Studies of the expression of effector molecules and/or receptors may provide additional powerful diagnostic surrogates for putative subtypes of IIP. An understanding of the alveolar microenvironment in patients with IIP is crucial to the development of new, meaningful therapeutic interventions for this disease. References 1. Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schoreder DR, Offord KP. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157: Daniil ZD, Gilchrist FC, Nicholson AG, Hansell DM, Harris J, Colby TV, dubois RM. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. 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J Comput Assist Tomogr 2000;24: Kim EY, Lee KS, Chung MP, Kwon OJ, Kim TS, Hwang JH. Nonspecific interstitial pneumonia with fibrosis: serial high-resolution CT findings with functional correlation. AJR 1999;173: Hartman TE, Primack SL, Kang EY, Swensen SJ, Hansell DM, McGuinness G, Muller NL. Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Chest 1996; 110: APPENDIX The University of Michigan Fibrotic Lung Disease Network includes: D. Arenberg, C. Brennan-Martinez, W. Bria, D. Dahlgren, S. Gay, C. Grum, J. Hampton, K. Hariharan, M. Keane, T. Ojo, R. Paine, M. Peters-Golden, R. Simon, T. Sisson, T. Standiford, and R. Strieter, University of Michigan, Division of Pulmonary and Critical Care, Ann Arbor, MI; P. Bachwich, C. Easton, and J. Mazur, Internal Medicine Clinic, Alpena, MI; S. Chaparala, G. Harrington, and N. Potempa, The Lung Center, Battle Creek, MI; S. Manawar, and J. Summer, Bay City, MI; P. Hukku, and J. Sung, Clawson, MI; R, Babcock, Clinton Township, MI; J. Belen, M. Dunn, D. Maxwell, R. Reagle, R. Sherman, and S. Simecek, Pulmonary and Critical Care Medicine Consultants, Commerce, MI; L. Victor, Oakwood Hospital, Dearborn, MI; B. DiGiovine, M. Eichenhorn, R. Hyzy, J. Popovich, Jr, and D. Spizarny, Henry Ford Hospital, Detroit, MI; B. Rabinowitz, Botsford General Hospital, Farmington Hills, MI; G. Ferguson, P. Kaplan, S. Sklar, and W. VanderRoest, Pulmonary and Critical Care Specialists, Farmington Hills, MI; O. Filos, V. Rao, M.V. Thomas, J. Varghese, J. Vyskocil, and F. Wadenstorer, Pulmonary Associates, PC, Flint, MI; J. Cantor, W. Katz, R. Johnson, Jr, D. Listello, and J. Wilt, Grand Valley Internal Medicine, Grand Rapids, MI; C. Acharya, W. Couwenhoven, T. Daum, M. Harrison, M. Koets, G. Sandman, and G. VanOtteren, Michigan Medical Professional Company, Grand Rapids, MI; S. Kraker, Michigan Medical, PC, Holland, MI; M. Greenberger, A. O Neill, and D. Wu, Huntington Woods, MI; R.C. Albertson III, J. Chauncey, T. Murray, and G. Patten, Pulmonary Clinics of Southern Michigan, Jackson, MI; T. Abraham, J. Dirks, B. Dykstra, G. Grambau, and J. Schoell, Associated Pulmonary and Critical Care Specialists, PC, Kalamazoo, MI; R. Brush, S. Jefferson, J. Miller, S. Schuldheisz, and M. Warlick, Pulmonary and Cricial Care Associates, PC, Kalamazoo, MI; J. Armstrong,

6 Flaherty, Travis, Colby, et al.: Histopathologic Variability 1727 A. Atkinson, T. Kantra, L. Rawsthorne, and D. Young, Pulmonary and Critical Care Consultants, Lansing, MI; A. Abbasi, C.M. Gera, G. Kashyap, and J. Morlock, Pulmonary Services, Lansing, MI; S. Danek, and A. Saari, Respiratory Medicine, Marquette, MI; E. Obeid, Central Michigan Healthcare System, Mt. Pleasant, MI; D. Hoch, and A. Kleaveland, Muskegon Pulmonary Associates, Muskegon, MI; A. Allam, and M.A. Gad Jr, Owosso Medical Group, Owosso, MI; A. Desai, U. Dhanjal, and A. Sethi, Lung Associates, Pontiac, MI; F. Ahmad, R. Elkus, L. Kaiser, L. Rosenthal, and D. Sak, St. Joseph s Hospital, Pontiac, MI; R. Ailani, M. Basha, A. Hadar, and S. Holstine, Physician HealthCare Network, Port Huron, MI; M.W. Al-Ameri, R. Go, and M. Kashlan, Pulmonary, Critical Care, and Sleep, PC, Rochester Hills, MI; K. Aggarwal, Rochester, MI; W. Hanna, and R. Marchese, Roseville, MI; R. Begle, D. Erb, K.P. Ravikrishnan, J. Seidman, and S. Sherman, William Beaumont Hospital, Royal Oak, MI; M. Ivey, Spring Lake, MI; S. Deskins, A. Palmer, and S. Shastri, Lakeside Healthcare Specialists, St. Joseph, MI; R. DiLisio, S. Galens, K. Grady, D. Harrington, R. Herbert, C. Hughes, J. Lee, A. Starrico, K. Stevens, M. Trunsky, and W. Ventimiglia, Pulmonary and Critical Care Associates, St. Clair Shores, MI and Troy, MI; D. Mahajan, Taylor, MI; H. Kaplan, and L. Tankanow, Pulmonary Medicine Associates, Warren, MI; M. Pensler, Henry Ford Wyandotte Hospital, Wyandotte, MI; F.O. Horton III, A. Nathanson, and R. Wainz, Toledo Pulmonary and Sleep Specialists, Toledo, OH.