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Division of Pulmonary and Critical Care Medicine, Department of Medicine
the Departments of Biostatistics, Pathology
Cardiothoracic Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania
ABSTRACT
We examined small airway morphometry from resected lung specimens in 25 patients with severe emphysema undergoing lung volume reduction surgery (LVRS) and correlated their pathologic findings to changes in FEV1 6 months after LVRS. Patients were classified into two groups: responders had a more than 12% and a more than 200-ml change in FEV1 at 6 months, and nonresponders had 12% or less and/or 200 ml or less change in FEV1. Epithelial height (EH) and perimeters and areas of peribronchial smooth muscle, epithelium, and subepithelial space were measured quantitatively. The degrees of interstitial fibrosis, vascular sclerosis, goblet cell hyperplasia, squamous metaplasia, chronic inflammation, peribronchial fibrosis, and bullous disease were assessed semiquantitatively. Despite similar baseline characteristics, nonresponders had a greater EH (0.045 vs. 0.035 mm, p = 0.025), greater EH adjusted for basement membrane perimeter (0.040 vs. 0.011, p = 0.016), greater epithelial area adjusted for basement membrane area (0.561 vs. 0.499, p = 0.040), and less bullous disease (1.7 vs. 2.6, p = 0.011) compared with responders. We found a linear relationship between percentage change in FEV1 and bullous disease and inverse relationships between percentage change in FEV1 and interstitial fibrosis, goblet cell hyperplasia, peribronchial fibrosis, and vascular sclerosis. We conclude that small airway morphometry and lung histopathology in patients with severe emphysema have an important influence on changes in FEV1 6 months after LVRS.
Key Words: emphysema pathology, surgical pulmonary disease, chronic obstructive/pa (pathology) pulmonary surgical procedures respiratory function tests
Significant variability has been reported in postoperative lung function in patients with severe emphysema after lung volume reduction surgery (LVRS). Several small, single-center studies have reported increases ranging from 21eC82% in FEV1 6 to 12 months after LVRS (1eC11). Differences between studies in patient selection, underlying medical condition, and medical therapy, as well as operative technique, may be factors accounting for some of this variability.
However, in our LVRS program, where the same group of pulmonologists and thoracic surgeons treat every patient, we have noted that some patients have a substantial improvement in postoperative FEV1 that is sustained in prolonged follow-up, whereas other seemingly similar patients during preoperative evaluation did not (12). Even the National Emphysema Treatment Trial, the largest and best characterized study of outcome after LVRS, reported substantial variability in postoperative FEV1 (13). This was evident even in the subgroup exhibiting the most favorable response to LVRS (e.g., upper lobe predominate emphysema by CT scan and low exercise performance on cardiopulmonary exercise testing). In this subgroup, 35% of patients had a decrease in FEV1 at 6 months in comparison with preoperative values; 65% of patients had an increase in FEV1, but the increases ranged from 1% to more than 20% despite similarities in demographic, radiologic, and physiologic baseline assessments. The reasons for such differences in LVRS outcome in such a homogeneous population of patients with severe emphysema characterized by extensive physiologic and radiologic tests are unknown.
One possible explanation is that patients undergoing LVRS have small airway obstruction because of variable combinations of emphysema and intrinsic small airway abnormalities. Although the physiologic and radiographic tests currently used to identify candidates for LVRS are useful for determining the severity of airflow obstruction, they are incapable of identifying whether the cause of airway obstruction is due to a loss of elastic recoil from emphysema or intrinsic small airway pathology (i.e., epithelial hyperplasia, subepithelial fibrosis, and peribronchial smooth muscle hypertrophy).
We reasoned that some of the variability in FEV1 changes after LVRS may be due to some patients having more extensive emphysema causing small airway obstruction than intrinsic small airway abnormalities and vice versa. Patients having disproportionately more emphysema as a cause of airway obstruction should have a better response to LVRS than those having predominately small airway abnormalities. Therefore, in this study, we examined small airway morphometry and lung histopathology from resected lung specimens in patients with severe emphysema undergoing LVRS and correlated lung histopathologic findings with postoperative FEV1. Some of the results of this study have been previously reported in the form of an abstract (14).
METHODS
A full description of the methods is found in the online supplement.
Patient Selection
Patients with severe, diffuse emphysema meeting criteria were enrolled into our single-institution prospective, randomized, controlled trial of LVRS versus optimized medical therapy (15). Twenty-five patients who underwent bilateral LVRS between February 1, 1995, and July 1, 1999, were identified and classified as either having a significant and sustained improvement in postoperative FEV1 and functional status or not. All patients had their surgical biopsies retrospectively reviewed by investigators blinded to their clinical data and outcome.
Patients were divided into two groups: responders and nonresponders. Compared with baseline, responders were defined as having a more than 12% and a more than 200-ml increase in FEV1 at 6 months; nonresponders were defined as having a 12% or less and/or a 200 ml or less increase in FEV1 at 6 months.
Pulmonary function testing was performed within 6 months before LVRS and at 6 months after surgery.
Radiologic evaluation was performed using a high-resolution computed tomography (CT) scan and quantitative lung perfusion scan. All patients had imaging data jointly reviewed for targeted resection by the same pulmonologist (G.C.) and thoracic surgeon (S.F.). Areas of the worst emphysema or most substantial underperfusion were targeted for resection, added by visual examination by the same thoracic surgeon (S.F.) at the time of extirpation in all patients. Bilateral LVRS was performed via median sternotomy.
Airway Selection
The lung specimens were inflated with 10% formalin and fixed for at least 12 hours. The specimens were then embedded in paraffin. Sections 4 e thick were cut and stained with hematoxylin and eosin.
All airways 2 mm or less in their greatest internal diameter (e.g., membranous bronchioles) and adjacent to blood vessels were analyzed microscopically using a magnification of x100. Digital photographs were taken using a Spot Insight color digital camera model 3.2.0 (Diagnostic Instruments, Inc., Sterling Heights, MI) attached to a Nikon optiphot microscope, using the SPOT Advanced software, version 3.4.5. Airways were excluded from analysis if the entire airway could not be included in the photograph, if the smooth muscle borders were not well defined, or if the epithelial layer was disrupted.
Quantitative Assessment
Using a modified version of a model previously described by Tiddens and colleagues (16), the histopathology of small airways was analyzed morphometrically using a National Institutes of Health public domain imaging program, Image J 1.23p (National Institutes of Health, Bethesda, MD). The measurements made are shown in Figure 1 and included the following: diameter of the lumen bounded by the respiratory epithelium, both longest and shortest dimensions; area and perimeter of the lumen bounded by respiratory epithelium (AI, PI); area and perimeter surrounded by the basement membrane (ABM, PBM), outer smooth muscle border (AOSM, POSM), and inner smooth muscle border (AISM, PISM); and epithelial cell height (EH), measured at 15 random locations along the PI of the airway. A goal of 10 airways per patient was measured. The investigators performing pathologic and morphometric airways assessments were blinded to the clinical data of each patient as well as to the specific identification of any airway. The following values were calculated based on the measurements collected previously here:
Epithelial layer area (EA) = ABM eC AI
Smooth muscle wall area (SMWA) = AOSM eC AISM
Subepithelial area (SE) = AISM eC ABM
The epithelial layer area, smooth muscle wall area, and subepithelial area were divided by the ABM of each airway, and the EH was divided by the PBM of each airway to adjust for differences in airway size.
Semiquantitative Assessment
A board-certified pathologist who specializes in lung pathology, who was blinded to all clinical information and the nature of the investigation, examined each of the resected specimens. Examination of the resected lung specimens was performed after fixation and coronal sectioning. Using a four-point scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe), the presence and magnitude of the following pathologic descriptions were graded semiquantitatively with a model previously described by Wright and colleagues (17) and Thurlbeck and colleagues (18): (1) interstitial fibrosis (e.g., increased interstitial collagen), (2) airway goblet cell hyperplasia, (3) squamous metaplasia of the airways, (4) peribronchial fibrosis, (5) chronic airway inflammation, and (6) vascular sclerosis. Bullous changes (dilated air spaces > 1 cm in diameter) were assessed by visual inspection of the gross resected lung specimen using a semiquantitative scale: 0 = bullae occupying less than 5% in the resected specimen, 1 = bullae occupying 1eC25%, 2 = bullae occupying 26eC50%, and 3 = bullae occupying more than 50%. Correlations were made between the bullous changes assessed grossly in the resected specimen and the hematoxylin and eosineCstained slides at the magnification of x1.
Data Analysis
Descriptive statistics are reported as mean ± overall SD, except where otherwise noted. A p value of less than 0.05 was considered statistically significant. An unpaired t test was used to compare baseline demographic and pulmonary function data between the two groups. A two-way analysis of variance (group, sample) was used to analyze the multisample histopathologic measurements (on normalized ranks if data failed the test for normality). The model used in the analysis was a linear mixed model modified to allow for modeling of the "within-subject" covariance structure. Different covariance structures were attempted with the final choice dictated by the goodness of fit. Pearson correlation coefficients were used to measure the relationships between change in FEV1 and histopathologic measurements. Multiple linear regression was used to develop a prediction equation for the percentage change in FEV1. Multiple logistic regression was used to predict the probability of change in FEV1 greater than 12%. A further description of the statistical analysis is included in the online supplement.
RESULTS
Patient Characteristics
There were 10 patients in the responder group and 15 patients in the nonresponder group. Baseline demographics, pulmonary function, exercise performance, oxygen requirements, medications, and blood gas values are summarized in Table 1. Preoperative pulmonary function testing was performed at 54 ± 46 days (mean ± SD) and 58 ± 43 days before LVRS in the responder and nonresponder groups, respectively (p = 0.84). All patients performed pulmonary function testing 6 months after LVRS. Between the two groups, there was no statistically significant difference in age, sex, race, smoking history, body mass index, medications, oxygen requirements, exercise tolerance, and pulmonary function, with the exception of FEV1; nonresponders had a lower FEV1 at baseline compared with responders (25 ± 8% predicted vs. 35 ± 9% predicted, p = 0.012). Additionally, nonresponders had a higher PaCO2 at baseline (47.2 ± 7.6 vs. 39.4 ± 6.0 mm Hg, p = 0.021). The absolute change, as well as the percentage change in FEV1 6 months after LVRS, was higher in responders than nonresponders (0.43 ± 0.19 vs. 0.02 ± 0.12 ml, p = < 0.001, and 53 ± 26% vs. 4 ± 20%, p = < 0.001).
Quantitative Assessment of Small Airways
One hundred ninety-two and 139 airways were screened in the nonresponder and responder groups, respectively. Forty-two and 46 airways in each group were excluded, leaving 150 airways in the nonresponder and 93 airways in the responder groups included in the final analysis.
The results of the quantitative assessment are summarized in Table 2. The internal lumen diameters, both longest and shortest dimensions, were similar in both groups (0.790 ± 0.281 vs. 0.817 ± 0.317 mm, p = 0.546, and 0.225 ± 0.161 vs. 0.241 ± 0.200 mm, p = 0.825, respectively). There were trends toward greater epithelial, smooth muscle wall, and subepithelial areas in the nonresponders compared with the responders, but the differences were not significantly different (Figure 2). EH was 29% greater in responders than nonresponders (0.045 ± 0.022 vs. 0.035 ± 0.019 mm, p = 0.025) (Figure 3). When adjusted for ABM, epithelial area of the nonresponders was 12% greater than the responders (0.561 ± 0.155 vs. 0.499 ± 0.164, p = 0.04) (Figure 4). Differences in smooth muscle wall area and subepithelial area between the two groups were not statistically different when adjusted for ABM. EH adjusted for PBM was 263% greater in nonresponders compared with responders (0.040 ± 0.018 vs. 0.011 ± 0.006, p = 0.016).
Multiple linear regression indicated three factors, internal lumen PI, PBM, and EH (EH is expressed in e), to be predictive of the percentage change in FEV1. The remaining clinical and demographic variables, as well as quantitative and semiquantitative assessments of small airways, were not significant. This analysis indicated that there was an 11.7% increase in FEV1 for each millimeter change in PI, a 17.1% decrease for each millimeter increase in PBM, and a 0.47% decrease for each micrometer increase in EH. The following formula was derived to estimate percentage change in FEV1 after LVRS based on these airway dimensions:
Similarly, using multiple logistic regression, the odds ratios for a percentage change in FEV1 greater than 12% were 2.73 for PI (95% confidence interval = 1.31eC5.69), 0.23 for PBM (95% confidence interval, 0.09eC0.54), and 0.972 for EH (measured in e, 95% confidence interval, 0.954eC0.990). The following formula can predict the probability of a percentage change in FEV1 greater than 12%:
Semiquantitative Assessment of Small Airways
Semiquantitative assessments of these 25 patients revealed incidental pathologic findings including aspergillomas (two patients), bronchiolitis obliterans organizing pneumonia (1), focal bronchiectasis (1), obliterative bronchiolitis (1), nonnecrotizing granulomas consistent with sarcoidosis (1), increased bronchial associated lymphoid tissue (1), and necrotizing granulomas (1). One patient had different degrees of interstitial and peribronchial fibrosis between one resected specimen compared with the contralateral specimen; in this case, the higher degree of fibrosis was included in the analysis. The results are summarized in Table 2. Nonresponders had less bullous disease than responders did (1.7 ± 0.8 vs. 2.6 ± 0.5, p = 0.011). There were trends toward greater degrees of interstitial fibrosis (e.g., increased interstitial collagen) and airway goblet cell hyperplasia in nonresponders compared with responders (1.4 ± 1.5 vs. 0.4 ± 0.7, p = 0.113 and 1.9 ± 1.5 vs. 0.8 ± 0.6 p = 0.063, respectively). There were no statistically significant differences between groups in the degrees of airway squamous metaplasia, peribronchial fibrosis, chronic airway inflammation, or vascular sclerosis.
Percent Change in FEV1 versus Airway Characteristics
The percentage change in FEV1 of each patient was related to the measured airway characteristics (both quantitative and semiquantitative). The results are summarized in Table 3. Statistically significant negative correlations were found between the change in FEV1 and EA (r = eC0.53, p = 0.007), EA/basement membrane area (r = eC0.35, p = 0.028), and EH (r = eC0.49, p = 0.002). Negative correlations were found between change in FEV1 and interstitial fibrosis (r = eC0.63, p = 0.001), goblet cell hyperplasia (r = eC0.51, p = 0.003), peribronchial fibrosis (r = eC0.44, p = 0.009), and vascular sclerosis (r = eC0.55, p = 0.003). A positive correlation was found between change in FEV1 and bullous disease (r = 0.62, p < 0.001). Examples of these correlations are depicted graphically in Figures 5 and 6.
DISCUSSION
Our study shows that an increase in FEV1 6 months after LVRS is associated with underlying lung pathology; nonresponders had greater small airway EH, greater epithelial area, more mucous metaplasia, and less bullous disease in comparison to responders. Moreover, small airway internal luminal PI, PBM, and EH had predictive value in determining postoperative LVRS changes in FEV1. In contrast to demographic, clinical, and physiologic variables, small airway morphometry and histopathology correlated with changes in postoperative spirometry.
Our data are in line with prior studies that have shown that smokers and patients with chronic obstructive pulmonary disease (COPD) with more severe airways obstruction are more likely to have thickened airways. Bosken and colleagues demonstrated in 60 smokers undergoing lung resectional surgery that membranous bronchiole wall thickness was greater in patients who were obstructed compared with patients who were nonobstructed (19). The muscle, epithelial, and connective tissue components of the walls were all increased in patients who were obstructed. Most recently, Hogg and colleagues demonstrated that in patients with COPD, the volume of the epithelium, lamina propria, smooth muscle, and adventitia, as well as total airway wall thickness, increased as the FEV1 declined (20). Others have shown significant increases in the smooth muscle component of the membranous or small airways of smokers (21). Mucous metaplasia (e.g., an increase in the presence and number of goblet cells) has also been reported in the peripheral airways of patients with COPD and contributes to thickened airways and irreversible or poorly reversible airways obstruction (22).
Why some patients manifest severe airways obstruction from prior cigarette smoking in the form of thickened airways, as opposed to small airway narrowing from emphysema induced decreased lung elastic recoil, is unclear. COPD has been described pathophysiologically as a state of chronic inflammation and injury of both airways and lung parenchymal structures that enact a dynamic state of repair (23). Various infections (24eC26) have been proposed to cause airway inflammation and epithelial injury that leads to small airway remodeling or alveolar tissue destruction. The intensity of airway inflammation by T-lymphocytes and macrophages has been shown to correlate with the severity of airways obstruction (27, 28) and nature and extent of the remodeling response (29). An imbalance between metalloproteinases and their tissue inhibitors has been hypothesized as a contributing factor to the development of airway inflammation and airflow obstruction (30). Higher levels of transforming growth factor-1 (31) and reduced epithelial expression of secretory component (32) have been reported to enhance the recruitment of macrophages and neutrophils to the small airways in smokers and cause airflow obstruction. The importance of genetic factors in affecting the histopathologic and phenotypic response to smoking is a matter of active investigation (33, 34).
Whether it is the severity of the inflammatory response, the type of infectious or noninfectious agent inducing inflammation, the location of the inflammatory response in the airway or lung parenchyma, or some aspect of remodeling during the repair stages that results in some patients having predominately thickened airways and others having emphysema, is unclear. What is clear from our data, however, is that thickened airways portend a worse outcome after LVRS in comparison to patients with thinner airways having predominately emphysema.
FEV1 was lower in our nonresponders to LVRS, but the rest of the preoperative pulmonary function tests, including lung volumes, diffusion capacity and 6-minute walk distance were similar between responders and nonresponders. The failure of standard pulmonary function data to more effectively discriminate between the small airway morphometry of the responders (e.g., thinner airways and more emphysema) and nonresponders (e.g., thicker airways and less emphysema) after LVRS is not unexpected. Gelb and colleagues (35) previously reported that patients with severe small airways disease and no or only trivial emphysema on pathologic examination may mimic the physiologic derangements found on pulmonary function testing in patients with severe emphysema (e.g., reduced diffusing capacity, marked hyperinflation, increased total lung capacity, and severe expiratory airflow obstruction).
Others have shown a good correlation with the morphologic diagnosis of emphysema and chest CT findings (36). In 24 patients with COPD (FEV1 1.1 L) who underwent lung resection, emphysema grade determined by chest CT correlated significantly with pathological emphysema scoring (r = 0.86, p = 0.001). In 17 of these patients, significant abnormalities were also identified in the small airways, which included airway wall inflammation and muscle and goblet cell hypertrophy. A potential explanation for the variability in the pathologic extent of emphysema found in resected specimens of our patients and their chest CT appearance could be that they had more severe airflow obstruction than described in others reports and that small airways abnormalities contributed disproportionately to the airway obstruction of our patients.
Alternatively, our center's ability to detect emphysema during chest CT examination could have been qualitatively inferior to other reports. However, Flaherty and colleagues (37) reported that the sensitivities and negative predictive values of a preoperative chest CT were limited in predicting a more than 12% predicted and a more than 200-ml increase in postoperative FEV1 compared with preoperative baseline. These data suggest that qualitative grading for emphysema using a chest CT to guide LVRS resection is limited. Greater use of computer-based chest CT algorithms to score emphysema objectively shows promise in improving interpretation, thereby avoiding misclassification of the cause of airway obstruction (36, 38).
There are several drawbacks in this study. First, there were slight differences in the baseline characteristics of the patients in each group. The nonresponders had a lower mean FEV1 at baseline compared with the responders, which may have contributed to the differences in the post LVRS changes in FEV1. However, Table 3 demonstrates that the correlations between airway measurements and lung histopathology and post-LVRS FEV1 changes were highly significant across the spectrum of patients in both groups.
In addition, the timing of preoperative lung function testing was variable. We based the changes in pulmonary function on the most recent spirometry data prior to LVRS compared with spirometry at 6 months after LVRS to define best the effects of the surgery on pulmonary function. We realize the drawback of not having a set time point to define "pre-LVRS" pulmonary function, but as this was a retrospective study, this was not done in a controlled manner. Of note, the amount of time that the pulmonary function tests were performed before LVRS was not significantly different between the two groups.
Tissue sampling bias was another potential concern. The amount of tissue sampled was small and may not be representative of the remaining lung tissue. The portion of lung examined for this study was resected from the most diseased portions of the lung. We assumed that the resected specimens provided insight into the small airway morphometry and intrinsic airway abnormalities in the remaining lung tissue. This remains an assumption that needs to be further explored in necropsy studies or in explants of patients with COPD obtained during lung transplantation.
In summary, this study provides preliminary evidence that differences in small airways morphometry and histopathology exist between those patients that have a significant increase in FEV1 after LVRS at 6 months compared with those that do not. Nonresponders had thicker epithelial layers, more interstitial and peribronchial fibrosis, vascular sclerosis, goblet cell hyperplasia, and less bullous disease. Examination of small airways morphometry during inspection of resected lung tissue at the time of LVRS resection may provide insight into the patient's subsequent postoperative lung function; however, prospective validation of our findings is required.
Acknowledgments
The authors acknowledge the contributions of Nidal Sakka, M.D., in identification of the patient database.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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