We have retrospectively studied 53 patients with idiopathic pulmonary fibrosis and a histologic diagnosis of usual interstitial pneumonia and evaluated the prognostic significance of four individual histologic features (fibroblastic foci [FF], interstitial mononuclear cell infiltrate, established fibrosis, and intra-alveolar macrophages) using a semiquantitative scale of 0–6. An objective count of FF was also undertaken. Using weighted kappa coefficients, interobserver agreement between pathologists was moderate to good (0.56–0.76). Subjective and objective FF scores were strongly associated (RS = 0.88, < 0.00005). Mortality was independently linked to a high FF score, p = 0.006, and a low percent predicted carbon monoxide diffusing capacity (DlCO), p = 0.01. For pulmonary function, on univariate analysis, the strongest correlations were observed between increasing interstitial mononuclear cell infiltrate or FF scores and greater declines in forced vital capacity (FVC) or DlCO at 6 months. Multivariate models revealed that increasing FF scores were independently associated with greater declines in FVC and DlCO at both 6 and 12 months. Increasing interstitial mononuclear cell infiltrate scores were also independently linked to functional decline, but only at 6 months. These data suggest a reproducible method on biopsy for predicting rate of disease progression in patients with idiopathic pulmonary fibrosis.
Several histologic patterns of idiopathic interstitial pneumonias have been described in relation to idiopathic pulmonary fibrosis (IPF) (1), but the current consensus is that in patients undergoing surgical lung biopsies, diagnoses of IPF should be restricted to those patients with a pattern of usual interstitial pneumonia (UIP) (2). Clinically, patients with IPF, synonymous with lone cryptogenic fibrosing alveolitis (IPF/CFA), have chronically progressive disease, with a mean survival from the onset of dyspnea of 3–6 years (3–9). Disease progression has historically been monitored through clinical status and lung function tests, although with the advent of high-resolution computerized tomography (HRCT), there is potential for further refinement, with the serial imaging findings providing data relating to disease progression (10).
Although identifying a pattern of UIP on surgical lung biopsy provides important prognostic data in relation to other patterns of idiopathic interstitial pneumonia (11–14), there are few studies analyzing the individual histologic features comprising this pattern (15). Early studies of IPF/CFA suggested that patients could be divided into those with cellular and fibrotic diseases on biopsy appearances, but these cohorts contained patients with a pattern of desquamative interstitial pneumonia (DIP), which is now believed to represent a separate disease process rather than an early phase of IPF (1). There are also several studies that attempt to grade the pathologic findings of “cellularity” and “fibrosis” in relation to IPF (3–5, 7, 16–23), but when analyzed critically (1), only one examines the individual histologic subtypes of interstitial pneumonias, as defined at the time (18).
The histologic pattern of UIP is well-characterized, with the cardinal feature being a patchy distribution of temporally heterogenous fibrosis, the fibrosis comprising areas of established fibrosis with adjacent foci of fibroblastic proliferation, so-called fibroblastic foci (FF). Recent interest in IPF/CFA has centered on the prognostic significance of these foci, and data suggest that they are important (24). The purpose of this study was to test the hypothesis that individual histologic features, in particular extent of FF, related to the rate of disease progression and mortality in IPF/CFA, using archival pathologic material.
All patients presenting between 1979 and 1998 who fulfilled the clinical criteria for a diagnosis of IPF/CFA (2, 5), and who had undergone surgical lung biopsies underwent an independent biopsy review by two pathologists. Of these, 59 showed a pattern of UIP. One patient was rejected due to postoperative death, and four patients had no follow-up data. One more patient was rejected as biopsy occurred 9 months before presentation at our institution. Of the remaining 53 patients, all had pulmonary function tests within 6 weeks of surgical lung biopsy. In those patients who had undergone HRCT scans (n = 41), all showed features compatible with IPF/CFA. The 53 patients had been treated after biopsy with high dose prednisolone alone (n = 14), or with prednisolone 10 mg daily in combination with cyclophosphamide (n = 25), azathioprine (n = 8), cyclosporin (n = 1), or α interferon (n = 1). One patient received prednisolone 8 mg daily, one patient received penicillamine only, and two were not treated. Some of these patients have been included in other published series relating to histologic patterns of interstitial pneumonia in CFA (14, 25).
Sequential lung function data on 43 patients were available from the time of biopsy. Measurements were made less than 6 weeks before biopsy in all cases. Percentage changes in carbon monoxide diffusing capacity (DlCO) and forced vital capacity (FVC) from baseline values were calculated at 6 months (range 4–9 months) and at 1 year (range 9–15 months). Results were expressed as percentages of values predicted from the subject's age, sex, and height. Lung volumes were measured using an Ohio water-seal spirometer (Ohio instruments, Atlanta, GA), and measures of gas transfer (DlCO) were made by the single-breath technique using a P.K Morgan respirometer (P.K Morgan, Chatham, Kent, UK).
All cases fulfilled documented criteria for a diagnosis of UIP, a definition which now excludes the pattern of end-stage lung (14, 26), and subsequent scoring was undertaken independently and without knowledge of the clinical data. Twenty-eight patients had undergone biopsies at two different sites. One patient was biopsied at three separate sites, giving a total number of 83 separate biopsies. A semiquantitative assessment was undertaken for each individual biopsy using a scale of 0–6 for four individual histologic features: the extent of FF, the extent of the interstitial mononuclear cell infiltrate (IM), the extent of established fibrosis (EF), and the extent of intra-alveolar macrophage accumulation (AM). For FF, an absence of fibroblastic proliferation was scored as 0, and a level equivalent to that seen in Figure 1Awas scored as 6. For IM, a score of 0 represented no inflammation, and a score of 6 represented the degree of infiltration that would be expected in a pattern of lymphocytic interstitial pneumonia. For EF, a score of 0 represented no fibrosis, and a score of 6 represented end-stage or honeycomb lung. For AM, a score of 0 or 1 was considered within normal limits, and a score of 6 represented the degree of accumulation seen in desquamative interstitial pneumonia (DIP). Areas of end-stage lung (honeycomb lung) were not scored with regard to macrophage accumulation. In cases with biopsies from two different sites, an average score was taken. To assess the accuracy of semiquantitatively assessing the number of FF, a second objective count was also undertaken using the following methodology. Each biopsy was viewed at low-power magnification (×40), and the numbers of FF were counted within a standard area (8.82 mm2). This was undertaken in three separate areas where activity appeared to be most marked within each biopsy. In 11 biopsies, where three separate areas were unavailable due to the small size of the sample, only two regions were assessed in eight cases and one region in three cases. When available, scores were averaged to provide an index of “x” foci/mm2 for each sample. In cases with biopsies from two different sites, an average score was taken, unless a biopsy showed end-stage lung disease (n = 5) or was normal (n = 1). In these instances, the count from a single site was used for analysis.
Statistical analyses were performed using STATA software (Stata data analysis software; Computing Resource Center, Santa Monica, CA). Interobserver variation was quantified using the kappa coefficient of agreement and using a weighted kappa coefficient of agreement (using quadratic weighting) (27) to take into account the degree of disagreement on a semiquantitative categorical scale. In such observer variation studies, less than 0.2 is considered poor, 0.2–0.4 fair, 0.4–0.6 moderate, 0.6–0.8 good, and more than 0.8 excellent (28, 29). Correlations involving histologic scores were evaluated using Spearman's rank correlation coefficient.
The prognostic value of histologic scores in predicting mortality was examined using proportional hazards regression, with the inclusion of percent predicted DlCO as a covariate (to control for the global severity of disease) (30). The histologic determinants of change in FVC at 6 and 12 months were examined using stepwise regression; histologic indices not contributing to equation explanatory power (p > 0.20) were excluded.
The study was approved by the Royal Brompton Hospital ethics committee.
*Unweighted κ Coefficients of Agreement from Cherniack and colleagues (32)
Unweighted κ Coefficient of Agreement
Weighted κ Coefficient of Agreement
|Fibroblastic foci||0.03, 0.19||0.26||0.75|
|Interstitial mononuclear||0.17, 0.14||0.20||0.56|
|Alveolar macrophage||0.10, 0.23||0.21||0.64|
|Established fibrosis||0.29, 0.30||0.39||0.76|
The 53 patients were followed for a median of 24.0 months. Follow-up was complete in 48 (death, n = 46; alive at most recent follow-up, n = 2), and was censored at the time when lost to follow-up in 3 cases and at the date of lung transplantation in 2 cases. The mean (± SD) age was 55.6 (7.9); there were 45 males and 8 females. Mean (SD) baseline FVC and DlCO levels were 70.2% predicted (17.5) and 43.0% predicted (15.0), respectively. Examination of the proportional hazards model showed that mortality was independently linked to an increasing FF score, p = 0.006, and a decreasing percent predicted DlCO, p = 0.01. These findings were not influenced by adjustment for age and sex (neither of which was independently linked to mortality).
Follow-up pulmonary function data was available in 43 patients (6 months, n = 42; 1 year, n = 37). Median percentage changes from baseline (with ranges in parentheses) at 6 months were DlCO, −6.1% (−53.9 to +24.2%), and FVC, −3.4% (−32.9 to +17.2%). The corresponding changes at 12 months were DlCO, −12.8% (−67.8 to +37.4%), and FVC, −7.4% (−59.1 to +23.2%). On univariate analysis, shown in Table 2
Change in FVC at 6 mo
Change in FVC at 12 mo
Change in DlCO at 6 mo
Change in DlCO at 12 mo
|Fibroblastic foci||rs = −0.33‡||rs = −0.27§||rs = −0.22‖||rs = −0.22|
|Interstitial monocyte||rs = −0.36†||rs = 0.00||rs = −0.45*||rs = −0.11|
|Alveolar macrophage||rs = 0.10‡||rs = 0.25||rs = 0.01||rs = 0.27§|
|Fibrosis|| rs = −0.23||rs = −0.40†|| rs = 0.01|| rs = −0.17|
Examination of multivariate models, summarized in Table 3
Fibroblastic Foci Score (95% CI)
Interstitial Mononuclear Score (95% CI)
Alveolar Macrophage Score (95% CI)
Interstitial Fibrosis Score (95% CI)
|Change in FVC at 6 months, r 2 = 0.24||−2.9 (−5.5, −0.4)*||−5.1 (−9.5, −0.7)*|
|Change in FVC at 12 months, r 2 = 0.26||−4.2 (−8.4, 0.0)§||−7.5 (−14.0, −1.0)*|
|Change in DlCO at 6 months, r 2 = 0.23||−4.8 (−8.9, −0.6)†||−8.0 (−15.1, −0.49)†|
|Change in DlCO at 12 months, r 2 = 0.18||−6.3 (−12.4, −0.2)‡||5.9 (−0.8, 12.6)‖|
Since recognition of IPF/CFA as a distinct form of interstitial lung disease, there have been various attempts to relate progression of the disease to clinical, radiologic, and histopathologic features. Serial CT scans (10), lung function tests, and initial response to treatment have all been identified as parameters that provide data with regard to disease progression. However, few studies have correlated individual histopathologic features with disease progression in IPF/CFA. Early studies suggested that IPF/CFA could be subdivided into cellular and fibrotic phases, but this subdivision is no longer considered valid, as most cases classified as cellular probably represent DIP, now believed to represent a different entity rather than an early phase of UIP (1). Furthermore, the so-called fibrotic subgroup of IPF/CFA described in previous studies most likely represents a mixed cohort of cases of UIP and nonspecific interstitial pneumonia (NSIP) (14, 31). However, with the stricter definition of UIP and the recommendation that patients classified as IPF should only show a histologic pattern of UIP (2), the purpose of this study was to assess whether this histopathologically better-defined population of patients showed any correlation between microscopic features and deterioration in clinical disease.
The most important findings in our study were a strong correlation between increasing extent of FF, and both mortality and decrease in both DlCO and FVC at both 6 and 12 months after biopsy. This supports the most recent findings of King and colleagues, who also showed that an increase in the number of FF correlated with mortality in patients with IPF/CFA (24). Although our study is retrospective in nature, our findings support their prospective data that assessment of FF in UIP can predict the rate of disease progression in patients with IPF/CFA.
To validate our observations, we undertook an objective study of the extent of FF, and this correlated very strongly with our semiquantitative findings. This is especially of value to the pathologist, as it means that a simple visual assessment of the slide is all that is required to produce relevant data, rather than undertaking time-consuming objective analysis. We also assessed interobserver variation between the two pathologists for all histologic parameters to determine whether such a scoring system is reproducible. Previously, major interobserver variation has been documented in the semiquantitative scoring of histologic features of IPF/CFA (32), and without the use of a weighted kappa coefficient of agreement, nonweighted kappa coefficients in this study (Table 1) are similar to those previously published in relation to histologic parameters in UIP (32). However, the nonweighted kappa coefficient of agreement does not take into account the degree of disagreement in a semiquantitative scale, and usage of a weighted system, more appropriate in this type of analysis, showed moderate to good agreement between pathologists for all four parameters, indicating that such a scoring system is reproducible.
Of the other three parameters, IM also correlated significantly with decline in lung function for both DlCO and FVC, although this was only seen at 6 months. This was surprising, given the historical view that inflammation in IPF/CFA was associated with reversible disease and a better outcome. The reason for this adverse association in our study is not known, but it could well reflect a role of active chronic inflammation early in the development of fibrosis and its presence as an epiphenomenon related to fibroblastic activity. Nevertheless, these data highlight the fact that antiinflammatory drug therapy may still play an important ancillary role, as and when antifibrogenic agents are developed. In contrast to the degree of interstitial chronic inflammation, the increased AM scores were not strongly associated with decreases in lung function, undermining the concept of cellular and fibrotic phases of IPF/CFA, as both AM and IM were characteristics used to classify cases as being in the cellular phase. In this study, these two individual histologic features have disparate functional consequences, and these two histologic features should perhaps be viewed separately with regard to pathogenesis. Furthermore, EF was not consistently linked to subsequent change in lung function, despite the fact that functional impairment is strongly correlated with the extent of fibrosis on CT (33). One possible explanation for this apparent paradox is that survival is linked to the extent of honeycombing on CT rather than the overall extent of fibrosis (34), and further studies correlating histologic parameters with HRCT data are ongoing.
These data may also give an insight into the cohort of patients histologically classified as fibrotic NSIP. It has been suggested that FF represent the site of initial injury in IPF/CFA (35), and our study shows a wide range in their numbers. Given this wide range, some biopsies may contain few if any FF, and as temporal heterogeneity is the cardinal feature of UIP, those areas with no ongoing injury may well be classified as fibrotic NSIP on this basis. Indeed, both pathologists involved in this study recognize cases, which have been biopsied at different sites, where one biopsy shows a pattern typical of NSIP and the second shows a pattern of UIP. In these instances, the overall diagnosis is given as UIP, a practice supported by the recent study of Flaherty and coworkers on survival rates of patients with idiopathic interstitial pneumonia, and histologic variability between UIP and NSIP at different biopsies sites from the same patient (31). The theory that some cases of fibrotic NSIP may be in a spectrum with UIP (36) is also supported by CT data, first on a cohort of patients with NSIP where 32% showed imaging features more characteristic of UIP (37), and second in a study showing that considerable overlap in thin-section CT patterns exists between NSIP and UIP (38). Furthermore, in two previous studies on cohorts of patients with idiopathic interstitial pneumonia and IPF/CFA, 5-year survival of patients with fibrotic NSIP was significantly better than that of UIP, whereas survival approached that of UIP at 10 years, again suggesting that some cases of fibrotic NSIP may represent relatively inactive, and therefore more slowly progressive, IPF/CFA (13, 14).
In conclusion, these data suggest a reproducible method on biopsy for predicting rate of disease progression in patients with IPF/CFA. They also provide evidence that the FF is integral to the disease process.
The authors thank their colleagues in the Department of Thoracic Surgery, led by Mr. P. Goldstraw, for undertaking the biopsies and providing the tissue which made this work possible.
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