Fibroblastic Foci: Time To Be Counted?

Abstract

The last decade has seen a number of reappraisals of the interstitial lung diseases, and this process is continuing and iterative.1This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med. 2002; 165 (American Thoracic Society/European Respiratory Society International multidisciplinary consensus classification of the idiopathic interstitial pneumonias): 277-304Crossref PubMed Scopus (3356) Google Scholar2American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar3Statement on sarcoidosis: joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999.Am J Respir Crit Care Med. 1999; 160: 736-755Crossref PubMed Scopus (2163) Google Scholar One of the major impacts of these deliberations has involved the redefining of the diagnostic criteria for, and pathogenetic insights into idiopathic pulmonary fibrosis (IPF). The 2000 international consensus statement2American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar on IPF noted the following:The histologic hallmark and chief diagnostic criterion (of the usual interstitial pneumonia pattern of pathology that is present in IPF) is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change… The fibrotic zones are composed mainly of dense collagen, although scattered foci of proliferating fibroblasts (so-called fibroblastic foci) are a consistent finding.In 2002, an international multidisciplinary consensus classification of the idiopathic interstitial pneumonias included “fibroblastic foci typically scattered at the edges of dense scars” as one of the key histologic features of usual interstitial pneumonia (UIP).1This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med. 2002; 165 (American Thoracic Society/European Respiratory Society International multidisciplinary consensus classification of the idiopathic interstitial pneumonias): 277-304Crossref PubMed Scopus (3356) Google Scholar These changes in definition drew attention to the relative paucity of inflammation in the histopathologic appearances and the paradigm that fibrosis in IPF followed inflammation in a temporally linear pathway was challenged, although the debate continues.4Selman M King TE Pardo A Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar5Gauldie J Pro: Inflammatory mechanisms are a minor component of the pathogenesis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 165: 1205-1206Crossref PubMed Scopus (95) Google Scholar6Strieter RM Con: Inflammatory mechanisms are not a minor component of the pathogenesis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 165: 1206-1207Crossref PubMed Scopus (67) Google Scholar In this challenge, evidence was presented that supported the hypothesis that IPF was the product of repeated and recurrent epithelial cell injury and aberrant wound healing, a process that was modulated significantly by epithelial cell responses to injury. In this more recent paradigm, the concept was advanced that the earliest and possibly only morphologic change that was associated with progression to more established fibrosis was the presence and extent of fibroblastic foci. In other words, the importance of fibroblastic foci at the center of the pathogenetic process was emphasized.Since then, there have been numerous studies7Gomperts BN Belperio JA Rao PN et al.Circulating progenitor epithelial cells traffic via CXCR4/CXCL12 in response to airway injury.J Immunol. 2006; 176: 1916-1927Crossref PubMed Scopus (137) Google Scholar8Willis BC Liebler JM Luby-Phelps K et al.Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis.Am J Pathol. 2005; 166: 1321-1332Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar that have addressed the significance of the fibroblastic foci; did they evolve from local resident fibroblasts, circulating progenitor cells derived from bone marrow, or secondary to epithelial mesenchymal transformation? In parallel with these pathogenesis studies, there emerged a series of publications9Flaherty KR Colby TV Travis WD et al.Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease.Am J Respir Crit Care Med. 2003; 167: 1410-1415Crossref PubMed Scopus (221) Google Scholar10King Jr, TE Schwarz MI Brown K et al.Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.Am J Respir Crit Care Med. 2001; 164: 1025-1032Crossref PubMed Scopus (529) Google Scholar11Nicholson AG Fulford LG Colby TV et al.The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 166: 173-177Crossref PubMed Scopus (244) Google Scholar that explored the relationship between the number of fibroblastic foci and individual outcome.In this regard, King et al10King Jr, TE Schwarz MI Brown K et al.Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.Am J Respir Crit Care Med. 2001; 164: 1025-1032Crossref PubMed Scopus (529) Google Scholar studied the histopathologic features of surgical biopsy specimens from 87 patients with UIP to determine which histopathologic features best predicted survival. Outcome was poorer for individuals with more fibroblastic foci; neither interstitial cellularity nor fibrosis were associated with survival. Nicholson et al,11Nicholson AG Fulford LG Colby TV et al.The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 166: 173-177Crossref PubMed Scopus (244) Google Scholar who reported the retrospective analysis of 53 patients with UIP, confirmed the prognostic significance of fibroblastic foci. While the number of fibroblastic foci was independently strongly linked to outcome, interestingly there was also a modest association between interstitial mononuclear cell infiltrate and lung function decline, but only at 6 months and not at 1 year. In a third publication, Flaherty et al9Flaherty KR Colby TV Travis WD et al.Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease.Am J Respir Crit Care Med. 2003; 167: 1410-1415Crossref PubMed Scopus (221) Google Scholar found that there were fewer fibroblastic foci in patients with UIP as part of rheumatologic diseases than in those with IPF, and this is in keeping with the well-recognized better survival of the former.What can be inferred from these observations? If more fibroblastic foci are present in biopsy findings from those individuals with a worse outcome, it implies that they may be the direct result of lung injury, and also that more injury must have occurred in patients with higher numbers of fibroblastic foci in a relatively short time interval before the biopsy specimen was obtained. It can be concluded, therefore, that it is the greater intensity of injury that largely explains the worse subsequent progression and that fibroblastic foci represent the anatomic flags locating more recent lung injury. In this context, it might be argued that more precise quantification of the numbers of fibroblastic foci may be of both scientific and clinical relevance.This has been addressed in the article by Enomoto et al12Enomoto N Suda T Kato M et al.Quantitative analysis of fibroblastic foci in usual interstitial pneumonia.Chest. 2006; 130: 22-29Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar in the current issue of CHEST (see page 22). The authors utilized a charge-coupled device camera to capture the histopathologic images from surgical biopsy samples from patients with IPF and UIP in association with rheumatologic disease and quantified the proportion of biopsy area occupied by fibroblastic foci in the target image areas using image analysis software. They confirmed the poorer prognosis in patients whose biopsy samples of idiopathic UIP had higher numbers of fibroblastic foci and the lower prevalence of fibroblastic foci in patients with a rheumatologic disease compared with those with IPF. Although these observations are confirmatory rather than novel, what does provoke cause for thought are the authors’ implications that this quantitative methodology may provide more precise measurement against which to evaluate issues of pathogenesis at the bench and to predict prognosis. They also suggest that their methodology is simpler than having samples scored by two or more pathologists, with the inherent problems of reproducibility and thus accuracy. In this regard, comparisons were made on the same samples between the quantitative methodology and the semiquantitative methodology used in three previous studies. Although reasonable correlations were found between the quantitative analysis and each of the semiquantitative methodologies, reproducibility was greater using quantification.But does it really matter? For pathologists, the technique requires an outlay of approximately $10,000 for the technology, 30 to 60 min of training, and 20 to 30 min to assess one patient, arguably too much when the added value of more precise quantification has not been shown. However, it can be argued that progress is always impeded by imprecision and that the time has come to tighten up; the future will surely demand us to be less subjective. For the scientist, it seems less debatable; if we believe that these morphologic features really are at the core of disease pathogenesis then quantifying them has to provide useful information in aiding the understanding of their significance. As usual, time will tell on both of these issues, but this article provides us with an incremental, if at the moment relatively short, step forward. The last decade has seen a number of reappraisals of the interstitial lung diseases, and this process is continuing and iterative.1This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med. 2002; 165 (American Thoracic Society/European Respiratory Society International multidisciplinary consensus classification of the idiopathic interstitial pneumonias): 277-304Crossref PubMed Scopus (3356) Google Scholar2American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar3Statement on sarcoidosis: joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999.Am J Respir Crit Care Med. 1999; 160: 736-755Crossref PubMed Scopus (2163) Google Scholar One of the major impacts of these deliberations has involved the redefining of the diagnostic criteria for, and pathogenetic insights into idiopathic pulmonary fibrosis (IPF). The 2000 international consensus statement2American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar on IPF noted the following: The histologic hallmark and chief diagnostic criterion (of the usual interstitial pneumonia pattern of pathology that is present in IPF) is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change… The fibrotic zones are composed mainly of dense collagen, although scattered foci of proliferating fibroblasts (so-called fibroblastic foci) are a consistent finding. In 2002, an international multidisciplinary consensus classification of the idiopathic interstitial pneumonias included “fibroblastic foci typically scattered at the edges of dense scars” as one of the key histologic features of usual interstitial pneumonia (UIP).1This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med. 2002; 165 (American Thoracic Society/European Respiratory Society International multidisciplinary consensus classification of the idiopathic interstitial pneumonias): 277-304Crossref PubMed Scopus (3356) Google Scholar These changes in definition drew attention to the relative paucity of inflammation in the histopathologic appearances and the paradigm that fibrosis in IPF followed inflammation in a temporally linear pathway was challenged, although the debate continues.4Selman M King TE Pardo A Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar5Gauldie J Pro: Inflammatory mechanisms are a minor component of the pathogenesis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 165: 1205-1206Crossref PubMed Scopus (95) Google Scholar6Strieter RM Con: Inflammatory mechanisms are not a minor component of the pathogenesis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 165: 1206-1207Crossref PubMed Scopus (67) Google Scholar In this challenge, evidence was presented that supported the hypothesis that IPF was the product of repeated and recurrent epithelial cell injury and aberrant wound healing, a process that was modulated significantly by epithelial cell responses to injury. In this more recent paradigm, the concept was advanced that the earliest and possibly only morphologic change that was associated with progression to more established fibrosis was the presence and extent of fibroblastic foci. In other words, the importance of fibroblastic foci at the center of the pathogenetic process was emphasized. Since then, there have been numerous studies7Gomperts BN Belperio JA Rao PN et al.Circulating progenitor epithelial cells traffic via CXCR4/CXCL12 in response to airway injury.J Immunol. 2006; 176: 1916-1927Crossref PubMed Scopus (137) Google Scholar8Willis BC Liebler JM Luby-Phelps K et al.Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis.Am J Pathol. 2005; 166: 1321-1332Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar that have addressed the significance of the fibroblastic foci; did they evolve from local resident fibroblasts, circulating progenitor cells derived from bone marrow, or secondary to epithelial mesenchymal transformation? In parallel with these pathogenesis studies, there emerged a series of publications9Flaherty KR Colby TV Travis WD et al.Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease.Am J Respir Crit Care Med. 2003; 167: 1410-1415Crossref PubMed Scopus (221) Google Scholar10King Jr, TE Schwarz MI Brown K et al.Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.Am J Respir Crit Care Med. 2001; 164: 1025-1032Crossref PubMed Scopus (529) Google Scholar11Nicholson AG Fulford LG Colby TV et al.The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 166: 173-177Crossref PubMed Scopus (244) Google Scholar that explored the relationship between the number of fibroblastic foci and individual outcome. In this regard, King et al10King Jr, TE Schwarz MI Brown K et al.Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.Am J Respir Crit Care Med. 2001; 164: 1025-1032Crossref PubMed Scopus (529) Google Scholar studied the histopathologic features of surgical biopsy specimens from 87 patients with UIP to determine which histopathologic features best predicted survival. Outcome was poorer for individuals with more fibroblastic foci; neither interstitial cellularity nor fibrosis were associated with survival. Nicholson et al,11Nicholson AG Fulford LG Colby TV et al.The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2002; 166: 173-177Crossref PubMed Scopus (244) Google Scholar who reported the retrospective analysis of 53 patients with UIP, confirmed the prognostic significance of fibroblastic foci. While the number of fibroblastic foci was independently strongly linked to outcome, interestingly there was also a modest association between interstitial mononuclear cell infiltrate and lung function decline, but only at 6 months and not at 1 year. In a third publication, Flaherty et al9Flaherty KR Colby TV Travis WD et al.Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease.Am J Respir Crit Care Med. 2003; 167: 1410-1415Crossref PubMed Scopus (221) Google Scholar found that there were fewer fibroblastic foci in patients with UIP as part of rheumatologic diseases than in those with IPF, and this is in keeping with the well-recognized better survival of the former. What can be inferred from these observations? If more fibroblastic foci are present in biopsy findings from those individuals with a worse outcome, it implies that they may be the direct result of lung injury, and also that more injury must have occurred in patients with higher numbers of fibroblastic foci in a relatively short time interval before the biopsy specimen was obtained. It can be concluded, therefore, that it is the greater intensity of injury that largely explains the worse subsequent progression and that fibroblastic foci represent the anatomic flags locating more recent lung injury. In this context, it might be argued that more precise quantification of the numbers of fibroblastic foci may be of both scientific and clinical relevance. This has been addressed in the article by Enomoto et al12Enomoto N Suda T Kato M et al.Quantitative analysis of fibroblastic foci in usual interstitial pneumonia.Chest. 2006; 130: 22-29Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar in the current issue of CHEST (see page 22). The authors utilized a charge-coupled device camera to capture the histopathologic images from surgical biopsy samples from patients with IPF and UIP in association with rheumatologic disease and quantified the proportion of biopsy area occupied by fibroblastic foci in the target image areas using image analysis software. They confirmed the poorer prognosis in patients whose biopsy samples of idiopathic UIP had higher numbers of fibroblastic foci and the lower prevalence of fibroblastic foci in patients with a rheumatologic disease compared with those with IPF. Although these observations are confirmatory rather than novel, what does provoke cause for thought are the authors’ implications that this quantitative methodology may provide more precise measurement against which to evaluate issues of pathogenesis at the bench and to predict prognosis. They also suggest that their methodology is simpler than having samples scored by two or more pathologists, with the inherent problems of reproducibility and thus accuracy. In this regard, comparisons were made on the same samples between the quantitative methodology and the semiquantitative methodology used in three previous studies. Although reasonable correlations were found between the quantitative analysis and each of the semiquantitative methodologies, reproducibility was greater using quantification. But does it really matter? For pathologists, the technique requires an outlay of approximately $10,000 for the technology, 30 to 60 min of training, and 20 to 30 min to assess one patient, arguably too much when the added value of more precise quantification has not been shown. However, it can be argued that progress is always impeded by imprecision and that the time has come to tighten up; the future will surely demand us to be less subjective. For the scientist, it seems less debatable; if we believe that these morphologic features really are at the core of disease pathogenesis then quantifying them has to provide useful information in aiding the understanding of their significance. As usual, time will tell on both of these issues, but this article provides us with an incremental, if at the moment relatively short, step forward.