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Perspectives in lung pathology.

Compared with other organs, the lung is unique in its open connection with the outside world. Although various defense mechanisms are present, everything that passes through the airways is still a great influence, including environmental pollution, occupational exposure, and tobacco smoke. To a certain extent, these exposures themselves can cause pathology of the lung, but even more important may be the low-level exposures that, by themselves, do not cause clinically relevant pathology, but which do have profound effects on the microenvironment of the lung, most often by causing inflammatory changes. This means that often, the histopathologic picture is complicated by the confounding effects of such low-level exposures. Smoking is the most extensively known exposure in the population worldwide, followed by environmental pollution in the industrialized world (and, perhaps, exposure to fumes from indoor cooking in the nonindustrialized societies) and, somewhat less, by occupational exposure. These exposures will almost always affect the histopathologic presentation of lung pathology. Recent publications have shown that exposures like smoking also give rise to significant molecular changes (1-4) and, thus, will also affect research into the molecular background of pulmonary disease. As new therapeutic options based increasingly on molecular research emerge, confounding molecular effects, like those caused by smoking, become more and more relevant.

The advances in knowledge about lung disease and the many recent developments in molecular pathology and molecular diagnosis, in general, might suggest that there will be a reduced demand for traditional pulmonary pathology in the future. As already argued recently by Andrew Nicholson, (5) however, the problem diagnostic areas have not really changed during recent years, and diagnostic referrals have not decreased. Likely, this is partly due to our still-limited understanding of many areas of lung pathology. In addition, as indicated above, lung pathology is complicated by a combination of etiologic effects that result in complex histopathologic patterns, often further complicated by intricate clinical presentations and radiology. This is particularly the case for nonneoplastic lung pathology. Another confounding factor is that the lung has a large reserve capacity with respect to lung function. Therefore, diagnostic procedures are typically performed after disease has already progressed for quite some time (depending on the extent to which patients have already used their lung capacity). Such long-standing damage to the lung often results in a more or less common, final pathway for different diseases, with fibrotic and inflammatory changes, so that it is not always easy to discern the specific underlying etiology or disease entity.

In this special section on lung pathology, we have asked the authors to focus not primarily on a review of certain diagnostic areas in lung pathology, but, rather, on the challenging current concepts of either pathogenesis or diagnostics or on the authors' speculations on how present advances in pulmonary science will find their way into future approaches to diagnostic pulmonary pathology.

One of the primary, nonchronic, obstructive, smoking-related lung pathologies is respiratory bronchiolitis interstitial lung disease, which was included in the diagnostic categories in the 2002 American Thoracic Society and European Respiratory Society consensus article (6) on interstitial lung disease. Although criteria put forward at that consensus meeting provided more clarity in the separation of diagnostic categories in interstitial lung disease, the category of respiratory bronchiolitis interstitial lung disease still causes diagnostic confusion and difficulties in separation from smokers' respiratory bronchiolitis and other smoking-related lung disease. Churg et al present, in their contribution in this issue, an interesting perspective on the background of the pathologic changes in respiratory bronchiolitis interstitial lung disease and respiratory bronchiolitis, with their views and suggestions for a proper and more unified use of terminology, based on clinical, histopathologic, and pathogenetic features.

A rather enigmatic disease is lymphangioleiomyomatosis. (7) Lymphangioleiomyomatosis is a partly cystic lung disease, which sometimes, in its early phase, presents as a primarily interstitial lung disease that presently is included in the large group of perivascular epithelioid cell tumors. Although not malignant, lymphangioleiomyomatosis is still a potentially lethal disease, for which, for many years, only a few pathogenetic clues were known. Martignoni and colleagues shed more light on the genetic basis of this autosomal-dominant genetic disease. They discuss the relevant genes and pathways with a perspective that provides a basis for innovative therapeutic strategies for developing inhibitors of the relevant signaling pathways.

Considering the largely unchanged, poor prognosis of lung cancer patients, one development in recent years was the use of high-resolution computed tomography to identify lung lesions at an early stage and to include this in a screening program for lung cancer in subjects at risk. (8,9) Although initially this seemed a promising approach, during the first screening programs, it appeared that there were several unexpected findings, which placed this approach in a different perspective. Chirieac and Flieder review the different approaches that use high-resolution computed tomography screening, followed by local excision and diagnostic histopathology, and describe the pros and cons in recent developments in early detection of lung carcinoma, resulting in some challenging views and perspectives.

Sarcomatoid carcinoma of the lung is a category of lung malignancies that can be a diagnostic challenge often not readily solved on hematoxylin and eosin staining and sometimes even difficult although immunophenotyping is available. Franks and Galvin review the current histologic classification and diagnostic criteria that identify the 5 subtypes of sarcomatoid carcinoma of the lung and they discuss the most common tumors that are important in the differential diagnosis.

One of the new interesting developments in the treatment of lung cancer is targeted therapy using signaling pathway blocking agents; antiepidermal growth factor receptor is one of the best known, but likely many more will follow. (10-14) Until now, the success of such treatment was related to rather specific diagnostic groups. (10) This has increased the relevance of pathologists in adequately phenotyping tumors and has resulted in progressive combining of conventional microscopic morphology with molecular pathology. (11) Chilosi and Murer have given their perspective on the mixed adenocarcinomas of the lung and the proper classification applied to, or as they put it, "mandatory" for, targeted therapy.

With targeted therapy, and because of the increasing use of epidermal growth factor receptor-blocking agents in lung cancer therapy, pathologists and clinicians have focused on how to determine the relevant epidermal growth factor receptor status to determine eligibility for this therapy. Inamura and colleagues have, therefore, given their perspective on how epidermal growth factor receptor status in lung cancer is reflected in clinicopathologic features, and they give their opinion on how those features can be used to advantage by pathologists.

We have enjoyed the opportunity to contribute to this special section of the Archives. We hope readers will be challenged by the views put forward and that these views will find their way into practical, daily use in diagnostic pathology. We thank the authors of the contributions for their efforts to present up-to-date knowledge concisely and to provide provocative insights.

Accepted for publication September 8, 2009.


(1.) Schembri F, Sridhar S, Perdomo C, et al. MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci USA. 2009;106(7):2319-2324.

(2.) Spira A, Beane J, Shah V, et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A. 2004;101(27): 10143-10148.

(3.) Spira A, Beane JE, Shah V, et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 2007(3): 361-366.

(4.) Beane J, Sebastiani P, Liu G, Brody JS, Lenburg ME, Spira A. Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression. Genome Biol. 2007;8(9):R201.

(5.) Nicholson AG. Whither thoracic pathology? Histopathology. 2009;54(1):1-2.

(6.) American Thoracic Society and European Respiratory Society. International multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2002;165(2):277-304.

(7.) McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest. 2008;133(2):507-516.

(8.) Flieder DB, Vazquez M, Carter D, et al. Pathologic findings of lung tumors diagnosed on baseline CT screening. Am J Surg Pathol. 2006;30(5):606-613.

(9.) Vazquez M, Carter D, Brambilla E, et al. Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications. Lung Cancer. 2009;64(2):148-154.

(10.) Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol. 2008;21(suppl)2:S16-S22.

(11.) Ladanyi M. Targeted therapy of cancer: new roles for pathologists. Mod Pathol. 2008;21(suppl 2):S1.

(12.) Daigo Y, Nakamura Y. From cancer genomics to thoracic oncology: discovery of new biomarkers and therapeutic targets for lung and esophageal carcinoma. Gen Thorac Cardiovasc Surg. 2008;56(2):43-53.

(13.) Brambilla E, Gazdar A. Pathogenesis of lung cancer signalling pathways: roadmap for therapies. Eur Respir J. 2009;33(6):1485-1497.

(14.) Sakamoto H, Shimizu J, Horio Y, et al. Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of epidermal growth factor receptor gene mutation from preinvasive to invasive adenocarcinomas. J Pathol. 2007;212(3):287-294.

Wim Timens, MD, PhD; Bruno Murer, MD

From the Department of Pathology, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands (Dr Timens); and the Department of Pathology, General Hospital Mestre, Venice, Italy (Dr Murer).

The authors have no relevant financial interest in the products or companies described in this article.

Correspondence: Wim Timens, MD, PhD, Department of Pathology, University Medical Center Groningen, HPC EA10, Hanzeplein 1, 9713 GZ Groningen, the Netherlands (e-mail:

Wim Timens, MD, PhD, studied Medicine at the University of Groningen, the Netherlands, and received his doctor of medicine degree in 1983. After a short period as a research fellow, he followed the residency training program at the Department of Pathology, University Hospital Groningen (now part of the University Medical Center Groningen), and was board-registered as a pathologist in 1990. In 1988, he received a doctor of philosophy degree with a thesis on the structure and function of the human spleen. In 1990, he worked as a postdoc at the Cross-Cancer Institute (Edmonton, Canada), and later that year, he joined the faculty of the Department of Pathology at the University Hospital Groningen. In 1992, he was appointed in this department as an associate professor and, in 1994, as a full professor in pathology. Although he started his career in hematopathology and immunopathology, areas in which he also started his research interests, he soon became very interested in--and challenged by--pulmonary pathology. In the past 18 years, he has dedicated his diagnostic pathology work to the whole area of pulmonary diseases. He has worked on different research themes involving lung pathology and has been involved in, and leads, many research projects, most with external funding and, almost invariably, in close collaboration with the Department of Pulmonology and several other disciplines. He has published more than 180 peer-reviewed, scientific papers and, in addition, several book chapters and reviews. Within his research themes, there is a strong focus on the pathogenesis of obstructive lung diseases, which is a main research area at the University Medical Center Groningen. He chairs the Groningen Research Institute on Asthma and COPD and has been a member of the Scientific Board of the Netherlands Asthma Foundation for many years.

Currently chief of the Pathology Service of the Ospedale dell'Angelo in Venice, Italy, and professor of pathology at the University of verona, Bruno Murer, MD, graduated in 1975 from the University of Ferrara and completed his specialization in pathology at the University of Parma in 1980. After completing a residency in Anatomic Pathology at the General Hospital, University School of Medicine (Ancona, Italy), he spent 6 months as a general surgical pathologist at Hammersmith Hospital in London. He worked for 17 years at Regional Hospital, University of Ancona, Italy, as a general surgical pathologist but with a specific interest in cardiovascular pathology, especially congenital heart diseases, and pulmonary pathology. During that time, he spent 2 months in Amsterdam, the Netherlands, to study pulmonary hypertension in congenital heart diseases under the guidance of C. A. Wagenvoort, MD, PhD, and 3 months at the Brompton Hospital in London under the guidance of B. Corrin, MD, PhD. In 1993, he moved to the Regional Hospital of Mestre, Venice, Italy, where he currently practices as director of Surgical Pathology Service. He is one of the founding members of the Italian Pulmonary Pathology Group and of the Italian Mesothelioma Study Group. He has worked on different research projects on pulmonary pathology and mesotheliomas in collaboration with clinicians and pathologists. As part of these groups of collaborating clinicians and pathologists, Dr Murer has contributed in providing knowledge in the fields of pulmonary pathology and mesotheliomas. He has published more than 150 peer-reviewed, scientific articles, book chapters, and reviews. Dr Murer is on the board of Pathologica, the official journal of the Italian Society of Pathology, and of the Archives of Pathology & Laboratory Medicine.
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Title Annotation:Special Section--Insights and Controversies in Lung Pathology
Author:Timens, Wim; Murer, Bruno
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:4EUNE
Date:Jan 1, 2010
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