European Respiratory Society
Pathology of the Lung

Pathological examination forms a key element in the final diagnosis of a variety of malignant and non-malignant respiratory disorders, and directs treatment. Research has contributed to important advances in the pathological diagnosis of these respiratory disorders. This book is a complete overview of diagnostic procedures and pathological examination data, which help support the clinician in the decision-making process. This Monograph covers the pathology of neoplastic diseases, infections, obstructive and interstitial lung diseases, and pulmonary manifestations of systemic diseases.

  • European Respiratory Society Monographs
  1. Page vii
  2. Page viii
  3. Page 1
    Correspondence: J.T. Stocker, Dept of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA. Fax: 1 3012951640; E-mail: jstocker

    A new and expanded classification of congenital pulmonary airway malformations (CPAM) of the lung identifies lesions on the basis of the likely site of origin and clinical and pathological features. Within the five types, recent reports have demonstrated an association of CPAM type 1 with bronchioloalveolar carcinoma (BAC), and a degree of confusion in separating CPAM type 4 from the purely cystic form of pleuropulmonary blastoma.

    The CPAM type 1 lesion has been noted to contain clusters of mucogenic cells in ∼35% of cases, and these clusters are thought to predispose the patient to the development of BAC. The CPAM type 4 lesion, with its large and often thick-walled cysts lined with alveolar lining cells, may be confused with the cysts of type I pleuropulmonary blastoma, although its cyst walls contain subepithelial foci of rhabdomyosarcoma, almost exclusively underlying stretches of cuboidal-to-columnar epithelium, rather than the alveolar cell epithelium of CPAM type 4.

    Other cystic or pseudocystic lung lesions include post-infarction peripheral cysts resulting from intrauterine pulmonary artery thrombosis. Similarly appearing cysts have been noted in Down’s syndrome. Air-filled cysts within the interstitium are a feature of acute and persistent interstitial pulmonary emphysema, and are limited to the interlobular septa. Fluid-filled cysts of congenital pulmonary lymphangiectasia are present within the interlobular septa, and extend laterally from the septa beneath the pleura. Congenital pulmonary lymphangiectasia is also frequently associated with congenital malformations of the heart. Bronchogenic cysts are rarely seen in infants, and are solid lesions usually separate from the lung. Extralobar sequestrations are also nonaerated lesions separate from the lung and occasionally found within or beneath the diaphragm. Intralobar sequestrations are usually acquired lesions (through infection), and may display air- or fluid-filledcysts,representing re-epithelialisedpost-infectiousabscesses. Finally,one ofthe most common pulmonary lesions in infants and children, infantile lobar emphysema,is not cystic but simply the overinflation of a segment of lung.

  4. Page 21
    Correspondence: M.K. Dishop, Dept of Pathology, MC 1-2261, Texas Children’s Hospital, 6621 Fannin St, Houston, TX 77030, USA. Fax: 1 8328251032; E-mail:

    The diagnosis of diffuse lung disease in infants remains a challenge for both pulmonologists and pathologists, given the rarity of these disorders and the similarity of clinical presentation in many cases.

    Since 2000, advances in diagnosis include the discovery of a new gene affecting surfactant metabolism (adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3)) and description of two new entitities specifically affecting the infant lung (pulmonary interstitial glycogenosis and neuroendocrine cell hyperplasia of infancy). Mutations in the ATP-binding cassette transporter gene, ABCA3, are now recognised as a cause of both respiratory failure in infancy and chronic progressive lung disease in older children and adolescents. Recognition of the histological patterns and ultrastructural abnormalities associated with the inherited surfactant dysfunction disorders should prompt mutation testing of the three known causative genes: surfactant protein (SFTP) B and SFTPC, and now ABCA3.

    Pulmonary interstitial glycogenosis (also called infantile cellular interstitial pneumonia) refers to a histological pattern of interstitial widening by glycogen-rich stromal cells seen predominantly in early infancy. This may be an isolated finding, or, more often, is recognised in association with other underlying lung diseases, such as impaired alveolar growth due to prematurity, pulmonary hypoplasia or congenital heart disease. Neuroendocrine cell hyperplasia of infancy is now recognised as a pathological correlate to the syndrome of persistent tachypnoea of infancy. Since lung biopsy specimens from these patients may appear near-normal on initial histological review, application of bombesin immunohistochemistry is necessary in order to identify the increased number of airway neuroendocrine cells needed for diagnosis. Both pulmonary interstitial glycogenosis and neuroendocrine cell hyperplasia of infancy are disorders of unknown aetiology, as it is unclear whether these are manifestations of abnormal lung development, or alternatively reactive phenomena occurring post-natally in response to infection, environmental stimuli or other forms of lung injury.

  5. Page 37
    Correspondence: K.M. Kerr, Dept of Pathology, University of Aberdeen School of Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZD, UK. Fax: 44 1224663002; E-mail:

    Squamous dysplasia (SD)/carcinoma in situ (CIS) of the bronchus is a precursor lesion for bronchogenic squamous cell carcinoma. It is found most frequently in tobacco smokers, often associated with invasive carcinoma. It comprises a range of lesions of increasing atypia, with complex criteria for distinguishing mild, moderate and severe dysplasia and CIS based on abnormal cytology and architecture of a squamous-type epithelium. SD/CIS must be distinguished from basal cell hyperplasia and squamous metaplasia, themselves likely precursors of SD/CIS, from reactive atypia seen in a number of situations and from invasive squamous cell carcinoma. Lesions of SD/CIS are small, often incidental, findings in bronchial biopsy specimens, and published criteria are difficult to apply.

    Atypical adenomatous hyperplasia (AAH) occurs in alveolated lung. It is the precursor of localised bronchioloalveolar carcinoma,and also of peripheral invasive adenocarcinoma. AAH lesions are small and consist of alveoli lined with atypical bronchioloalveolar cells. They most frequently occur in lung bearing invasive adenocarcinoma. AAH must be distinguished from reactive proliferations of type II pneumocytes associated with diffuse interstitial lung diseases or with localised fibro-inflammatory lesions.Distinction between AAH and bronchioloalveolar carcinoma is both important and challenging, and is based upon the degree of cellular atypia, stratification, crowding and increased cell size. Other differential diagnoses of AAH include micronodular pneumocyte hyperplasia, peribronchiolar metaplasia, and alveolar and papillary adenomas.

    Diffuse idiopathic pulmonary neuroendocrine cell (PNEC) hyperplasia is an extremely rare condition, in which proliferation of PNECs forms multiple carcinoid tumourlets and fibrosis of airways leading to airflow limitation. Carcinoid tumours may also develop. Differential diagnoses include other forms of PNEC hyperplasia, either incidental in occurrence or associated with fibro-inflammatory diseases, such as bronchiectasis. The relationship between these other forms of PNEC hyperplasia and carcinoid tumours is unclear.

  6. Page 63
    Correspondence: R. Pirker, Dept of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18, A-1090 Vienna, Austria. Fax: 43 1404004461; E-mail:

    Since the mid 1990s, major progress has been achieved in the systemic therapy of lung cancer. These achievements include new cytotoxic drugs, the establishment of adjuvant chemotherapy in patients with completely resected nonsmall cell lung cancer (NSCLC) and improved supportive care. Of major clinical relevance are new concepts that have become available through the development of targeted therapies.

    Targeted therapies have entered clinical practice, or are undergoing clinical evaluation, either as a single treatment modality or in combination with chemotherapy or radiotherapy. Growth factors and their receptors have become important targets. Epidermal growth factor receptor (EGFR) directed tyrosine kinase inhibitors, such as erlotinib, improve symptoms and prolong survival in patients with advanced NSCLC who have previously been treated with chemotherapy. Intensive research on the prediction of response to these agents is ongoing. Cetuximab, in combination with palliative chemotherapy, is being evaluated in phase III trials, and other EGFR-directed monoclonal antibodies are in earlier stages of clinical development. Several dual kinase or multikinase inhibitors are undergoing clinical evaluation in patients with advanced NSCLC.

    Inhibition of angiogenesis also holds great promise, and can be achieved by means of various strategies, including blockade of the vascular endothelial growth factor (VEGF)/VEGF receptor pathway. Bevacizumab, an anti-VEGF monoclonal antibody, increases the efficacy of paclitaxel/carboplatin in selected patients with advanced nonsquamous NSCLC. Several other targeted therapies (matrix metalloproteinase inhibitors, farnesyl transferase inhibitors, aprinocarsen and bexarotene) did not improve outcome in selected groups with lung cancer.

    Tumour vaccines are at various stages of clinical development, but, to date, no benefit could be demonstrated in phase III trials. Gene therapy has also been attempted, but still requires the development of vectors that can be administered systemically. In order to successfully use targeted therapies, a detailed knowledge of the molecular events involved in tumour growth is necessary. Molecular pathology needs to determine clinically useful targets and provide reliable methods for their determination in patients with lung cancer.

  7. Page 85
    Correspondence: J-F. Cordier, Louis Pradel Hospital, Université Claude Bernard, 28 avenue Doyen Lépine, 69677 Lyon Cedex, France. Fax: 33 472357653; E-mail:

    The management of rare primary pulmonary tumours is a paradigm of the cooperation between clinicians and pathologists from establishment of the diagnosis to treatment. From a pathological point of view, rare primary pulmonary tumours are defined as tumours of unusual histological type in the lung. From an epidemiological point of view, they may be defined by an overall prevalence of <1% of all lung tumours. Rare pulmonary tumours represent a wide range of diverse tumoral processes, which may be classified into three main pathological groups: 1) rare tumours derived from orthotopic tissues; 2) rare lung tumours derived from ectopic tissues; and 3) rare lung tumours derived from haematopoietic tissues.

    The first step in the diagnosis of rare primary pulmonary tumours is to recognise possible specific clinical and radiological features that, even if infrequent, may suggest the diagnosis. The second is to establish the definite pathological diagnosis, and the third to ensure that it is primary in nature. In order to illustrate the close cooperation between the pathologist and the clinician, five rare primary pulmonary tumours of special interest are described in this chapter: myofibroblastic tumour; sarcomas; epithelioid haemangioendothelioma; mucoepidermoid carcinoma; and pulmonary lymphoma, especially mucosa-associated lymphoid tissue lymphoma.

    Therapeutic strategy consists of upfront surgical resection when possible, ensuring both the diagnosis and the first step of treatment. The role of radiotherapy and/or chemotherapy mainly depends upon the aggressiveness and curability of the tumour. The overall prognosis of rare pulmonary neoplasms remains better than that of nonsmall cell lung cancer. Large multicentric observational studies to establish pathological databases, to generate basic research and therapeutic trials, and eventually to assess actualised state-of-the-art recommendations for management and treatment are warranted to improve knowledge of rare primary pulmonary tumours.

  8. Page 134
    Correspondence: H.H. Popper, Dept of Pathology, Laboratories for Molecular Cytogenetics, Environmental and Respiratory Pathology, Medical University of Graz, Auenbruggerplatz 25, Graz, A-8036, Austria. Fax: 43 31638583646; E-mail:

    Smoking is a habit, better called an addiction, which has profound effects upon human health and affects many organ systems. Even without obvious disease, many deleterious effects of (cigarette) smoke exposure are present. Furthermore, whereas the increased risk of (lung) cancer is best known, many other smoke-induced diseases are now known, with some occurring frequently, such as chronic obstructive pulmonary disease, and others with a lower frequency. The present chapter gives an overview of the effects different smoke components have on the cells and compartments of the normal lung, and in what way these factors contribute to increased health risks. It also provides a concise overview of nonmalignant smoking-related diseases in the human lung.

  9. Page 153
    Correspondence: J.L. Wright, Room GF 164, Dept of Pathology, University Hospital, 2211 Wesbrook Mall, Vancouver BC V6T 2B5, Canada. Fax: 1 6048227104; E-mail:

    There has been a resurgence of interest in the pathophysiological mechanisms involved in chronic obstructive pulmonary disease since the early 1990s. The present chapter presents an overview of new information in two important areas in human disease, namely the role of the lymphocyte and exacerbations. The role of the extracellular matrix is much more important, and more complicated, than early work suggested. This is followed by an analysis of new data in both humans and animals. Finally, new information gleaned from animal studies is described and discussed.

  10. Page 170
    Correspondence: P.S. Hasleton, Dept of Histopathology, Clinical Sciences Block, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK. Fax: 44 1612766348; E-mail:

    Interstitial lung diseases are heterogeneous, encompassing a variety of aetiological factors. There is considerable variability in histological appearance over time in an individual patient and across the patient population. Light and electron microscopy reveal common themes, such as injury and apoptosis of the cellular elements of the lung parenchyma, basement membrane fragmentation, alveolar collapse and hyaline membrane formation. Organising inflammation and fibrogenesis are more variable features.

    The different histological patterns may represent a temporal sequence of changes within the evolution of disease, with focal or diffuse alveolar damage, as seen in adult respiratory distress syndrome or acute interstitial pneumonia. Alternatively, they represent a range of possible end-points, perhaps reflecting different aetiological factors. For instance, usual interstitial pneumonia is seen as a nonimmune-mediated process. This range of outcome is also informed by genetic or other variation in expression and function of pro-fibrotic mediators. The strong clinical association between interstitial lung disease and connective tissue diseases provides a clear argument for a role for auto-immunity in the pathogenesis of some interstitial pneumonia. Clear differentiation of immune interstitial pneumonia from other types has not been achieved, due to both inherent and sampling variability.

    There is considerable evidence for an activation of the adaptive immune system in interstitial lung disease, and also for the generation of auto-antibodies. However, the precise role of immune dysregulation in the pathogenesis of this disease remains unknown.

  11. Page 189
    Correspondence: A. Churg, Dept of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5 Canada. Fax: 1 6048227635; E-mail:

    Chronic hypersensitivity pneumonitis (HP) is defined as HP with radiological evidence of fibrosis. Pathologically a variety of patterns are seen, including those which resemble usual interstitial pneumonia (UIP), fibrotic nonspecific interstitial pneumonia (NSIP) and peribronchiolar fibrosis. Cases of chronic HP typically show poorly formed granulomas, individual giant cells or Schaumann bodies, which are all crucial clues to the correct diagnosis. Areas of subacute HP (purely cellular infiltrates, usually in a centrilobular pattern) are also frequently present. It is unknown what proportions of chronic HP cases do not show any of these identifying features and, thus, are pathologically indistinguishable from UIP or fibrotic NSIP. Chronic HP has a distinctly worse prognosis than subacute HP, but whether the specific patterns of fibrosis impact on survival is not yet known.

  12. Page 199
    Correspondence: T.V. Colby, Dept of Pathology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. Fax: 1 4803018372; E-mail:

    The pulmonary pathology associated with inflammatory bowel disease is reviewed in the current chapter. Lung disease in this setting may be directly related to inflammatory bowel disease (IBD), secondary to other complications of IBD, or associated with therapy given for IBD. Cases that reach pathological evaluation include examples of inflammatory lesions of the subglottic region, trachea and large airways, inflammatory and obstructive lesions of the bronchioles, a variety of patterns of diffuse interstitial lung disease, and necrobiotic parenchymal nodules.