Does interstitial lung disease predispose to lung cancer?

PURPOSE OF REVIEW: This review examines the evidence for the causality and pathogenesis of lung cancer associated with interstitial lung disease. RECENT FINDINGS: Although cigarette smoking is the leading cause of lung cancer, several other conditions either predispose to lung cancer or increase the risk of lung cancer in smokers. The evidence supports an increased risk of lung cancer due to specific fibrotic and inflammatory lung diseases (termed interstitial lung diseases), including idiopathic pulmonary fibrosis, systemic sclerosis, and certain pneumoconioses. The potential pathogenetic mechanisms indicate that recurrent injury and inflammation result in genetic alterations that predispose to lung cancer. SUMMARY: Idiopathic pulmonary fibrosis, systemic sclerosis, and certain pneumoconioses are associated with an independent increased risk of lung cancer; however, a unifying pathogenetic mechanism to explain the causality of this association has not been described. In addition, the inconsistently reported lung cancer frequencies call attention to the need for prospective studies of good quality.     

Autoimmunity and interstitial lung disease

PURPOSE OF REVIEW: The pathogenesis of idiopathic pulmonary fibrosis as well as that of several other interstitial lung diseases is poorly understood. The role of autoimmunity in interstitial lung diseases associated with connective tissue disorders such as systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis as well as the vasculitides is well established. There is at least some evidence in the literature that supports the role of autoimmunity as one of the mechanisms of alveolar injury responsible for idiopathic pulmonary fibrosis. This review is an attempt to summarize the studies on this subject. RECENT FINDINGS: Repeated extraneous insults and exposures are considered to be responsible for recurrent alveolar injury, inflammation, dysregulated tissue repair, and fibroproliferation resulting in pulmonary fibrosis. The presence of autoantibodies in the sera of patients with idiopathic pulmonary fibrosis has been demonstrated in a few studies. Several autoantibodies, including anti-Sm antibodies, antibodies to U1 ribonucleoproteins, and antibodies to U3 ribonucleoproteins, have been demonstrated in connective tissue disorders, many of which are associated with interstitial lung involvement. Autoimmunity has been also suggested as a possible mechanism of rejection caused by bronchiolitis obliterans after lung transplantation. SUMMARY: It might seem that the role of autoimmunity in interstitial lung disease has been underestimated or even underinvestigated. The subject requires further investigation, especially with regard to the problems of lung allograft rejection due to bronchiolitis obliterans of nonalloimmunity origin and the failure of patients with idiopathic pulmonary fibrosis to respond to most forms of currently available therapy.     

Association of malignancy with diseases causing interstitial pulmonary changes

A number of studies have shown a high incidence of lung cancer in patients with idiopathic pulmonary fibrosis (9.8 to 38%) compared to control subjects (2 to 6.4%). A similar trend occurs in other entities that affect the interstitial lung compartment, such as systemic sclerosis and sarcoidosis, as well as occupational diseases. The pathogenesis of lung cancer in patients with diffuse pulmonary fibrosis is still unclear. Recent progress in molecular and cellular biology has shed some light on the possible interactions of several types of inflammatory cells, following the deleterious effects of toxic factors leading to alveolitis, and destruction and disorganization of lung parenchyma, which results in fibrosis. Further research in the field would enhance our understanding of the pathogenic mechanisms of cancer development in these patients, and to explain the reason for the different incidence of lung cancer in patients with various interstitial lung diseases.     

Smoking-related interstitial lung diseases: a concise review.

Interstitial lung diseases (also known as diffuse infiltrative lung diseases) are a heterogeneous group of parenchymal lung disorders of known or unknown cause. These disorders are usually associated with dyspnoea, diffuse lung infiltrates, and impaired gas exchange. The majority of interstitial lung diseases are of unknown cause. Known causes of interstitial lung disease include inhalation of organic and inorganic dusts as well as gases or fumes, drugs, radiation, and infections. This review summarizes the clinical, radiological, and histopathological features of four interstitial lung disorders that have been linked to smoking. These disorders include desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, pulmonary Langerhans' cell histiocytosis, and idiopathic pulmonary fibrosis. Available evidence suggests most cases of desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and pulmonary Langerhans' cell histiocytosis are caused by cigarette smoking in susceptible individuals. Smoking cessation should be a main component in the initial therapeutic approach to smokers with these interstitial lung diseases. In addition, smoking appears to be a risk factor for the development of idiopathic pulmonary fibrosis.     

Tabakrauchen und Lungenerkrankungen

Chronic cigarette smoking is the leading cause of preventable death and primarily affects the airways and lung parenchyma. It is a well-established prime risk factor for the development of chronic obstructive pulmonary disease (COPD) and lung cancer. Chronic cigarette smoking exacerbates pre-existing diseases of the airways and the lung parenchyma such as asthma and various forms of interstitial lung diseases. Additional exposure, e.g. in an occupational setting to asbestos fibres or silica, may act synergistically to increase the risk of lung cancer and pulmonary fibrosis and also of COPD. This paper gives a synopsis of smoking-induced pulmonary diseases with respect to epidemiology and pathology and how cigarette smoking affects the prognosis.     

Incidence of lung cancer in systemic sclerosis

During a study of lung function in patients with systemic sclerosis, we followed 71 patients with this diagnosis for a mean of 5 years. During this period, 3 cases of lung cancer were observed in the group, giving a post hoc incidence of lung cancer of 8.6 cases/1000 persons/year compared to an expected incidence of 0.52 cases/1000 persons/year. The relative risk ratio for lung cancer in systemic sclerosis patients is 16.5. There was no definite association of lung cancer with cigarette smoking, but all 3 patients had either radiographic or pulmonary function evidence of interstitial pulmonary fibrosis. Although bronchoalveolar carcinoma is the most prevalent histologic type of lung cancer associated with systemic sclerosis in the reported cases in the literature, this was not present in any of our patients.     

Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: report of eight cases and review of the literature

INTRODUCTION: Smoking can cause a variety of pulmonary interstitial diseases. Pulmonary fibrosis has traditionally been considered a non-smoking-related disease. Recently, however, evidence of smoking-induced fibrosis has emerged. SUBJECTS AND METHODS: A group of eight patients from the pulmonary clinic in Rabin Medical Center with a combine presentation of fibrosis and emphysema was identified retrospectively. All patients underwent chest computed tomography and pulmonary function tests. One patient underwent lung-heart transplantation and a complete review of his lung pathology was obtained. Transbronchial biopsy was performed in 3 additional patients and echocardiography was performed to evaluate the pulmonary vasculature. RESULTS: Upper-lobe emphysema with bulluos changes was found in all patients. In addition, a basal interstitial process was recognized, ranging from ground glass opacities to severe pulmonary fibrosis, with honeycombing. The radiological findings matched the pathological results of combined emphysema and usual interstitial pneumonia. Pulmonary function tests were also in accord, showing severe hypoxemia with mild obstruction, normal-to-mildly reduced lung volumes and a severe decrease in diffusion capacity. Most of the patients had moderate-to-severe pulmonary hypertension as well as diffuse coronary artery disease. CONCLUSION: Our findings are in line with emerging evidence that the spectrum of interstitial damage caused by smoke includes not only Langerhans cell hystiocytosis, respiratory bronchiolitis or desquamative interstitial pneumonia but also advanced usual interstitial pneumonitis as well. We believe that in some patients smoking plays a destructive role by a variety of mechanisms and can cause emphysema, lung fibrosis as well as pulmonary vasculopathy and hypertension. Future studies are needed to define the genetics and pathophysiology of this uncommonly reported clinical syndrome.     

Lung transplantation in interstitial lung disease

Interstitial lung disease is a heterogeneous group of illnesses, some of which may progress to a fibrosing stage and cause respiratory failure. For selected candidates, lung transplantation is the ultimate therapeutic option. We review data on lung transplantation for various interstitial lung diseases. We address indications, procedures, and outcomes for patients undergoing transplantation. Unique issues affecting morbidity, mortality, and recurrence of disease are discussed. We review the literature of transplantation for specific interstitial lung diseases and the outcomes of transplantation for interstitial lung diseases. Candidates with idiopathic pulmonary fibrosis experience high mortality on the waiting list, but derive significant survival benefit from lung transplantation. Recurrence is reported for several interstitial lung diseases after lung transplantation. Survival with lung transplantation for interstitial lung diseases is comparable with that attained in recipients with other indications. Lung transplantation is a well-tolerated, effective therapy for respiratory failure in interstitial lung disease.     

Pulmonary fibrosis associated with tracheobronchial aspiration. A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology.

Tracheobronchial aspiration of gastric secretions has been suggested in published reports as a possible cause for idiopathic pulmonary fibrosis. Forty-eight of 131 patients with roentgenographic evidence of pulmonary fibrosis had no established etiologic diagnosis after individualized evaluations. They were prospectively studied by upper gastrointestinal series to determine the incidence of gastroesophageal reflux. The incidence of both hiatal hernia and reflux were statistically higher in the study group than in a group of 270 age-matched controls who had upper gastrointestinal series for the usual indications; (2) a subgroup of 15 patients who had pulmonary fibrosis and serologic evidence which suggested immune-mediated diseases; and (3) a subgroup of 23 patients with pulmonary fibrosis of established etiology. The patients in the study group could be further characterized by clinical and roentgenographic presentations, low maximum-mid-expiratory flow rates, and lung biopsies compatible with interstitial fibrosis. These observations and other cited evidence are supportive of the concept that repeated, small tracheobronchial aspirations of gastric acid secretions over a long period of time may cause interstitial pulmonary fibrosis.     

Indikationen und Ergebnisse der Lungentransplantation bei idiopathischer Lungenfibrose

Lung transplantation is an established therapy option for patients with various end stages of pulmonary diseases and presently the worldwide frequency is about 3,500 procedures per year. Unfortunately, the shortage of donor organs leads to approximately every sixth patient in western countries dying before a donor organ is available. The most frequent underlying clinical indications are emphysema, pulmonary fibrosis and cystic fibrosis. In a recent analysis 23 % of all recipients worldwide had a diagnosis of idiopathic pulmonary fibrosis. In experienced centers, candidates for transplantation are chosen according to disease-specific factors under prognostic aspects after excluding contraindications. However, there are several challenges for lung transplantation. The number of lung transplantations performed is limited by the supply of donor organs and the long-term survival rates are still inferior compared to other forms of solid organ transplantation. Nevertheless, lung transplantation offers a survival benefit in carefully selected patients with interstitial lung diseases, especially with idiopathic pulmonary fibrosis.     

Advances in the treatment of rheumatic interstitial lung disease

PURPOSE OF REVIEW: Interstitial lung disease frequently complicates the rheumatic diseases. The purpose of this review is to outline recent advances and current concepts regarding the management of these interstitial lung diseases. RECENT FINDINGS: Several histologic lesions cause interstitial lung disease in rheumatic diseases, including nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, and acute interstitial pneumonia. Although the relative frequency of occurrence of these histopathologic lesions is not definitively established, it seems that nonspecific interstitial pneumonia accounts for a large proportion of rheumatic disease-associated interstitial lung diseases. Although usual interstitial pneumonia generally responds poorly to corticosteroid therapy, other forms of interstitial pneumonia are often steroid responsive and have a more favorable long-term prognosis. Pulmonary hypertension is increasingly recognized as a complication of these interstitial lung diseases. Treatment of pulmonary hypertension in these patients provides clinical benefit and may suppress pulmonary inflammation and fibrosis. Lung transplantation is a treatment option for selected patients with severe pulmonary involvement and limited life expectancy. SUMMARY: Interstitial lung disease is common in the rheumatic diseases, may be caused by a variety of lesions that respond differently to treatment, and may lead to the development of pulmonary hypertension. Whether the prognosis of interstitial lung disease associated with rheumatic disease is similar to that associated with the idiopathic interstitial pneumonias is not known. Treatment of these interstitial lung diseases should take into account the specific histologic lesion, the activity of the underlying rheumatic disease, and associated pulmonary hypertension, if present. The diagnosis of a rheumatic disease is no longer an absolute contraindication to lung transplantation.     

Correlation between circulating fibrocytes, and activity and progression of interstitial lung diseases

Background and objective: Interstitial lung diseases (ILD) are characterized by progressive interstitial pulmonary fibrosis and a decline in lung function. Fibrocytes are bone marrow‐derived mesenchymal progenitor cells that may play a role in the pathogenesis of pulmonary fibrosis. Circulating fibrocyte numbers have been correlated with the prognosis of patients with idiopathic pulmonary fibrosis. The aim of the present study was to evaluate the relationship between circulating fibrocytes, and parameters of disease activity and progression in several groups of patients with ILD. Methods: The study population comprised 41 patients with ILD and seven healthy control subjects. Circulating CD45⁺ collagen‐I⁺ fibrocytes were evaluated by flow cytometry. Results: The number of circulating fibrocytes was significantly increased in all patients with ILD and particularly in patients with idiopathic interstitial pneumonitis and interstitial pneumonitis associated with collagen vascular disease as compared with healthy control subjects. The numbers of circulating fibrocytes were significantly correlated with pulmonary function test parameters and with serum levels of sialylated carbohydrate antigen, a marker of disease activity. Temporal changes in circulating fibrocyte numbers were evaluated in two patients, and the results suggested that these changes correlated with the activity of ILD. Conclusions: The results from this study provide further evidence for the role of circulating fibrocytes in fibrotic lung diseases.     

Surgical biopsy: its appropriateness in diagnosing interstitial lung disease

PURPOSE OF REVIEW: Our goal is to update advances in the use of surgical lung biopsy in the idiopathic interstitial pneumonias. We discuss an approach for identifying patients with idiopathic interstitial pneumonias who may benefit from surgical lung biopsy, newer surgical approaches and complications and risks of surgery. RECENT FINDINGS: A consensus statement on idiopathic interstitial pneumonias has described the natural history and response to therapy of idiopathic interstitial pneumonias. The statement discussed selection of patients with idiopathic interstitial pneumonias for surgical lung biopsy and avoidance of unneeded biopsy, particularly for patients with 'classical' radiographic findings of idiopathic pulmonary fibrosis. Video-assisted thoracoscopic lung biopsy continues to be the standard procedure for surgical lung biopsy. Newer approaches have used outpatient surgery for selected patients, earlier removal of chest tubes and modifications of surgical technique. At-risk patients include those with respiratory failure, rapid progression of disease, pulmonary hypertension and advanced disease. SUMMARY: Standard video-assisted thoracoscopic lung biopsy should be considered in patients with interstitial lung diseases of unknown cause who have a subacute course, ground-glass opacities on high-resolution computed tomography or features atypical for idiopathic pulmonary fibrosis, as these patients may respond to therapy. A step-wise process for selection of patients for surgical lung biopsy is recommended.     

Management of pulmonary hypertension resulting from interstitial lung disease

Pulmonary hypertension affects right ventricular function by imposing an afterload on the right ventricle and, therefore, as pulmonary hypertension worsens, it ultimately reduces cardiac output. It is clear that in interstitial lung disease, progression of the underlying process with the loss of lung parenchyma contributes substantially to outcome. However, the additional burden of pulmonary hypertension often results in rapid deterioration. Pulmonary hypertension may be treatable and thus may enable the patient to survive until other therapy is effective. Until recently, part of the hesitancy in treating pulmonary hypertension in patients with secondary pulmonary hypertension, has been the limited availability of oral or intravenous drugs that affect the pulmonary circuit without causing excessive systemic vasodilatation. The current drugs available for the treatment of pulmonary hypertension, including prostacyclin and endothelin receptor blockers, have been limited by their high costs and, in the case of prostacyclin, the drug delivery systems. Nitric oxide, which has been used both acutely and chronically for pulmonary hypertension in a variety of diseases, also has limited availability. The role of sildenafil and inhaled prostacyclin remains to be evaluated. The use of these agents in the setting of interstitial lung disease needs to be studied, including combination therapy and early initiation of therapy. Their effect on tissue damage, fibrosis, and inflammation needs to be assessed as well as their effect on the arteriopathy and their potential to cause ventilation-perfusion (V/Q) mismatching. There now appears to be evidence to support treating pulmonary hypertension in patients with interstitial lung disease, with a potential for clinical benefit and a molecular basis for doing it.     

Pulmonary Involvement in Systemic Sclerosis

Scleroderma, also known as progressive systemic sclerosis (SSc), is a multisystem autoimmune disorder characterized by inflammation and fibrosis involving the skin as well as internal organs such as the vasculature, esophagus, and the respiratory tract. Pulmonary involvement consists most often of interstitial fibrosis and pulmonary vascular disease leading to pulmonary arterial hypertension (PAH). Bronchiectasis is an uncommon pulmonary manifestation of systemic sclerosis. Pulmonary hemorrhage with acute renal failure and diffuse alveolar hemorrhage in the absence of a history of renal involvement or penicillamine intake have rarely been reported in patients with systemic sclerosis.On high resolution CT, evidence of interstitial disease is seen in approximately 90% of patients, the main findings being a fine reticular pattern involving the subpleural regions of the lower lobe. Other common findings include ground-glass opacities, honeycombing, and parenchymal micronodules. The most distinctive pulmonary histologic findings in patients with scleroderma are the vascular changes found in PAH in the absence of significant interstitial fibrosis.There is no strong evidence that any drug alters the course of the two main types of lung disease in systemic sclerosis. This apparent failure of therapy may reflect the fact that pulmonary involvement is usually identified at an established or late stage. It has been suggested that, for fibrosing alveolitis, corticosteroids are most effective if given in combination with cyclophosphamide. In some patients with SSc, PAH has been considered as a major cause of morbidity and mortality. Centrally infused prostacyclin (epoprostenol) and its subcutaneously infused analog treprostinil improve hemodynamics, as well as the quality of life and survival in these patients. Iloprost has also shown a positive effect on PAH in SSc patients. More recently, bosentan, an endothelin receptor antagonist, has proved effective in controlling PAH after 6 months' treatment. Sildenafil has been used as a selective pulmonary vasodilator in SSc patients with isolated PAH. This drug decreased mean pulmonary artery pressure and pulmonary vascular resistance, and increased cardiac output, with much improvement of the physical condition of the patients. Lung transplant can be considered as a last option.Clinicians must be aware of the possibility of lung disease in patients with SSc so that it can be treated as early as possible.     

Smoking‐related idiopathic interstitial pneumonia: A review

For many years, cigarette smoking has been considered as the leading cause of chronic obstructive pulmonary disease and lung cancer. Recently, however, it has also been associated with the development of diffuse interstitial lung diseases. In the latest classification of the major idiopathic interstitial pneumonias (IIP), the term smoking‐related IIP has been introduced, including two entities, namely desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis‐interstitial lung disease (RB‐ILD). Other entities in which smoking has a definite or suggested role include pulmonary Langerhan's cell histiocytosis, smoking‐related interstitial fibrosis, combined pulmonary fibrosis and emphysema syndrome and idiopathic pulmonary fibrosis. In this review, we will focus on the mechanisms of smoking‐related lung damage and on the clinical aspects of these disorders with the exception of idiopathic pulmonary fibrosis, which will be reviewed elsewhere in this review series.     

Induced sputum in interstitial lung diseases

PURPOSE OF REVIEW: Induced sputum is a particularly useful procedure since it provides information on the cellular and molecular constituents in inflammation. Extensive work has demonstrated the application of induced sputum in the management of asthma, chronic obstructive pulmonary disease and chronic bronchitis, but less attention has been paid to its efficacy in diagnosing interstitial lung diseases. This review analyzes the applications of induced sputum in the assessment of sarcoidosis, nongranulomatous interstitial lung diseases, occupational lung diseases and other systemic diseases with or without lung involvement. RECENT FINDINGS: T cell subsets in induced sputum in combination with pulmonary function testing can serve as predictors with high specificity and sensitivity in diagnosing sarcoidosis, using multivariate logistic regression models which can be easily implemented in clinical practice. Differential cell counts in induced sputum are as useful as bronchoalveolar lavage for identifying neutrophilic inflammation in patients with nongranulomatous interstitial lung diseases (e.g. idiopathic pulmonary fibrosis) and detecting chronic rejection in bronchiolitis obliterans syndrome. Sputum analysis has also been shown to be a useful tool for diagnosing, assessing and monitoring occupational lung disorders. SUMMARY: We suggest integrating induced sputum technology to the well-established criteria for the diagnosis of interstitial lung diseases, especially when there are clinical contraindications for performing bronchoscopy or when tissue confirmation is absent for any reason.     

Lack of evidence for a role of Epstein-Barr virus in the increase of lung cancer in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is known as an independent risk factor for lung cancer. Because Epstein-Barr virus (EBV) may be involved in the genesis of IPF as well as certain malignancies, we investigated whether EBV contributes to the increased incidence of lung cancer in IPF The formalin-fixed and paraffin-embedded lung sections were prepared from 22 lung cancer patients with IPF and 22 lung cancer patients without IPF All ofthe IPF patients pathologically showed usual interstitial pneumonia. In situ hybridization for EBV-encoded small non-polyadenylated RNAs failed to show positive signals in the cancer tissues of either IPF or non-IPF patients. This study did not provide evidence for an etiologic role of EBV in the development of lung cancer in IPF.     

Rheumatic diseases and malignancy--is there an association?

An association between rheumatic diseases and malignancy has been claimed in a variety of settings. This editorial reviews published data addressing the overall risk of malignancy, and of particular types of cancer, in the context of various autoimmune rheumatic diseases. For patients with Sj?gren's syndrome, systemic sclerosis with pulmonary fibrosis, or with dermatomyositis/polymyositis there is a documented association with an increased risk of malignant disease. Patients with rheumatoid arthritis may also have an increased risk of cancer. It is still controversial whether systemic lupus erythematosus is associated with an increased risk of developing malignancy. More epidemiologic studies are needed to try and clarify many of these associations, in particular the potential risks associated with cytotoxic therapy.