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Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease
ARTICLE IN PRESS Respiratory Medicine (2007) 101, 1840–1843
CASE REPORT
Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease$ L.J. Reyesa, J. Majo ´b, D. Pericha, F. Morella, a
Servei de Pneumologia, Hospital Universitari Vall d’Hebron, Departement de medicina UAB, Passeig Vall d’Hebron, 119-129, 08035, Barcelona, Spain b Servei d’Anatomia Patolo `gica, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron, 119-129, 08035, Barcelona, Spain Received 31 May 2005; accepted 25 October 2005
KEYWORDS Neuroendocrine cells; Hyperplasia; Pulmonary fibrosis
Summary Study objectives: Two patients diagnosed with interstitial lung disease (ILD) secondary to pulmonary neuroendocrine cell (PNEC) hyperplasia are presented. Background: Pulmonary neuroendocrine cell hyperplasia (PNECH) is a rare entity worldwide and few cases presenting as ILD have been reported. Following the consensus criteria established by the American Thoracic Society (ATS) and the European Respiratory Society (ERS), three patients from among 500 ILD patients over the last 10 years in our institution were diagnosed with PNECH. The diagnosis was established by open lung biopsy using specific stains to demonstrate neuroendocrine cells in lung tissue. Methods: Patients were questioned on their medical and pathological history, occupational or environmental exposure to toxic substances and any relationship with smoking. In addition, were recorded symptoms at presentation, physical signs, analytic and respiratory function results, chest X-ray and CT scan features, bronchoscopy findings including bronchoalveolar lavage and transbronchial biopsy, and open lung biopsy findings. Results: In these two patients, PNECH was the only cause of their diffuse lung disease. Clinical signs and symptoms (cough, expectoration and progressive dyspnea) were similar to other idiopathic interstitial pneumonias and radiologic features (ground-glass infiltrates in mosaic pattern) were consistent with those of nonspecific interstitial pneumonia or the onset of hypersensitivity pneumonitis.
Abbreviations: PNEC, pulmonary neuroendocrine cells; ILD, interstitial lung disease; PNECH, Pulmonary neuroendocrine cell hyperplasia; BAL, bronchoalveolar lavage; HRCT, high-resolution computer tomography; ACE, angiotensin converting enzyme; LDH, lactic dehydrogenase; ANA, antinuclear antibodies $ This study was supported in part by Red Respira—ICSI—RTIC-03/11 and is part of the Doctoral Thesis of Dr. Leonardo Reyes, Universitat Auto `noma de Barcelona. Corresponding author. Tel.: +34 93 2746157; fax: +34 93 2746083. E-mail address: [email protected] (F. Morell). 0954-6111/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2005.10.024
ARTICLE IN PRESS Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease
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Functional respiratory alterations were consistent with restrictive pattern. Transbronchial and open biopsy findings are described, as well as the treatment and course of the disease. The two patients had a favorable outcome. Conclusions: Two cases of ILD secondary to PNEC hyperplasia are presented, with clinical and radiological findings that might be mistaken for other types of idiopathic interstitial pneumonias. The disease course is described and the possible etiopathogenic role that PNECs might play in the development of lung fibrosis is discussed. & 2005 Elsevier Ltd. All rights reserved.
Introduction
Case studies (Table 1)
Pulmonary neuroendocrine cells (PNEC) are epithelial cells distributed along the bronchial mucosa.1,2 Their main activity is paracrine in nature3 and it is more pronounced during the fetal and neonatal period, when they play a major role in pulmonary development.1–3 Pulmonary neuroendocrine cell hyperplasia (PNECH) was first described in persons living at high altitudes as a probable regenerative or adaptive response to hypoxia.4–6 It has also been associated with several lung processes, such as bronchiectasis,5 emphysema,5 cystic fibrosis,7 tuberculosis,8 abscesses,8 other chronic inflammatory lung diseases,5–8 and pulmonary fibrosis.9 Few reported cases of PNECH have manifested clinically as diffuse interstitial lung disease (ILD).9–12 Synthesis of various substances by the hyperplastic neuroendocrine cells, such as bombesin, which exert chemotactic and mitogenic effects on fibroblasts and smooth muscle cells, could lead to inflammation and subsequent fibrosis of the airways.9,13
Case 1: A 67-year-old woman, who born and lived for 37 years at 497 m above sea level. She had a chronic cough and slight (occasionally greenish) expectoration. At physical examination ‘‘velcro’’ crackles were audible. The chest-X-ray showed a bilateral interstitial pattern. High-resolution computer tomography (HRCT) of thorax disclosed areas of ground glass in a mosaic distribution. Function testing was consistent with a restrictive ventilatory pattern (Table 1). Bronchoalveolar lavage (BAL) was normal (macrophages 89%, lymphocytes 9%, and polymorphonuclear cells 2%). Transbronchial and bronchial biopsies were inconclusive. Open lung biopsy showed structurally preserved lung parenchyma with fibrosis and slight bronchiolar lymphohistiocytic inflammation with neuroendocrine cell hyperplasia. Chromogranin stain was positive for neuroendocrine cells and demonstrated the presence of a tumorlet. The patient was started on long-term inhaled b2 agonists plus corticosteroids, with frank improvement of clinical symptoms and respiratory function parameters, which has persisted over the last 2 years. Case 2: A 40-year-old woman, living in a city located more than 2000 m above sea level. Three years before referral to our institution, the patient developed progressive dyspnea and a dry cough. At physical examination only wheezing was audible. Chest X-ray showed a diffuse interstitial pattern and HRCT of thorax demonstrated ground glass infiltrates, septal thickening and fibrotic honeycombing. Open lung biopsy was decided and PNEC hyperplasia was diagnosed. The patient was started on oral and inhaled corticosteroids, long-term b2 agonists and anticholinergic agents, with functional improvement. Only dyspnea of grade I persisted up to 5 years later.
Material and methods Patients Among the 500 patients with diffuse ILD consecutively studied in our hospital outpatient clinic in last 10 years, 140 (28%) of them being submitted to open lung biopsy, only two patients were diagnosed with PNECH.
Diagnostic protocol The consensus criteria about pulmonary fibrosis of the American Thoracic Society (ATS) and European Respiratory Society (ERS) were followed for diagnosis and treatment.14,15
Discussion PNCH is a rare entity worldwide and few cases presenting as diffuse ILD have been reported in two
ARTICLE IN PRESS 1842
L.J. Reyes et al.
Table 1 Clinical, analytic, functional, and radiologic characteristics, and diagnosis, treatment and follow up of three patients with PNEC hyperplasia. Case 1
Case 2
Age/sex Occupation
67/W Housewife
High altitude Smoker Prior medication
497 m No Nifedipine, diosmin, diazepam and enalapril Chronic contact of hydrochloric acid and bleach. Cough with slight expectoration and progressive dyspnea Crepitant rales, bronchospam and slight fever
40/W Worker in waste water treatment plant 42000 m No No
Contact with toxic substances Symptoms Physical signs
Diverse substances in a waste water treatment plant. Progressive dyspnea and progressive dry cough Wheezing
Initial lung function
FVC 1.02 (42%) FEV1 1.02 (49.5%) FVC % FEV1 84% TLC 3.39 (84%) RV 1.85 (95%)
FVC 1.85 (55%) FEV1 1.48 (56%) FVC % FEV1 80% TLC 3.29 (85%) RV 1.29 (86%)
Final lung function
FVC 2.37 (58%) FEV1 1.93 (61%) FVC % FEV1 95% TLC 2.98 (74%) RV 1.56 (80%)
FVC 3.00 (87%) FEV1 2.70 (95%)
Chest X-ray Chest HRCT
Diffuse interstitial pattern Ground glass infiltrates, with area of mosaic pattern in geographic distribution and bronchiectasis Lymphoplasmocytic bronchitis, intra-alveolar foam cells Neuroendocrine cell hyperplasia and tumorlet Oral corticosteroids, inhaled corticosteroids, b adrenergic agents Occasional episodes of cough and bronchospasm stable after 2 years Diffuse esophageal spasm
Diffuse interstitial pattern Ground glass infiltrates, bronchiectasis and mediastinal lymphadenopathy Mild mixed bronchitis
Transbronchial biopsy Open lung biopsy Treatment
Follow up Complications
series of patients (Pub-Med 1975–2004).9,13 It is also noteworthy that in the largest series of diffuse ILD patients in recent years, published in the USA and Europe (15–20), none of the patients included has had a diagnosis of PNEC hyperplasia. Among the 200 causes of diffuse ILD for which assessment and treatment have been standardized by the ATS/ERS, PNEC hyperplasia is categorized within the group of rare diffuse ILD (21–22). The symptoms at presentation in the two published series and in the present study consist of progressive dyspnea and dry cough. Bilateral crepitant rales in the lung bases on inspiration were
Neuroendocrine cell hyperplasia Oral corticosteroids, inhaled corticosteroids, b adrenergic agents Considerable improvement Stable for 5 years Cushingoid syndrome
detected in only 25% of patients and there was no clubbing or cyanosis. In our patients ‘‘velcro’’ crackles were detected in one patient, and wheezing in another. The most common radiologic findings in the published cases were reticulonodular infiltrates,9,13 whereas in the present series a combination of reticular and alveolar infiltrates was found. The described chest HRCT features include in those series diffuse ground glass infiltrates, specifically in a mosaic pattern, and airway wall thickening with occasional micronodules, findings that are also found of nonspecific interstitial pneumonia (21) and hypersensitivity pneumonitis (22); these features were
ARTICLE IN PRESS Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease also evident in our patients. The literature does not provide relevant data with regard to BAL findings. Patients in the present study were treated with oral and inhaled corticosteroids; inhaled b-adrenergic agents were added when there was associated clinical hyperreactivity. The response was good in two patients.
References 1. D’Agati VD, Perzin KH. Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature. Cancer 1985;55:2472–6. 2. Johnson DE, Georgieff MK. Pulmonary neuroendocrine cells, their secretory products and their potential roles in health and chronic lung disease in infancy. Am Rev Respir Dis 1989; 140:1807–12. 3. Gosney JR, Sissons MCJ, Allibone RO. Neuroendocrine cell populations in normal human lungs: a quantitative study. Thorax 1998;43:878–82. 4. Gould VE, Linnoila RI, Memoli VA, Warren WH. Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias and neoplasms. Lab Invest 1983;49: 519–37. 5. Gosney JR, Sissons M, Allibone RO, Blakey AF. Pulmonary endocrine cells in chronic bronchitis and emphysema. J Pathol 1989;157:127–33. 6. Gosney JR. Pulmonary endocrine pathology. Oxford: Butterworth-Heinemann LTD; 1992.
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7. Johnson DE, Wobken JD, Landrum BG. Changes in bombesin, calcitonin and serotonin immunoreactive pulmonary neuroendocrine cells in cystic fibrosis and after prolonged mechanical ventilation. Am Rev Respir Dis 1988;137: 123–31. 8. Ramo ´n M, Arnau A, Navarro R, Galbis J, Traves V. Tumorlet pulmonar. A propo ´sito de cinco casos. Arch Bronconeumol 1996;32:489–91. 9. Aguayo SM, Miller YE, Waldron Jr JA, Bogin RM, Sunday ME, Staton Jr GW, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992;327:1285–8. 10. Ranchod M. The histogenesis and development of pulmonary tumorlets. Cancer 1977;39:1135–45. 11. Churg A, Warnock ML. Pulmonary tumorlet: a form of peripheral carcinoid. Cancer 1976;37:1469–77. 12. Miller MA, Mark GJ, Kanarek D. Multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type, with restrictive and obstructive lung disease. Am J Med 1978; 65:373–8. 13. Armas OA, White D, Erlandson R, Rosai J. Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease. Am J Surg Pathol 1995;19(8): 963–70. 14. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000;161:646–64. 15. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of idiopathic interstitial pneumonias: general principles and recommendations. Am J Respir Crit Care Med 2002;165: 277–304.
CASE REPORT
Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease$ L.J. Reyesa, J. Majo ´b, D. Pericha, F. Morella, a
Servei de Pneumologia, Hospital Universitari Vall d’Hebron, Departement de medicina UAB, Passeig Vall d’Hebron, 119-129, 08035, Barcelona, Spain b Servei d’Anatomia Patolo `gica, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron, 119-129, 08035, Barcelona, Spain Received 31 May 2005; accepted 25 October 2005
KEYWORDS Neuroendocrine cells; Hyperplasia; Pulmonary fibrosis
Summary Study objectives: Two patients diagnosed with interstitial lung disease (ILD) secondary to pulmonary neuroendocrine cell (PNEC) hyperplasia are presented. Background: Pulmonary neuroendocrine cell hyperplasia (PNECH) is a rare entity worldwide and few cases presenting as ILD have been reported. Following the consensus criteria established by the American Thoracic Society (ATS) and the European Respiratory Society (ERS), three patients from among 500 ILD patients over the last 10 years in our institution were diagnosed with PNECH. The diagnosis was established by open lung biopsy using specific stains to demonstrate neuroendocrine cells in lung tissue. Methods: Patients were questioned on their medical and pathological history, occupational or environmental exposure to toxic substances and any relationship with smoking. In addition, were recorded symptoms at presentation, physical signs, analytic and respiratory function results, chest X-ray and CT scan features, bronchoscopy findings including bronchoalveolar lavage and transbronchial biopsy, and open lung biopsy findings. Results: In these two patients, PNECH was the only cause of their diffuse lung disease. Clinical signs and symptoms (cough, expectoration and progressive dyspnea) were similar to other idiopathic interstitial pneumonias and radiologic features (ground-glass infiltrates in mosaic pattern) were consistent with those of nonspecific interstitial pneumonia or the onset of hypersensitivity pneumonitis.
Abbreviations: PNEC, pulmonary neuroendocrine cells; ILD, interstitial lung disease; PNECH, Pulmonary neuroendocrine cell hyperplasia; BAL, bronchoalveolar lavage; HRCT, high-resolution computer tomography; ACE, angiotensin converting enzyme; LDH, lactic dehydrogenase; ANA, antinuclear antibodies $ This study was supported in part by Red Respira—ICSI—RTIC-03/11 and is part of the Doctoral Thesis of Dr. Leonardo Reyes, Universitat Auto `noma de Barcelona. Corresponding author. Tel.: +34 93 2746157; fax: +34 93 2746083. E-mail address: [email protected] (F. Morell). 0954-6111/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2005.10.024
ARTICLE IN PRESS Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease
1841
Functional respiratory alterations were consistent with restrictive pattern. Transbronchial and open biopsy findings are described, as well as the treatment and course of the disease. The two patients had a favorable outcome. Conclusions: Two cases of ILD secondary to PNEC hyperplasia are presented, with clinical and radiological findings that might be mistaken for other types of idiopathic interstitial pneumonias. The disease course is described and the possible etiopathogenic role that PNECs might play in the development of lung fibrosis is discussed. & 2005 Elsevier Ltd. All rights reserved.
Introduction
Case studies (Table 1)
Pulmonary neuroendocrine cells (PNEC) are epithelial cells distributed along the bronchial mucosa.1,2 Their main activity is paracrine in nature3 and it is more pronounced during the fetal and neonatal period, when they play a major role in pulmonary development.1–3 Pulmonary neuroendocrine cell hyperplasia (PNECH) was first described in persons living at high altitudes as a probable regenerative or adaptive response to hypoxia.4–6 It has also been associated with several lung processes, such as bronchiectasis,5 emphysema,5 cystic fibrosis,7 tuberculosis,8 abscesses,8 other chronic inflammatory lung diseases,5–8 and pulmonary fibrosis.9 Few reported cases of PNECH have manifested clinically as diffuse interstitial lung disease (ILD).9–12 Synthesis of various substances by the hyperplastic neuroendocrine cells, such as bombesin, which exert chemotactic and mitogenic effects on fibroblasts and smooth muscle cells, could lead to inflammation and subsequent fibrosis of the airways.9,13
Case 1: A 67-year-old woman, who born and lived for 37 years at 497 m above sea level. She had a chronic cough and slight (occasionally greenish) expectoration. At physical examination ‘‘velcro’’ crackles were audible. The chest-X-ray showed a bilateral interstitial pattern. High-resolution computer tomography (HRCT) of thorax disclosed areas of ground glass in a mosaic distribution. Function testing was consistent with a restrictive ventilatory pattern (Table 1). Bronchoalveolar lavage (BAL) was normal (macrophages 89%, lymphocytes 9%, and polymorphonuclear cells 2%). Transbronchial and bronchial biopsies were inconclusive. Open lung biopsy showed structurally preserved lung parenchyma with fibrosis and slight bronchiolar lymphohistiocytic inflammation with neuroendocrine cell hyperplasia. Chromogranin stain was positive for neuroendocrine cells and demonstrated the presence of a tumorlet. The patient was started on long-term inhaled b2 agonists plus corticosteroids, with frank improvement of clinical symptoms and respiratory function parameters, which has persisted over the last 2 years. Case 2: A 40-year-old woman, living in a city located more than 2000 m above sea level. Three years before referral to our institution, the patient developed progressive dyspnea and a dry cough. At physical examination only wheezing was audible. Chest X-ray showed a diffuse interstitial pattern and HRCT of thorax demonstrated ground glass infiltrates, septal thickening and fibrotic honeycombing. Open lung biopsy was decided and PNEC hyperplasia was diagnosed. The patient was started on oral and inhaled corticosteroids, long-term b2 agonists and anticholinergic agents, with functional improvement. Only dyspnea of grade I persisted up to 5 years later.
Material and methods Patients Among the 500 patients with diffuse ILD consecutively studied in our hospital outpatient clinic in last 10 years, 140 (28%) of them being submitted to open lung biopsy, only two patients were diagnosed with PNECH.
Diagnostic protocol The consensus criteria about pulmonary fibrosis of the American Thoracic Society (ATS) and European Respiratory Society (ERS) were followed for diagnosis and treatment.14,15
Discussion PNCH is a rare entity worldwide and few cases presenting as diffuse ILD have been reported in two
ARTICLE IN PRESS 1842
L.J. Reyes et al.
Table 1 Clinical, analytic, functional, and radiologic characteristics, and diagnosis, treatment and follow up of three patients with PNEC hyperplasia. Case 1
Case 2
Age/sex Occupation
67/W Housewife
High altitude Smoker Prior medication
497 m No Nifedipine, diosmin, diazepam and enalapril Chronic contact of hydrochloric acid and bleach. Cough with slight expectoration and progressive dyspnea Crepitant rales, bronchospam and slight fever
40/W Worker in waste water treatment plant 42000 m No No
Contact with toxic substances Symptoms Physical signs
Diverse substances in a waste water treatment plant. Progressive dyspnea and progressive dry cough Wheezing
Initial lung function
FVC 1.02 (42%) FEV1 1.02 (49.5%) FVC % FEV1 84% TLC 3.39 (84%) RV 1.85 (95%)
FVC 1.85 (55%) FEV1 1.48 (56%) FVC % FEV1 80% TLC 3.29 (85%) RV 1.29 (86%)
Final lung function
FVC 2.37 (58%) FEV1 1.93 (61%) FVC % FEV1 95% TLC 2.98 (74%) RV 1.56 (80%)
FVC 3.00 (87%) FEV1 2.70 (95%)
Chest X-ray Chest HRCT
Diffuse interstitial pattern Ground glass infiltrates, with area of mosaic pattern in geographic distribution and bronchiectasis Lymphoplasmocytic bronchitis, intra-alveolar foam cells Neuroendocrine cell hyperplasia and tumorlet Oral corticosteroids, inhaled corticosteroids, b adrenergic agents Occasional episodes of cough and bronchospasm stable after 2 years Diffuse esophageal spasm
Diffuse interstitial pattern Ground glass infiltrates, bronchiectasis and mediastinal lymphadenopathy Mild mixed bronchitis
Transbronchial biopsy Open lung biopsy Treatment
Follow up Complications
series of patients (Pub-Med 1975–2004).9,13 It is also noteworthy that in the largest series of diffuse ILD patients in recent years, published in the USA and Europe (15–20), none of the patients included has had a diagnosis of PNEC hyperplasia. Among the 200 causes of diffuse ILD for which assessment and treatment have been standardized by the ATS/ERS, PNEC hyperplasia is categorized within the group of rare diffuse ILD (21–22). The symptoms at presentation in the two published series and in the present study consist of progressive dyspnea and dry cough. Bilateral crepitant rales in the lung bases on inspiration were
Neuroendocrine cell hyperplasia Oral corticosteroids, inhaled corticosteroids, b adrenergic agents Considerable improvement Stable for 5 years Cushingoid syndrome
detected in only 25% of patients and there was no clubbing or cyanosis. In our patients ‘‘velcro’’ crackles were detected in one patient, and wheezing in another. The most common radiologic findings in the published cases were reticulonodular infiltrates,9,13 whereas in the present series a combination of reticular and alveolar infiltrates was found. The described chest HRCT features include in those series diffuse ground glass infiltrates, specifically in a mosaic pattern, and airway wall thickening with occasional micronodules, findings that are also found of nonspecific interstitial pneumonia (21) and hypersensitivity pneumonitis (22); these features were
ARTICLE IN PRESS Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease also evident in our patients. The literature does not provide relevant data with regard to BAL findings. Patients in the present study were treated with oral and inhaled corticosteroids; inhaled b-adrenergic agents were added when there was associated clinical hyperreactivity. The response was good in two patients.
References 1. D’Agati VD, Perzin KH. Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature. Cancer 1985;55:2472–6. 2. Johnson DE, Georgieff MK. Pulmonary neuroendocrine cells, their secretory products and their potential roles in health and chronic lung disease in infancy. Am Rev Respir Dis 1989; 140:1807–12. 3. Gosney JR, Sissons MCJ, Allibone RO. Neuroendocrine cell populations in normal human lungs: a quantitative study. Thorax 1998;43:878–82. 4. Gould VE, Linnoila RI, Memoli VA, Warren WH. Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias and neoplasms. Lab Invest 1983;49: 519–37. 5. Gosney JR, Sissons M, Allibone RO, Blakey AF. Pulmonary endocrine cells in chronic bronchitis and emphysema. J Pathol 1989;157:127–33. 6. Gosney JR. Pulmonary endocrine pathology. Oxford: Butterworth-Heinemann LTD; 1992.
1843
7. Johnson DE, Wobken JD, Landrum BG. Changes in bombesin, calcitonin and serotonin immunoreactive pulmonary neuroendocrine cells in cystic fibrosis and after prolonged mechanical ventilation. Am Rev Respir Dis 1988;137: 123–31. 8. Ramo ´n M, Arnau A, Navarro R, Galbis J, Traves V. Tumorlet pulmonar. A propo ´sito de cinco casos. Arch Bronconeumol 1996;32:489–91. 9. Aguayo SM, Miller YE, Waldron Jr JA, Bogin RM, Sunday ME, Staton Jr GW, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992;327:1285–8. 10. Ranchod M. The histogenesis and development of pulmonary tumorlets. Cancer 1977;39:1135–45. 11. Churg A, Warnock ML. Pulmonary tumorlet: a form of peripheral carcinoid. Cancer 1976;37:1469–77. 12. Miller MA, Mark GJ, Kanarek D. Multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type, with restrictive and obstructive lung disease. Am J Med 1978; 65:373–8. 13. Armas OA, White D, Erlandson R, Rosai J. Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease. Am J Surg Pathol 1995;19(8): 963–70. 14. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000;161:646–64. 15. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of idiopathic interstitial pneumonias: general principles and recommendations. Am J Respir Crit Care Med 2002;165: 277–304.