Correspondence

Idiopathic Hyperplasia of Pulmonary Neuroendocrine Cells

N Engl J Med 1993; 328:581-582February 25, 1993

Article

To the Editor:

The report of Aguayo et al. (Oct. 29 issue)1 concerning “idiopathic” diffuse hyperplasia of pulmonary neuroendocrine cells associated with airway disease hypothesizes that these cells underwent primary hyperplasia. Although a small subgroup of patients may fit this hypothesis, many may have identifiable reasons for chronic hypoxia (and thus probably secondary hyperplasia, a phenomenon well described in the carotid body). How many of the patients described were residents of Denver? The authors themselves cite the study by Gould et al. documenting neuroendocrine hyperplasia in the lungs of 6 of 20 Bolivian natives who were long-term dwellers at high altitude2. How many had long-term exposure to secondhand smoke? What were their occupations?

Hyperplasia of pulmonary neuroendocrine cells is most commonly seen in association with inflammatory or fibrosing lung diseases with established causes: bronchiectasis (particularly cystic fibrosis), chronic obstructive pulmonary disease, and bronchogenic carcinoma (most patients with bronchogenic carcinoma also have chronic obstructive disease). The pathogenesis of lung disease in these patients is unlikely to be related to neuroendocrine-cell secretory products, except perhaps late in the course. . . .

Patients with multiple microscopic “tumorlets” have the prognosis associated with their lung disease (bronchiectasis and the like)3; the tumorlets themselves are not associated with substantial morbidity. They do not invade or metastasize (rarely, they go to regional nodes). The exception to this benign behavior appears to occur in patients with radiographically apparent nodules (as in Patients 4, 5, and 6 of Aguayo et al.) or a syndrome associated with “ectopic” hormone production,4 in which case a diagnosis of carcinoid tumor (not tumorlet) and treatment with chemotherapy are appropriate.

Joyce E. Johnson, M.D.
Vanderbilt University, Nashville, TN 37232

4 References

1. 1

   Aguayo SM, Miller YE, Waldron JA Jr, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992;327:1285-1288
   Full Text | Web of Science | Medline

2. 2

   Gould VE, Linnoila RI, Memoli VA, Warren WH. Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms. Lab Invest 1983;49:519-537
   Web of Science | Medline

3. 3

   Whitwell F. Tumourlets of the lung. J Pathol Bacteriol 1955;70:529-541
   CrossRef | Web of Science | Medline

4. 4

   Rodgers-Sullivan RF, Weiland LH, Palumbo PJ, Hepper NGG. Pulmonary tumorlets associated with Cushing's syndrome. Am Rev Respir Dis 1978;117:799-806
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We concluded that our patients had an idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells because they had none of the usual clinical conditions or chronic airway diseases associated with neuroendocrine-cell hyperplasia. Three of these patients lived in Colorado (at a substantially lower altitude than the people described by Gould and coworkers), but the other three resided at sea level. None of these patients had hypoxemia or any obvious exposure to cigarette smoke or other airway irritants. We agree that chemotherapy is not indicated in the majority of patients with carcinoid tumorlets because tumorlets grow slowly, they rarely metastasize, and the prognosis of such patients is primarily determined by the underlying lung disease, usually a chronic fibrotic airway disorder.

We disagree, however, with the prevalent perception that “the pathogenesis of lung disease in these patients is unlikely to be related to neuroendocrine-cell secretory products.” In fact, a major point of the paper, in addition to the description of a previously overlooked clinical syndrome, was to propose the hypothesis that neuroendocrine cells may have a pathogenic role in the airway-wall remodeling of chronic airway disorders. Our case series does not provide any direct evidence of cause and effect in support of this hypothesis. It demonstrates, however, that neuroendocrine-cell hyperplasia and airway-wall remodeling coexist even in patients in whom there is no other obvious explanation for airway disease and chronic airflow obstruction.

The potential clinical importance of these observations is that airway-wall remodeling is a major factor in causing chronic airflow obstruction and nonspecific airway hyperreactivity1. For example, an important difference between cigarette smokers in whom airflow obstruction develops and those in whom it does not is increased airway-wall thickening that does not appear to be explained by differences in intensity of smoking or degrees of inflammation2. Experimental and clinical evidence suggests that alterations of neuroendocrine-cell physiology in response to cigarette smoke may occur very early, even before there is any clinically detectable airway disease3,4. It is noteworthy that neuroendocrine-cell hyperplasia does not occur in every cigarette smoker, but only in those susceptible smokers in whom airway disease develops5. Therefore, neuroendocrine-cell secretory products may have a pathogenic role in smoking-related lung disorders. Further investigations will test the hypothesis that neuroendocrine-cell secretory products are important in the pathogenesis of airway-wall remodeling and airflow obstruction.

Samuel M. Aguayo, M.D.
Atlanta Veterans Affairs Medical Center, Decatur, GA 30033

York E. Miller, M.D.
Denver Veterans Affairs Medical Center, Denver, CO 80220

Talmadge E. King, Jr., M.D.
National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206

5 References

1. 1

   Wiggs BR, Bosken CH, Pare PD, James A, Hogg JC. A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992;145:1251-1258
   Web of Science | Medline

2. 2

   Bosken CH, Wiggs BR, Pare PD, Hogg JC. Small airway dimensions in smokers with obstruction to airflow. Am Rev Respir Dis 1990;142:563-570
   CrossRef | Web of Science | Medline

3. 3

   Tabassian AR, Nylen ES, Linnoila RI, Snider RH, Cassidy MM, Becker KL. Stimulation of hamster pulmonary neuroendocrine cells and associated peptides by repeated exposure to cigarette smoke. Am Rev Respir Dis 1989;140:436-440
   CrossRef | Web of Science | Medline

4. 4

   Aguayo SM, Kane MA, King TE Jr, Schwarz MI, Grauer L, Miller YE. Increased levels of bombesin-like peptides in the lower respiratory tract of asymptomatic cigarette smokers. J Clin Invest 1989;84:1105-1113
   CrossRef | Web of Science | Medline

5. 5

   Aguayo SM, King TE Jr, Waldron JA Jr, Sherritt KM, Kane MA, Miller YE. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 1990;86:838-844
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Luis M. Montuenga, Laura Guembe, M. Angela Burrell, M. Elena Bodegas, Alfonso Calvo, Jesús J. Sola, Pilar Sesma, Ana C. Villaro. (2003) The diffuse endocrine system: from embryogenesis to carcinogenesis. Progress in Histochemistry and Cytochemistry 38:2, 153-272
   CrossRef

2. 2

   Lech Chyczewski, Jacek Niklinski, Elzbieta Chyczewska, Wieslawa Niklinska, Wojciech Naumnik. (2001) Morphological aspects of carcinogenesis in the lung. Lung Cancer 34, S17-S25
   CrossRef