Demonstration of Pulmonary Neuroendocrine Cell Hyperplasia with Tumorlets in a Patient with Chronic Cough and a History of Multiple Medical Problems, The

Military Medicine, May 2005 by Carmichael, Mark G, Zacher, Lisa L

A 58-year-old woman presented with chronic cough felt to be multifactorial secondary to asthma, gastroesophageal reflux disease, and chronic sinusitis. Additional medical history included obstructive sleep apnea, type 2 diabetes, and hypertension. She had a 40- year history of tobacco use, but quit 10 years ago. Her examination was significant for obesity and cobble stoning of the oropharynx. Pulmonary function testing and arterial blood gases were unrevealing. Chest films were normal. High-resolution computed tomography revealed multiple focal lucencies in a mosaic pattern consistent with air trapping and small airways disease. Bronchoscopy revealed normal airways and a noninflammatory bronchoalveolar lavage. Transbronchial biopsies revealed inflammatory infiltrates of the peribronchiolar interstitium. Lung biopsy revealed pulmonary neuroendocrine cell hyperplasia with tumorlets that stained positive for neuroendocrine tissue. We present the case of a woman with chronic cough, multiple medical problems, and pulmonary neuroendocrine cell hyperplasia with tumorlets.

Introduction

Pulmonary neuroendocrine cells (PNEC) are a normal part of the parenchyma of the lung whose role remains uncertain. Neuroendocrine cells' role in fetal lung tissue is likely that of paracrine regulation during development, but their numbers decrease substantially in the healthy adult lung. PNEC hyperplasia has long been found in response to chronic pulmonary diseases and hypoxia such as cystic fibrosis, bronchiectasis, and in response to cigarette smoking, but the pathologic significance of neuroendocrine cell hyperplasia is unclear.1,2

Recent work has hypothesized that PNEC hyperplasia may induce airways disease and destruction of lung parenchyma in the absence of underlying lung disease or cigarette smoking, thus being a primary cause of airway disease and not a reactive process. This hypothesis was supported by a case series of six patients with diffuse hyperplasia of neuroendocrine cells with tumorlets without a history of cigarette smoking or known lung disease.1 Each of the six patients described reported cough and exertional dyspnea of several years as central features of their disease. Five patients had a slowly progressive course with one patient rapidly progressing to death. Pathologic findings were consistently that of fibrosis of lung parenchyma, likely in response to neuropeptide secretion by neuroendocrine cells.3

A case described by Arioglu et al.4 reported Cushing's syndrome caused by corticotropin secretion of pulmonary neuroendocrine tumorlets, highlighting the variable nature of this entity. We present the case of a woman with a chronic cough of several years duration found to have PNEC hyperplasia with tumorlets as a possible explanation for her symptoms.

Case Report

A 58-year-old woman with a past medical history significant for chronic cough felt to be multifactorial secondary to asthma, gastroesophageal reflux disease, and chronic sinusitis presented to the pulmonary medicine clinic complaining of 6 years of chronic cough. Additional medical history includes obstructive sleep apnea, type 2 diabetes, and hypertension. She had a 40-year history of tobacco use but quit 10 years ago. Review of systems was significant for shortness of breath and dyspnea on exertion.

Medications included ipratropium, fluticasone, salmeterol, metaproterenol, guaifenesin, beclomethasone, fexofenadinepseudoephedrine, omeprazole, diltiazem, hydrochlorothiazide, metformin, and simvastatin. She had been on an angiotensin-converting enzyme inhibitor, but stopped years ago secondary to her chronic cough.

Physical examination revealed an obese woman (body mass index of 40) in no distress. She was afebrile, with a pulse of 98, a blood pressure of 144/82, her respirations were 14, and her O2 saturation was 91% on room air. Her head and neck examination was significant for moderate cobble stoning of the posterior oropharynx. Her lungs were clear to auscultation with normal air movement bilaterally, and there was no clubbing or cyanosis. Cardiac examination was normal and there was no peripheral edema.

Pulmonary function tests and arterial blood gases over 4 years were similar and unchanged. The pulmonary function test results were: forced vital capacity (FVC), 3.23 L (91% of predicted); forced expiratory volume (FEV) FEV^sub 1^, 2.73 L (91% of predicted); and FEV^sub 1^:FVC ratio. There was an 11% increase in FEV^sub 1^ in response to bronchodilators. Her lung volumes and DLCO were normal. Her arterial blood gases were; pH 7.41; PaCO^sub 2^, 39; PaO^sub 2^, 58;02 saturation, 88%; and normal COHb. Her A-a gradient was 30 mm Hg at 4,000 feet.

Serial chest films over 4 years were normal and unchanged. High-resolution computed tomography (HRCT) revealed multiple focal lucencies in a mosaic pattern, more pronounced on expiration in both lungs, consistent with air trapping and small airways disease (Fig. 1).

Bronchoscopy revealed normal airways and a noninflammatory bronchoalveolar lavage. Transbronchial biopsies revealed inflammatory infiltrates of the peribronchiolar interstitium.