Diffuse Idiopathic Neuroendocrine Cell Hyperplasia Causing Severe Airway Obstruction in a Patient with a Carcinoid TumorAdams H.a · Brack T.a · Kestenholz P.b · Vogt P.c · Steinert H.C.d · Russi E.W.a
Departments of aPulmonary Medicine and bThoracic Surgery, cInstitute of Clinical Pathology and dDivision of Nuclear Medicine, Zurich University Hospital, Zurich, Switzerland
We report a 57-year-old female with severe airway obstruction who underwent resection of a tumor of unknown dignity during lung volume reduction surgery. The nodule consisted of a well-differentiated neuroendocrine tumor (carcinoid), and severe chronic obstructive lung disease was due to diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, a very rare cause of obliterative bronchiolitis. Radionuclide ablative therapy of the neuroendocrine tissue was considered but not found to be feasible due to a low lung/background ratio of the radiotracer.
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In patients with severe chronic airway obstruction and pulmonary emphysema, nodules of unknown dignity may be subjected to integrative lung volume reduction surgery (LVRS)  without unacceptable loss of lung function. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) may be accompanied by neuroendocrine tumors and is an extremely rare etiology of symptomatic airway obstruction [2, 3].
We report on a patient with severe airway obstruction who underwent resection of a nodule of undetermined dignity without loss of lung function following LVRS. The tumor was a carcinoid, and DIPNECH caused severe chronic airway obstruction. Lung transplantation was refused by the patient. Thus we evaluated if pulmonary neuroendocrine cells could be tagged by a radiotracer to evaluate potential specific radionuclide ablative therapy.
A 57-year-old, never-smoking woman with severe airway obstruction was referred for workup of a nodule in the left upper lung lobe of undetermined dignity. The patient’s dyspnea limited her daily activities, and her 6- and 12-min walking distances were 315 and 360 m, respectively. She was on long-term oxygen therapy.
Besides her farm labor, she had been working as a waitress when she first noted mild dyspnea on exertion 20 years ago. Treatment with bronchodilators did not relief her shortness of breath. Physical examination revealed a 57-year-old patient (body mass index 29.9 kg/m2) with a hyperinflated chest and muffled breath sounds. Pulmonary function test documented severe irreversible airway obstruction with hyperinflation: FVC: 1.83 liters (67% predicted), FEV1 0.74 liters (32% predicted), FEV1/FVC: 37%, TLC 6.72 liters (141% predicted), RV/TLC: 0.69. The diffusing capacity for carbon monoxide was normal: 20 ml/mm Hg/min (88% predicted). Arterial blood gases on room air confirmed chronic hypoxic and hypercapnic respiratory failure: pH: 7.38, paO2: 53.5 mm Hg, paCO2: 50.3 mm Hg. A chest CT showed a non-calcified nodule (2.5 × 1.5 cm) in the left upper lung lobe and multiple smaller nodules in other parts of both lungs (fig. 1). Flexible bronchoscopy was unrevealing. Whole-body positron emission tomography using 18F-fluoro-2-deoxy-D-glucose (FDG) demonstrated an increased focal FDG accumulation in the left upper lung. No other pathological FDG accumulation was found.
|Fig. 1. CT scan showing a lobulated, non-calcified nodule (2.5 × 1.5 cm) in the left upper lobe, patchy areas of ground glass opacities in both lungs and several small nodules in both lungs.|
The patient underwent resection of the tumor and an intraoperatively performed frozen section revealed a typical carcinoid. A lobectomy of the left upper lobe was performed, and a tumor stage pT1 pN0 was determined. Histological examination of lung tissue distant from the tumor showed numerous tumorlets that compressed and obliterated the bronchioles (fig. 2) so that peripheral airway disease secondary to DIPNECH was diagnosed. Postoperative lung function remained unchanged compared to preoperative values.
|Fig. 2. Peripheral airway occluded by multiple neuroendocrine cells. Elastica-van Giesson staining. The insert shows immunoreactivity to synaptophysin at a different location of the same specimen.|
We performed both a somatostatin receptor scintigraphy with 111In-octreotide and a 123I-metaiodobenzylguanidine (MIBG) scintigraphy. Both radiopharmaceuticals have a high affinity to neuroendocrine tumors and can also be marked with therapeutic radionuclides, 90Y-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Thy3-octreotide and 131I-MIBG. MIBG is also accumulating in injured endothelial cells in chronic obstructive lung disease. Both diagnostic scans were performed to evaluate the uptake in the lung in order to evaluate specific radionuclide treatment for ablation of the neuroendocrine tissue. 111In-octreotide scintigraphy showed no increased accumulation in the lung. 123I-MIBG scintigraphy demonstrated increased pathological radiotracer accumulation in the left upper lung. However, physiological high radiotracer accumulation was found in the salivary glands, thyroid, heart, and liver. Therefore, neither approach was suited for therapeutic ablative radionuclide treatment. Lung transplantation was discussed, but declined by the patient.
LVRS may improve shortness of breath, quality of life and lung function in appropriately selected patients [4,5,6] with severe pulmonary emphysema and even in patients with obliterative bronchiolitis and severe hyperinflation . LVRS also enables the resection of lung tumors in severely hyperinflated patients with poor lung function previously deemed inoperable . Our patient tolerated the resection of the left upper lobe without complication, and the degree of shortness of breath during exercise and her lung function remained unchanged after lobectomy.
DIPNECH is found in patients with various lung diseases  and in persons living at high altitude . It can be observed in smokers with chronic obstructive pulmonary disease and in non-smokers, causing obstructive ventilatory defects in few of them. This obliteration of the peripheral airways is extremely rare, and few cases have been described particularly in elderly non-smoking women. Of the 22 cases found in the literature, only 5 had severe airway obstruction comparable to our patient (table 1) [2, 3,9,10,11,12].
|Table 1. DIPNECH presenting with obliterative bronchiolitis and airway obstruction|
DIPNECH is assumed to be a pre-invasive lesion for neuroendocrine neoplasia . Typical morphological correlates are for example intraepithelial hyperplasia of neuroendocrine cells and the so-called tumorlets, which are interstitial clumps of neuroendocrine cells with a diameter <5 mm. Other morphological characteristics like desquamative and obliterative accumulations of neuroendocrine cells, mainly in the lower airways, may occur [3, 10]. DIPNECH can also be found in lungs simultaneously with neuroendocrine tumors [2, 3, 11]. Miller  reported 19 patients, with obliterative bronchiolitis occurring in 8 of them. Only 4 had airway obstruction. We found but 1 case report where a patient with DIPNECH and obliterative bronchiolitis received a single lung transplant . Since our patient declined lung transplantation and cytotoxic drugs are reported to be ineffective , we explored if the neuroendocrine lung tissue could selectively be tagged and ablated by a radiopharmaceutical. MIBG was found to accumulate in the neuroendocrine lung tissue but showed physiological accumulation in various organs as well, thus we abstained from ablation.
E.W. Russi, MD, FCCP
Department of Pulmonary Medicine
University Hospital, Rämistrasse 100
CH–8091 Zürich (Switzerland)
Tel. +41 44 255 38 28, Fax +41 44 255 44 51, E-Mail firstname.lastname@example.org
Received: April 22, 2004
Accepted: August 16, 2004
Published online: August 30, 2005
Number of Print Pages : 4
Number of Figures : 2, Number of Tables : 1, Number of References : 13
Respiration (International Journal of Thoracic Medicine)
Vol. 73, No. 5, Year 2006 (Cover Date: September 2006)
Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (print), 1423–0356 (Online)
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