Clinical report
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: Report of two cases
Hiperplasia neuroendocrina difusa pulmonar idiopática: estudio de dos casos
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(b) The same area showing positivity for CD 56 with immunohistochemistry that corresponds with a neuroendocrine cell hyperplasia (asterisk, objective magnification 60×). (c) Paratracheal lymph node of case number 1 stained with hematoxylin and eosin technique showing a little focus of neuroendocrine epithelial cells that corresponds with a metastatic typical carcinoid marked with an asterisk (objective magnification 20×). Insert: immunohistochemical technique using cytokeratins, which highlights the metastatic neuroendocrine cells. (d) CT of case number 2. We can observe a subcentimeter nodule in the middle lobe (arrow) and a bilateral mosaic pattern.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The term diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder commonly misdiagnosed. Aguayo et al. described it for the first time more than 25 years ago, showing a hyperplasia confined to the respiratory epithelium layer without penetration of the basement membrane.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> This entity encompasses symptomatic patients with airway disease as well as asymptomatic patients with neuroendocrine cell hyperplasia associated with multiple tumorlets/carcinoids tumors. The World Health Organization (WHO) in the spectrum of pulmonary neuroendocrine tumors also considers DIPNECH as preneoplastic lesion, because it is commonly observed in patients with peripheral carcinoid tumours.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In this paper, we analyze clinical, physiological, radiological and histological features of DIPNECH documenting two new cases.</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Case reports</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Case 1</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 71-year-old female patient was referred to our department to perform a lung biopsy because of the suspected diagnosis of a diffuse lung disease. She was a no smoker, suffered a Von Willebrand disease and was diagnosed years before of bronchial asthma and chronic cough. There were no alterations in the physical examination and pulmonary function test was: FEV1 61%, FVC 69% and DLCO 56%.</p><p id="par0020" class="elsevierStylePara elsevierViewall">CT showed a bilateral mosaic pattern and subcentimeter nodules in right lower lobe, middle lobe, left lower lobe and left upper lobe. There was also a solid lesion in the anterior segment of right upper lobe. We decided to perform a PET because the lesion of the right upper lobe was larger than previous in the last radiological study. PET showed again an interstitial mosaic pattern and a solid lesion with spiculated rims of 1.6<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1.2<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>0.8<span class="elsevierStyleHsp" style=""></span>cm in the anterior segment of the right upper lobe with a SUV of 5.7<span class="elsevierStyleHsp" style=""></span>g/ml. The rest of the subcentimeter nodules did not show glucose uptake. Bronchoscopy did not reveal any endobronchial finding.</p><p id="par0025" class="elsevierStylePara elsevierViewall">We performed a right upper lobectomy with systematic lymph node dissection. The histological study of the specimen showed a necrotizing granulomatous inflammation with acid-alcohol resistant bacillus (BAAR) forming a nodular area of 1.6<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>cm in the lobe. In the rest of the tissue we only observed a mild focal dilatation of the bronchioles, and a minor peribronchiolar lymphocyte inflammation. We did not find parenchymal fibrosis but we observed three microscopic nodules lesser than 3<span class="elsevierStyleHsp" style=""></span>mm made up of low-grade neuroendocrine cells (3 tumorlets). Despite we did not identify morphological changes of interstitial lung disease, a diffuse neuroendocrine cell hyperplasia was observed in the mucosa of multiple bronchioles. This fact went unnoticed with hematoxylin and eosin staining technique but was clearly recognized in the immunohistochemical work-up (these cells were positive for CD56 and Cytokeratins) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>a and b). Five peribronchial lymph nodes did not showed granulomas or neoplasm. Nevertheless, in the paratracheal and subcarinal lymph stations we observed two little microscopic nodules (1.5<span class="elsevierStyleHsp" style=""></span>mm and 2<span class="elsevierStyleHsp" style=""></span>mm respectively) of epithelial neuroendocrine cells that were positive for CD 56 and TTF1. We did not find pleomorphism, neither necrosis and nor significant mitotic activity was observed. Expression of Ki 67 was minor than 2% (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>c). Postoperative evolution elapsed without complications and the patient was discharged seven days after surgery.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Case 2</span><p id="par0030" class="elsevierStylePara elsevierViewall">A 56-year-old woman was admitted to our hospital to perform a lung biopsy in the context of an interstitial lung disease. Se was a smoker of 20 cigarettes per day and suffered epilepsy treated with Carbamazepine that was suspended because of the possible relation with the interstitial pattern. She presented moderate effort dyspnea and chronic cough since youth.</p><p id="par0035" class="elsevierStylePara elsevierViewall">CT demonstrated a nodule in the middle lobe of 0.6<span class="elsevierStyleHsp" style=""></span>cm, a nodule in the left lower lobe of 1<span class="elsevierStyleHsp" style=""></span>cm and a bilateral mosaic pattern (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>d). It was performed a PET that demonstrated a lower hypermetabolism in both nodules. Pulmonary function test was: FEV1 44%, FVC 60% and KCO 69%. Bronchoscopy did not show any finding.</p><p id="par0040" class="elsevierStylePara elsevierViewall">We performed biopsies of right upper lobe and right lower lobe and a wedge resection to treat the nodule of the middle lobe. The definitive pathology results showed a diffuse neuroendocrine cell hyperplasia with multiple tumorlets in the biopsies from right upper lobe and right lower lobe and a typical carcinoid of 0.7<span class="elsevierStyleHsp" style=""></span>cm in the nodule of the middle lobe. Postoperative progress was satisfactory. The patient was discharged 2 days after surgery.</p></span></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion</span><p id="par0045" class="elsevierStylePara elsevierViewall">Neuroendocrine cells in the adult lung are part of the normal epithelial layer of the respiratory tract comprising about 1% of all cells. These specialized cells receive neural impulses and secrete several hormonally substances, mainly under reduced oxygen tension.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Since DIPNECH was reported in 1992,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> several authors have reviewed additional cases, some of them were associated with carcinoids.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Clinical symptoms and radiological findings of DIPNECH are indistinguishable from other diffuse lung diseases. Like in our two cases, the majority of patients appear to be non-smoker women, with an age range of 36–76 years at diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3,4</span></a> Symptomatic patients can suffer nonproductive cough, dyspnea and/or wheezing with a very slow worsening over several years.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2–4</span></a> Moreover, many of them, like one of our cases are diagnosed of asthma or chronic obstructive pulmonary disease or gastro-oesophageal reflux.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Physical examination is usually nonspecific and pulmonary function test might be normal or showing an obstructive pattern, however a restrictive or mixed pattern can also be noted.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> The presence of different types of pulmonary function test can be explained by the underlying pathophysiology. Constrictive bronchiolitis resulting in luminal narrowing and mural scarring can be associated with DIPNECH and give rise to obstructive symptoms. By other hand, the secretion of neuropeptides by the same hyperplasic cells can lead to an interstitial fibrosis and restrictive physiology as well.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Conventional chest radiology is not useful to diagnose DIPNECH. CT findings include mosaic attenuation (due to constrictive bronchiolitis), bronchial wall thickening, bronchiectasis and mucoid impactions.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Mosaic pattern with air trapping is characterized by a patchwork of low-attenuation lung that is interposed with normally ventilated higher attenuation lung. In symptomatic patients, like in our cases, evidence of small airway obstruction in the form of mosaicism and the coexistence of multiple pulmonary nodules may be seen in high resolution CT.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,6</span></a> In asymptomatic patients, the disease is diagnoses incidentally by thoracic imaging performed for other reason.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,3,6</span></a> Single or multiple lung nodules are the most frequent radiological finding in patients with DIPNECH. An octreotide scan is useful for the detection and staging neuroendocrine tumors because they present and over-expression of somatostatine receptors.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> In our cases we did not performed this technique because their physicians did not suspected this disease.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Microscopically, DIPNECH is defined as the presence of a widespread hyperplasia of the pulmonary neuroendocrine cells confined to the bronchiolar epithelium without penetration through the basement membrane. Extension beyond the basement membrane is called tumorlet (<5<span class="elsevierStyleHsp" style=""></span>mm) or carcinoids tumors (>5<span class="elsevierStyleHsp" style=""></span>mm). The exact frequency of carcinoid tumor development in DIPNECH is unknown, Nasar et al. found 40% in his cases,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> and Koo and cols suggest that this entity represent different stages along a spectrum of neuroendocrine proliferation.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> Neuroendocrine cells express chromogranin A, synaptophysin, neuron specific enolase and CD56.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> They can also show a weak positivity for TTF-1.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The management of patients with DIPNECH is predominantly close surveillance. Most patients with DIPNECH have a stable clinical course. Treatment with bronchodilators and inhaled corticosteroids provide symptomatic relief. Systemic steroids have been shown to be beneficial in some cases by possibly reducing the inflammatory response induced by secretions of neuroendocrine cells.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Azithromycin has also shown benefit in stabilizing the clinical course in some cases possibly due to its immunomodulatory effects.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> Therapy with somatostatin analogs has been shown to improve the symptoms in some patients with DIPNECH, possible by reducing the hyperplasia and fibrosis by suppression of peptide production.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> In our cases, the patient number one did not receive any treatment for DIPNECH because first she is being treated of tuberculosis. The second patient received oral corticosteroids and after reducing them, she is receiving nowadays somatostatin analogs. The role of surgery is not clearly defined. However, the treatment principle remains surgical intervention for early disease and predominantly palliative therapy in metastatic disease. Curiously, progressive disease with obliterative bronchiolitis requiring lung transplantation has been reported.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Contributions</span><p id="par0070" class="elsevierStylePara elsevierViewall">(I) Conception and design: all authors; (II) Administrative support: none; (III) Provision of study materials or patients: all authors; (IV) Collection and assembly of data: E. García-Fontán and M Blanco; (V) Data analysis and interpretation: all authors; (VI) Manuscript writing: all authors; (VII) Final approval of manuscript: all authors.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interests</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1142223" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results and discussion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1072948" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1142222" "titulo" => "Resumen" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Resultados y discusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1072947" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0010" "titulo" => "Case reports" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Case 2" ] ] ] ] ] 5 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Contributions" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-02-19" "fechaAceptado" => "2018-03-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1072948" "palabras" => array:4 [ 0 => "DIPNECH" 1 => "Interstitial lung disease" 2 => "Lung biopsy" 3 => "Carcinoid tumor" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1072947" "palabras" => array:4 [ 0 => "Hiperplasia neuroendocrina difusa pulmonar" 1 => "EPID" 2 => "Biopsia pulmonar" 3 => "Tumor carcinoide" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder characterized by a proliferation of neuroendocrine cells within the lung. It is classically described as a disease with persistent cough, dyspnea and wheezing in non-smoker middle aged females. CT of the chest reveals diffuse air trapping with mosaic pattern.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We present two cases of DIPNECH that were sent to our department to perform a lung biopsy with the diagnostic suspicion of diffuse interstitial disease. Both cases were women with a history of chronic cough and moderate effort dyspnea.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results and discussion</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The aim of this paper is that physicians take into account this diagnostic entity before treating as an asthmatic a patient with these characteristics, not forgetting that they are prenoplastic lesions.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results and discussion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introducción</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">La hiperplasia neuroendocrina difusa pulmonar idiopática (HNDPI) es una patología poco frecuente que se caracteriza por la proliferación de células neuroendocrinas en el parénquima pulmonar. Se describe clásicamente como una enfermedad que afecta a mujeres de mediana edad no fumadoras y que presentan tos persistente, disnea y sibilancias. La TC muestra una imagen de patrón en mosaico como resultado del atrapamiento aéreo.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pacientes y métodos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Presentamos dos casos de HNDPI que fueron enviados a nuestro servicio para realizar una biopsia pulmonar con la sospecha diagnóstica de enfermedad intersticial difusa. Ambos casos fueron mujeres con antecedentes de tos crónica y disnea de esfuerzo moderado.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Resultados y discusión</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este documento es que los facultativos tengan en cuenta este diagnóstico antes de tratar como asmática a una paciente con estas características, no olvidando además que son lesiones preneoplásicas.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Resultados y discusión" ] ] ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1869 "Ancho" => 2482 "Tamanyo" => 439747 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">(a) Hematoxylin and eosin staining technique showing the mucosa of a terminal bronchiole with cilia in the epithelium and neuroendocrine cells (asterisk). (b) The same area showing positivity for CD 56 with immunohistochemistry that corresponds with a neuroendocrine cell hyperplasia (asterisk, objective magnification 60×). (c) Paratracheal lymph node of case number 1 stained with hematoxylin and eosin technique showing a little focus of neuroendocrine epithelial cells that corresponds with a metastatic typical carcinoid marked with an asterisk (objective magnification 20×). Insert: immunohistochemical technique using cytokeratins, which highlights the metastatic neuroendocrine cells. (d) CT of case number 2. We can observe a subcentimeter nodule in the middle lobe (arrow) and a bilateral mosaic pattern.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airway disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.M. Aguayo" 1 => "Y.E. Miller" 2 => "J.A. Waldron" 3 => "R.M. Bogin" 4 => "M.E. Sunday" 5 => "G.W. 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