Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a rare disease previously overlooked, is gradually being recognized as an important precursor state to pulmonary neuroendocrine tumors. The very insidious onset of symptom presentation makes early diagnosis of DIPNECH almost impossible in clinical settings. In this report, we present a case of persistent and worsening cough for over five years with waxing and waning lung nodules of varying sizes which were eventually diagnosed as DIPNECH on biopsy. However, due to the location and the multiplicity of these nodules, surgical resection was not an option in this case. The diagnostic workup including imaging and biopsy, management options, and possible prognosis of DIPNECH are discussed in detail. This report highlights the growing recognition of DIPNECH as a clinical entity to be aware of during the formulation of a differential diagnosis for patients presenting with chronic unrelenting cough and associated lung nodules.

Diffuse idiopathic hyperplasia of neuroendocrine cells is an extremely rare condition. It is a widespread proliferation of neuroendocrine cells, without primary process justifying it. Usually symptomatic in most cases, asymptomatic forms are also described. We describe three cases, 2 women and 1 man, average age 63 years (range 57-71) who presented with bilateral pulmonary nodules. Average follow-up: one year and three months (range 1 month-3 years). The two women had cough, progressive dyspnea and airflow obstruction in the spirometry, and were treated for asthma and chronic obstructive pulmonary disease, respectively, with little relief of symptoms. The remaining patient consulted for diagnosis of pulmonary nodules of unknown cause and a suspicion of metastatic disease. The biopsies diagnostic were: in the first and third case diffuse idiopathic hyperplasia of euroendocrine cells - tumorlets; and in the second case typical carcinoid tumor and diffuse idiopathic hyperplasia of neuroendocrine cells. The first patient controlled the symptoms with maximum bronchodilator therapy. The second patient presented immediate postoperative severe bronchospasm and respiratory failure which required ventilatory assistance, atrial fibrillation with rapid ventricular response (both signs interpreted as paraneoplastic syndromes) which responded favorably to the empirical octeotride management. The third patient is asymptomatic and in control. The diffuse neuroendocrine cell hyperplasia represents a diagnostic challenge because of the rarity of this condition. Lung biopsy in patients with multiple, bilateral pulmonary nodules and clinical history of cough and progressive dyspnea should be considered to confirm this entity.
La hiperplasia difusa idiopática de células neuroendocrinas es una entidad extremadamente infrecuente caracterizada por una proliferación generalizada de células neuroendocrinas, sin proceso primario que lo justifique, generalmente, aunque también están descriptas formas asintomáticas. Se describen los casos de dos mujeres y un hombre, edad promedio 63 años (rango 57-71) que consultaron por presentar nodulillos pulmonares bilaterales. Promedio de seguimiento: 1 año, 3 meses (rango 1 mes-3 años). Las dos mujeres presentaban tos, disnea progresiva y obstrucción al flujo aéreo en el estudio espirométrico, fueron tratadas por asma y enfermedad pulmonar obstructiva crónica respectivamente con poco alivio de los síntomas. El tercer paciente, varón, consultó por hallazgo incidental en una tomografía de tórax, de nódulos pulmonares, con razonable sospecha de enfermedad metastásica de origen desconocido. En sendas biopsias se diagnosticaron: en el primer y tercer caso hiperplasia neuroendócrina difusa idiopática-tumorlets; y en el segundo caso tumor carcinoide típico e hiperplasia neuroendocrina difusa idiopática. En el primer caso los síntomas se controlaron con tratamiento broncodilatador máximo. La segunda paciente tuvo en el postoperatorio, insuficiencia respiratoria que requirió asistencia respiratoria mecánica y fibrilación auricular con alta respuesta ventricular, interpretados ambos signos como síndromes paraneoplásicos, que respondieron favorablemente a la administración empírica de octeotride. El tercer paciente se halla asintomático y en control. La hiperplasia difusa de células neuroendócrinas representa un desafío diagnóstico. La biopsia pulmonar en pacientes con nodulillos pulmonares múltiples, bilaterales e historia clínica de tos y disnea progresiva debe ser considerada para confirmar esta entidad.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder that is commonly underdiagnosed. In 2015, it was recognized by the World Health Organization (WHO) classification of lung tumors as a premalignant lesion. DIPNECH syndrome is characterized by cough, exertional dyspnea, wheezing, and, less frequently, hemoptysis. We report the clinical and histological features and imaging findings in four cases of DIPNECH from our institution (Torrejon University Hospital, Madrid, Spain) between the years 2012 and 2019. DIPNECH represents a rare and poorly understood pulmonary disorder. Our limited single-center experience shows the slow and stable evolution of the disease. However, some exceptional cases may progress poorly if distant metastases occur.

Spread through air spaces (STAS) is a recently proposed invasion way of lung cancer, including neuroendocrine (NE) neoplasms. However, if this phenomenon is a real one or an artifact while manipulating lung specimens, it is still matter of debate.
Three consecutive patients with newly diagnosed diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) were reviewed for STAS.
In well-fixed lung specimens, DIPNECH was seen to coexist with atypical carcinoid, bifocal typical carcinoid and adenocarcinoma in the three patients, respectively. While STAS was not observed at the growing edges of tumors, a few freely-floating aggregates of hyperplastic NE cells within air spaces were noticed to emanate from foci of NE hyperplasia and tumorlets and in intimate association with normal bronchiolar cells and erythrocytes to denote artifactual derivation upon tissue manipulation.
Traveling of hyperplastic NE cells through air spaces is likely to artifactually occur via knife, surgeon or other way, thus challenging invasion by STAS.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder which can be an incidental finding in imaging tests performed during the investigation of another condition, or is the final diagnosis in patients evaluated for chronic obstructive complaints. To explore the possible association between specific histopathology features and the mode of clinical presentation, we retrieved the clinical, functional, radiological, and pathological data of all 13 patients diagnosed with DIPNECH at our Institution over a 14-year period (2000-2014). As compared to patients with incidental disease (6/13, 46 %), patients with symptomatic disease were younger [mean (SD): 57.7 vs. 68.7 years, p = 0.046], were more likely to have mosaic attenuation (100 vs. 0 %, p = 0.001) and small multiple nodules (100 vs. 17 %, p = 0.005) at CT, and showed a significantly higher number of foci of linear neuroendocrine proliferation [median (IQR): 28 (13-37) vs. 6 (5-13), p = 0.018] and of tumorlets [median (IQR): 10 (8-20) vs. 1 (1-1), p = 0.002] at histology. Incidental disease was found in association with pulmonary adenocarcinoma in five out of six patients (83.3 %). The results of our study provide preliminary evidence that symptomatic patients with DIPNECH represent a specific subset characterized by younger age and a higher burden of foci of neuroendocrine proliferation.