Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Research Articles

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia of the Lung (DIPNECH): Current Best Evidence.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is recognized as a preneoplastic condition by the World Health Organization. We reviewed our experience with 30 patients and performed a systematic review of the English literature to collect best evidence on the clinical features and disease course in 169 additional patients. Some patients presented with one or more carcinoid tumors associated with multiple small pulmonary nodules on imaging studies and showed DIPNECH as a somewhat unexpected pathologic finding. Others presented with multiple small pulmonary nodules that raised suspicion of metastatic disease on imaging. A third subset was presented with previously unexplained respiratory symptoms. In most patients, DIPNECH was associated with a good prognosis, with chronological progression into a subsequent carcinoid tumor noted in only one patient and death attributed directly to DIPNECH in only two patients. There is no best evidence to support the use of octreotide, steroids, or bronchodilators in DIPNECH patients.

The Clinical Course of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia

Current understanding of the clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is poor and based predominantly on small case series. In our clinical experience, we have found that the diagnosis of DIPNECH is frequently delayed because respiratory symptoms are ascribed to other lung conditions. The objectives of this study were to collect and analyze longitudinal clinical data on pulmonary physiology, chest high-resolution CT (HRCT) imaging, and therapies to better delineate the course of disease. We established a cohort of patients (N = 30) with DIPNECH seen at our institution. We used descriptive statistics to summarize cohort characteristics and longitudinal analytic techniques to model FEV1 % predicted (FEV1%) over time. All subjects were women who presented with long-standing cough and dyspnea. The majority had an FEV1% < 50% at the time of diagnosis. Forty percent were given a diagnosis of asthma as the cause for physiologic obstruction. The mean FEV1% for the entire cohort showed no statistically significant decline over time, but 26% of the subjects experienced a 10% decline in FEV1 within 2 years. Among the pathology samples available for review, 28% (five of 18) had typical carcinoids and 44% had associated constrictive bronchiolitis. We propose clinical diagnostic criteria for DIPNECH that incorporate demographic, pulmonary physiology, HRCT imaging, and transbronchial and surgical lung biopsy data. DIPNECH is a female-predominant lung disease manifested by dyspnea and cough, physiologic obstruction, and nodules on HRCT imaging. Additional research is needed to understand the natural history of this disease and validate the proposed diagnostic criteria.

Pulmonary Peripheral Carcinoids after Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Tumorlets: Report of 3 Cases.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets are neuroendocrine cells proliferations smaller than 5 mm. The former confines to bronchial/bronchiolar wall, while the latter broke through epithelial basement membrane. The authors present 3 cases of DIPNECH and tumorlets associated with a typical peripheral carcinoid tumor without underlying lung disease. The patients presented with nonspecific pulmonary symptoms: 3 females, 60, 72, and 84 years old, whose CT-scans showed well-defined pulmonary nodules, 2.2, 1.6, and 1.4 cm, respectively; first patient was submitted to lobectomy and the others underwent surgical biopsy. Whitish/brownish lobulated tumors corresponded to typical carcinoids (less than 2 mitoses/2 mm2 and without necrosis); polygonal/elongated cells under lobular pattern expressed CD56, chromogranin A, synaptophysin, and CK7; Ki-67 positivity was between 1 and 3%. Bronchial/bronchiolar wall neuroendocrine cell hyperplasia and several neuroendocrine nodules under 5 mm, with identical morphologic and immunoexpression, were observed, without lung disease. Typical carcinoid associated with DIPNECH and tumorlets without other pulmonary diseases is rare. Sporadic cases may recall embryonal neuroendocrine differentiation potentiality to develop peripheral hyperplasia, most commonly in underoxygenated parenchyma. The described cases are elucidative of peripheral spectrum of neuroendocrine cell tumour evolution, reinforcing higher female incidence as in central carcinoids, still without a clear preneoplastic lesion.

A Rare Case of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare clinical condition with only about 100 cases reported in the literature. It is characterized by primary hyperplasia of pulmonary neuroendocrine cells (PNECs) which are specialized epithelial cells located throughout the entire respiratory tract, from the trachea to the terminal airways. DIPNECH appears in various forms that include diffuse proliferation of scattered neuroendocrine cells, small nodules, or a linear proliferation. It is usually seen in middle-aged, nonsmoking women with symptoms of cough, dyspnea, and wheezing. We present a 45-year-old, nonsmoking woman who presented with symptoms of DIPNECH associated with bilateral pulmonary nodules and left hilar adenopathy. Of interest, DIPNECH in our patient was associated with metastatic pulmonary carcinoids, papillary carcinoma of the left breast, oncocytoma and angiomyolipoma of her left kidney, and cortical nodules suggestive of tuberous sclerosis. She had video assisted thoracoscopic surgery (VATS), modified radical mastectomy with reconstruction, and radical nephrectomy. She is currently symptom-free most of the time with over two years of follow-up.

DIPNECH (Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia): A Rare Syndrome or Undiagnosed?

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is considered a rare syndrome and knowledge of its pathophysiology is scarce. Classified as pre-neoplastic lesion of carcinoid tumours currently there are many questions regarding the best approach to follow-up and treatment this patients. Mainly affects females, there is no apparent relationship to smoking habit and is often confused with obstructive airway disease. The diagnosis is histological and sometimes can be observed simultaneously a triple pattern consisting of DIPNECH, tumourlets and carcinoid tumour. We report the case of a 35-years-old woman, non-smoker with DIPNECH in association with typical carcinoid tumour and tumourlets.

Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

ObjectiveThe objective of the study was to describe the imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) on computed tomography (CT). Materials and methodsElectronic medical records were searched for patients with pathology-proven DIPNECH who had a CT available for review. Eleven patients were included. ResultsThe most common finding on CT was small pulmonary nodules which were present in all patients and were multiple (≥5) in 7/11 patients. Other CT findings included mosaic pattern attenuation and bronchial wall thickening/bronchiectasis. ConclusionDIPNECH should be considered as a diagnostic possibility when multiple small pulmonary nodules are identified on CT, particularly if there is an associated carcinoid tumor.

S40 A comparison of asthmatic and non-asthmatic severe small airway disease

IntroductionWe present a series of cases referred to our severe asthma clinic that symptomatically appear like asthma, yet physiology demonstrated one of the more uncommon types of severe Small Airway...

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia with a Central and Peripheral Carcinoid and Multiple Tumorlets: A Case Report Emphasizing the Role of Neuropeptide Hormones and Human Gonadotropin-Alpha

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH.

Association of small foci of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with adenocarcinoma of the lung

DIPNECH is regarded as a precursor lesion of neuroendocrine lung tumors, specifically carcinoids. A relationship with lung adenocarcinomas has not been clearly established so far. We present a series of four cases with a concomitant presence of adenocarcinoma and DIPNECH in the lung.The cases were retrieved from the archives of the Institutes of Pathology of the Jena University Hospital and the Charité, Berlin. The clinical data were collected from the hospital information system. The microscopic findings of adenocarcinoma and DIPNECH were reviewed. A panel of neuroendocrine and epithelial markers was analyzed immunohistochemically. In addition, the H&E slides of a series of 82 lung carcinomas were reevaluated for the presence of DIPNECH foci and the parameters of the IASLC/ATS/ERS classification for lung adenocarcinoma.DIPNECH foci were composed of small intramucosal nests of proliferating pulmonary neuroendocrine cells alongside or at the periphery of terminal airways. All detected foci measured less than 5mm in maximal diameter and showed a consistent reactivity against Synaptophysin. They did not express epithelial markers of squamous cell carcinoma and adenocarcinoma. In three cases, the DIPNECH foci were clearly associated with the adenocarcinoma, while in one case, they were observed in the non-neoplastic lung tissue. The adenocarcinoma with DIPNECH inside mainly showed low grade histology, while the fourth case was intermediate to high grade. The histologic evaluation of the HE slides of the other 82 lung cancer cases showed no suspected or definite DIPNECH foci. Within this series, we could confirm the prognostic significance of the IASLC/ATS/ERS classification of lung adenocarcinoma.Our series suggest that a subset of lung adenocarcinoma is characterized by the concomitant presence of DIPNECH within the tumor, suggesting a causal relationship. These adenocarcinomas seem to be low grade ones, and may have a particular tumorigenesis and clinical behavior. These observations need to be confirmed in larger tumor collectives. We could confirm the prognostic relevance of the new adenocarcinoma classification.

Bronchiolitis: adopting a unifying definition and a comprehensive etiological classification

Bronchiolitis is an inflammatory and potentially fibrosing condition affecting mainly the intralobular conducting and transitional small airways. Secondary bronchiolitis participates in disease process of the airways and/or the surrounding lobular structures in the setting of several already defined clinical entities, mostly of known etiology, and occurs commonly. Primary or idiopathic bronchiolitis dominates and characterizes distinct clinical entities, all of unknown etiology, and occurs rarely. Secondary bronchiolitis regards infections, hypersensitivity disorders, the whole spectrum of smoking-related disorders, toxic fumes and gas inhalation, chronic aspiration, particle inhalation, drug-induced bronchiolar toxicities, sarcoidosis and neoplasms. Idiopathic or primary bronchiolitis defines clinicopathologic entities sufficiently different to be designated as separate disease entities and include cryptogenic constrictive bronchiolitis, diffuse panbronchiolitis, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, neuroendocrine hyperplasia in infants, bronchiolitis obliterans syndrome in lung and allogeneic hematopoietic cell transplantation, connective tissue disorders, inflammatory bowel disease and bronchiolitis obliterans organizing pneumonia. Most of the above are pathological descriptions used as clinical diagnosis. Acute bronchiolitis, though potentially life threatening, usually regresses. Any etiology chronic bronchiolitis contributes to morbidity and/or mortality if it persists and/or progresses to diffuse airway narrowing and distortion or complete obliteration. Bronchiolitis in specific settings leads to bronchiolectasis, resulting in bronchiectasis.

Precursor lesions of endocrine system neoplasms

The concept of precursor lesions of endocrine neoplasms is a new and interesting topic in endocrine pathology. A variety of clinicopathological conditions are associated with a sequence of cellular changes from hyperplasia to neoplasia; dysplasia is, in contrast, quite rare. The majority of precursor lesions is associated with familial genetic syndromes. These include C-cell hyperplasia in thyroid that is associated with familial medullary thyroid carcinoma, adrenal medullary hyperplasia as a precursor of phaeochromocytomas in MEN2 syndrome, rare pituitary adenohypophyseal cell hyperplasia in familial syndromes associated with pituitary adenomas, MEN1-related precursor gastric enterochromaffin-like cell (ECL) hyperplasia, and duodenal gastrin producing (G) and/or somatostatin producing (D) cell hyperplasia that give rise to type II gastric neuroendocrine tumours (NETs) and duodenal NETs, respectively, and MEN1- or VHL-related islet hyperplasia, islet dysplasia and ductulo-insular complexes that are associated with pancreatic NETs. Other hyperplasias are not thought to be associated with genetic predisposition. Some are attributed to inflammation; autoimmune chronic atrophic gastritis-related ECL hyperplasia can progress to type I gastric NETs, and EC (enterochromaffin) cell or L cell hyperplasia associated with inflammatory bowel diseases can progress to colorectal NETs. In the lung, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia can give rise to peripherally-located low grade pulmonary NETs and tumourlets (neuroendocrine microtumours <5 mm). Rarely, secondary hyperplasias develop into autonomous neoplasms, as in tertiary hyperparathyroidism or pituitary thyrotroph adenomas in primary hypothyroidism. While some precursor lesions, such as thyroid C cell hyperplasia, represent frankly premalignant conditions, others may represent a sequence of proliferative changes from hyperplasia to benign neoplasia that may also progress to malignancy.

Facts and fiction: premalignant lesions of lung tissues

Lung cancer is now the leading cause of death from cancer in Australia. Most patients are diagnosed with late-stage disease. Although diagnosis at pre-invasive stages could theoretically improve outcomes, mooted precursor lesions are often asymptomatic and often undetectable by non-invasive investigations. Nonetheless, they merit study to identify early and essential molecular steps involved in lung carcinoma pathogenesis, with the aim of developing therapies targeted against one or more such steps. Some lung cancers appear to develop via a series of progressive morphological changes with correlating molecular alterations, but others seem to arise in histologically normal epithelium, and these differences may reflect anatomically and functionally distinct epithelial compartments of the respiratory tract. Pre-invasive precursor lesions recognised by the World Health Organization (WHO) include squamous metaplasia with dysplasia and carcinoma in situ, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Other lesions that likely represent pre-invasive lesions, but which are not currently WHO-listed, include human papillomavirus (HPV)-related respiratory papillomatosis and mesothelioma in situ. No single cancer stem cell marker has been identified. Field cancerisation plays an important role in lung cancer development, and includes the spread of pre-invasive clones along the respiratory epithelium or the occurrence of multiple separate foci of pre-invasive abnormalities such as squamous dysplasia and carcinoma in situ.In addition to well-characterised step-wise progression in squamous cell carcinomas and some adenocarcinomas, alternative pathways exist, and are currently being investigated. In addition, molecular techniques, including miRNA screening on blood samples or cytology samples--such as sputum samples--may become clinically relevant and more accurate in predicting lung cancer progression.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia With Multiple Synchronous Carcinoid Tumors

The spectrum of pulmonary neuroendocrine cell proliferation ranges from reactive hyperplasia to small cell carcinoma and includes diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. A case is reported and features of this disease are described according to the published evidence. The entity was first included in the WHO classification of tumors in 1999 and is considered a preneoplastic condition for carcinoid tumors. Patients generally report slowly progressive dyspnea and cough, and have airflow obstruction, multiple pulmonary nodules and/or radiological signs of air trapping, although asymptomatic cases with normal pulmonary function have been described. Histologically, it is characterized by neuroendocrine cell proliferation in the airway epithelium, in most cases beyond the basal membrane forming tumorlets and carcinoid tumors that are frequently multiple. The prognosis is favorable in most cases.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) masquerading as metastatic carcinoma with multiple pulmonary deposits

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder presenting with multiple pulmonary nodules in association with a typical mosaic perfusion pattern on computed tomography. In this case, the absence of mosaic perfusion led to an erroneous initial diagnosis of pulmonary metastases from an unknown primary malignancy. This illustrates the importance of considering differential diagnoses when presented with imaging findings compatible with pulmonary metastases from an unknown primary, and highlights the importance of histopathologic confirmation in such cases.

What is DIPNECH?

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder that is being diagnosed more frequently with the increasing availability of advanced imaging and more accurate histopathology. It occurs most commonly in nonsmoking, middle-aged women. High-resolution computed tomography (HRCT) findings include mosaic attenuation due to constrictive bronchiolitis and small (<5 mm) randomly distributed pulmonary nodules. It is important to recognize this condition as it is considered a precursor of peripheral carcinoid tumors. This article will present a case of this uncommon condition with review of the literature, imaging findings, and clinical presentation.

Hiperplasia difusa idiopática de células neuroendocrinas pulmonares con tumores carcinoides múltiples sincrónicos

The spectrum of pulmonary neuroendocrine cell proliferation ranges from reactive hyperplasia to small cell carcinoma and includes diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. A case is reported and features of this disease are described according to the published evidence. The entity was first included in the WHO classification of tumors in 1999 and is considered a preneoplastic condition for carcinoid tumors. Patients generally report slowly progressive dyspnea and cough, and have airflow obstruction, multiple pulmonary nodules and/or radiological signs of air trapping, although asymptomatic cases with normal pulmonary function have been described. Histologically, it is characterized by neuroendocrine cell proliferation in the airway epithelium, in most cases beyond the basal membrane forming tumorlets and carcinoid tumors that are frequently multiple. The prognosis is favorable in most cases.

Vorläuferläsionen des Lungenkarzinoms

The World Health Organization (WHO) 2004 classification includes 3 categories of pulmonary preneoplastic lesions, including squamous dysplasia and carcinoma in situ (CIS) for squamous cell carcinoma, atypical adenomatous hyperplasia (AAH) for the majority of adenocarcinomas and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) for carcinoids. The distinction of the 3 grades of squamous dysplasia and CIS is mainly based on the degree by which the basal cell zone is expanded, the degree of cellular atypia and the level of mitoses. The category AAH consists of a proliferation of atypical epithelial cells with Clara cells or type 2 pneumocyte features. They grow along the alveolar septae in a lepidic fashion, sometimes reaching into the terminal bronchioles. In contrast to the newly described adenocarcinoma in situ (AIS), AAH is smaller (≤ 5 mm), has a lower cell density and a lower degree of cellular atypia. The putative cancer stem cells of peripheral adenocarcinomas reside in the bronchioloalveolar duct junction, while those of central squamous cell carcinomas are located in the basal cell compartment of the bronchi. This review provides an overview of the current knowledge on preneoplastic lesions of the lungs and their clinical impact.

Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)

To compare the morphology and antigenic profile of pulmonary neuroendocrine cells (PNECs) proliferating as a reaction to pulmonary injury with those proliferating in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in which carcinoids develop. The morphology and expression of a range of antigens including markers of epithelial differentiation [cytokeratins, thyroid transcription factor (TTF)-1], neuroendocrine antigens [neural cell adhesion molecule (NCAM), chromogranin, protein gene product (PGP) 9.5, neurone-specific enolase (NSE), synaptophysin], peptide products [gastrin-releasing peptide (GRP), calcitonin, calcitonin gene-related peptide (CGRP)] and inactivator [common acute lymphoblastic leukaemia antigen (CALLA)] and antigens involved in cell proliferation and death (p53, p16, p27, Rb, Bcl-2, c-kit, Ki67) were studied in four cases of reactive PNEC proliferation and seven cases of DIPNECH. Proliferation was more florid in DIPNECH. There was no major shift in antigen expression with proliferation in either group apart from CALLA, which was expressed only by proliferating cells and not by solitary PNECs. There were differences between the groups in expression of p53, p16 and Ki67, which were seen more consistently and earlier in proliferation in DIPNECH. These data suggest that there are early and fundamental differences in cell kinetics between the reactive PNEC proliferation that occurs in response to pulmonary injury and that seen in the pre-neoplastic condition of DIPNECH.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) in a 37-Year-Old Woman With Insidious Cough and Dyspnea

INTRODUCTION: DIPNECH is a rare pulmonary disease that has an insidious presentation that may lead to delayed diagnosis. We describe a case of DIPNECH in a young women with a two year history of cough and mild dyspnea.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: 7-year follow-up of a rare clinicopathologic syndrome

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare clinical pathological syndrome. There have been only 49 cases of DIPNECH reported in the literature so far. We report a case of a 69-year-old nonsmoking man with a 7-year follow-up. The initial CT scan from December 2003 showed persistent nonspecific bilateral reticulonodular infiltrates. In January 2004, the patient underwent a video-assisted thoracoscopic wedge resection of his right lower lobe for further diagnostic workup. Pathology of the resected wedge of the right lower lobe revealed a diffuse idiopathic pulmonary cell hyperplasia (DIPNECH) highlighted by staining for the neuroendocrine typical carcinoid markers, such as marker CD 56. All the performed CT scans over a 7-year period showed no progression of the bilateral pulmonary lesion. The bilateral pulmonary nodules were stable in terms of size, number and form. The yearly control with chest CT scans will be continued. The neuroendocrine cell hyperplasia is confined to the airway mucosa without penetration through the basement membrane and appears in a diffuse pattern, generally in close association with obliterative bronchiolar fibrosis. DIPNECH is characterized by a mixed obstructive and/or restrictive ventilation pattern with bilateral reticulonodular infiltrates and a predilection for middle-aged women. Little is known about the clinical course and treatment for DIPNECH.