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DIPNECH--a preneoplastic lesion or a separate biological entity?


Among all pulmonary neoplastic lesions in adults, DIPNECH, or diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, remains extremely rare with less than 100 cases reported worldwide [1]. Although it has been postulated to create an international data center to gather information about newly diagnosed cases, as for December 2013, the initiative was not accomplished and the need for establishing such a database remains at high importance. There is strong evidence that DIPNECH leads to carcinogenesis in case of pulmonary carcinoid tumors, so suggestions were made to alter the classification of pulmonary neuroendocrine tumors by dividing them in two groups, one consisting of typical and atypical carcinoids as low-grade malignancies of the lung originating from DIPNECH and the other, containing the high-grade malignant neoplasms, like the small-cell carcinoma and the large-cell neuroendocrine carcinoma of the lung [2-5]. However, some case reports show a picture of DIPNECH as a separate disease and in those particular cases, even in follow-up, there is no sign for further cancer development on its basis. The disease itself may cause death by pulmonary failure [6]. In this article the reader will find an overview of case reports and general reference papers considering DIPNECH based on electronic search. The search was conducted using standard on-line browsing engines through the libraries of National Center for Biotechnology Information, National Library of Medicine and National Institutes of Health, Bethesda, MD, USA. The keywords used to perform the search were DIPNECH and diffuse idiopathic neuroendocrine cell hyperplasia. All the records regarding NEHI or neuroendocrine hyperplasia of infants were intentionally omitted as NEHI is an interstitial lung disease and has not been classified as a preneoplastic lesion. 1. The WHO classification

According to WHO classification of lung tumors, DIPNECH is a separate lesion regarded to as a preneoplastic condition for tumorlets, and typical/atypical carcinoids, but only those located peripherally [1]. In the revised edition of this classification dating 2001, the atypical adenomatous hyperplasia or AAH was also mentioned as a separate entity, developing into adenocarcinoma of the lung [1]. These two conditions are since described as the only proven-to-be preneoplastic changes in the lung. In some cases, proliferating pulmonary neuroendocrine cells develop into tumorlets- small changes in the respiratory epithelium less than 5mm in diameter, sharing histological features with carcinoids. However, carcinogenesis of pulmonary neoplasms, including neuroendocrine tumors, remains a subject to discuss due to unknown origins of cancer cell lines [3, 5, 7].

2. The pulmonary neuroendocrine cells

DIPNECH originates in an uncontrolled linear growth of pulmonary neuroendocrine (NE) cells. These cells are very similar to those existing in gastrointestinal tract when observed in light microscopy, first described by Kultschitzky [5], so they are also known as pulmonary Kultschitzky-like cells, Feyrter cells, or enterochromoffin cells. Pulmonary NE cells create part of the APUD system and pulmonary neuroendocrine system, playing a major role in the development of lung tissue in embryos and behaving as chemoreceptors in post-embryonic life [3, 4, 6]. Although their morphology resembles neuronic cells, the pulmonary NE cells develop undoubtedly from endodermic precursors [5]. These cells are the first to differentiate in the epithelium at the earliest stages of lung development, controlling further growth and organization of pulmonary tissue. In fully formed human lung, most NE cells exist solitarily in the ciliated epithelium or can be found in groups, known as pulmonary neuroendocrine bodies (NEBs). When fully formed, these cells secrete serotonin in response to low oxygen concentrations based on particle pressure detected by chemoreceptors on the luminal part of their cell membrane. Serotonin or 5-HT (5-hydroxytriptamin) acts on vascular endothelium causing vasoconstriction [5, 8]. Thanks to this mechanism, bloodstream is being redirected from less airy areas of the lung to those with higher oxygen concentration, providing more effective gas exchange. There are suggestions, that pulmonary NE cells may also control processes of regeneration after lung injury [4].

3. Clinical symptoms and radiologic findings

Although typical clinical features of a patient diagnosed with DIPNECH are the age between 60 and 70 years, female, it may also occur in much younger individuals of both genders [9]. The patients are mostly asymptomatic and in such a case, the finding is incidental. Some of them develop symptoms, such as unproductive cough and episodes of dyspnea, so DIPNECH is often mistaken for asthma bronchiale [10]. The majority of those patients have never smoked a cigarette in their entire life. When it comes to radiologic diagnostics, the findings are sometimes very similar to metastases with an unknown primary tumor [11]. In high resolution computed tomography (HR CT) scans, the image shows multiple micronodules, often with associated mosaic attenuation and ground-glass pattern with evidence for centrilobular distribution, air tapping and constrictive bronchiolitis [4]. Some sources describe linear proliferations of pulmonary NE cells with tumorlets, visible in the peripheral parts of the lung on high resolution CT scans [9, 12, 13].

4. Morphology and immunohistochemistry

Although clearly visible in radiographic examinations, DIPNECH is diagnosed by the 'golden standard' of tissue biopsy, examined in light microscopy with immunohistochemical staining [8]. The markers of neuroendocrinity in pulmonary NE cells, used specifically in our laboratory practice, are CD56 or NCAM, synaptophysin and chromogranin A.

5. Antigen profiling

Above other functions of pulmonary NE cells, some investigators distinguish their role in the process of lung tissue regeneration after injury. It has not yet been specified, what kind of injury may cause a diffuse and uncontrolled growth of NE cells. A mechanism has been described, in which primary linear proliferation is followed by aggregation of NE cells and the creation of tumorlet lesions, which seems to be the closest to further carcinogenesis [5, 8, 14]. Despite that, there is no evidence for malignant transformation in a pulmonary NE hyperplasia as a response to tissue damage [5,8].

In the matter of antigen profiling, a huge research was carried out and reported by Gosney et al. [8]. The workgroup divided antigen staining into four groups. First group included epithelial differentiation factors, such as cytokeratins of classes 7 (CK7), 20 (CK20) and 34bE12, and thyroid transcription factor (TTF)-1. The second group contained markers of neuroendocrine differentiation, that is (NCAM; CD56), chromogranin A (ChrA), protein gene product (PGP) 9.5, neurone-specific enolase (NSE) and synaptophysin (syn). The following two groups of antigens included markers for major peptide products of pulmonary NE cells, such as gastrin-releasing peptide (GRP), calcitonin, calcitonin gene related peptide (CGRP) and number of proteins involved in cell proliferation and the process of apoptosis [8, 15].

The results of this research showed, that there is virtually no difference in antigen profiles for proliferating pulmonary NE cells, either the growth is ongoing as a reaction to postulated injury or is it described as idiopathic [7, 16-18]. A point of malignant transformation was not yet discovered.


There is much controversy in attempts to finding a universal precursor cell, or a mechanism that leads to the development of lung cancer [4, 6, 8, 19-22]. Pulmonary neuroendocrine tumors seem to be a topic to discuss in the first place as possibly presenting the strongest evidence for earliest stages of carcinogenesis [5, 8]. Despite this fact, subtle molecular and genetic changes in the development of pulmonary neoplasms remain beyond reach, so as are triggers causing them to occur. When DIPNECH is taken into consideration as a separate lesion, it seems that a specific group of pulmonary malignancies is not combined with cigarette smoke or environmental pollution [23-25]. There is a strong need for the creation of a database, working similar to an internet portal, in first place gathering data about DIPNECH, such as case reports and analysis. It will also give the ability to contact other researchers and exchange scientific information by traditional resources. Major points of interest here are to improve the diagnostic ratio for this condition and to allow scholars and scientists to work on this problem and additionally find clues for other carcinogenic mechanisms in the lung.

Conflict of interests

The authors of this paper declare no competing interests in the publication of this manuscript.


[1.] Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, Sheppard MN, Nicholson AG. Diffuse idiopathic pulmonary neuroendocrine cell hyper-plasia: an under-recognised spectrum of disease. Thorax 2007 Mar; 62(3): 248-52.

[2.] Brambilla E, Travis WD, Colby TV, Corrinz B, Shimosato Y. The new World Health Organisation classification of lung tumours. Eur Respir J 2001 Dec; 18(6): 1059-68.

[3.] Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol 2010 Oct; 21 (Supplement 7): vii65-vii71, doi: 10.1093/annonc/mdq380

[4.] Benson REC, Rosado-de-Christenson ML, Martinez-Jimenez S, Kunin JR, Pettavel PP. Spectrum of Pulmonary Neuroendocrine Proliferations and Neoplasms. RadioGraphics 2013 Oct.; 33(6): 1631-49.

[5.] Swarts DRA, Ramaekers FCS, Speel E-JM. Molecular and cellular biology of neuroendocrine lung tumors: Evidence for separate biological entities. Bioch Biophys Acta. 2012 Dec; 1826(2): 255-71.

[6.] Coletta ENAM, Voss LR, Lima MS, Arakaki JSO, Camara J, D'Andretta Neto C, de Castro Pereira CA. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia accompanied by airflow obstruction. J Bras Pneumol. 2009 May; 35(5): 489-94.

[7.] Rizvi SMH, Goodwill J, Lim E, Yap YK, Wells AU, Hansell DM, Davis P, Abdel-Ghani S, Goldstraw P, Nicholson AG. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and nonneuroendocrine cell carcinomas. Histopathology. 2009 Sep; 55(3): 332-37.

[8.] Gosney JR, Williams IJ, Dodson AR, Foster CS. Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathology. 2011 Oct; 59(4): 751-62.

[9.] Warth A, Herpel E, Schmahl A, Storz K, Schnabel PA. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in association with an adenocarcinoma: a case report. J Med Case Rep. 2008 Jan; 25(2):21.

[10.] Stenzinger A, Weichert W, Henselb M, Brunsc H, Dietela M, Erbersdobler A. Incidental postmortem diagnosis of DIPNECH in a patient with previously unexplained 'asthma bronchiale'. Pathol Res and Pract 2010 Nov; 206(11): 785-7.

[11.] Lee JS, Brown KK, Cool C, Lynch DA. Diffuse Pulmonary Neuroendocrine Cell Hyperplasia: Radiologic and Clinical Features. J Comp Assist Tomogr 2002 Mar-Apr.; 26(2): 180-4.

[12.] Kalari S, Jung M, Kernstine KH, Takahashi T, Pfeifer GP. The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells. Oncogene 2013 Jul; 32(30): 3559-68.

[13.] Anevlavis S, Cancellieri A, Livi V, Patelli M, Trisolini R. A 66-Year-Old Woman With Dry Cough and Exertional Dyspnea. CHEST 2012 Sep; 142(3): 802-5.

[14.] Ge Y, Eltorky MA, Ernst RD, Castro CY. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Ann Diagn Pathol 2007 Apr; 1192): 122-6.

[15.] Falkenstern-Ge RF, Kimmich M, Friedel G, Tannapfel A, Neumann V, Kohlhaeu M. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: 7-year follow-up of a rare clinicopathologic syndrome. J Canc Res Clin Oncol 2011 Oct.; 137(10): 1495-8.

[16.] Ruffini E, Bongiovanni M, Cavallo A, Filosso PL, Giobbe R, Mancuso M, Molinatti M, Oliaro A. The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothoracic Surg 2004 Jul; 26(1): 165-72.

[17.] Kerr KM. Pulmonary preinvasive neoplasia. J Clin Path. 2001 Apr; 54(4): 257-71.

[18.] Walker CM, Vummidi D, Benditt JO, Godwin JD, Pipavath S. What is DIPNECH? Clin Imaging 2012 Sep-Oct; 36(5): 647-9.

[19.] Tippett VM, Wathen CG. Diffuse idiopathic neuroendocrine cell hyperplasia: an unusual cause of breathlessness and pulmonary nodules. BMJ Case Rep. 2010 Dec; 2.

[20.] Adams H, Brack T, Kestenholz P, Vogt P, Steinert HC, Russi EW. Diffuse Idiopathic Neuroendocrine Cell Hyperplasia Causing Severe Airway Obstruction in a Patient with a Carcinoid Tumor. Respiration. 2006; 73(5): 690-3.

[21.] Montoro Zulueta FJ, Martinez Prieto M, Verdugo Cartas MI, Esteban Rodriguez I, Hernandez Muniz S. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyper-plasia With Multiple Synchronous Carcinoid Tumors. Arch Bronconeumol. 2012 Dec; 48(12): 472-5.

[22.] Dvorackova J, Macak J, Buzrla P. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: Case report and review of literature. Cesk slov Patol. 2013 Apr; 49(2): 99-102.

[23.] Fisseler-Eckhoff A, Demes M. Review of Neuroendocrine Tumors of the Lung. Cancers. 2012; 4: 777-98.

[24.] Rekhtman N. Neuroendocrine Tumors of the Lung. An Update. Arch Pathol Lab Med. 2010 Nov; 134(11): 1628-38.

[25.] Gottschling S, Jensen K, Herth JF, Thomas M, Schnabel PA, Herpel E. Lack of Prognostic Significance of Neuroendocrine Differentiation and Stem Cell Antigen Co-Expression in Resected Early-stage Non-small Cell Lung Cancer. Anticancer Res. 2013 Mar; 33(3): 981-90.

Dawidziuk T. *, Sawicka E, Chyczewski L.

The Department of Medical Pathomorphology, Medical University of Bialystok, Poland

* Corresponding author

Department of Medical Pathomorphology Medical University of Bialystok 13 J. Waszyngtona street, 15-269 Bialystok, Poland e-mail:

Received: 28.11.2013

Accepted: 9.12.2013
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Title Annotation:diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Author:Dawidziuk, T.; Sawicka, E.; Chyczewski, L.
Publication:Progress in Health Sciences
Article Type:Report
Date:Dec 1, 2013
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