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Ten Years of Chronic Cough in a 64-Year-Old Man With Multiple Pulmonary Nodules FREE TO VIEW

Whittney A. Warren, DO; Scott S. Dalane, MD; Bryce D. Warren, PhD; Paul G. Peterson, MD; Rodney D. Boyum, MD; William Kelly, MD
Author and Funding Information

aDepartment of Pulmonary and Critical Care, Walter Reed National Military Medical Center, Bethesda, MD

bDepartment of Radiology, Walter Reed National Military Medical Center, Bethesda, MD

cDepartment of Pathology, Walter Reed National Military Medical Center, Bethesda, MD

dUniformed Services University of the Health Sciences, Bethesda, MD

CORRESPONDENCE TO: Whittney A. Warren, DO, Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889


Copyright 2016, . All Rights Reserved.


Chest. 2016;150(3):e81-e85. doi:10.1016/j.chest.2016.03.040
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Published online

A 64-year-old male former smoker with a history of prostate cancer presented to our pulmonary clinic, complaining of nonproductive cough for 10 years. Prior evaluation included treatment for upper airway cough syndrome and gastroesophageal reflux, stopping angiotensin-converting enzyme inhibitor, and initiation of inhaled β-agonists. Esophageal pH monitoring indicated silent reflux, and proton pump inhibitor therapy was started. He continued to cough and complain of dyspnea. Physical examination produced unremarkable results, with no evidence of lymphadenopathy. Pulmonary function tests showed a pseudo-restrictive pattern with air trapping, hyperreactivity, and incomplete bronchodilator responsiveness: FEV1, 2.48 L (69% of predicted); FVC, 3.57 L (75% of predicted); FEV1/FVC, 92%; total lung capacity, 7.00 L (100% of predicted); and residual volume, 3.05 L (136% of predicted). Laboratory studies, including a complete metabolic panel, prostate-specific antigen test, and complete blood count, yielded normal results.

Figures in this Article

Ten years earlier, a 13-mm smooth lingular nodule was identified on chest CT scan that had been stable over the previous 2-year serial imaging, was not fluorodeoxyglucose-positron emission tomography (FDG-PET) avid, and was presumed benign. Present-day chest radiographs and CT imaging (10 years later) revealed growth of the nodule to 18 mm with a standardized uptake value (SUV) of 1.3 on FDG-PET. In addition, there were numerous bilateral 2- to 7-mm pulmonary nodules minimally increased in size from initial evaluation with diffuse mosaic attenuation. The remainder of the PET scan lacked evidence of malignancy. Bronchoscopy indicated no endobronchial lesions, and bronchoalveolar lavage showed monocyte predominance with negative cultures and cytology. Finally, age-appropriate cancer screening (colonoscopy) was done to eliminate extrapulmonary malignancy.

Left upper lobectomy and tumor immunostaining demonstrated positive expression of chromogranin and synaptophysin, but no expression of p63 and cytokeratin 5/6 (CK5/6). There was no evidence of lymph node metastasis, but there were foci of neuroendocrine cell hyperplasia, multiple parenchymal tumorlets, and inflammatory changes.

What is the diagnosis?

Diagnosis: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) associated with typical carcinoid tumor

Clinical Discussion

DIPNECH is a rare condition defined by the World Health Organization (WHO) as a carcinoid precursor absent in other neuroendocrine cancers. Most patients with symptoms have indolent, progressive shortness of breath, wheezing, and nonproductive cough for an average of 15 years prior to diagnosis; however, nearly one-half of patients are asymptomatic at the time of diagnosis., Paraneoplastic symptoms associated with ectopic hormone production are rare. Patients are usually misclassified as having difficult-to-control asthma or chronic obstructive pulmonary disease. On spirometry, one-half of the patients have obstructive ventilatory defects, while 13% have restrictive patterns and 17% show mixed abnormalities. The majority of patients are nonsmokers and a diagnosis of DIPNECH should be considered in the nonsmoker with multiple pulmonary nodules and evidence of obstructive airway disease. A history of smoking should not be used to exclude the diagnosis, as one-third of patients will have a history of tobacco use. Because of the nonspecific clinical presentation preoperative diagnosis is rare, but should be considered in the typical patient demographic: women aged 45 to 67 years, with cough, dyspnea, and wheezing. In this case the patient was male with a significant smoking history. Like many patients with this condition, his diagnosis was delayed as alternative explanations for his cough and shortness of breath were explored. On diagnosis of carcinoid tumor with multiple simultaneous carcinoid tumorlets in addition to several foci of neuroendocrine cell hyperplasia (Fig 1), DIPNECH as the etiology of his cough became clear. The typical clinical course is indolent, with 83% 5-year survival. Disease progression has been reported in the literature, although few treatments have been validated. Resection of the dominant tumor is advised, and there may be a role for somatostatin analogs for patients with progressive symptoms to achieve disease stabilization. Chemotherapy, steroids, and transplantation have been tried for symptomatic treatment with variable success.

Figure 1
Figure Jump LinkFigure 1 Histopathologic findings from left upper lobectomy (hematoxylin and eosin stain; original magnification, ×40), demonstrating 0.4-mm focus of neuroendocrine cell hyperplasia. Printed with written consent from the patient.Grahic Jump Location
Radiologic Discussion

Chest imaging often provides the first diagnostic clue in the diagnosis of DIPNECH and may be the only indication that the patient’s nonspecific respiratory symptoms are secondary to this rare condition. Initial chest radiographs are typically normal or reveal multiple pulmonary nodules prompting further evaluation by CT imaging. In this patient, the initial CT scan revealed a dominant lingular nodule (Fig 2A) as well as scattered smaller noncalcified nodules and diffuse mosaic attenuation (Fig 2B). Follow-up FDG-PET CT imaging revealed mild FDG avidity in the lingular nodule with a maximum SUV of 1.3 (Fig 2C). Following the left upper lobectomy for typical carcinoid in the lingula, the patient underwent serial CT examinations. The most recent examination revealed diffuse mosaic attenuation with scattered noncalcified nodules (Fig 2D), all of which were stable or minimally increased in size up to a maximum of 7 mm in the right middle lobe. The findings of diffuse mosaic attenuation and scattered noncalcified nodules in the appropriate clinical context suggest the diagnosis of DIPNECH. There are numerous etiologies for mosaic attenuation, but the broad category of small-airways disease accounts for one-third of cases. The remaining cases are caused by parenchymal lung disease or vascular pathology. This patient underwent only inspiratory imaging; however, expiratory imaging is useful in exploring the differential of mosaic attenuation. In obstructive small-airways disease, the darker areas of mosaic attenuation will remain hyperlucent on exhalation, consistent with air trapping. If all areas of mosaic attenuation become uniformly more dense on expiratory imaging it is suggestive of vascular or parenchymal disease. Normal size and distribution of blood vessels throughout the lungs suggests underlying parenchymal disease, with regions of higher attenuation being abnormal. In chronic pulmonary thromboembolic disease, low-attenuation regions are abnormal and the vessel diameter will be smaller. Scattered noncalcified nodules also have a broad differential, including granulomas, intraparenchymal lymph nodes, and metastases. In DIPNECH, parenchymal nodules correspond to nests of pulmonary neuroendocrine cell hyperplasia, which are classified as carcinoid tumors when measuring 5 mm or larger. A search for mediastinal lymphadenopathy is critical as metastatic spread has been reported in up to 27% of patients with carcinoid tumors. Other CT findings associated with DIPNECH include bronchial wall thickening and mild bronchiectasis.,,

Figure 2
Figure Jump LinkFigure 2 A, CT scan of the chest with contrast (10 years prior to presentation) revealing lingular nodule (arrow) and diffuse mosaic attenuation. Printed with written consent from the patient. B, CT scan of the chest with contrast (10 years prior to presentation) demonstrating other scattered nodules (arrow) and multiple areas of mosaic attenuation (asterisk). Printed with written consent from the patient. C, Positron emission tomography-CT axial fusion image of the chest (10 years prior to presentation) with a standardized uptake value of 1.3 for the lingular nodule. Printed with written consent from the patient. D, Most recent CT scan of the chest revealed diffuse mosaic attenuation with scattered noncalcified nodules (arrow). Printed with written consent from the patient.Grahic Jump Location

Octreotide scanning is a type of scintigraphy using a somatostatin analog chelated to indium-111 and has a greater sensitivity than PET for well-differentiated neuroendocrine tumors. The opposite is true for poorly differentiated neuroendocrine tumors. In well-differentiated neuroendocrine tumors low-level FDG avidity is expected because of low metabolic activity. It is important to note that there is no absolute SUV threshold for malignancy, and any level of uptake that is greater than the surrounding tissue is abnormal. This patient’s postoperative octreotide scan produced negative results despite persistent serum (chromogranin) and urine (5-hydroxyindoleacetic acid [5-HIAA]) biochemical evidence of tumorlets, likely because the micronodules were below the size threshold for detection of about 10 mm.,

Pathologic Discussion

Pulmonary neuroendocrine, or Kulchitsky-type, cells are sparse airway epithelial cells that release bioactive amines and the peptides serotonin, chromogranin A, gastrin-releasing peptide (GRP), and calcitonin. Neuroendocrine hyperplasia is a premalignant finding limited to the basement membrane or airway wall and occurs spontaneously or as a reactive process. Neuroendocrine cellular proliferations measuring < 5 mm are classified as carcinoid tumorlets. Carcinoid tumors are > 5 mm. Coexistence of all three often occurs in DIPNECH. DIPNECH is found in 5% of patients undergoing carcinoid resection. The gold standard for diagnosis is surgical biopsy, although the more recent literature suggests transbronchial biopsy may be adequate if sufficient tissue is obtained. The typical finding is diffuse hyperplasia of neuroendocrine cells with multiple carcinoid tumorlets and peribronchial fibrosis that focally obliterates airways (Figs 1, 3, 4). Interstitial fibrosis associated with DIPNECH is postulated to be secondary to the production of bombesin and GRP, which stimulate fibroblasts and, with elevated serotonin levels, enhance bronchoconstriction. The result is dyspnea, cough, and wheeze that should be distinguished from other etiologies of bronchoconstriction such as bronchial asthma, as bronchodilator therapy in patients with DIPNECH may have little benefit. These airway changes can be seen as obstructive disease on pulmonary function testing and can produce the mosaic pattern seen on high-resolution CT scanning. Neuroendocrine cell hyperplasia can be seen on hematoxylin and eosin staining, but is readily apparent via synaptophysin and chromogranin immunostaining (Fig 1). It consists of groups of polygonal cells with round uniform nuclei in the basal region of the bronchiolar epithelium. In this case, immunohistochemical stains of the carcinoid tumor demonstrated expression of chromogranin A and synaptophysin, but no expression of p63 and CK5/6 (Fig 5). These tumors can also show expression of GRP, calcitonin, and human chorionic gonadotropin (hCG)-α. Neuroendocrine tumors associated with DIPNECH are usually typical carcinoids, although there are several reported cases of atypical carcinoid associated with DIPNECH. In 2015 the WHO defined DIPNECH as a proliferation of pulmonary neuroendocrine cells that can be limited to bronchial mucosa, extend locally to form tumorlets, or develop into carcinoid tumors. The patient presented met these criteria. Pulmonary neuroendocrine cell hyperplasia not meeting these criteria can occur in a number of other conditions such as tobacco smoke inhalation, chronic high-altitude exposure, bronchiectasis, and interstitial fibrosis. The diagnosis of DIPNECH is considered to be a precursor to malignancy and the literature does describe patients receiving a diagnosis of DIPNECH before the diagnosis of a carcinoid tumor. However, the majority of patients receive simultaneous diagnoses of DIPNECH and carcinoid tumor.

Figure 3
Figure Jump LinkFigure 3 Histopathologic findings from left upper lobectomy (hematoxylin and eosin stain, original magnification, ×40) demonstrating typical carcinoid. Printed with written consent from the patient.Grahic Jump Location
Figure 4
Figure Jump LinkFigure 4 Histopathologic findings from left upper lobectomy (hematoxylin and eosin stain; original magnification, ×10) demonstrating a 2.3-mm carcinoid tumorlet. Printed with written consent from the patient.Grahic Jump Location
Figure 5
Figure Jump LinkFigure 5 Histopathologic findings from left upper lobectomy (chromogranin A immunohistochemical stain), consistent with carcinoid (original magnification, ×10). Printed with written consent from the patient.Grahic Jump Location

The patient was started on inhaled corticosteroids, long-acting β-agonist, and, as needed, short-acting β-agonist for treatment of the obstructive component of the pulmonary disease along with pulmonary rehabilitation. He has had some symptomatic improvement. Serum and urine carcinoid markers have minimally increased over 9 months without increase in symptoms, decrement in pulmonary function test results, or radiographic progression. Somatostatin analogs may be considered in the future if the patient shows evidence of clinical or radiographic decline.

Author contributions: W. A. W. drafted the manuscript, acquired the figures presented, approved of the final version to be published, has agreed to be accountable for all aspects of the work, and will ensure the accuracy and integrity of the work. S. S. D., B. D. W., R. D. B., P. G. P., and W. K. critically revised the manuscript, approved of the final version for publication, made substantial contributions to conception and design, or acquisition and interpretation of images, and have agreed to be accountable for all aspects of the work and will ensure the accuracy and integrity of the work.

Financial/nonfinancial disclosures: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Davies S.J. .Gosney J.R. .Hansell D.M. .et al Diffuse idio-pathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62:248-252 [PubMed]journal. [CrossRef] [PubMed]
 
Gorshtein A. .Gross D.J. .Barak D. .et al Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity. Cancer. 2012;118:612-619 [PubMed]journal. [CrossRef] [PubMed]
 
Nassar A.A. .Jaroszewski D.E. .Helmers R.A. .Colby T.V. .Patel B.M. .Mookadam F. . Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med. 2011;184:8-16 [PubMed]journal. [CrossRef] [PubMed]
 
Lee J.S. .Brown K.K. .Cool C. .Lynch D.A. . Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features. J Comput Assist Tomogr. 2002;26:180-184 [PubMed]journal. [CrossRef] [PubMed]
 
Carr L.L. .Chung J.H. .Achcar R.D. .et al The clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Chest. 2015;147:415-422 [PubMed]journal. [CrossRef] [PubMed]
 
Kligerman S.J. .Henry T. .Lin C.T. .Franks T.J. .Galvin J.R. . Mosaic attenuation: etiology, methods of differentiation and pitfalls. Radiographics. 2015;35:1360-1380 [PubMed]journal. [CrossRef] [PubMed]
 
Gosney J.R. .Travis W.D. . Diffuse idiopathic neuroendocrine cell hyperplasia.Travis W.D..Brambilla E..Muller-Hermelink H.K..Harris C.C.. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus, and Heart.  :76-77 [PubMed]journal
 
Chassagnon G. .Favelle O. .Marchand-Adam S. .De Muret A. .Revel M.P. . DIPNECH: when to suggest this diagnosis on CT. Clin Radiol. 2015;70:317-325 [PubMed]journal. [CrossRef] [PubMed]
 
Benson R.E.C. .Rosado-de-Christenson M.L. .Martinez-Jimenez S. .Kunin J.R. .Pettavel P.P. . Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 2013;33:1631-1649 [PubMed]journal. [CrossRef] [PubMed]
 
Koo C.W. .Baliff J.P. .Torigian D.A. .Litzky L.A. .Gefter W.B. .Akers S.R. . Spectrum of pulmonary neuroendocrine cell proliferation: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, tumorlet, and carcinoids. AJR Am J Roentgenol. 2010;195:661-668 [PubMed]journal. [CrossRef] [PubMed]
 
Foran P.J. .Hayes S.A. .Blair D.J. .Zakowski M.F. .Ginsberg M.S. . Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Clin Imaging. 2015;39:243-246 [PubMed]journal. [CrossRef] [PubMed]
 
Wang X.J. .Gong J.S. .Suzuki K. .Morcos S.K. . Evidence based imaging strategies for solitary pulmonary nodule. J Thorac Dis. 2014;6:872-887 [PubMed]journal. [PubMed]
 
Squires M.H. .Volkan Adsay N. .Schuster D.M. .et al Octreoscan versus FDG-PET for neuroendocrine tumor staging: a biological approach. Ann Surg Oncol. 2015;22:2295-2301 [PubMed]journal. [CrossRef] [PubMed]
 
Caplin M.E. .Baudin E. .Ferolla P. .et al Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604-1620 [PubMed]journal. [CrossRef] [PubMed]
 
Marchevsky A.M. .Wirtschafter E. .Walts A.E. . The spectrum of changes in adults with multifocal pulmonary neuroendocrine proliferations: what is the minimum set of pathologic criteria to diagnose DIPNECH? Hum Pathol. 2015;46:176-181 [PubMed]journal. [CrossRef] [PubMed]
 
Oba H. .Nishida K. .Takeuchi S. .et al 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-α. Endocr Pathol. 2013;24:220-228 [PubMed]journal. [CrossRef] [PubMed]
 
Travis W.D. .Brambilla E. .Burke A.P. .Marx A. .Nicholson A.G. . World Health Organization Classification of Tumours of the Lung, Pleura, Thymus and Heart.  2015;:78-79 [PubMed] IARC Press Lyon, Francejournal
 
Marchevsky A.M. .Walts A.E. . Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Semin Diagn Pathol. 2015;32:438-444 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Histopathologic findings from left upper lobectomy (hematoxylin and eosin stain; original magnification, ×40), demonstrating 0.4-mm focus of neuroendocrine cell hyperplasia. Printed with written consent from the patient.Grahic Jump Location
Figure Jump LinkFigure 2 A, CT scan of the chest with contrast (10 years prior to presentation) revealing lingular nodule (arrow) and diffuse mosaic attenuation. Printed with written consent from the patient. B, CT scan of the chest with contrast (10 years prior to presentation) demonstrating other scattered nodules (arrow) and multiple areas of mosaic attenuation (asterisk). Printed with written consent from the patient. C, Positron emission tomography-CT axial fusion image of the chest (10 years prior to presentation) with a standardized uptake value of 1.3 for the lingular nodule. Printed with written consent from the patient. D, Most recent CT scan of the chest revealed diffuse mosaic attenuation with scattered noncalcified nodules (arrow). Printed with written consent from the patient.Grahic Jump Location
Figure Jump LinkFigure 3 Histopathologic findings from left upper lobectomy (hematoxylin and eosin stain, original magnification, ×40) demonstrating typical carcinoid. Printed with written consent from the patient.Grahic Jump Location
Figure Jump LinkFigure 4 Histopathologic findings from left upper lobectomy (hematoxylin and eosin stain; original magnification, ×10) demonstrating a 2.3-mm carcinoid tumorlet. Printed with written consent from the patient.Grahic Jump Location
Figure Jump LinkFigure 5 Histopathologic findings from left upper lobectomy (chromogranin A immunohistochemical stain), consistent with carcinoid (original magnification, ×10). Printed with written consent from the patient.Grahic Jump Location

Tables

References

Davies S.J. .Gosney J.R. .Hansell D.M. .et al Diffuse idio-pathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62:248-252 [PubMed]journal. [CrossRef] [PubMed]
 
Gorshtein A. .Gross D.J. .Barak D. .et al Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity. Cancer. 2012;118:612-619 [PubMed]journal. [CrossRef] [PubMed]
 
Nassar A.A. .Jaroszewski D.E. .Helmers R.A. .Colby T.V. .Patel B.M. .Mookadam F. . Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med. 2011;184:8-16 [PubMed]journal. [CrossRef] [PubMed]
 
Lee J.S. .Brown K.K. .Cool C. .Lynch D.A. . Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features. J Comput Assist Tomogr. 2002;26:180-184 [PubMed]journal. [CrossRef] [PubMed]
 
Carr L.L. .Chung J.H. .Achcar R.D. .et al The clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Chest. 2015;147:415-422 [PubMed]journal. [CrossRef] [PubMed]
 
Kligerman S.J. .Henry T. .Lin C.T. .Franks T.J. .Galvin J.R. . Mosaic attenuation: etiology, methods of differentiation and pitfalls. Radiographics. 2015;35:1360-1380 [PubMed]journal. [CrossRef] [PubMed]
 
Gosney J.R. .Travis W.D. . Diffuse idiopathic neuroendocrine cell hyperplasia.Travis W.D..Brambilla E..Muller-Hermelink H.K..Harris C.C.. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus, and Heart.  :76-77 [PubMed]journal
 
Chassagnon G. .Favelle O. .Marchand-Adam S. .De Muret A. .Revel M.P. . DIPNECH: when to suggest this diagnosis on CT. Clin Radiol. 2015;70:317-325 [PubMed]journal. [CrossRef] [PubMed]
 
Benson R.E.C. .Rosado-de-Christenson M.L. .Martinez-Jimenez S. .Kunin J.R. .Pettavel P.P. . Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 2013;33:1631-1649 [PubMed]journal. [CrossRef] [PubMed]
 
Koo C.W. .Baliff J.P. .Torigian D.A. .Litzky L.A. .Gefter W.B. .Akers S.R. . Spectrum of pulmonary neuroendocrine cell proliferation: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, tumorlet, and carcinoids. AJR Am J Roentgenol. 2010;195:661-668 [PubMed]journal. [CrossRef] [PubMed]
 
Foran P.J. .Hayes S.A. .Blair D.J. .Zakowski M.F. .Ginsberg M.S. . Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Clin Imaging. 2015;39:243-246 [PubMed]journal. [CrossRef] [PubMed]
 
Wang X.J. .Gong J.S. .Suzuki K. .Morcos S.K. . Evidence based imaging strategies for solitary pulmonary nodule. J Thorac Dis. 2014;6:872-887 [PubMed]journal. [PubMed]
 
Squires M.H. .Volkan Adsay N. .Schuster D.M. .et al Octreoscan versus FDG-PET for neuroendocrine tumor staging: a biological approach. Ann Surg Oncol. 2015;22:2295-2301 [PubMed]journal. [CrossRef] [PubMed]
 
Caplin M.E. .Baudin E. .Ferolla P. .et al Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604-1620 [PubMed]journal. [CrossRef] [PubMed]
 
Marchevsky A.M. .Wirtschafter E. .Walts A.E. . The spectrum of changes in adults with multifocal pulmonary neuroendocrine proliferations: what is the minimum set of pathologic criteria to diagnose DIPNECH? Hum Pathol. 2015;46:176-181 [PubMed]journal. [CrossRef] [PubMed]
 
Oba H. .Nishida K. .Takeuchi S. .et al 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-α. Endocr Pathol. 2013;24:220-228 [PubMed]journal. [CrossRef] [PubMed]
 
Travis W.D. .Brambilla E. .Burke A.P. .Marx A. .Nicholson A.G. . World Health Organization Classification of Tumours of the Lung, Pleura, Thymus and Heart.  2015;:78-79 [PubMed] IARC Press Lyon, Francejournal
 
Marchevsky A.M. .Walts A.E. . Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Semin Diagn Pathol. 2015;32:438-444 [PubMed]journal. [CrossRef] [PubMed]
 
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