Proliferation Of Neuroendocrine Cells Research Articles

Notch1 and Notch3 signaling interplay regulates pancreatic neuroendocrine cell proliferation

Notch1 and Notch3 signaling interplay regulates pancreatic neuroendocrine cell proliferation

Congenital Pulmonary Airway Malformation Type 1 with Pulmonary Neuroendocrine Cell Hyperplasia in an Adult Male: a Rare Case Report

Abstract Introduction/Objective Congenital pulmonary airway malformations (CPAM) is rare, usually diagnosed in the pediatric population, and may occur in adults. Pulmonary neuroendocrine cell hyperplasia (PNECH) mimicking diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) associated with CPAM has not been described previously. We report a case of CPAM Type 1 with PNECH. Methods/Case Report A 33-year-old male, with past medical history of latent tuberculosis (TB) by Quantiferon blood testing, recurrent pneumonia, recurrent lung abscesses, and lung cavitary lesion for three years, presented with fever, cough with hemoptysis, shortness of breath, and left-sided chest pain. Computerized tomography of chest displayed a 10.8 cm cavitary lesion in the left lower lobe of the lung. The patient underwent left lower lobectomy of the lung. Grossly, the lobectomy specimen revealed a 10.5 cm irregular cavity communicating to the superior segmental bronchus of the left lower lobe. Microscopically, the dominant large cyst was surrounded by lung parenchyma and small cystically dilated spaces resembling bronchioles under the fibrotic pleura. The large cyst was lined by respiratory epithelium with rare pathognomonic mucous cells in clusters. Cyst walls contained smooth muscle, small islands of cartilage, and focal intense acute and chronic inflammatory cell infiltrates with hemorrhage. There were multiple foci of proliferation of pulmonary neuroendocrine cells centered around bronchioles surrounding the large cyst. The neuroendocrine cells were arranged from individual cells and cellular aggregates to larger tumorlets, highlighted by Synaptophysin and Chromogranin immunostains. No granuloma or necrosis was present. No acid-fast bacilli or fungal microorganisms were identified by special stains. The findings are consistent with CPAM type 1, with PNECH. Results (if a Case Study enter NA) NA Conclusion Our study demonstrates a histologically diagnosed adult congenital pulmonary airway malformations type 1 with an incidental pulmonary neuroendocrine cell hyperplasia, which mimics diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. To the best of our knowledge, this is the first report of such an association.

Beyond the Obvious: Spectrum of Neuroendocrine Proliferation and Tumors in the Biliary Tree - A Case Series

Abstract Introduction/Objective Neuroendocrine tumors (NETs) in the biliary system are extremely uncommon and often pose a diagnostic challenge due to their non-specific presentation and radiological features. While typically NETs form mass lesions causing biliary obstruction, to the best of our knowledge, microscopic neuroendocrine cell proliferation without mass formation has not been formally reported in the literature. This study aims to describe the clinicopathological features of a series of NETs/neuroendocrine cell proliferation involving the biliary tree. Methods/Case Report Surgical resections of NETs/neuroendocrine cell proliferation affecting the extrahepatic bile ducts and gallbladder were identified from the electronic pathology databases of five institutions between January 2010 and May 2023. The clinical data was obtained through chart review, and histologic findings were reviewed by a gastrointestinal pathologist at each institution. Results (if a Case Study enter NA) The study involved six patients with a mean age of 66 years (range: 58-75 years, males:3, females:3). The patients presented with abdominal pain or biliary obstruction. Pathologic examination revealed that three cases showed visible mass-forming lesions (1.6-2.4 cm) in the gallbladder or common bile duct, diagnosed as well-differentiated NETs. The remaining three cases had no grossly visible masses but showed incidental microscopic neuroendocrine cell proliferation/NETs (either in cystic duct or common bile duct) ranging from 0.2-0.4 cm, all associated with biliary lithiasis. All patients recovered after surgical resection without metastasis or recurrence, except for one patient who died a month after surgery due to an unrelated cause (multisystem organ failure). Conclusion This study highlights the spectrum of neuroendocrine proliferation in the biliary tree, ranging from microscopic incidental findings to grossly visible mass-forming NETs, which may result in variable clinical management and outcomes. Notably, incidental neuroendocrine proliferations were found to be associated with biliary lithiasis in all 3 cases, raising a possibility of a potential neuroendocrine metaplastic pathogenesis, which should be explored more via additional studies.

Radiological–pathological correlation in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): imaging and histopathology

To review histologically confirmed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) cases and carry out a detailed pathological-radiological correlation to see if computed tomography (CT) can be used to confidently identify DIPNECH. Twenty-three histologically confirmed DIPNECH patients in the shared database of two NHS Trusts were reviewed. CT images were reviewed by two independent radiologists, each of them with >10 years of experience in thoracic imaging. All histological specimens were reviewed by a single pathologist with >25 years of experience. The diagnosis of DIPNECH was made according to the current World Health Organization (WHO) definition included in the WHO 2015 classification of pulmonary tumours. The results on histology were compared to the presence of nodules and air trapping on CT. Demographic information and, when available, molecular imaging studies and pulmonary function tests were also considered. There are prototypal clinical and radiological findings reflecting the presence of underlying histological DIPNECH: middle-aged women with multiple small and scattered nodules due to the clustering and proliferation of neuroendocrine cells. At least one larger, dominant, lung nodule reflecting a carcinoid tumour is very common and mosaic attenuation/air trapping is seen approximately in 50% of cases in inspiratory scans. Airflow obstruction is rarely associated with histological bronchial or peribronchial fibrosis, which suggests other mechanisms must be involved in its development. CT can be used to predict pathological DIPNECH in the appropriate clinical setting. It is important to consider DIPNECH to avoid overdiagnosis of more sinister conditions such as lung cancer or metastases.

DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition.

DIPNECH is an increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course, and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mTOR inhibitors are most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms "diffuse" and "idiopathic". We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Pulmonary Carcinoid Tumorlet in the Explanted Lungs for Lung Transplantation: A Case Series of 15 Patients

Pulmonary carcinoid tumorlet (PCT) is defined as small proliferation of neuroendocrine cells that invade the adjacent basement membrane. It is often associated with chronic pulmonary inflammatory processes. However, the characteristics of PCT in end-stage lung diseases remain unclear. We conducted a retrospective cohort study of the explanted lungs after transplantation at our institution between January 1999 and October 2020. Patients who underwent re-transplantation were excluded. Pulmonary carcinoid tumorlet was incidentally discovered in the explanted lungs from 15 patients (1.1%) out of 1367 lung transplants performed during the study period. Nine patients (60.0 %) were women, with a median age of 59 years (IQR: 57-62) at transplant. Underlying pulmonary indications for lung transplantation were chronic obstructive pulmonary disease (9/15, 60.0%), interstitial lung disease (2/15, 13.0%), pulmonary vascular disease (2/15, 13.0%), alpha-1 antitrypsin deficiency (1/15, 7.0%), and bronchiectasis (1/15, 7.0%). Of the patients who underwent bilateral lung transplantation (13/15, 86.7%), PCT was found in the right lung in 10 patients (10/13, 76.9%). Thirteen patients had one lesion, 1 patient had 2 lesions and 1 patient had multiple lesions. Our study shows that PCT is generally uncommon, but when it occurs, it occurs more frequently on the right side and in female patients with end-stage pulmonary disease. Chronic obstructive pulmonary disease may be a predisposing factor for developing PCT.

Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling.

GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synthetic somatostatin (SST) analogs (SSAs), such as octreotide (OCT) or lanreotide (LAN). However, even cells expressing low levels of SST receptors (SSTRs) may exhibit significant responses to OCT, which suggests the possibility that SSAs signal through alternative mechanisms, e.g., transforming growth factor (TGF)-β. This signaling mode has been demonstrated in the established panNET line BON but not yet in other permanent (i.e., QGP) or primary (i.e., NT-3) panNET-derived cells. Here, we performed qPCR, immunoblot analyses, and cell counting assays to assess the effects of SST, OCT, LAN, and TGF-β1 on neuroendocrine marker expression and cell proliferation in NT-3, QGP, and BON cells. SST and SSAs were found to regulate a set of neuroendocrine genes in all three cell lines, with the effects of SST, mainly LAN, often differing from those of OCT. However, unlike NT-3 cells, BON cells failed to respond to OCT with growth arrest but paradoxically exhibited a growth-stimulatory effect after treatment with LAN. As previously shown for BON, NT-3 cells responded to TGF-β1 treatment with induction of expression of SST and SSTR2/5. Of note, the ability of NT-3 cells to respond to TGF-β1 with upregulation of the established TGF-β target gene SERPINE1 depended on cellular adherence to a collagen-coated matrix. Moreover, when applied to NT-3 cells for an extended period, i.e., 14 days, TGF-β1 induced growth suppression as shown earlier for BON cells. Finally, next-generation sequencing-based identification of microRNAs (miRNAs) in BON and NT-3 revealed that SST and OCT impact positively or negatively on the regulation of specific miRNAs. Our results suggest that primary panNET cells, such as NT-3, respond similarly as BON cells to SST, SSA, and TGF-β treatment and thus provide circumstantial evidence that crosstalk of SST and TGF-β signaling is not confined to BON cells but is a general feature of panNETs.

Quantitative Airway Assessment of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) on CT as a Novel Biomarker.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) occurs due to abnormal proliferation of pulmonary neuroendocrine cells. We hypothesized that performing a quantitative analysis of airway features on chest CT may reveal differences to matched controls, which could ultimately help provide an imaging biomarker. A retrospective quantitative analysis of chest CTs in patients with DIPNECH and age matched controls was carried out using semi-automated post-processing software. Paired segmental airway and artery diameters were measured for each bronchopulmonary segment, and the airway:artery (AA) ratio, airway wall thickness:artery ratio (AWTA ratio) and wall area percentage (WAP) calculated. Nodule number, size, shape and location was recorded. Correlation between CT measurements and pulmonary function testing was performed. 16 DIPNECH and 16 control subjects were analysed (all female, mean age 61.7 +/- 11.8 years), a combined total of 425 bronchopulmonary segments. The mean AwtA ratio, AA ratio and WAP for the DIPNECH group was 0.57, 1.18 and 68.8%, respectively, compared with 0.38, 1.03 and 58.3% in controls (p < 0.001, <0.001, 0.03, respectively). DIPNECH patients had more nodules than controls (22.4 +/- 32.6 vs. 3.6 +/- 3.6, p = 0.03). AA ratio correlated with FVC (R2 = 0.47, p = 0.02). A multivariable model incorporating nodule number, AA ratio and AWTA-ratio demonstrated good performance for discriminating DIPNECH and controls (AUC 0.971; 95% CI: 0.925-1.0). Quantitative CT airway analysis in patients with DIPNECH demonstrates increased airway wall thickness and airway:artery ratio compared to controls. Quantitative CT measurement of airway wall thickening offers a potential imaging biomarker for treatment response.

Necrolytic migratory erythema as a cutaneous manifestation of a pancreatic neuroendocrine tumor.

Glucagonoma syndrome is a rare entity defined by the existence of necrolytic migratory erythema (NME), elevated serum glucagon levels, and an underlying alpha-cell secreting tumor of the pancreas [ [1] John A.M. Schwartz R.A. Glucagonoma syndrome: a review and update on treatment. J Eur Acad Dermatology Venereol. 2016; 30: 2016-2022 Crossref PubMed Scopus (42) Google Scholar ]. We present the case of a female with clinical manifestations of this syndrome. In this paper, we describe the case of a 38-year-old woman referred to the dermatology department to investigate pruritic lesions located on the lower extremity, with subsequent extension to the axillae, groin, and intergluteal region, and pubis (Fig. 1). After several attempts, a skin biopsy specimen revealed histopathologic features suggestive of NME. Further evaluations revealed the presence of 8 centimeters nonmetastatic glucagonoma, located at the tail of the pancreas. 68Ga-DOTA TOC and an 18F-FDG PET identified a mild uptake of the lesion (Fig. 1). The glucagon level was >500 pg/mL. The patient was diagnosed with glucagonoma syndrome, and a caudal pancreatectomy was subsequently performed. Microscopy and the immunohistochemical study were consistent with a glucagonoma (Fig. 2). After surgery, the cutaneous manifestation was resolved, with normalization of glucagon levels. This uncommon case report adds information about an infrequent neuroendocrine tumor with cutaneous expression. Early recognition and diagnosis must support by radiological and nuclear medicine imaging tests [ [2] Jensen R.T. Cadiot G. Brandi M.L. et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012; 95: 98 Crossref PubMed Scopus (371) Google Scholar ]. Surgery is the initial treatment of choice. Fig. 2Skin biopsy revealing irregular acanthosis of the epidermis with loss of the stratum granulosum and edema of the superficial portion of the epidermis (A). Hematic extravasation and presence of abundant focal polynuclear cells alternating with areas of parakeratosis (B). Histological study reveals a nodular tumor of 8 × 4.5 × 3.5 cm, located in the tail of the pancreas with an intact capsular surface surrounded by adipose tissue (C). In the sections performed, a proliferation of neuroendocrine cells is identified, growing in an anastomosing, gyriform, pseudorosette trabecular pattern (D). Cells with ample eosinophilic cytoplasm and enlarged nuclei with central macronucleolus. Two mitoses are identified in 42 high magnification fields corresponding to less than one mitosis per 2 mm2 (E). Cells show intense positivity for chromogranin (F) and glucagon (G). View Large Image Figure Viewer Download Hi-res image

Metastatic multiple gastric neuroendocrine tumors with a long history of proton pump inhibitor use: A case report

It is widely accepted that gastric neuroendocrine tumors (NETs) develop due to enterochromaffin-like (ECL) cell proliferation following exposure to hypergastrinemia, which causes hyperplastic-dysplastic-neoplastic changes. Here we describe the case of a 46-year-old female patient diagnosed with metastatic NETs by liver biopsy and evaluated at an external center. At our hospital, nodular structures extending from the cardia to the antrum were observed by gastroscopy, considered the primary tumor focus. Histopathological examination revealed a trabecular-insular pattern, with microNETs consisting of monotone cells with round-oval nuclei and surrounding neuroendocrine cell hyperplasia foci and fundic gland polyps. The patient had a history of regular proton pump inhibitor (PPI) use for 10 years and a serum gastrin of 9240 pg/mL. A 3-cm metastatic lesion in the left lobe of the liver was observed in whole-body imaging with octreotide. By gastrectomy, we observed a large number of nodular lesions in the corpus-antrum and a 3-cm diameter lesion in the hepatectomy material. Histopathological examination revealed NETs in multiple foci with submucosal invasion in the stomach. The Ki-67 proliferative index was 3%. Metastatic tumors of similar morphology were found in the liver and three of the greater curvature lymph nodes. We made a diagnosis of multiple gastric NETs (Grade 2). In Type I gastric NETs, the neuroendocrine cell proliferation spectrum up to NET is observed as a result of hypergastrinemia due to atrophic gastritis. Also, in experimental studies, prolonged hypergastrinemia has been reported to cause ECL cell neoplasms in animals treated with PPIs. Although our case could be accepted as Type 1 NET, the possibility of developing NET secondary to long-term PPI use should also be considered.

Abstract 2308: Inhibition of fatty acid synthesis and concurrent lipid deprivation decreases neuroendocrine cancer cell proliferation and colony formation

Abstract Introduction. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the second most common digestive cancer in terms of prevalence, can be particularly challenging to treat due to resistance to current clinical regimens. Lipid metabolism provides an important energy source for cancer cells; cells increase lipid supply by endogenous synthesis or exogenous uptake. Both processes can become dysregulated in cancer, but little is known about the role of either pathway in neuroendocrine tumors (NETs). The goal of this project was to determine whether inhibition of lipid synthesis with concurrent lipid deprivation affects NET cell proliferation and survival. Methods. (i) Expression and localization of fatty acid synthase (FASN) in NET patient samples (n=39) and human cell lines (BON, QGP-1, and NT-3) were examined with immunohistochemistry and immunoblotting, respectively. (ii) NET neutral lipid stores were determined with immunofluorescent analysis of Bodipy 493/503 staining. (iii) To study the role of lipid synthesis and lipid uptake on colony formation, NET cells were treated with TVB-3664 with or without FA depletion for 10d. Colonies were visualized with sulforhodamine B (SRB) dye staining and quantified with photospectrometry. (iv) To study the effect of lipid synthesis and uptake on proliferation, NET cells were treated with TVB-3664 with or without FA depletion for 72h, 96h, and 120h. Cellular growth was determined with SRB assays. (v) The effect of TVB-3664 on cyclin D1 and β-catenin expression in NET cells was determined with immunoblotting. Results. (i) FASN was detected in the cytoplasm of all 39 NET primary and metastatic tissue samples; scores of 5 or 6 indicated robust expression in 38/39 samples. Among cell lines, FASN expression was highest in BON cells followed by similar levels in QGP-1 and NT-3 cells. (ii) TVB-3664 treatment or lipid deprivation for 5d reduced neutral lipid storage in BON cells; combined TVB-3664 treatment with FA depletion for 5d fully depleted BON lipid stores. (iii) TVB-3664 treatment, but not FA deprivation, reduced NET colony formation by ~25% in BON cells and ~50% in QGP-1 cells. TVB-3664 treatment with FA deprivation reduced colony formation by ~65% in BON cells and ~75% in QGP-1 cells. (iv) TVB-3664 treatment or FA deprivation reduced NET cell proliferation at 72h, 96h, and 120h. (v) TVB-3664 treatment reduced cyclin D1 expression in BON and QGP-1 cells and β-catenin levels in BON cells. Conclusions. Our findings indicate that FASN is robustly expressed in NET patient samples and cell lines. Inhibition of endogenous lipid synthesis with concurrent lipid deprivation reduces colony formation and proliferation of NET cells. Importantly, our findings show that lipid metabolism promotes NET cell growth and that targeting de novo lipogenesis may be a potential treatment strategy for advanced GEP-NETs. Citation Format: Jeremy Johnson, Yekaterina Y. Zaytseva, Jennifer Castle, B. Mark Evers, Piotr Rychahou. Inhibition of fatty acid synthesis and concurrent lipid deprivation decreases neuroendocrine cancer cell proliferation and colony formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2308.

IGF2BP1 Promotes Proliferation of Neuroendocrine Neoplasms by Post-Transcriptional Enhancement of EZH2.

Simple SummaryNeuroendocrine neoplasms (NEN) are very heterogeneous malignancies arising at different sites of the body that show an increasing incidence in recent decades. Here, we show that IGF2 mRNA binding protein 1 (IGF2BP1) is highly expressed in NEN cell lines, leading to enhanced cell proliferation. This oncogenic function relies on post-transcriptional stimulation of EZH2 expression by IGF2BP1, resulting in epigenetic silencing of cell cycle inhibitors via tri-methylation of histone H3 at lysine 27 (H3K27me3). Combinatorial pharmacological targeting of IGF2BP1, EZH2, and the EZH2-activator Myc leads to synergistic antiproliferative and proapoptotic effects in NEN cells, representing a novel therapeutic strategy in neuroendocrine malignancies.Neuroendocrine neoplasms (NENs) represent a heterogenous class of highly vascularized neoplasms that are increasing in prevalence and are predominantly diagnosed at a metastatic state. The molecular mechanisms leading to tumor initiation, metastasis, and chemoresistance are still under investigation. Hence, identification of novel therapeutic targets is of great interest. Here, we demonstrate that the RNA-binding Protein IGF2BP1 is a post-transcriptional regulator of components of the Polycomb repressive complex 2 (PRC2), an epigenic modifier affecting transcriptional regulation and proliferation: Comprehensive in silico analyses along with in vitro experiments showed that IGF2BP1 promotes neuroendocrine tumor cell proliferation by stabilizing the mRNA of Enhancer of Zeste 2 (EZH2), the catalytic subunit of PRC2, which represses gene expression by tri-methylation of histone H3 at lysine 27 (H3K27me3). The IGF2BP1-driven stabilization and protection of EZH2 mRNA is m6A-dependent and enhances EZH2 protein levels which stimulates cell cycle progression by silencing cell cycle arrest genes through enhanced H3K27 tri-methylation. Therapeutic inhibition of IGF2BP1 destabilizes EZH2 mRNA and results in a reduced cell proliferation, paralleled by an increase in G1 and sub-G1 phases. Combined targeting of IGF2BP1, EZH2, and Myc, a transcriptional activator of EZH2 and well-known target of IGF2BP1 cooperatively induces tumor cell apoptosis. Our data identify IGF2BP1 as an important driver of tumor progression in NEN, and indicate that disruption of the IGF2BP1-Myc-EZH2 axis represents a promising approach for targeted therapy of neuroendocrine neoplasms.

Bronchiectasis: Retrospective Analysis of Clinical and Pathological Findings in a Tertiary-Care Hospital.

Background Bronchiectasis is still a challenging chronic lung disease in developing countries. Patients with bronchiectasis can also have pulmonary hypertension. There are sparse data on the prevalence of pulmonary hypertension in patients with bronchiectasis. Materials and methods. Archived H&E-stained slides of 141 patients histopathologically diagnosed with bronchiectasis were reevaluated. Cases were categorized into 4 subgroups based on histology: tubular, varicose, follicular, and cystic. In addition, concomitant histopathological changes were also reevaluated. For patients with available CT sections, main, right, and left pulmonary artery (PA) diameters and PA/aorta ratio were measured with regard to pulmonary hypertension. Results Of the cases, 70% (n = 89) were female and 30% (n = 52) were male, with a mean age of 36.58 in females and 33.84 in males. Histopathologically, 43% (n = 68) of the cases showed follicular, 37% (n = 59) showed varicose, 35% (n = 56) showed tubular, and 28% (n = 45) showed cystic bronchiectasis morphology. All cases showed chronic inflammation, fibrosis, muscle destruction, and cartilage destruction. Aspergillus were present in 11% of the cases showing cystic morphology. Approximately 17% of the cases (n = 24) were found to have neuroendocrine cell proliferations. In cases with medial hypertrophy, a statistically significant increase in the left pulmonary artery diameter was radiologically determined. Conclusions Medial hypertrophy was found to be significant with regard to indicating a radiological increase in left pulmonary artery diameter. Vascular changes observed in bronchiectasis cases and the presence of neuroendocrine cell proliferations should be specified in pathology reports, and aspergilloma should be carefully investigated in cases with predominant cystic morphology.

MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts

The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA polymerase II (RNAPII) is slow and non-productive on a large group of cell-cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells.

Is the combination of bilateral pulmonary nodules and mosaic attenuation on chest CT specific for DIPNECH?

BackgroundDiffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterized by multifocal proliferation of pulmonary neuroendocrine cells. On chest CT, DIPNECH exhibits bilateral pulmonary nodules and mosaic attenuation in most patients. We sought to: (1) assess the specificity of this pattern (i.e., bilateral pulmonary nodules together with mosaic attenuation) for DIPNECH; (2) describe its differential diagnosis; and (3) identify the clinico-radiologic features that may help prioritize DIPNECH over other diagnostic considerations.MethodsWe searched the Mayo Clinic records from 2015 to 2019 for patients with bilateral pulmonary nodules and mosaic attenuation on CT who had a diagnostic lung biopsy. A thoracic radiologist reviewed all CT scans. Chi-square test was used for categorical variables, and odds ratios were utilized to measure the association between certain variables and DIPNECH.ResultsFifty-one patients met our inclusion criteria; 40 (78%) were females and 34 (67%) were never-smokers. Median age was 65 (interquartile range 55–73) years. Lung biopsy was surgical in 21 patients (41%), transbronchial in 17 (33%), and transthoracic in 12 (24%); explanted lungs were examined in 1 (2%). Metastatic/multifocal cancer was the most common diagnosis, and was found in 17 (33%) cases. Bronchiolitis was diagnosed in 12 patients (24%), interstitial lung disease in 10 (20%), and DIPNECH in 5 (10%). Previous diagnosis of an obstructive lung disease (odds ratio 15.8; P = 0.002), and peribronchial nodular distribution on CT (odds ratio 14.4; P = 0.006) were significantly correlated with DIPNECH. Although statistical significance was not reached, DIPNECH nodules were more likely to display solid attenuations (80% vs. 67%, P = 0.45), and were more numerous; > 10 nodules were seen in 80% of DIPNECH cases vs. 52% in others (P = 0.23). Because DIPNECH primarily affects women, we analyzed the women-only cohort and found similar results.ConclusionsVarious disorders can manifest the CT pattern of bilateral pulmonary nodules together with mosaic attenuation, and this combination is nonspecific for DIPNECH, which was found in only 10% of our cohort. Previous diagnosis of an obstructive lung disease, and peribronchial distribution of the nodules on CT increased the likelihood of DIPNECH vs. other diagnoses.

A RARE CASE OF CHRONIC COUGH

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Chronic cough is one of the most common symptoms for which outpatient care is sought. The differential diagnosis is broad, and many patients undergo extensive evaluation. We here report a rare case of chronic cough with progressive dyspnea due to Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia( DIPNECH), followed by a brief literature review of DIPNECH. CASE PRESENTATION: 70-year-old female, non smoker, history of Crohn's disease presented to the Pulmonology clinic in 2005 with cough and shortness of breath. PFT's showed restrictive pattern. CT scan showed multiple bilateral pulmonary nodules. Bronchoscopy could not identify cause. On periodic CT, lung nodules remained stable. In the meantime, she continued to have chronic cough and progressively worsening shortness of breath. She received multiple trials of steroids, antibiotics, and inhalers with mild improvement. Repeat PFT's now showed severe obstructive disease. Her coughing spells made it difficult to perform on PFTs. She underwent repeat bronchoscopy with extensive testing, including bacterial, fungal, malignancy, and autoimmune causes of her symptoms, all of which came back negative. The working diagnosis was necrobiotic nodules secondary to her Crohn's disease vs. Asthma. She was put on a prolonged steroid course and developed severe side effects like muscle weakness, mood changes, tremors and worsening kidney function. The patient was hesitant to go back on steroids. She had suffered for 17 years. A trial of steroid-sparing medication CellCept was considered. However, before committing the patient to these, a wedge biopsy of the pulmonary nodule was performed and revealed neuroendocrine cells that stained positive for synaptophysin, chromogranin, and CD56.8 confirming the diagnosis of DIPNECH. The patient was subsequently referred to oncology and started on Octreotide infusions causing significant improvement in symptoms. DISCUSSION: DIPNECH is a rare condition that is becoming increasingly recognized. It is typically characterized by an insidious onset with chronic nonproductive cough, exertional dyspnoea, and wheezing, spuriously attributed to Asthma, chronic obstructive pulmonary disease, or GERD. Indeed, the diagnosis of DIPNECH is usually made several years after the onset of clinical symptoms, often following the incidental discovery of a lung nodule (or nodules) on imaging, usually computed tomography (CT). It is characterized histologically by a diffuse, bronchiolo-centric proliferation of neuroendocrine cells at the periphery of the lung, radiologically by ground-glass opacity, mosaic attenuation with air trapping, bronchial wall thickening, and pulmonary nodules and, Clinically by symptoms of airflow limitation. CONCLUSIONS: We hope this case can increase awareness of DIPNECH among clinicians as patients may otherwise be misdiagnosed and undergo unnecessary treatments or procedures causing permanent harm. REFERENCE #1: Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia 1Margaret Wei, MD and 2Mehri Manouchehr-Pour CLINICAL VIGNETTE1UCLA Department of Medicine2UC Riverside Department of Cell, Molecular, and Developmental Biology DISCLOSURES: No relevant relationships by Venkatkiran Kanchustambham, source=Web Response No relevant relationships by Swetha Saladi, source=Web Response No relevant relationships by Khurram Shafique, source=Web Response No relevant relationships by Vinita Vaidya, source=Web Response

Cross-talk among MEN1, p53 and Notch regulates the proliferation of pancreatic neuroendocrine tumor cells by modulating INSM1 expression and subcellular localization.

Genomic analysis of Pancreatic Neuroendocrine Tumors (PanNETs) has revealed that these tumors often lack mutations in typical cancer-related genes such as the tumor suppressor gene p53. Instead, PanNET tumorigenesis usually involves mutations in specific PanNET-related genes, such as tumor suppressor gene MEN1. Using a PanNET mouse model, human tissues and human cell lines, we studied the cross-talk among MEN1, p53 and Notch signaling pathways and their role in PanNETs. Here, we show that reactivation of the early developmental program of islet cells underlies PanNET tumorigenesis by restoring the proliferative capacity of PanNET cells. We investigated the role of INSM1, a transcriptional regulator of islet cells’ development, and revealed that its expression and subcellular localization is regulated by MEN1 and p53. Both human and mouse data show that loss of MEN1 in a p53 wild-type genetic background results in increased nuclear INSM1 expression and cell proliferation. Additionally, inhibition of Notch signaling in a p53 wild-type background reduces the proliferation of PanNET cells, due to repression of INSM1 transcription and nuclear localization. Our study elucidates the molecular mechanisms governing the interactions of INSM1 with MEN1, p53 and Notch and their roles in PanNET tumorigenesis, suggesting INSM1 as a key transcriptional regulator of PanNET cell proliferation.

A miR-375/YAP axis regulates neuroendocrine differentiation and tumorigenesis in lung carcinoid cells

Lung carcinoids are variably aggressive and mechanistically understudied neuroendocrine neoplasms (NENs). Here, we identified and elucidated the function of a miR-375/yes-associated protein (YAP) axis in lung carcinoid (H727) cells. miR-375 and YAP are respectively high and low expressed in wild-type H727 cells. Following lentiviral CRISPR/Cas9-mediated miR-375 depletion, we identified distinct transcriptomic changes including dramatic YAP upregulation. We also observed a significant decrease in neuroendocrine differentiation and substantial reductions in cell proliferation, transformation, and tumor growth in cell culture and xenograft mouse disease models. Similarly, YAP overexpression resulted in distinct and partially overlapping transcriptomic changes, phenocopying the effects of miR-375 depletion in the same models as above. Transient YAP knockdown in miR-375-depleted cells reversed the effects of miR-375 on neuroendocrine differentiation and cell proliferation. Pathways analysis and confirmatory real-time PCR studies of shared dysregulated target genes indicate that this axis controls neuroendocrine related functions such as neural differentiation, exocytosis, and secretion. Taken together, we provide compelling evidence that a miR-375/YAP axis is a critical mediator of neuroendocrine differentiation and tumorigenesis in lung carcinoid cells.

An Update on the Management of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH).

DIPNECH is caused by an idiopathic proliferation of pulmonary neuroendocrine cells which can lead to bronchiolitis and multifocal lung neuroendocrine tumors. Patients often present with chronic cough and dyspnea. Larger NETs may develop malignant potential. Somatostatin analogs can palliate chronic symptoms, particularly cough. Surgical resection can be considered for relatively large (e.g. >1 cm), progressive tumors.

COEXISTENCE OF PULMONARY FIBROSIS AND PROLIFERATION OF PULMONARY NEUROENDOCRINE CELLS FORMING TUMORLET

Tumorlet is a disease rarely diagnosed in clinical practice. It is characterized by pulmonary neuroendocrine cell (PNEC) proliferation which invades the bronchiolar basement membrane and forms nodules with a diameter smaller than 5 mm. Case report: 72-year-old female patient was suffered for many years from progressive dyspnea and coughing with evidence of pulmonary fibrosis on high resolution computed tomography (HRCT). As a result of a lung biopsy, based on immunohistochemical tests, a 2 mm cluster of neuroendocrine cells (NEC) was found and it was diagnosed as tumorlet. Due to a long-term, insidious progress of the disease, as well as sex and age of the patient, the case emphasizes that differential diagnosis should include tumorlet as well as diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) as a more extensive manifestation of neuroendocrine cell proliferation in the respiratory tract.