Cells Of Diffuse Neuroendocrine System Research Articles

Clinicopathological and survival features of neuroendocrine tumors: A retrospective analysis of 153 cases, our current remarks on a heterogeneous tumor group, and still unmet future expectations.

Neuroendocrine neoplasms (NENs) originate from the diffuse neuroendocrine cell system and constitute a heterogeneous group of tumors exhibiting diverse clinical and biological characteristics. NENs include well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). In the present study, we performed a retrospective analysis of patients diagnosed with NET to evaluate clinicopathological characteristics, treatment and outcomes. Data from 153 patients diagnosed with NET who were treated and followed up at three tertiary care centers from November 2002 to June 2021 were retrospectively evaluated. Clinicopathological and prognostic factors, treatment modalities and survival data were analyzed. Kaplan-Meier analysis was used to assess survival data and comparisons were performed using the logrank test. Median age (IQR) was 53 (18-80) years. 85.6% of the patients had gastro-entero-pancreatic (GEP)-NET. The primary tumor was resected in 95 patients (62.1%) and metastasectomy were performed in 22 patients (14.4%). Seventy-eight patients received systemic therapy for metastatic disease. Patients were followed up for a median of 22 (IQR = 33.8) months. The estimated one-year and three-year survival rate was 89.8% and 74.4%, respectively. Median progression-free survival (PFS) were 10.1, 8.5, and 4.2 months after first-, second- and third-line therapy, respectively. The number of systemic treatment options and diagnostic tools for NETs has significantly improved in the last few years. NET classification, which treatment will be more appropriate for which group of patients, the molecular basis of this disease and the development of treatment strategies are open-ended questions that still need to be investigated.

Update on Epidemiology, Diagnosis, and Biomarkers in Gastroenteropancreatic Neuroendocrine Neoplasms.

Simple SummaryNeuroendocrine neoplasms are divided into two groups: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. The progress in diagnostic methods, including pathology optimization and imaging, might be one of the reasons for the increasing incidence of gastroenteropancreatic neuroendocrine neoplasms; however, the remaining biological factors are undetermined. Rapid advances in molecular diagnostic and treatment strategies in recent years have significantly contributed to personalized management for patients with these rare neoplasms. This review aimed to provide an update on the epidemiology, diagnosis, and biomarkers in gastroenteropancreatic neuroendocrine neoplasms.Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas; it is essential to understand the pathological classification according to the mitotic count and Ki67 proliferation index. In addition, with the advent of molecular-targeted drugs and somatostatin analogs and advances in endoscopic and surgical treatments, the multidisciplinary treatment of GEP-NENs has made great progress. In the management of GEP-NENs, accurate diagnosis is key for the proper selection among these diversified treatment methods. The evaluation of hormone-producing ability, diagnostic imaging, and histological diagnosis is central. Advances in the study of the genetic landscape have led to deeper understanding of tumor biology; it has also become possible to identify druggable mutations and predict therapeutic effects. Liquid biopsy, based on blood mRNA expression for GEP-NENs, has been developed, and is useful not only for early detection but also for assessing minimal residual disease after surgery and prediction of therapeutic effects. This review outlines the updates and future prospects of the epidemiology, diagnosis, and management of GEP-NENs.

Enterectomia en el tratamiento del carcinoide neuroendocrino obstructivo en un perro: relato de caso

Carcinoids in dogs are rare neoplasms of the diffuse neuroendocrine cell system. The term neuroendocrine tumor has been proposed and the clinical manifestation is related to the location. Despite the low rate of growth and metastasis, such neoplasms are often malignant and must undergo surgical resection. When this is done properly, the outcome is usually satisfactory. The objective of this study was to describe a case of carcinoid in a 10-year-old female with tenesmus and presence of fecaloma. The patient was received at a private veterinary clinic and, after clinical consultation and imaging examinations, she was submitted to the enterotomy and removal of fecaloma in the descending colon. The obstruction of the intestinal flow was resulting from a neoplastic mass in a pre-pubic region, also resected and forwarded for analysis. The histopathological revealed neuroendocrine carcinoid and the dog was followed for 60 days after the procedure, without signs of recurred or metastasis. Therefore, it is understood that neuroendocrine carcinoids should be considered as a cause of tenesmus and constipation in dogs, especially in the elderly, and the prognosis is favorable when patients undergo the surgical procedure with adequate resection of the tumor.

Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life.

Peptide receptor radionuclide therapy (PRRT), developed over the last two decades, is carried out using radiopharmaceuticals such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (177Lu-Dotatate). These radiocompounds are obtained by labeling a synthetic somatostatin analog with a β-emitting radioisotope. The compounds differ from each other in terms of their energetic features (due to the radionuclide) and peptide receptor affinity (due to the analog) but share the common characteristic of binding specific membrane somatostatin receptors that are (generally) overexpressed in neuroendocrine neoplasms (NENs) and their metastases. NENs are tumors arising from diffuse neuroendocrine system cells that are classified according to grading based on Ki67 percentage values (Grades 1 and 2 are classed as neuroendocrine tumors [NETs]) and to the anatomical site of occurrence (in this paper, we only deal with gastroenteropancreatic [GEP]-NETs, which account for 60%–70% of all NENs). They are also characterized by specific symptoms such as diarrhea and flushing (30% of cases). Despite substantial experience gained in the area of PRRT and its demonstrable effects in terms of efficacy, safety, and improvement in quality of life, these compounds are still not registered (registration of 177Lu-Dotatate for the treatment of midgut NETs is expected soon). Thus, PRRT can only be used in experimental protocols. We provide an overview of the work of leading groups with wide-ranging experience and continuity in data publication in the area of GEP-NET PRRT and report our own personal experience of using different dosage schedules based on the presence of kidney and bone marrow risk factors. Our results on the retreatment of patients previously administered 90Y-DOTA-Tyr3-octreotide with a low dosage of 177Lu-Dotatate are also included. A comment on potential future developments of PRRT in GEP-NETs is provided.

Pre-surgical bronchoscopic treatment for typical endobronchial carcinoids

Carcinoids are tumors that originate from diffuse neuroendocrine system cells (APUD cells) and represent 1–2% of all pulmonary tumors.Although surgical resection remains the mainstay of treatment, bronchoscopic radical resection of typical carcinoids in selected cases exhibiting endoluminal growth and small implant base has also been explored. Bronchoscopic removal of endobronchial lesions may also reduce the risk of post-obstructive infections and improve pulmonary function, allowing the patient to undergo surgery in better clinical and respiratory state.In this paper we have evaluated the impact on surgical planning and outcome of preoperative bronchoscopic resection in treatment of endobronchial typical carcinoids.Our observations further support the role of bronchoscopic treatment before surgery in endobronchial typical carcinoids.

Small-cell neuroendocrine carcinoma cervix: A case report of an aggressive tumor

Neuroendocrine tumors comprise a broad family of tumors that arise from the diffuse neuroendocrine cell system. Small-cell neuroendocrine carcinoma cervix is a rare tumor, accounting for up to 2% of cervical carcinomas. These are highly aggressive tumors, characterized by early distant metastasis and worse prognosis compared to other histological types occurring in the cervix. Distant sites of recurrence including lung and bone are more common (28%) than local failure (13%). We report a case of a 60-year-old woman whose disease progressed during treatment with an eventual fatal outcome.

Neuroendocrine tumor of the rectum: A case report

Neuroendocrine tumors are a frequent and clinically enigmatic group of tumors originating from the cells of diffuse neuroendocrine system. The incidence of neuroendocrine tumors of the rectum is 0.86 per 100,000 people. In our paper, the patient was 58 years old, sent to a gastroenterologist because of intermittent abdominal bloating and positive findings on a fecal occult test. Upper endoscopy diagnosed an ulcer in the duodenal bulb, which explained the positivity of the fecal occult test. Using colonoscopy at 10th centimeter in the rectum a sessile polypoid resizing of 15 millimeters was found, and the histopathologic findings showed that it was an interstitial colitis, without the elements of malignant cells. Computed tomography of the pelvis showed a lesion in the rectal region that had infiltrated the wall of the rectum without propagation to the surrounding structures and with no enlarged lymph nodes. Histopathological material was sent to immunohistochemistry, which showed that it were welldifferentiated neuroendocrine tumors, with the invasion of the lamina muscularis propria and positive staining for chromogranin A and neuron-specific enolase, and the nuclear antigen Ki-67 was 17%. The values of chromogranin A levels in serum were three times higher than normal. 15 months after the tumor was removed surgically, computerized tomography scan showed multiple lesions in the liver. Octreoscan (somatostatin receptor scintigraphy) confirmed multiple lesions in the liver with the expression of somatostatin receptors. A rare case of tumor was shown, diagnosed in a nonspecific way, that at the time of diagnosis, despite its size and infiltration into the muscle tissue did not have distant metastases.

Neuroendocrine tumors of the gynecologic tract: Select topics

Tumors of the diffuse neuroendocrine cell system (DNES) may arise in any component of the gynecologic tract, including the vulva, vagina, cervix, endometrium, and ovary. Overall such tumors in the gynecologic tract are rare, constituting only 2% of gynecologic cancers, comprising a spectrum of tumors of variable biologic potential. Due to the rarity of such tumors, pathologists experience may be limited and these may present diagnostic challenges. Currently the nomenclature employed is still that of the pulmonary classification systems, carcinoid, atypical carcinoid, small and large cell neuroendocrine carcinoma that broadly correlates to low/grade 1, intermediate/grade 2, and high grade/grade 3 of the WHO gastroenteropancreatic neuroendocrine tumors classification. Furthermore in keeping with the lung, proliferative rate is assessed based on mitotic index rather than Ki-67 staining. In this review we cover select neuroendocrine tumors of the gynecologic tract.

Current Advances in Diagnosis of Hepatic Metastases from Neuroendocrine Carcinomas

Copyright: © 2013 Bacchetti S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Neuroendocrine carcinomas (NEC) arising in various locations constitute a morphologically heterogenous group of lesions. They originate from the dispersed or diffuse neuroendocrine cell system. Hepatic metastases are common in NEC, especially in patients with gastro entero pancreatic disease as the portal vein drains directly into the liver [1]. Liver metastases are found at presentation in 44-85% of patients with midgut tumors and are the most common imaging finding [2,3]. However, liver metastases can be present in patients with NEC involving other sites (for instance head and neck areas). The presence of metastases is an important prognostic factor for survival [47]. The accurate identification of suspected malignant hepatic mass (es) is mandatory and imaging modalities are fundamental [1].

Cloning and expression of neuron-specific enolase in the corpus luteum of dairy goats

Neuron-specific enolase (NSE) is the key molecular marker for diffuse neuroendocrine system (DNES) cells, its expression in the pregnant corpus luteum (CL) of dairy goats was studied by the immunofluorescence method and the ultra structural characteristics of luteal cells were detected by the electron microscopy to identify the existence of DNES cells in the pregnant CL of dairy goats. Besides, the coding sequence of dairy goats NSE gene was cloned and its biological information was analyzed. Results revealed that NSE immunopositive cells exhibited widespread cytoplasmic staining throughout the whole pregnant CL. In addition, these cells showed typical characteristics of DNES cells in the electron microscopy. These results suggested that many DNES cells exist in the pregnant CL of dairy goats. Meanwhile, we identified the coding sequence of dairy goats NSE (GenBank Accession No. JN887466). Its nucleotide sequence homology was found to be 97.9%, 89.3%, 90% and 92.6%, respectively, compared with that of Bos taurus, Rattus norvegicus, Mus musculus and Homo sapiens, while the amino acid sequence homology was 99.1%, 97%, 97.2% and 98.2% respectively. These results first showed that the functional amino acids coded by the NSE gene were highly conserved in Caprine, B. taurus, R. norvegicus, M. musculus and H. sapiens. It was implied that the gene NSE in dairy goats had close homology to that of NSE of other species. Our findings demonstrated the possible existence of DNES cells in pregnant CL, providing new clue for further understanding of interactions between the neuroendocrine and reproductive systems. Characterization of gene sequence of dairy goats NSE will enable us to synthesize interference RNA for further study on the role of NSE on the formation, function and apoptosis of pregnant CL in dairy goats.

Contemporary methods of therapy and follow-up of neuroendocrine tumours of the gastrointestinal tract and the pancreas

The growing interest in neuroendocrine tumours is due to the dynamic growth of detection of this type of cancer. Neuroendocrine tumours (neuroendocrine neoplasms – NENs / neuroendocrine tumours – NETs) derive from glands, groups of endocrine cells and diffuse neuroendocrine system cells. Mainly they derive from the gastrointestinal tract (gastroenteropancreatic-neuroendocrine tumours – GEP-NETs). Currently the modified WHO classification from 2010 is widely used. An important element in the choice of treatment is histological maturity based on mitotic activity and on assessment of proliferation activity (Ki-67). The treatment of choice is surgery. In most cases, complete surgical removal is impossible because of the advanced staging at the time of diagnosis. In well-differentiated neoplasms where the expression of somatostatin receptors is expected, patients are qualified for somatostatin analogues therapy. Poorly differentiated lesions are qualified for chemotherapy. In the guidelines of ENETS (European Neuroendocrine Tumor Society) from 2007 the rules concerning monitoring depending on the WHO classification were specified.

The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion

Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98-99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50 = 1.8 × 10-6 M; IC50 = 3.7 × 10-8 M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT₁ (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT₁ transcription was regulated by PKA/MAPK and PI₃K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.

Immunocytochemical Identification and Localization of Diffuse Neuroendocrine System (DNES) Cells in Gastrointestinal Tract of Channel Catfish ( Ictalurus punctatus)

To detect distribution and relative frequency of diffuse neuroendocrine system (DNES) cells in the gastrointestinal tract of channel catfish ( Ictalurus punctatus), the intestinal tract of channel catfish was divided into seven portions from proximal to distal: the enlarged area after oesophagus, cardia, fundus, pylorus, and anterior, middle, and posterior intestine. Immunohistochemical method using the strept avidin-biotin-complex (SABC) was employed. All antisera between seven portions of the channel catfish were compared statistically using statistical package for the social science (SPSS). Five types of DNES cells were determined: neuropeptide Y-immunoreactive (NPY-IR) cells were demonstrated in both anterior and middle intestine; serotonin (5-HT) immunoreactive cells were detected throughout the whole gastrointestinal tract; vasoactive intestinal peptide (VIP) positive cells were at the highest frequency in pylorus; glucagon-immunoreactive (GLU-IR) cells were moderate in number in the fundus and anterior, middle intestine, and no immunoreactivity was determined in the other portions; somatostatin (SOM) positive cells were more abundant in the anterior and middle intestine. The regional distribution and relative frequency of immunoreactive cells in the channel catfish, Ictalurus punctatus, are essentially similar to those of other fish. However, some characteristics are observed in this species, which further proved that the diversity of the physiological function of DNES cells was based on their morphology.

Pharmacotherapy of neuroendocrine cancers

Background: Neuroendocrine tumors (NETs) of the diffuse neuroendocrine cell system often present a considerable diagnostic and therapeutic challenge. Methods: We have reviewed the literature on NET treatment between 1979 and 2008 (PubMed search: carcinoid or neuroendocrine tumor/tumour + treatment or management), and summarized current therapeutic options and recommendations. Results: The majority of tumors are diagnosed at a stage that the only curative treatment, radical surgical intervention, is no longer an option. Biotherapy with somatostatin analogs is currently the most efficient treatment to achieve palliation. The interferon class of agents may have a role in selected individuals but substantial adverse events often limit their use. Conventional chemotherapy has minimal efficacy but may have some utility in undifferentiated or highly proliferating neuroendocrine carcinomas and pancreatic NETs. Hepatic metastases, depending on size, location and number, may be amenable to surgical resection, embolization or radio-frequency ablation. Peptide receptor targeted radiotherapy may lead to reduction in tumor size but in most circumstances has a tumor-stabilizing effect. A variety of antiangiogenesis and growth factor-targeted agents have been evaluated but to date the results have failed to meet expectations. Thus, long-acting somatostatin analogs remain the only effective pharmacotherapeutic option that improves symptomatology and quality of life with minimal adverse effects.

Formation of diffuse neuroendocrine system in human ontogenesis

The review of literature presents data on formation of the diffuse neuroendocrine system (DNES) in human early ontogenesis and its role in development of organs and vitally important functional systems of the fetus. It is emphasized that impairment of structural development and/or changes of the functional state of DNES cells under effects of unfavorable environmental factors can underlie embryopathies, fetopathies, and disorders of early postnatal adaptations of children.

Neuroendocrine tumors of the gastrointestinal tract

The diffuse neuroendocrine cell system of the gastrointestinal tract gives rise to the neuroendocrine neoplasms. The WHO classification distinguishes between well differentiated neuroendocrine tumors of benign or uncertain behavior, well differentiated neuroendocrine carcinomas of low grade malignancy and poorly differentiated neuroendocrine carcinomas of high grade malignancy. The well differentiated neuroendocrine tumors and carcinomas correspond to the carcinoids of earlier classifications. Further biological and prognostic classification of these neoplasms must consider the localization of the tumors within the gastrointestinal tract. This system allows a clinically relevant diagnosis and includes all so far known tumor entities.

Effect of natural confinement on the gill cell types and bony elements of Lebias fasciata (Teleostei, Cyprinodontidae): A morphological and immunohistochemical analysis

Histochemical and immunohistochemical techniques were used to investigate the effect of stress from heavy metals on the respiratory epithelia of the cyprinodont Lebias fasciata living in confined natural environments with different degrees of pollution (brackish swamps of Faro‐Ganzirri and Lesina). This effect was evaluated on cytokeratins and calcium‐binding proteins, with particular reference to the presence of neuronal nitric oxide synthase in the cells of the diffuse neuroendocrine system (DNS). A morphometric examination was also performed to identify possible cranio‐facial and vertebral anomalies; however, the results were negative for all specimens from the two environments. Regarding the presence of heavy metals, only slight differences were found between the two environments, except for the higher concentration of aluminum in the Lesina swamp. In the gills of individuals from the latter environment, the epithelium presented a morphologically and immunohistochemically modified structure, with a concomitant over‐production of mucus; this acts as a barrier to oxygen diffusion, causing strong hypoxia. Therefore, it is hypothesized that the high number of DNS cells and nerve fibers im‐munopositive to nNOS in the respiratory epithelium of Lebias fasciata specimens from lesina is a local reaction to hypoxia.

NCAM expression in the pulmonary neural and diffuse neuroendocrine cell system

NCAM expression in the pulmonary neural and diffuse neuroendocrine cell system

NCAM expression in the pulmonary neural and diffuse neuroendocrine cell system.

Neural cell adhesion molecule (NCAM)--a membrane protein involved in cell-cell adhesion within the central and peripheral nervous systems--was demonstrated to be a sensitive and specific marker for neuroepithelial bodies (NEB) and neural tissue elements in the cat lung. Using the streptavidin-biotin immunoperoxidase method, NCAM reactive sites were investigated with monoclonal and polyclonal antibodies on serial section of Bouin fixed, paraffin embedded lung tissue. Moreover, NCAM expression was compared with that of neuron-specific enolase (NSE) on adjacent sections. The most obvious NCAM staining was obtained with the monoclonal antibody. From newborn to adult life, cell surface labeling was identified on NEB cells. In mature cat lung, they were no longer positive. Solitary neuroendocrine cells (NEC) were always negative. In contrast to the transient postnatal immunoreactivity of NEB cells, nerve fibers and ganglion cells were stained throughout all life stages and studied. The distribution of NCAM in NEB, nerve fibers and ganglion cells was similar to that NSE, except in the adult lung. This study reveals that during lung growth shared NCAM antigens exist between the pulmonary nervous and endocrine system, whereas in mature lung NCAM proteins are confined to neural tissue elements. The difference in NCAM expression between NEB and NEC might suggest an involvement of NCAM in the formation of contacts between NEB cells and nerves.