pancreas. in usage, the term "carcinoid" has often been applied to both, although sometimes it is restrictively applied to nets of gi origin (as herein), or alternatively to those tumors which secrete functional hormones or polypeptides associated with clinical symptoms, as discussed. carcinoid tumors main article: carcinoid carcinoids most commonly affect the small bowel, particularly the ileum, and are the most common malignancy of the appendix. many carcinoids are asymptomatic and are discovered only upon surgery for unrelated causes. these coincidental carcinoids are common; one study found that one person in ten has them. many tumors do not cause symptoms even when they have metastasized. other tumors even if very small can produce adverse effects by secreting hormones. ten per cent (10%) or less of carcinoids, primarily some midgut carcinoids, secrete excessive levels of a range of hormones, most notably serotonin (5-ht) or substance p, causing a constellation of symptoms called carcinoid syndrome: flushing diarrhea asthma or wheezing congestive heart failure (chf) abdominal cramping peripheral edema heart palpitations a carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure can occur if large amounts of hormone are acutely secreted, which is occasionally triggered by factors such as diet, alcohol, surgery chemotherapy, embolization therapy or radiofrequency ablation. chronic exposure to high levels of serotonin causes thickening of the heart valves, particularly the tricuspid and the pulmonic valves, and over a long period can lead to congestive heart failure. however, valve replacement is rarely needed. the excessive outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency, and thus pellagra, which is associated with dermatitis, dementia, and diarrhea. many other hormones can be secreted by some of these tumors, most commonly growth hormone that can cause acromegaly, or cortisol, that can cause cushing's syndrome. occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. bowel obstruction can occur, sometimes due to fibrosing effects of net secretory products with an intense desmoplastic reaction at the tumor site, or of the mesentery. pancreatic neuroendocrine tumors main article: pancreatic neuroendocrine tumor pancreatic neuroendocrine tumors (pannets) are often referred to as "islet cell tumors", or "pancreatic endocrine tumors" the pannet denomination is in line with current who guidelines. historically, pannets have also been referred to by a variety of terms, and are still often called "islet cell tumors" or "pancreatic endocrine tumors". originate within the pancreas. pannets are quite distinct from the usual form of pancreatic cancer, adenocarcinoma, which arises in the exocrine pancreas. about 95 percent of pancreatic tumors are adenocarcinoma; only 1 or 2% of clinically significant pancreas neoplasms are gep-nets. well or intermediately differentiated pannets are sometimes called islet cell tumors; neuroendocrine cancer (nec) (synonymous with islet cell carcinoma) is more aggressive. up to 60% of pannets are nonsecretory or nonfunctional, which either don't secrete, or the quantity or type of products such as pancreatic polypeptide (ppoma), chromogranin a, and neurotensin do not cause a clinical syndrome, although blood levels may be elevated. functional tumors are often classified by the hormone most strongly secreted by the pancreatic neuroendocrine tumor, as discussed in that main article. other in addition to the two main categories of gep-net, there are rarer forms of neuroendocrine tumors that arise anywhere in the body, including within the lung, thymus and parathyroid. bronchial carcinoid can cause airway obstruction, pneumonia, pleurisy, difficulty with breathing, cough, and hemoptysis, or may be associated with weakness, nausea, weight loss, night sweats, neuralgia, and cushing's syndrome. some are asymptomatic.animal neuroendocrine tumors include neuroendocrine cancer of the liver in dogs, and devil facial tumor disease in tasmanian devils. familial syndromes most pancreatic nets are sporadic. however, neuroendocrine tumors can be seen in several inherited familial syndromes, including: multiple endocrine neoplasia type 1 (men1) multiple endocrine neoplasia type 2 (men2) von hippel-lindau (vhl) disease neurofibromatosis type 1 tuberous sclerosis carney complex given these associations, recommendations in net include family history evaluation, evaluation for second tumors, and in selected circumstances testing for germline mutations such as for men1. pathophysiology nets are believed to arise from various neuroendocrine cells whose normal function is to serve at the neuroendocrine interface. neuroendocrine cells are present not only in endocrine glands throughout the body that produce hormones, but are found in all body tissues. diagnosis markers symptoms from secreted hormones may prompt measurement of the corresponding hormones in the blood or their associated urinary products, for initial diagnosis or to assess the interval change in the tumor. secretory activity of the tumor cells is sometimes dissimilar to the tissue immunoreactivity to particular hormones. synaptophysin immunohistochemistry of neuroendocrine tumor, staining positively. given the diverse secretory activity of nets there are many other potential markers, but a limited panel is usually sufficient for clinical purposes. aside from the hormones of secretory tumors, the most important markers are: chromogranin a (cga), present in 99% of metastatic carcinoid tumors urine 5-hydroxyindoleacetic acid (5-hiaa) neuron-specific enolase (nse, gamma-gamma dimer) synaptophysin (p38) newer markers include n-terminally truncated variant of hsp70 is present in nets but absent in normal pancreatic islets. high levels of cdx2, a homeobox gene product essential for intestinal development and differentiation, are seen in intestinal nets. neuroendocrine secretory protein-55, a member of the chromogranin family, is seen in pancreatic endocrine tumors but not intestinal nets. imaging for morphological imaging, ct-scans, mris, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are commonly used. multiphase ct and mri are typically used both for diagnostics and for evaluation of therapy. the multiphase ct should be performed before and after an intravenous injection of an iodine-based contrast agent, both in the late arterial phase and in the portal venous phase (triple-phase study). while mri is generally superior to ct, both for detection of the primary tumor and for evaluation of metastases, cect is more widely available, even at academic institutions. therefore, multiphase ct is often the modality of choice. advances in nuclear medicine imaging, also known as molecular imaging, have improved diagnostic and treatment paradigms in patients with neuroendocrine tumors. this is because of its ability to not only identify sites of disease but also characterize them. neuroendocrine tumours express somatostatin receptors providing a unique target for imaging. octreotide is a synthetic modification of somatostatin with a longer half-life. octreoscan, also called somatostatin receptor scintigraphy (srs or ssrs), utilizes intravenously administered octreotide that is chemically bound to a radioactive substance, often indium-111, to detect larger lesions with tumor cells that are avid for octreotide. somatostatin receptor imaging can now be performed with positron emission tomography (pet) which offers higher resolution, three-dimensional and more rapid imaging. gallium-68 receptor pet-ct is much more accurate than an octreotide scan. thus, octreotide scanning for net tumors is being increasingly replaced by gallium-68 dotatoc scan. imaging with fluorine-18 fluorodeoxyglucose (fdg) pet may be valuable to image some neuroendocrine tumors. this scan is performed by injected radioactive sugar intravenously. tumors that grow more quickly use more sugar. using this scan, the aggressiveness of the tumor can be assessed. however, neuroendocrine tumors are often slow growing and indolent, and these do not show well on fdg-pet. functional imaging with gallium-labelled somatostatin analog and 18f-fdg pet tracers ensures better staging and prognostication of neuroendocrine neoplasms. the combination of somatostatin receptor and fdg pet imaging is able to quantify somatostatin receptor cell surface (sstr) expression and glycolytic metabolism, respectively. the ability to perform this as a whole body study is highlighting the limitations of relying on histopathology obtained from a single site. this is enabling better selection of the most appropriate therapy for an individual patient. histopathology nuclei of neuroendocrine tumors often show granular "salt-and-pepper" chromatin, as seen here on h&e stain and pap stain. small intestinal neuroendocrine tumor at bottom third of image, showing the typical intramural (within the wall) location, and overlying intact epithelium. h&e stain features in common neuroendocrine tumors, despite differing embryological origin, have common phenotypic characteristics. nets show tissue immunoreactivity for markers of neuroendocrine differentiation (pan-neuroendocrine tissue markers) and may secrete various peptides and hormones. there is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers. widely used neuroendocrine tissue markers are various chromogranins, synaptophysin and pgp9.5. neuron-specific enolase (nse) is less specific. the nuclear neuroendocrine marker insulinoma-associated protein-1 (insm1) has proven to be sensitive as well as highly specific for neuroendocrine differentiation. nets are often small, yellow or tan masses, often located in the submucosa or more deeply intramurally, and they can be very firm due to an accompanying intense desmoplastic reaction. the overlying mucosa may be either intact or ulcerated. some gep-nets invade deeply to involve the mesentery. histologically, nets are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. the cells may align variously in islands, glands or sheets. high power examination shows bland cytopathology. electron microscopy can identify secretory granules. there is usually minimal pleomorphism but less commonly there can be anaplasia, mitotic activity, and necrosis. some neuroendocrine tumor cells possess especially strong hormone receptors, such as somatostatin receptors and uptake hormones strongly. this avidity can assist in diagnosis and may make some tumors vulnerable to hormone targeted therapies. argentaffin and hormone secretion nets from a particular anatomical origin often show similar behavior as a group, such as the foregut (which conceptually includes pancreas, and even thymus, airway and lung nets), midgut and hindgut; individual tumors within these sites can differ from these group benchmarks: foregut nets are argentaffin negative. despite low serotonin content, they often secrete 5-hydroxytryptophan (5-htp), histamine, and several polypeptide hormones. there may be associated atypical carcinoid syndrome, acromegaly, cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck. these tumors can metastasize to bone. midgut nets are argentaffin positive, can produce high levels of serotonin 5-hydroxytryptamine (5-ht), kinins, prostaglandins, substance p (sp), and other vasoactive peptides, and sometimes produce corticotropic hormone (previously adrenocorticotropic hormone ). bone metastasis is uncommon. hindgut nets are argentaffin negative and rarely secrete 5-ht, 5-htp, or any other vasoactive peptides. bone metastases are not uncommon. treatment several issues help define appropriate treatment of a neuroendocrine tumor, including its location, invasiveness, hormone secretion, and metastasis. treatments may be aimed at curing the disease or at relieving symptoms (palliation). observation may be feasible for non-functioning low-grade neuroendocrine tumors. if the tumor is locally advanced or has metastasized, but is nonetheless slowly growing, treatment that relieves symptoms may often be preferred over immediate challenging surgeries. intermediate and high grade tumors (noncarcinoids) are usually best treated by various early interventions (active therapy) rather than observation (wait-and-see approach). treatments have improved over the past several decades, and outcomes are improving. in malignant carcinoid tumors with carcinoid syndrome, the median survival has improved from two years to more than eight years. detailed guidelines for managing neuroendocrine tumors are available from esmo, nccn and a uk panel. the nci has guidelines for several categories of net: islet cell tumors of the pancreas, gastrointestinal carcinoids, merkel cell tumors and pheochromocytoma/paraganglioma. however, effective predictive biomarkers are yet to be discovered. similarly, recent advances in understanding neuroendocrine tumor's molecular and genomic alterations still have to find their ways into a definitive management strategy. surgery even if the tumor has advanced and metastasized, making curative surgery infeasible, surgery often has a role in neuroendocrine cancers for palliation of symptoms and possibly increased lifespan. cholecystectomy is recommended if there is a consideration of long-term treatment with somatostatin analogs.: 46 symptomatic relief in secretory tumors, somatostatin analogs given subcutaneously or intramuscularly alleviate symptoms by blocking hormone release. a consensus review has reported on the use of somatostatin analogs for gep-nets. these medications may also anatomically stabilize or shrink tumors, as suggested by the promid study (placebo-controlled prospective randomized study on the antiproliferative efficacy of octreotide lar in patients with metastatic neuroendocrine midgut tumors): at least in this subset of nets, average tumor stabilization was 14.3 months compared to 6 months for placebo. the clarinet study (a randomized, double-blind, placebo-controlled study on the antiproliferative effects of lanreotide in patients with enteropancreatic neuroendocrine tumors) further demonstrated the antiproliferative potential of lanreotide, a somatostatin analog and recently approved fda treatment for gep-nets. in this study, lanreotide showed a statistically significant improvement in progression-free survival, meeting its primary endpoint.