Neuroendocrine tumor

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body. Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, including a similar histological appearance, having special secretory granules, and often producing biogenic amines and polypeptide hormones. The term "neuro" refers to the dense core granules (DCGs), similar to the DCGs in the serotonergic neurons storing monoamines. The term "endocrine" refers to the synthesis and secretion of these monoamines. The neuroendocrine system includes endocrine glands such as the pituitary, the parathyroids and the neuroendocrine adrenals, as well as endocrine islet tissue embedded within glandular tissue such as in the pancreas, and scattered cells in the exocrine parenchyma. The latter is known as the diffuse endocrine system.

Conceptually, there are two main types of NET within the gastroenteropancreatic neuroendocrine tumors (GEP NET) category: those which arise from the gastrointestinal (GI) system and those that arise from the 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.

Most pancreatic NETs are sporadic. However, neuroendocrine tumors can be seen in several inherited familial syndromes, including:

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. 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.

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. NCCN and a UK panel. 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.

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.

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. The disease in sixty five percent of patients treated with lanreotide in the study had not progressed or caused death at 96 weeks, the same was true of 33% of patients on placebo. This represented a 53% reduction in risk of disease progression or death with lanreotide based on a hazard ratio of .47. Lanreotide is the first and only FDA approved antitumor therapy demonstrating a statistically significant progression free survival benefit in a combined population of patients with GEP NETS. Other medications that block particular secretory effects can sometimes relieve symptoms. Its effectiveness is somewhat uncertain, but low doses can be titrated within each person, often considering the effect on the blood leukocyte count;

Most gastrointestinal carcinoid tumors tend not to respond to chemotherapy agents, showing 10 to 20% response rates that are typically less than 6 months. Combining chemotherapy medications has not usually been of significant improvement The peptide receptor may be bound to lutetium 177, yttrium 90, indium 111 and other isotopes including alpha emitters. This is a highly targeted and effective therapy with minimal side effects in tumors with high levels of somatostatin cell surface expression, because the radiation is absorbed at the sites of the tumor, or excreted in the urine. The radioactively labelled hormones enter the tumor cells which, together with nearby cells, are damaged by the attached radiation. Not all cells are immediately killed; cell death can go on for up to two years. PRRT was initially used for low grade NETs. It is also very useful in more aggressive NETs such as Grade 2 and 3 NETs provided they demonstrate high uptake on SSTR imaging to suggest benefit.

Metastases to the liver can be treated by several types of hepatic artery treatments based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 70–80 percent of their nutrients and 50% their oxygen supply from the portal vein, and thus can survive with the hepatic artery effectively blocked. Hepatic artery embolization (HAE) occludes the blood flow to the tumors, achieving significant tumor shrinkage in over 80%. for neuroendocrine metastases to the liver delivers radioactive microsphere therapy (RMT) by injection into the hepatic artery, lodging (as with HAE and HACE) in downstream capillaries. In contrast to hormone delivered radiotherapy, the lesions need not overexpress peptide receptors. The mechanical targeting delivers the radiation from the yttrium labeled microspheres selectively to the tumors without unduly affecting the normal liver. This type of treatment is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, including neuroendocrine malignancies. and supported by the crowdfunding campaign iCancer was used in a Phase 1 trial against NET in 2016. Further efforts towards more personalized therapies in neuroendocrine tumors are undertaken i. a. combining drug screening platforms and patient derived ex vivo cell cultures that mimic relevant aspects of the original tumors.

Although estimates vary, the annual incidence of clinically significant neuroendocrine tumors is approximately 2.5–5 per 100,000; two thirds are carcinoid tumors and one third are other NETs. The prevalence has been estimated as 35 per 100,000, As diagnostic imaging increases in sensitivity, such as endoscopic ultrasonography, very small, clinically insignificant NETs may be coincidentally discovered; being unrelated to symptoms, such neoplasms may not require surgical excision.

Small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907. They were named carcinoid tumors because their slow growth was considered to be "cancer like" rather than truly cancerous. neuroendocrine cells sometimes produce various types of hormones and amines, and the differences between these schema have often been confusing. Nonetheless, these systems all distinguish between well differentiated (low and intermediate grade) and poorly differentiated (high grade) NETs. Cellular proliferative rate is of considerable significance in this prognostic assessment.