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Neuroendocrine Tumors

Overview

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. Many are benign, while some are malignant. 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, such as looking similar, having special secretory granules, and often producing biogenic amines and polypeptide hormones.

Symptoms - Neuroendocrine Tumors

Conceptually, there are two main types of NET within this 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.

Carcinoid tumors

(about two thirds of GEP-NETs) 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. Many tumors do not cause symptoms even when they have metastasized. 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, surgerychemotherapy, 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 (PanNET)

(about one third of GEP-NETs) 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.

Causes - Neuroendocrine Tumors

Carcinoid tumors

It's not clear what causes carcinoid tumors. In general, cancer occurs when a cell develops mutations in its DNA. The mutations allow the cell to continue growing and dividing when healthy cells would normally die.

The accumulating cells form a tumor. Cancer cells can invade nearby healthy tissue and spread to other parts of the body.

Doctors don't know what causes the mutations that can lead to carcinoid tumors. But they know that carcinoid tumors develop in neuroendocrine cells.

Neuroendocrine cells are found in various organs throughout the body. They perform some nerve cell functions and some hormone-producing endocrine cell functions. Some hormones that are produced by neuroendocrine cells are cortisol, histamine, insulin and serotonin.

Risk factors

Factors that increase the risk of carcinoid tumors include:

  • Age: Older adults are more likely to be diagnosed with a carcinoid tumor than are younger people or children.
  • Sex: Women are more likely than men to develop carcinoid tumors.
  • Family history: A family history of multiple endocrine neoplasia, type I (MEN I), increases the risk of carcinoid tumors. In people with MEN I, multiple tumors occur in glands of the endocrine system.

Prevention - Neuroendocrine Tumors

Not known.

Diagnosis - Neuroendocrine Tumors

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.

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)
  • 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

CT-scans, MRIs, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are common diagnostic tools. CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, but generally not tumors under 1 cm.

Advances in nuclear medicine imaging, also known as molecular imaging, has 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. Neuronedocrine tumours express somatostatin receptors providing a unique target for imaging. Octreotide is a synthetic modifications 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 OctreoScan.

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.

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.

Classification

1.WHO

The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin:

  • well-differentiated neuroendocrine tumours, further subdivided into tumors with benign and those with uncertain behavior
  • well-differentiated (low grade) neuroendocrine carcinomas with low-grade malignant behavior
  • poorly differentiated (high grade) neuroendocrine carcinomas, which are the large cell neuroendocrine and small cell carcinomas.

Additionally, the WHO scheme recognizes mixed tumors with both neuroendocrine and epithelial carcinoma features, such as goblet cell cancer, a rare gastrointestinal tract tumor.

Placing a given tumor into one of categories depends on well-defined histological features: size, lymphovascular invasion, mitotic counts, Ki-67 labelling index, invasion of adjacent organs, presence ofmetastases and whether they produce hormones.

2.Anatomic distribution

Traditionally, neuroendocrine tumors have been classified by their anatomic site of origin. NETs can arise in many different areas of the body, and are most often located in the intestine, pancreas or the lungs. The various kinds of cells that can give rise to NETs are present in endocrine glands and are also diffusely distributed throughout the body, most commonly Kulchitsky cells or similar enterochromaffin-like cells, that are relatively more common in the gastrointestinal and pulmonary systems.

NETs include certain tumors of the gastrointestinal tract and of the pancreatic islet cells, certain thymus and lung tumors, and medullary carcinoma of the parafollicular cells of the thyroid. Tumors with similar cellular characteristics in the pituitary, parathyroid, and adrenomedullary glands are sometimes included or excluded.

Within the broad category of neuroendocrine tumors there are many different tumor types: this outline is presented to facilitate retrieving information. Neuroendocrine tumors are uncommon in many of these areas, and frequently represent only a very small proportion of the tumors or cancers at these locations.

  • Pituitary gland: Neuroendocrine tumor of the anterior pituitary
  • Thyroid gland: Neuroendocrine thyroid tumors, particularly medullary carcinoma
  • Parathyroid tumors
  • Thymus and mediastinal carcinoid tumors
  • Pulmonary neuroendocrine tumors
    • bronchus
    • pulmonary carcinoid tumors: typical carcinoid (TC; low-grade); atypical carcinoid (AC; intermediate-grade)
    • small-cell lung cancer (SCLC)
    • large cell neuroendocrine carcinoma of the lung (LCNEC)
  • Extrapulmonary small cell carcinomas (ESCC or EPSCC)
  • Gastroenteropancreatic neuroendocrine tumors (GEP-NET)
    • Foregut GEP-NET (foregut tumors can conceptually encompasses not only NETs of the stomach and proximal duodenum, but also the pancreas, and even thymus, lung and bronchus)
      • Pancreatic endocrine tumors (if considered separately from foregut GEP-NET)
    • Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon)
      • appendix, including well differentiated NETs (benign); well differentiated NETs (uncertain malignant potential); well differentiated neuroendocrine carcinoma (with low malignant potential); mixed exocrine-neuroendocrine carcinoma (goblet cell carcinoma, also called adenocarcinoid and mucous adenocarcinoid)
    • Hindgut GEP-NET
  • Liver and gallbladder
  • Adrenal tumors, particularly adrenomedullary tumors
  • Pheochromocytoma
  • Peripheral nervous system tumors, such as:
    • Schwannoma
    • paraganglioma
    • neuroblastoma
  • Breast
  • Genitourinary tract
    • urinary tract carcinoid tumor and neuroendocrine carcinoma
    • ovary
    • neuroendocrine tumor of the cervix
    • testes
  • Merkel cell carcinoma of skin (trabecular cancer)
  • Several inherited conditions:
    • multiple endocrine neoplasia type 1 (MEN1)
    • multiple endocrine neoplasia type 2 (MEN2)
    • von Hippel-Lindau (VHL) disease
    • neurofibromatosis type 1
    • tuberous sclerosis
    • Carney complex

Prognosis - Neuroendocrine Tumors

Identifying the stage of disease is an important step in planning the appropriate treatment for neuroendocrine tumors. NETs may (1) be contained in a particular area of the body (localized), (2) have spread to nearby tissues or lymph nodes (regional), or (3) have spread throughout the body (metastatic). 

Unfortunately, more than 50 percent of NETs have already spread to other parts of the body by the time they are diagnosed. NETs metastasize most often to the liver, peritoneal cavity or bone.

Treatment - Neuroendocrine Tumors

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.

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.

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 approved FDA treatment for GEP-NETS. In this study, lanreotide showed a statistically significant improvement in progression-free survival, meeting its primary endpoint. Sixty five percent of patients treated with lanreotide in the study had not progressed or died at 96 weeks, as compared to 33% of patients whose disease had not progressed or died on placebo. This represented a 53% reduction in risk of disease progression or death with lanreotide based on a hazard ratio of .47. 

Other medications that block particular secretory effects can sometimes relieve symptoms.

Chemotherapy

Interferon is sometimes used to treat GEP-NETs. Its effectiveness is somewhat uncertain, but low doses can be titrated within each person, often considering the effect on the blood leukocyte count; Interferon is often used in combination with other agents, especially somatostatin analogs such as octreotide.

1. Gastronintestinal neuroendocrine tumors

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 showing 25 to 35% response rates that are typically less than 9 months.

The exceptions are poorly differentiated (high-grade or anaplastic) metastatic disease, where cisplatin with etoposide may be used and Somatostatin Receptor Scintigraphy (SSRS) negative tumors which had a response rate in excess of 70% compared to 10% in strongly positive SRSS carcinoid tumors.

Everolimus (Afinitor) is approved by the FDA in the indication Treatment of adult patients with progressive, well-differentiated, non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin, with unresectable, locally advanced or metastatic disease. Everomilus is also approved for locally advanced, metastatic or unresectable progressive NET of pancreatic origin. 

2. PanNETs

Some targeted therapies for pancreatic NETs include everolimus (Afinitor) and sunitinib (Sutent) in unresectable, locally advanced or metastatic PanNETs. Some PanNETs are more responsive to chemotherapy than gastroenteric carcinoid tumors. Several agents have shown activity and combining several medicines, particularly doxorubicin with streptozocin and fluorouracil (5-FU or f5U), is often more effective. Although marginally effective in well-differentiated PETs, cisplatin with etoposide is active in poorly differentiated neuroendocrine cancers (PDNECs).

Radionuclide therapy

Peptide receptor radionuclide therapy (PRRT) is a type of radioisotope therapy (RIT) in which a peptide or hormone conjugated to a radionuclide or radioligand is given intravenously, the peptide or neuroamine hormone previously having shown good uptake of a tracer dose, using Somatostatin receptor imaging as detailed above. This type of radiotherapy can attack all lesions in the body, not just liver metastases. The peptide receptor may be bound to lutetium-177, yttrium-90 or indium-111. 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.

Hepatic artery

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%. In hepatic artery chemotherapy, the chemotherapy agents are given into the hepatic artery, often by steady infusion over hours or even days. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.
  • Hepatic artery chemoembolization (HACE), sometimes called transarterial chemoembolization (TACE), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides.
  • Selective internal radiation therapy(SIRT) 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.

Other therapies

Radiofrequency ablation (RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and current is applied to generate heat; the tumor cells are killed by cooking.

Cryoablation is similar to RFA; an endothermic substance is injected into the tumors to kill by freezing. Cryoablation has been less successful for GEP-NETs than RFA

Resources - Neuroendocrine Tumors

Not supplied.
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