Neuroendocrine tumor

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What is a neuroendocrine tumor

What is a neuroendocrine tumor

Neuroendocrine tumours are rare tumors composed of neuroendocrine cells, which are cells that produce and secrete regulatory hormones and are present throughout the nervous and endocrine/hormonal systems. Neuroendocrine cells have features like nerve cells and hormone-producing cells, release hormones into the blood in response to signals from the nervous system. As neuroendocrine cells are distributed widely throughout your body, tumors of these cells can occur at many sites, but primary sites include the gastrointestinal tract, pancreas, rectum, lungs, and appendix. The majority of neuroendocrine tumors can be divided into two classes: carcinoid and pancreatic neuroendocrine tumors. Pheochromocytoma is a rare form of neuroendocrine tumor.

Most neuroendocrine tumors are malignant, except insulinoma. They commonly spread to the lymph nodes and the liver. Some other uncommon sites of distant spread include the bone, lung, brain and other organs. Despite the ability to metastasize/spread, most malignant neuroendocrine tumors are slow-growing. An exception is the poorly differentiated small cell neuroendocrine carcinoma, which is highly malignant, fast-growing, but rare.

Examples of neuroendocrine tumors are:

Carcinoid tumor;
Pancreatic neuroendocrine tumor or islet cell tumor;
Gastrinoma;
Insulinoma;
Glucagonoma;
VIPoma (vasoactive intestinal polypeptide tumor);
Paraganglioma;
Pheochromocytoma;
Medullary thyroid carcinoma;
Poorly differentiated small cell neuroendocrine carcinoma.
Glucagonomas are among the rarest of the neuroendocrine tumors.

Neuroendocrine tumors are generally rare. The incidence of pancreatic neuroendocrine tumor is 0.1-1 per million per year. Over 100,000 people in the U.S. are living with neuroendocrine cancers. It is estimated that over 12,000 people are diagnosed each year, and the number of those diagnosed is increasing by more than five percent annually. The majority of all neuroendocrine tumor patients are initially misdiagnosed, and the time from onset of symptoms to proper diagnosis often exceeds five years. Because symptoms vary widely depending on where the cancer happens, a diagnosis is frequently made only after the cancer has spread/metastasized to other parts of the body.

Many physicians and specialists are not aware of current diagnostic and treatment options. Too often, doctors still believe neuroendocrine tumors are benign, slow growing, and do not metastasize. The most prevalent symptoms are diarrhea, constipation, flushing, abdominal pain, wheezing, heart palpitations, and blood pressure fluctuations.

Depending on whether the neuroendocrine tumors lead to a specific clinical syndrome, they are termed “functionally active” and “functionally inactive”. Functionally active neuroendocrine tumors produce clinical symptoms because of excessive hormone release from the tumor cell.

Examples of neuroendocrine tumors that may be functionally active are:

insulinoma,
gastrinoma,
VIPoma,
glucogonoma (producing the glucagonoma syndrome),
carcinoid tumor (producing the carcinoid syndrome).

Neuroendocrine carcinoid tumor

Carcinoid commonly refers to neuroendocrine tumors that originate in the gastrointestinal (GI) tract, lungs, appendix and thymus, although they can also occur in the lymph nodes, brain, bone, gonads (ovaries and testes) and skin. Carcinoid tumors are usually indolent (slow-growing) by nature and develop over the course of many years, however, aggressive, fast-growing forms of carcinoid cancer also exist.

Carcinoid tumors can secrete a variety of functional hormones and chemicals although not all carcinoid tumors do. A few of the substances that are commonly secreted by carcinoid tumors are: serotonin, chromogranin A, histamine, pancreatic polypeptide and gastrin. Carcinoid tumors are referred to as functioning if they secrete hormones that cause a clinical syndrome.

Functioning carcinoid tumors that occur in the digestive tract and pancreas release the substances they produce directly into the hepatic portal vein (a blood vessel in the abdominal cavity) which carries them directly to the liver where they are metabolized (broken down). Since the liver metabolizes these substances, their message is not sent to the rest of the body. Consequently, tumors of the digestive tract and pancreas are not usually detected until they have metastasized to the liver or cause obstructive symptoms.

When carcinoid metastasizes to the liver, the liver is not always able to metabolize all of the hormones secreted. This excess of hormone called hypersecretion can cause an array of symptoms called carcinoid syndrome.

Carcinoids that occur in areas outside of the intestine and pancreas such as the lung and stomach do not release their hormones into the hepatic portal vein but release them directly into the bloodstream, bypassing the liver. Consequently, individuals with carcinoid in these locations can sometimes develop carcinoid syndrome without liver metastases as well as other symptoms and syndromes.

Common symptoms associated with Carcinoid Syndrome include diarrhea, flushing of the skin, abdominal cramping, asthma, arthritis, niacin deficiency, swelling of the feet, and wheezing. Carcinoid Syndrome occurs in approximately 10% of all individuals diagnosed with carcinoid and can lead to right-sided heart failure. Carcinoid Syndrome is most common in individuals with liver metastases from ileal carcinoids.

Individuals with Carcinoid Syndrome can also experience carcinoid crisis which can occur spontaneously or be stress induced. A Carcinoid Crisis can be a life-threatening event that requires careful monitoring. Symptoms of a Carcinoid Crisis may include severe hypotension or hypertension, irregular and/or rapid heartbeat, wheezing, prolonged flushing, severe dyspnea (shortness of breath), and peripheral cyanosis (lack of oxygenated blood).

Carcinoid is classified as a rare cancer. Recent studies have determined that 4 to 5 out of every 100,000 people are diagnosed yearly with a neuroendocrine tumor and that there are over 100,000 people currently living with neuroendocrine tumors within the United States. For reasons not well understood, the incidence of carcinoid is rising. Since most individuals with carcinoid are asymptomatic until the tumors metastasize, the average time between tumor development and diagnosis is between 5 to 10 years. Survival rates for individuals with carcinoid vary and depend on tumor type, location, extent of metastases, and many other factors. Currently, surgery is the only cure for localized tumors (those which have not spread) and there is no cure for metastatic carcinoid.

Neuroendocrine carcinoid tumor classifications

Carcinoid tumors can develop almost anywhere in the body. Carcinoid tumors can be classified by location, histology and biological activity in the following way:

Embryonic Gut Derivation

Foregut Carcinoid Tumors

Carcinoid tumors located in the lungs, thymus, stomach, first part of the duodenum (small intestine), or the pancreas.

Gastric Carcinoids (carcinoids of the stomach) are further classified as:

Type 1: Associated with chronic atrophic gastritis (inflammation of the stomach lining) caused by hypergastrinemia (high levels of the hormone gastrin).
Type 2: Implicated with Zollinger Ellison Syndrome and MultipleEndocrine Neoplasia Type 1 (MEN-1).
Type 3: Sporadic, not associated with hypergastrinemia, can cause Atypical Carcinoid S yndrome and are frequently malignant.

Neuroendocrine tumor lung (carcinoids in the lungs) are further classified as:

Typical Pulmonary Carcinoids (benign or low-grade malignant): Considered to be well-differentiated, commonly located in the center of the lungs, and rarely metastasize.
Atypical Pulmonary Carcinoids (low-grade malignant): Poorly differentiated, commonly located in the periphery of lungs, characterized by frequent mitoses (cellular division), and frequently metastasize.

Midgut Carcinoid Tumors

Located in the small intestine, appendix, or right colon (large intestine).

Hindgut Carcinoid Tumors

Located in the transverse colon, sigmoid colon, or rectum.

Presence of Clinical Syndrome

Functioning

A functioning carcinoid tumor secretes biochemically active substances such as hormones, which cause specific clinical syndromes such as Carcinoid Syndrome or Zollinger-Ellison syndrome.

Non-functioning

A non-functioning carcinoid tumor secretes specific substances but these substances are either inactive and/or do not cause any clinical syndrome.

Inherited Versus Sporadic

Sporadic

Cancer causing mutations arise randomly

Inherited

Cancer causing mutations are inherited due to MEN-1 or other familial factors

Carcinoid tumors can be familial or sporadic. Inherited carcinoid cancer refers to carcinoid cancer which is genetically inherited whereas sporadic carcinoid cancer has no hereditary basis. Carcinoid tumors are generally thought to be sporadic, except for a small proportion of which occur as a part of MEN (multiple endocrine neoplasia) syndromes. Other familial factors contribute to a small proportion of carcinoid tumors; these are less understood than MEN-1 causes.

Histological Features

Carcinoid tumors are graded based on how fast they are growing. The World Health Organization in 2017 updated the classification system based upon their clinical pathological criteria, regardless of origin, size, or anatomical extent of the tumor.

Grade 1 (Low grade) well-differentiated
Grade 2 (Intermediate grade) well-differentiated
Grade 3 (High grade) poorly differentiated, occasionally well-differentiated

Differentiation is based on one measure called a Ki-67 index. The Ki-67 index calculates the number of cells that are dividing as a way to see if it is a slow-growing (well differentiated) or fast-growing tumor (poorly differentiated). Well-differentiated tumors have a Ki-67 index below 20% and poorly differentiated tumors have a Ki-67 index between 20-100%.

Neuroendocrine carcinoid tumor symptoms

Carcinoid tumors can cause life-threatening symptoms from both hormone hypersecretion (over production) as well as tumor growth and invasion. The majority of individuals with carcinoid tumors are asymptomatic until the tumors metastasize to the liver and cause symptoms of tumor secretion. However, as the tumors grow they can cause obstructive symptoms.

Obstructive Symptoms

Midgut and Hindgut

Individuals with midgut and (in rare cases) hindgut carcinoids may experience symptoms such as abdominal pain, nausea, and vomiting, even though diagnostic scanning shows nothing. Many individuals diagnosed with liver metastases have reported having undiagnosed abdominal pain for several years prior to their diagnosis of carcinoid.

Foregut

Individuals with bronchial (lung) carcinoids most commonly present with obstructive symptoms. These symptoms may include chronic lung infection such as bronchitis and pneumonia, breathing difficulties, chest pain, and chronic cough. Less commonly, symptoms may include weakness, nausea, sweating, and Cushing’s Syndrome.

Carcinoid Syndrome

Carcinoid tumors can secrete a variety of hormones which can cause many clinical symptoms such as flushing and diarrhea. Symptoms occurring together may be classified as a syndrome. Carcinoid Syndrome occurs in approximately 10% of individuals with carcinoid tumors and is most commonly found in individuals with midgut carcinoid tumors that have metastasized to the liver. In midgut carcinoid tumors, carcinoid syndrome does not normally develop until the tumors have metastasized since the liver is able to break down the excess hormones produced by these tumors. However, once the tumors develop in the liver, the liver is no longer able to break down the excess hormones, and symptoms from them may occur. Carcinoid tumors that develop outside of the midgut can cause carcinoid syndrome without liver metastases, but rarely do.

Typical Carcinoid Syndrome

Typical Carcinoid Syndrome is the most common form of Carcinoid Syndrome and is most often caused by midgut carcinoids that have metastasized to the liver. Excess serotonin is the hormone most frequently related to Carcinoid Syndrome. The syndrome is characterized by brief episodes of flushing, diarrhea, cough, wheezing, shortness of breath, heart disease, and in rare cases, pellagra. Flushing and diarrhea are the two main symptoms that are associated with Carcinoid Syndrome. Diarrhea can be mild to severe which may lead to weight loss and lifestyle changes. The flushing may be light pink to a deep red and occurs in the face and in the nipple-line. It may be triggered by stress, alcohol, exercise and certain types of foods.

Atypical Carcinoid Syndrome

Atypical Carcinoid Syndrome is rare and is associated with foregut carcinoid tumors. It is characterized by extended episodes of flushing, headache, shortness of breath, and in rare cases, lacrimation (tears). The flushing can be deep purple and last for hours. It may be followed by increased blood flood to the limbs (arms and legs) and to the trunk (chest, stomach and back). This flush is not brought on by food.

Carcinoid Crisis

Individuals with Carcinoid Syndrome can also experience Carcinoid Crisis which can occur spontaneously or be stress induced. A Carcinoid Crisis can be a life-threatening event that requires careful monitoring. Symptoms of a Carcinoid Crisis may include severe hypotension or hypertension, irregular and/or rapid heartbeat, wheezing, prolonged flushing, severe dyspnea (shortness of breath), and peripheral cyanosis (lack of oxygenated blood).

Carcinoid Heart Disease

Carcinoid tumors can secrete a variety of hormones and vasoactive substances such as serotonin. When these substances are released from liver metastases, the right side of the heart is exposed to them. As a result, patients may experience Carcinoid Heart Disease characterized by plaque lesions in the right side of the heart. Carcinoid Heart Disease can cause right-sided heart failure. Carcinoid Heart Disease is most common on the right side of the heart but can also occur on the left side. While serotonin production is related to development of Carcinoid Heart Disease, there is evidence of increased cardiac lesions during somatostatin analog therapy. All carcinoid cancer patients should be familiar with Carcinoid Heart Disease and discuss appropriate monitoring with their physician.

Cushing’s Syndrome

Bronchial (lung) carcinoid tumors can also secrete the adrenocorticotropic hormone (ACTH) which may cause Cushing’s Syndrome. Cushing’s Syndrome is characterized by excessive upper body weight gain, skin disorders (bruising and poor healing), baldness, and psychological disorders such as depression and anxiety.

Zollinger-Ellison Syndrome

Gastrinomas hypersecrete (over produce) gastrin causing Zollinger-Ellison Syndrome. Symptoms of Zollinger-Ellison Syndrome include diarrhea and peptic-ulcers. Patients with Zollinger-Ellison Syndrome may also develop gastric carcinoid as a result of prolonged gastrin hypersecretion.

Neuroendocrine carcinoid tumor diagnosis

Carcinoid tumors, like many neuroendocrine tumors, can be very difficult to diagnose. It is common for individuals with carcinoid cancer to remain asymptomatic until the tumors have metastasized or grown large enough to affect normal bodily functions. After an individual develops symptoms, diagnosis can be problematic since the symptoms of carcinoid cancer can mimic other diseases.

If your physician suspects you have a carcinoid tumor, there are specific biochemical tests which measure tumor markers and imaging tests that can help confirm a diagnosis and potentially determine the tumor type, location, load, and prognosis. A tissue biopsy of a suspected tumor is, in most cases, the only definitive test.

If you have already been diagnosed with carcinoid cancer, biochemical and imaging tests are very important tools for disease staging and clinical management.

Biochemical Testing for Carcinoid

Neuroendocrine tumors, such as carcinoid, produce a variety of substances which include hormones, proteins, and biogenic amines. Some tumors are termed functional since they are able to secrete an active form of these substances, which can cause a specific clinical syndrome such as Carcinoid Syndrome, Zollinger-Ellison Syndrome, and Cushing’s Syndrome. However, most carcinoid tumors are non-functioning and are not associated with a characteristic clinical syndrome either because the substances secreted are biologically inactive or because they do not cause any specific symptoms.

The substances secreted by a carcinoid tumor can be measured by biochemical tumor markers. Biochemical tumor markers can be divided into two categories: those which are specific to a particular carcinoid tumor location and those which are general. The most common tumor markers are:

Chromogranin A (CgA) in Carcinoid

Chromogranin A is a secretory protein that is common to most neuroendocrine tumor cells, including carcinoid and is a general tumor marker for neuroendocrine tumors. Since it is secreted into the bloodstream it can be measured by a simple blood test. Blood plasma levels of CgA have been shown to relate to prognosis. In patients treated with somatostatin analogues, CgA should be used with caution as somatostatin analogs can affect CgA levels. It has been recommended that CgA readings be taken at consistent time periods from somatostatin analog treatment.

5-hydroxyindoleacetic acid (5-HIAA) Testing in Carcinoid

5-HIAA is a metabolite (a product from the breakdown) of serotonin. Serotonin is one of the most commonly secreted hormones by carcinoid tumors of the midgut and sometimes those of the foregut. Consequently, 5-HIAA is usually elevated in midgut carcinoids but not in any others. A 24-hour urine collection is used to measure 5-HIAA levels. While 5-HIAA levels are commonly used to monitor patients with metastatic carcinoid tumors, studies have documented metastatic carcinoid tumors without elevated 5-HIAA levels. 5-HIAA can also be elevated in patients with celiac, Whipple’s disease, and afterward in those eating tryptophan-rich foods.

Certain foods such as bananas, walnuts, avocados, and caffeine can also have an effect on 5-HIAA levels. Be sure to speak with your physician for a complete list before testing.

All neuroendocrine tumors, including carcinoid tumors, secrete hormones. However, what they secrete depends upon the type of tumor and the tumor location. Secretions of neuroendocrine tumors can sometimes change over time and so your physician may recommend evaluating a panel of markers over time. Generally speaking, all markers should be evaluated at a fasting state and at a consistent interval from long-acting somatostatin analog treatment.

Cardinoid Tumor Imaging

Along with biochemical testing, there are several imaging techniques which are useful to help determine a carcinoid tumor’s location, size, and extent of metastases. The imaging technique used and the combination thereof depend upon the primary tumor type, location, presence or absence of hormonal symptoms (functioning vs. non-functioning), and extent of the disease. Imaging is especially important when liver metastases are suspected because liver function tests can be an unreliable predictor of liver metastases.

Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)

Computed Tomography (CT) is an imaging technique that uses a highly specialized X-Ray machine and computers to create multiple cross sectional images of the body. CT can generate images of different body tissues as well as help detect tumors.

Magnetic Resonance Imaging (MRI) uses radio waves, a powerful magnetic field and a computer to generate detailed (2 or 3 dimensional) images of the body. These images are very useful in contrasting different types of tissue as well as detecting abnormal growths such as tumors within the body. MRI can create better images than CT, but is less commonly used.

CT/MRI are useful imaging techniques when used to visualize foregut carcinoids (those of the lungs, thymus, stomach and pancreas), to define the extent of metastasis (particularly liver and lymph-node metastasis), and to image secondary effects of midgut and hindgut carcinoids (such as scaring of the intestinal wall caused by tumor growth). CT/MRI can be used to detect midgut carcinoids although the detection of midgut carcinoids is often difficult due to the environment of the intestine and tumor size.

Somatostatin Receptor Scintigraphy

Somatostatin Receptor Scintigraphy is a type of radionuclide scan that uses the radionuclide (radioactive substance), such as 111-In-DTPA-octreotide, with a highly specialized machine to detect carcinoid tumors. The radionuclide is injected into a patient’s vein, it can travel through the bloodstream and bind to carcinoid tumors.

Octreotide acetate is a synthetic (man-made), radio-labeled analogue of the naturally occurring hormone somatostatin. Over 90% of all carcinoid tumor cells have receptors for somatostatin. Octreotide acetate, like somatostatin, is able to bind to two of the five receptors (receptors two and five) on carcinoid tumors.

Somatostatin Receptor Scintigraphy is used to find the tumors which bind octreotide acetate. If the octreotide acetate binds to the tumors, doctors can visualize them through the use of an imaging machine. Scans can be done at different intervals following an octreotide acetate injection: 4 hours, 24 hours and 48 hours. However, a scan at 24 hours after octreotide injection is preferred. An octreotide scan is able to detect carcinoid tumors that bind octreotide and are larger than 1 – 1 1/2cm.

Patients who are being treated with a somatostatin analogue are strongly encouraged to temporarily discontinue treatment before undergoing Somatostatin Receptor Scintigraphy because somatostatin analogues used for treatment and for the scan compete for the same receptors. Patients should speak with their physicians to determine when and for how long they should discontinue treatment to maximize Somatostatin Receptor Scintigraphy.

Somatostatin Receptor Scintigraphy is not only useful in imaging carcinoid tumors but is also commonly used to predict response to somatostatin analogue therapy as well as peptide receptor radionuclide therapy.

Positron Emission Tomography (PET)

Positron Emission Tomography (PET) is another form of radionuclide scan that uses a radioactive material and a special scanning device to detect cancerous tumors. Most commonly, the radionuclide 18F-labelled deoxyglucose (FDG) is used to detect many forms of cancer. However, FDG is not effective in detecting most carcinoid tumors with the exception of tumors with high proliferative activity and low differentiation. Instead, 68Ga-DOTA-TOC is the radionuclide that is most commonly used with PET to detect carcinoid.

PET with 68Ga-DOTA-TOC works in a similar fashion to octreotide in that like octreotide,68Ga-DOTA-TOC is able to bind to specific receptors on carcinoid tumors. Once bound, the tumors can be visualized with a PET scan. However, 68Ga can be accumulated much faster by carcinoid tumors and so the scan for the tumors can be done approximately one hour after the 68Ga has been administered. There is evidence that like SRS, 68Ga can be used to predict response to PRRT. 68Ga-DOTA-TOC has been effective in detecting carcinoid tumors that are greater in size than 0.5 cm.

Other radionuclides that are used with PET are: 11C-labelled L-dihydroxyphenylalanine, 18F L-dihydroxyphenylalanine, and 5-Hydroxly-L-tryptophan.

Endoscopy

Endoscopy is a medical procedure that uses an endoscope to view the lining of multiple organs and tracts of the body. An endoscope is a flexible or rigid tube that has imaging capabilities and can enable small surgical procedures. Endoscopy can be used to visualize carcinoid tumors in the lungs and gastrointestinal tract (stomach, small and large intestine and rectum).

Neuroendocrine carcinoid tumor treatment

Due to their varied nature and primary locations, carcinoid cancers can be very difficult to treat. Carcinoid tumors can be benign to highly malignant, indolent (slow growing) to very aggressive in development, and range from asymptomatic to causing debilitating syndromes. As a result, a multi-disciplinary team consisting of specialist physicians in neuroendocrine tumors (gastroenterologists, oncologists, and endocrinologists), surgeons, radiologists, nuclear medicine specialists, histopathlogists, and clinical nurse specialists are often recommended.

Treatment must be tailored to each patient’s tumor burden and symptoms. Treatments may be focused on inhibiting tumor growth or symptom relief. Often, this means that any given treatment plan may consist of a combination and/or series of several treatments. Be sure to discuss your treatment options thoroughly with your physician(s). Ultimately, all treatment decisions should be made by the patient.

Surgery for Carcinoid Tumors

The surgical treatment of carcinoid tumors depends on the tumor type, location, extent of metastases, as well as other factors. Surgery can often be curative for individuals whose tumors are localized (have not spread) and do not cause syndrome. For individuals who have metastases, surgery can often increase survival and provide palliative care depending on tumor size and location. A multimodal approach combining surgery with embolization or other treatment methods may also be possible for patients with liver metastases. For all patients who undergo surgery, continued and extensive follow up is recommended.

Carcinoid Tumors of the Appendix

Carcinoid tumors are the most common appendiceal tumor and most frequently are benign. These tumors are often incidentally discovered during surgery and are usually removed by an appendectomy. An appendectomy is the complete removal of the appendix, which can be done either laparoscopically or as an open procedure. Low incidence of metastasis has been observed in patients undergoing appendectomy with tumors smaller than two cm.

Carcinoid Tumors of the Intestine

The majority of carcinoid tumors originate in the gastrointestinal tract. Of these, intestinal carcinoids are the most common. After diagnosis of an intestinal carcinoid, a small bowel resection may be preformed. A small bowel resection is the surgical removal of one or more parts of the small intestine. The extent of the resection depends on a variety of factors, including tumor size, number, and extent of metastasis. If the tumor has metastasized to the surrounding tissues and liver, a more invasive surgery may be conducted. In certain cases, the removal of these tumors can help to decrease Carcinoid Syndrome, alleviate abdominal pain, prevent further metastases and increase survival.

Carcinoid Tumors of the Liver

The liver is the most common site for carcinoid tumors to metastasize but it is rare for the liver to be the primary site of carcinoid development. The type and extent of surgery for liver metastasis is contingent upon tumor type, size, location, disease progression, site of origin and other factors. Liver resection, the surgical removal of part of the liver, is a common treatment protocol for individuals for whom a complete resection is possible. For individuals for whom a complete resection is not possible, surgery, in combination with other treatment modalities, may be used to debulk (decrease) tumor burden. Resection and debulking (for individuals for whom the majority of tumor burden is removed) have resulted in increased survival and a decrease in disease symptoms. Presence of liver metastasis is a major prognostic factor with presence of liver metastasis indicating worse outcome.

In certain cases, a two-stage surgical resection can be done for patients with extensive liver metastases. The first phase of a two-stage resection involves the radical resection of a portion of the left side of the liver with right portal vein ligation to encourage the left side of the liver to regenerate. After the liver is allowed to regenerate, the right side of the liver is then removed.

In a very small group of individuals with carcinoid liver metastases, orthotopic liver transplantation has been used. Orthotopic liver transplantation is the process in which the diseased liver is completely removed and replaced with a healthy, donor liver.

Currently, there is little clinical evidence on the results of radical, two-part liver resections and orthotopic liver transplantation. Due to the lack of clinical evidence, the benefit of these procedures, in particular orthotopic liver transplantation, has yet to be determined.

Carcinoid Tumors of the Lung

Bronchial carcinoid tumors can develop almost anywhere in the lungs. Surgical management is the recommended treatment for most bronchial carcinoids. The type and extent of the surgery depends on the nature, location and size of the tumor(s). A lobectomy, which is the surgical removal of one lung lobe, is the most common surgical method used to treat bronchial carcinoids. If more than one lobe is affected and surgery is possible, an individual may undergo a bilobectomy, which is the surgical removal of two lung lobes or a pneumonectomy, which is the surgical removal of a lung. A sleeve resection, which is the surgical removal of a section of bronchus or trachea along with the infected lobe, may also be used to remove bronchial carcinoids. A wedge resection, which is the surgical removal of the affected lung tissue and the surrounding margins, may be used to remove the tumor and leave the lung lobe. A wedge resection is less invasive than a lobectomy and is the preferred treatment method when clinically possible.

Carcinoid Tumors of the Lymph Nodes

Lymph nodes are often the site of carcinoid metastases. When an individual is diagnosed with carcinoid and is a surgical candidate, the lymph nodes surrounding the affected area should be examined for metastases and removed if affected. A lymphadenectomy is the surgical removal of one or more groups of lymph nodes.

Rectal Carcinoids

Rectal carcinoids represent just over 10% of all carcinoids and are most commonly incidentally found during routine endoscopic cancer screenings. Treatment of rectal carcinoids depends on the size and invasiveness of the tumor. Tumors that are < 1 cm can usually be treated by an endoscopic excision, a minimally invasive surgical procedure which involves the removal of the tumor and the surrounding tissues. However the histological features of these tumors should still be examined to make sure they have not invaded the surrounding tissue. Tumors that are ≥1 cm will need further investigation and depending on size and invasiveness may require a rectal resection, the surgical removal of a portion of the rectum.

Stomach Carcinoids

The surgical removal of gastric carcinoids will depend on their type, size, quantity, extent of invasiveness and response to somatostatin analogues. Endoscopic excision, a minimally invasive surgical procedure, can be used for smaller type I and II gastric carcinoids. A gastric resection (gastrectomy), the partial or complete surgical removal of the stomach, may be done for individuals who have large and multiple type I or II gastric carcinoids as well as for nearly all type III gastric carcinoids.

Non-Surgical Therapies for Carcinoid Tumors

If curative surgery is not possible, other treatment options are available to individuals with carcinoid cancer. Currently, there is no non-surgical curative treatment, but there are several non-surgical treatment options which can result in decreasing tumor bulk, halting tumor progression, and/or managing tumor symptoms. The type of treatment used is determined by tumor type, size, location, disease progression, as well as many other factors.

Somatostatin Analogues

The excess of hormones produced and secreted into the body by carcinoid tumors can cause several symptoms, which when grouped together may be classified as a syndrome, such as Carcinoid Syndrome or Cushing’s Syndrome. Most neuroendocrine tumors, including carcinoid, have five highly specialized receptors for the naturally occurring hormone somatostatin. When somatostatin is bound to these receptors, especially receptors two and five, it inhibits the release of the various hormones that cause many of the symptoms associated with carcinoid tumors. Synthetic analogues (man-made versions) of somatostatin can mimic somatostatin by binding to receptors two and five and inhibiting hormone secretion. Currently, there are two synthetic somatostatin analog products available. These somatostatin analogs have been proven to control, decrease and prevent symptoms associated with carcinoid. In a recent study, octreotide also demonstrated possible antitumor effects when compared to a placebo in patients with well-differentiated carcinoid tumors of midgut origin, limited hepatic tumor mass and a resected primary tumor.

Interferon-α

Interferons are naturally occurring proteins that are secreted by specialized cells in the body to activate the body’s natural protective response to harmful substances including some tumors. There are many types of interferon produced by the body. A synthetic version of one type, interferon-α, can be used in combination with somatostatin analogue for symptom management in individuals whose symptoms are not controlled by somatostatin analogues. However, interferon-α can have severe side-effects, such as myelosuppression (the decrease in bone marrow activity resulting in lower blood cell levels), fatigue, depression and changes in thyroid function.

Cytotoxic Chemotherapy

Cytotoxic chemotherapy is the use of anticancer drugs that target and kill rapidly proliferating (dividing) cells. Thus far, there has been little clinical evidence for the use of chemotherapeutic drugs in the treatment of well-differentiated (typical) carcinoid tumors. However, studies have demonstrated that poorly differentiated (atypical) carcinoid tumors are more responsive to chemotherapeutic drugs.

Ablative Therapies

Hepatic Artery Embolization

All cells require an adequate blood supply to survive. The human liver has two main sources of blood: the portal vein and hepatic artery. The portal vein supplies blood to most liver cells while tumor cells mostly depend on the hepatic artery for their blood supply. A hepatic embolization is a non-surgical procedure which involves the blockage of selective branches of the hepatic artery that supply tumor cells with blood. This blockage is made possible by the injection of embolic particles (specialized particles that cause a blockage) which travel to and cut off tumor blood supply. There are two types of embolization of the hepatic arteries: 1) bland embolization – the injection of just embolic particles, and 2) chemoembolization – the injection of embolic particles and chemotherapeutic agent (drug).

Individuals with liver metastases may be considered candidates for hepatic embolization or hepatic chemoembolization if they have non-resectable liver metastases, uncontrolled growth of liver metastases and/ or uncontrolled symptoms. However, other factors such as physical health and the extent of tumor growth must also be taken into consideration. These procedures can have very positive but short-term results of: a decrease in tumor size, a decrease in tumor symptoms, and a halt in tumor progression. Duration of response is highly variable. Individuals who are candidates may undergo more than one embolization.

Common side-effects of either procedure can include fever, fatigue, abdominal pain, nausea and vomiting. The severity of these varies for each individual.

Radioembolization

Radioembolization is a form of selective internal radiation therapy. It is a minimally invasive procedure that combines embolization and radiation therapy to target liver metastases. Radioembolization involves the injection of millions of radioactive microspheres (microscopic beads) into a branch of the hepatic artery which supplies blood to the tumor. From there, the microspheres travel to the tumor site where they inhibit the blood supply to the tumor and emit radiation effectively killing tumor cells.

Currently, there are two radioactive microsphere products available for patients with metastatic tumors to the liver, one made of glass and the other resin. Both products use Yttrium-90 (90Y), a beta emitting radionuclide. Individuals with liver metastases may be considered candidates for hepatic embolization or hepatic chemoembolization if they have non-resectable liver metastases, uncontrolled growth of liver metastases and/ or uncontrolled symptoms. Other factors such as physical health, extent of tumor burden and prior treatment therapies must also be taken into consideration. These procedures can have very positive but short-term results of: a decrease in tumor size, a decrease in tumor symptoms, and a halt in tumor progression. Currently, the role of radioembolization in combination with other therapies is not well understood.

Common side-effects of radioembolization can include fever, abdominal pain, fatigue, nausea and vomiting. The severity of these varies for each individual.

Radiofrequency Ablation

Radiofrequency ablation is a minimally invasive procedure that uses a high frequency electrical current to destroy tumor cells. Radiofrequency ablation involves placing a small probe into a tumor. Electrical currents (which are at the same range of radiofrequency) are sent through the probe. This effectively raises the temperature of the tumor tissue and destroys it. Radiofrequency ablation can be done laparoscopically but is more commonly done in combination with liver resection.

Individuals with inoperable carcinoid tumors may be candidates for radiofrequency ablation. Radiofrequency ablation has been shown to temporarily decrease tumor burden, stall tumor progression and temporarily relieve tumor symptoms. There are many limitations to radiofrequency ablation, including tumor size and tumor location. Tumors that are greater in diameter than 3 cm are difficult to eradicate and radiofrequency ablation cannot be used in tumors that are greater in diameter than 5 cm.

Peptide Receptor Radionuclide Therapy

Most neuroendocrine tumors, including carcinoid, have five highly specialized receptors that bind to the naturally occurring hormone somatostatin. A synthetic analogue (a man-made version) of somatostatin that is able to attach to two of these five somatostatin receptors.

Peptide receptor radionuclide therapy combines synthetic analogue with a radionuclide (a radioactive substance) to form highly specialized molecules called radiolabeled somatostatin analogues or radiopeptides. These radiopeptides can be injected into a patient and will travel throughout the body binding to carcinoid tumor cells that have receptors for them. Once bound, these radiopeptides emit radiation and kill the tumor cells they are bound to.

There are three radionuclides used to create radiopeptides: indium 111 (111In), yttrium 90 (90Y) and lutetium 177 (177Lu). These radiopeptides differ in the type of radiation they emit as well as the depth of tissue into which they penetrate. Tissue penetration is an important factor since a certain range of radiation is necessary to kill tumor cells but not damage surrounding, healthy tissues. 111In emits both Auger electrons and γ-radiation and has the shortest range of tissue penetration (10 µm), 90Y emits β-radiation and has a range of 12 mm, and 177Lu emits both β-radiation and γ-radiation and has a range of 2 mm ¹.

Studies have shown that in certain individuals, the short-term results of peptide receptor radionuclide therapy with 177Lu and 90Y (and 111In to a much lesser degree) are: a decrease in tumor size, a decrease in symptoms, and a halt in tumor progression.

Common side-effects of radiopeptide therapy are nausea, vomiting, and abdominal pain. Other less common side-effects are bone, liver and kidney toxicity, and mild hair loss.

Individuals whose tumors can be visualized by somatostatin receptor scintigraphy or 68 GA –DOTATE PET/ CT and have inoperable carcinoid tumors that are growing or individuals whose symptoms are not well managed by somatostatin analogues may be candidates for peptide receptor radionuclide therapy. However, the extent of tumor growth, kidney function, liver function, prior treatments, and many other factors must also be considered.

Molecular Targeted Therapies

Carcinoid tumors are formed by an abnormal growth of cells within the body. Normally, the growth and replication of all cells within the body is strictly regulated at a molecular and genetic level. However, tumors are made up of cells that have undergone multiple mutations in their genetic code, which allow them to grow and replicate without the normal controls. By understanding what molecular and genetic mutations have occurred, scientists can develop drug therapies that target these mutations (targeted therapies) effectively stopping tumor cell growth and even promoting tumor cell death. At this time, there are two molecular pathways for which novel targeted therapies are being developed.

Vascular Endothelia Growth Factor (VEGF) Inhibitors

All cells require an adequate blood supply to survive. Cancer cells, since they tend to replicate faster than normal cells, require an even greater blood supply. In order to achieve this, many tumors, including carcinoid, undergo angiogenesis, the development of new blood vessels. Vascular endothelial growth factor (VEGF) is a highly specialized chemical signal that cells produce in order to stimulate new blood vessel growth. In carcinoid tumors, this signal is over expressed. Targeted therapies called angiogenic inhibitors are currently being investigated to see if they can effectively suppress VEGF in carcinoid or inhibit pathways that would disrupt its production or effects.

Mammalian Target of Rapamycin (mTOR) Inhibitors

Normally, cells that have unfixable mutations in the genetic code will undergo apoptosis (programmed cell death). Carcinoid tumors cells, like other cancer cells, do not do this. Instead, their growth and death is unregulated. The mammalian target of rapamycin (mTOR) is a protein that is involved in many cellular pathways including cell growth and death. In carcinoid, mTOR is not regulated and consequently promotes tumor cell growth. Targeted therapies called mTOR inhibitors deactivate mTOR and prevent cellular growth and replication. FDA has approved a mTOR inhibitor for neuroendocrine tumor cancer.

Pancreatic neuroendocrine tumor

Pancreatic neuroendocrine tumors can include: nonfunctional tumors, insulinomas, glucagonomas, gastrinomas, VIPomas, somatostatinomas, GHRHomas, and other less frequent tumors. Pancreatic neuroendocrine tumors are usually indolent (slow-growing) by nature and develop over the course of many years, however, aggressive, fast growing pancreatic neuroendocrine tumors exist and different types of pancreatic neuroendocrine tumors exhibit different clinical courses and growth rates. Pancreatic neuroendocrine tumors vary in clinical course, location, and hormone secretion. Pancreatic neuroendocrine tumors can occur outside of the pancreas such as the duodenum and small intestine.

Since neuroendocrine tumor cells are derived from neuroendocrine cells, many of these tumor cells can behave like cells they originated from and can secrete a variety of functional hormones and chemicals. Pancreatic neuroendocrine tumors secrete Chromogranin A which can be used as a diagnostic and prognostic tool. A functioning pancreatic neuroendocrine tumor secretes biologically active hormones causing a characteristic clinical syndrome. Non-functioning pancreatic neuroendocrine tumors do not cause a characteristic clinical syndrome.

Functioning pancreatic neuroendocrine tumors can hyper-secrete (over produce) substances such as gastrin, insulin, a glucose secretion-regulating hormone, vasoactive intestinal peptide (VIP), and somatostatin, resulting in a characteristic clinical syndrome.

Pancreatic neuroendocrine tumors can occur outside of the pancreas such as duodenal gastrinomas and small intestinal somatostatinomas. Pancreatic neuroendocrine tumors are at times associated with low blood sugar (due to secretion of insulin), diabetes (due to secretion of a glucose secretion-regulating hormone ), or ulcer disease (due to secretion of gastrin). In other cases, neuroendocrine tumors may not secrete any hormones.

Pancreatic neuroendocrine tumors are classified as rare cancers. Recent studies have determined that 4 to 5 out of every 100,000 people are diagnosed yearly with a neuroendocrine tumor and that there are over 100,000 people currently living with neuroendocrine tumors within the U.S. Within this pancreatic neuroendocrine tumors are diagnosed in 0.3 – 0.4 out of every 100,000 people each year. For unknown reasons, the incidence of neuroendocrine tumors is currently rising.

Pancreatic neuroendocrine can be difficult to diagnosis with the average time between tumor development and diagnosis being between 5 and 10 years. Survival rates for individuals with pancreatic neuroendocrine tumors vary and depend upon tumor type, the location of the tumors, the size of the tumors, the extent and growth rate of liver and bone metastases, proliferative indices, presence of clinical syndromes and many other factors. Currently, surgery is the only option that offers hope for a cure.

Pancreatic neuroendocrine tumors can be associated with genetic syndromes such as Multiple Endocrine Neoplasia Type 1 (MEN1), Von Hippel-Lindau Disease (VHL), Tuberous Sclerosis Complex and Neurofibromatosis Type 1 (NF1). MEN1 is the most significant genetic syndrome – over 80% of patients with MEN1 develop pancreatic neuroendocrine tumors, over 40% of patients develop gastrinomas and smaller percentages develop other types of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumor classifications

Since neuroendocrine tumors, including pancreatic neuroendocrine tumors, represent a heterogeneous group of tumors, the World Health Organization in 2017 updated the classification system based upon their clinical pathological criteria, regardless of origin, size, or anatomical extent of the tumor.

Grade 1 (Low grade) well-differentiated neuroendocrine tumor
Grade 2 (Intermediate grade) well-differentiated neuroendocrine tumor
Grade 3 (High grade) poorly differentiated neuroendocrine carcinoma, occasionally well-differentiated neuroendocrine tumor

Presence of Clinical Syndrome

Pancreatic neuroendocrine tumors are classified as functioning or non-functioning.

Functioning

A functioning pancreatic neuroendocrine tumor secretes biochemically active substances such as hormones which cause specific clinical syndromes such as Carcinoid Syndrome or Zollinger-Ellison Syndrome.

Non-functioning

A non-functioning pancreatic neuroendocrine tumor secretes specific substances but these substances are either inactive and/or do not cause any clinical syndrome.

Functioning Pancreatic Neuroendocrine Tumors

Insulinoma

Characterized by excess secretion of insulin and pro-insulin which causes confusion, sweating, dizziness, weakness and unconsciousness. Prolonged hypoglycemia (low blood sugar) can have permanent impact on brain function. Insulinomas tend to be small and rarely metastasize, many report metastases in about 10% of patients. Insulinomas can be associated with MEN1.

Gastrinoma

Characterized by Zollinger-Ellison Syndrome caused by excess secretion of gastrin. Zollinger-Ellison syndrome causes diarrhea and peptic-ulcers. Patients with Zollinger-Ellison syndrome may also develop gastric carcinoid as a result of prolonged gastrin hypersecretion (over production). Patients frequently have liver and lymph node metastasis at diagnosis. Gastrinomas occur mainly in the duodenum and pancreas. When Gastrinomas occur in the duodenum they are frequently associated with MEN1. All patients with Zollinger-Ellison Syndrome should be screened for MEN1.

Glucagonoma

Characterized by hypersecretion of a glucose secretion-regulating hormone, which causes skin rash, diabetes, and weight loss. Glucagonomas occur mainly in the pancreas, are typically large, and are highly metastatic. Glucagonoma is rarely associated with MEN1.

VIPoma

Characterized by hypersecretion of Vasoactive Intestinal Peptide (VIP) which causes Verner-Morrison Syndrome. Symptoms of Verner-Morrison Syndrome include severe watery diarrhea, which can be life threatening.

Somatostatinoma

Somatostatinomas are primarily or exclusively composed of somatostatin-producing cells. Somatostatinomas are found in the pancreas and duodenum. Somatostatinomas may not provoke clinical symptoms or they may be characterized by clinical symptoms of gallbladder stones, diabetes, weight loss, and diarrhea.

Non-Functioning Pancreatic Neuroendocrine Tumors

Non-functioning pancreatic neuroendocrine tumors are not associated with characteristic clinical symptoms from secretion of hormones. Non-functioning pancreatic neuroendocrine tumors occur in the pancreas. They do not cause hormonal symptoms but can cause pain, weight loss and jaundice. Because there is no characteristic clinical syndrome associated with non-functioning pancreatic neuroendocrine tumors they can be difficult to diagnose and are often diagnosed after presenting with large tumors and liver metastases.

Inherited Versus Sporadic

Pancreatic neuroendocrine tumors can be sporadic or familial, when the patient has genetically inherited mutations, which predispose development of tumors.

Sporadic

Cancer causing mutation arise randomly

Inherited

Cancer causing mutations are inherited such in the case of MEN-I.

MEN1 is an autosomal dominant inherited syndrome characterized by multiple endocrine and non-endocrine tumors. The tumors most frequently observed in patients with MEN1 include parathyroid adenomas, pituitary adenomas, and pancreatic endocrine tumors.

VHL is an autosomal dominant inherited syndrome caused by a mutation in the VHL gene.

Pancreatic neuroendocrine tumor patients should always have a clinical examination including family history to exclude genetic syndromes like MEN1. Presence of MEN1 or another clinical syndrome may change the optimal treatment course and so it is important to rule out. If a patient has a genetic syndrome it may be advised that certain family members are tested as well.

Pancreatic neuroendocrine tumor symptoms

Pancreatic neuroendocrine tumors can cause life-threatening symptoms from both hormone hypersecretion (over production) as well as tumor growth and invasion. They may also be asymptomatic, however: as the tumors grow they can cause obstructive symptoms or symptoms from growth and invasion of surrounding tissue.

Obstructive Symptoms

Individuals with pancreatic neuroendocrine tumors may experience symptoms such as abdominal pain, nausea, and vomiting, even though diagnostic scanning shows nothing. Many individuals diagnosed with liver metastases have reported having undiagnosed abdominal pain for several years prior to their diagnosis.

Carcinoid Syndrome

Pancreatic neuroendocrine tumors can secrete a variety of hormones which can cause many clinical symptoms such as flushing and diarrhea. Symptoms occurring together may be classified as a syndrome.

Typical Carcinoid Syndrome

Carcinoid Crisis

Carcinoid Heart Disease

Pancreatic neuroendocrine tumors can secrete a variety of hormones and vasoactive substances such as serotonin. When these substances are released from liver metastases, the right side of the heart is exposed to them. As a result, patients may experience Carcinoid Heart Disease characterized by plaque lesions in the right side of the heart. Carcinoid Heart Disease can cause right-sided heart failure. Carcinoid Heart Disease is most common on the right side of the heart but can also occur on the left side. While serotonin production is related to the development of Carcinoid Heart Disease, there is evidence of increased cardiac lesions during somatostatin analog therapy. All neuroendocrine tumor patients should be familiar with Carcinoid Heart Disease and discuss appropriate monitoring with their physician.

Cushing’s Syndrome

Certain pancreatic neuroendocrine tumors can secrete adrenocorticotropic hormone (ACTH) causing Cushing’s Syndrome. Cushing’s Syndrome is characterized by excessive upper body weight gain, skin disorders (bruising and poor healing), baldness, and psychological disorders such as depression and anxiety.

Zollinger-Ellison Syndrome

Verner Morrison Syndrome

VIPomas hypersecrete Vasoactive Intestinal Peptide (VIP) which causes Verner-Morrison Syndrome. Symptoms of Verner-Morrison Syndrome include severe watery diarrhea, which can be life threatening.

Insulinoma Syndrome

Insulinomas hypersecrete insulin and pro-insulin which causes confusion, sweating, dizziness, weakness, and unconsciousness. Prolonged hypoglycemia (low blood sugar) can have permanent impact on brain function.

Glucagonoma Syndrome

Glucagonomas hypersecrete a glucose secretion-regulating hormone, which causes skin rash, diabetes, and weight loss.

Pancreatic neuroendocrine tumor diagnosis

Pancreatic neuroendocrine tumors, like many neuroendocrine tumors, can be very difficult to diagnose. It is common for individuals with pancreatic neuroendocrine tumors to remain asymptomatic until the tumors have metastasized or grow large enough to affect normal bodily functions. After an individual develops symptoms, diagnosis can be problematic since the symptoms of neuroendocrine tumors can mimic other diseases.

If your physician suspects you have a pancreatic neuroendocrine tumor, there are specific biochemical tests which measure tumor markers and imagining tests that can help confirm a diagnosis or pancreatic neuroendocrine tumor and potentially determine the tumor type, location, load, and prognosis. A tissue biopsy of a suspected tumor is, in most cases, the only definitive test to diagnosis a pancreatic neuroendocrine tumor.

If you have already been diagnosed with a pancreatic neuroendocrine tumor, biochemical and imaging tests are very important tools for disease staging and clinical management.

Pancreatic Neuroendocrine Tumor Biochemical Testing

Pancreatic neuroendocrine tumors produce a variety of substances which include hormones, proteins, and biogenic amines. Some tumors are termed functioning since they are able to secrete an active form of these substances, which can cause a characteristic clinical syndrome such as Carcinoid Syndrome, Zollinger-Ellison Syndrome, and Cushing’s Syndrome. Biochemical tests are necessary to diagnosis a functional pancreatic neuroendocrine tumor. However, most pancreatic neuroendocrine tumors are non-functioning and are not associated with a characteristic syndrome either because the substances secreted are biologically inactive or because they do not cause any specific symptoms.

The substances secreted by a pancreatic neuroendocrine tumor can be measured by biochemical tumor markers. Biochemical tumor markers can be divided into two categories: those which are specific to a particular type of pancreatic neuroendocrine tumor and those which are general. The most common tumor marker for pancreatic neuroendocrine tumors is Chromogranin A (CgA).

Chromogranin A is a secretory protein that is common to most neuroendocrine tumor cells, and is a general tumor marker for neuroendocrine tumors. CgA is a useful marker for diagnosing, staging and monitoring pancreatic neuroendocrine tumors. Since it is secreted into the bloodstream it can be measured by a simple blood test. Blood plasma levels of CgA have been shown to relate to prognosis. Somatostatin analogs can reduce CgA levels and so CgA should be used with caution among patients using somatostatin analogs.

Drugs such as PPI’s can also affect CgA levels, please discuss medications that may affect CgA levels with your physician. For patients with confirmed or suspected Zollinger-Ellison Syndrome, there can be risks to discontinuing PPI’s and patients should speak with a physician regarding appropriate use of PPI’s prior to CgA testing.

Other general markers for pancreatic neuroendocrine tumors include neuron specific enolase, pancreatic polypeptide, and pancreastatin. Specific tumor markers for functioning pancreatic neuroendocrine tumors include: gastrin, insulin, pancreatic polypeptide, glucose secretion-regulating hormone, somatostatin, and vasoactive intestinal peptide.

All neuroendocrine tumors, including pancreatic neuroendocrine tumors, secrete hormones. However, what they secrete depends upon the type of tumor and the tumor location. The following table depicts pancreatic neuroendocrine tumors by type, secreted substances, and symptoms associated with secreted substances.

Depending upon the tumor markers your physician is testing for there are certain foods and medications to avoid prior to testing. Speak with your physician to discuss foods and medications to discontinue prior to testing.

Pancreatic Neuroendocrine Tumor Imaging

Along with biochemical testing, there are several imaging techniques which are useful to help determine a tumor(s) location, size, and extent of metastases. The imaging technique used and the combination thereof depend upon the primary tumor type, location, presence or absence of hormonal symptoms (functioning vs. nonfunctioning), and extent of the disease. Imaging is especially important when liver metastases are suspected because liver function tests can be an unreliable predictor of liver metastases.

Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)

Computed Tomography (CT) is an imaging technique that uses a highly specialized X-Ray machine and computers to create multiple cross-sectional images of the body. CT can generate images of different body tissues as well as help detect tumors.

CT/MRI can be useful to detect both functioning and non-functioning tumors in the pancreas and to define the extent of metastasis (particularly liver and lymph node metastasis). Effectiveness of CT/MRI for pancreatic neuroendocrine tumors is dependent upon tumor size and location with difficulties visualizing tumors smaller than 3 centimeters, and tumors in the tail of the pancreas and duodenum. As gastrinomas, insulinomas, and duodenal somatostatinomas are frequently small they may be missed with CT/ MRI.

Both CT and MRI are useful to define liver metastasis in pancreatic neuroendocrine tumors and some studies have shown that these modalities have better results in imaging liver metastases than Somatostatin Receptor Scintography.

Somatostatin Receptor Scintigraphy (SRS) or Octreotide Scan

Somatostatin Receptor Scintigraphy (SRS) is a type of radionuclide scan that uses the radionuclide (radioactive substance) Octreotide (111-In-DTPA-octreotide) and a highly specialized machine to detect Neuroendocrine tumors. When octreotide is injected into a patient’s vein, it can travel through the bloodstream and bind to pancreatic neuroendocrine tumors.

Octreotide is a synthetic (man-made), radiolabeled analog of the naturally occurring hormone somatostatin. Over 90% of all neuroendocrine tumor cells have receptors for somatostatin. Different types of pancreatic neuroendocrine tumors express different levels of somatostatin receptors. Insulinomas less frequently express somatostatin receptors than other types of pancreatic neuroendocrine tumors. Octreotide, like somatostatin, is able to bind to two of the five receptors (receptors two and five) on pancreatic neuroendocrine tumors. SRS is used to find the tumors which bind octreotide. If the octreotide binds to the tumors, doctors can visualize them through the use of an imaging machine. Scans can be done at different intervals following an octreotide injection: 4 hours, 24 hours and 48 hours. However, a scan at 24 hours after octreotide injection is preferred. SRS can be used to detect neuroendocrine tumors that bind octreotide and are greater than 1- 1.5 cm. SRS can be used to find primary pancreatic neuroendocrine tumors as well as metastases to the liver, lungs, and bones.

Patients who are being treated with a somatostatin analog are strongly encouraged to temporarily discontinue treatment before undergoing SRS because somatostatin analogs used for treatment and for the scan compete for the same receptor. Patients should speak with their physicians to determine when and for how long they should discontinue treatment to maximize SRS.

SRS has varying effectiveness in detecting different types of pancreatic neuroendocrine tumors. SRS is useful in detecting gastrinomas, non-functioning tumors, somatostatinomas, and VIPomas. SRS is not as effective in detecting insulinomas because insulinomas express lower levels of somatostatin receptors and are frequently small.

SRS is not only useful in imaging tumors but because it is a functional imaging technique SRS is also commonly used to predict response to somatostatin analog therapy as well as peptide receptor radionuclide therapy (PRRT).

Positron Emission Tomography (PET)

Positron Emission Tomography (PET) is another form of radionuclide scan that uses a radioactive material and a special scanning device to detect cancerous tumors. Most commonly, the radionuclide 18F-labelled deoxyglucose (FDG) is used to detect many forms of cancer. However, FDG is not effective in detecting most tumors with the exception of tumors with high proliferative activity and low differentiation. Instead, 68Ga-DOTA-TOC is the radionuclide that is most commonly used with PET to detect pancreatic neuroendocrine tumors.

PET with 68Ga-DOTA-TOC works in a similar fashion to octreotide in that like octreotide, 68Ga-DOTA-TOC is able to bind to specific receptors on pancreatic neuroendocrine tumors. Once bound, the tumors can be visualized with a PET scan. However,68Ga can be accumulated much faster by pancreatic neuroendocrine tumors and so the scan for the tumors can be done approximately one hour after the 68Ga has been administered. 68Ga-DOTA-TOC has been effective in detecting pancreatic neuroendocrine tumors that are greater in size than 0.5 cm.

Endoscopy

Endoscopy is a medical procedure that uses an endoscope to view the lining of multiple organs and tracts of the body. An endoscope is a flexible or rigid tube that has imaging capabilities and can enable small surgical procedures. Endoscopic ultrasound can be used to locate small tumors in the pancreas and duodenum including those such as small gastrinomas and insulinomas that are often missed by CT, MRI, and SRS.

Pancreatic neuroendocrine tumor treatment

Pancreatic neuroendocrine tumors can be very difficult to treat. Pancreatic neuroendocrine tumors can be benign to highly malignant, indolent (slow growing) to very aggressive in development, and range from asymptomatic to causing debilitating syndromes. As a result, a multi-disciplinary team consisting of specialist physicians in NETs (gastroenterologists, oncologists, and endocrinologists), surgeons, radiologists, nuclear medicine specialists, histopathlogists, and clinical nurse specialists is often recommended.

Pancreatic Neuroendocrine Tumor treatment must be tailored to each patient’s tumor burden and symptoms. Treatments may be focused on inhibiting tumor growth or symptom relief. Often, this means that any given treatment plan may consist of a combination and/or series of several treatments. Be sure to discuss treatment options thoroughly with your physician(s). Ultimately, all treatment decisions should be made by the patient.

Pancreatic Neuroendocrine Tumor Surgery

The surgical treatment of pancreatic neuroendocrine tumors depends on the tumor type, location, extent of metastases, as well as other factors. For individuals who have metastases, surgery can often increase survival and provide palliative care depending on tumor size and location. For both local and metastatic tumors surgery can be helpful for reducing symptoms from tumor secretion. Surgical resection of a functioning pancreatic neuroendocrine tumor should be considered when possible. A multimodal approach combining surgery with embolization or other treatment methods may also be possible for patients with liver metastases. For all patients who undergo surgery, continued and extensive follow up is recommended.

Insulinomas

Insulinomas are frequently small with indolent behavior. In these cases treatment is indicated to relieve the characteristic syndrome from hormone hypersecretion. The type and extent of the surgery depend on the nature, location, and size of the tumor(s). For small benign insulinomas enucleation can be performed. Pancreatic enucleation is an operation when the tumor is removed from the pancreas without removing any pancreatic tissue. For cases where tumors are larger than 1 or 2 cm, where aggressive behavior is suspected, or where there is suspected local, liver, or lymph node invasion pancreatoduodenectomy or aggressive pancreatic resection may be indicated. Pancreatic-duodectonomy also known as a Whipple Procedure is an extensive surgical operation of the pancreas, duodenum and other organs.

Gastrinoma

Since the advent of medications such as Proton Pump Inhibitors (PPI’s) to control symptoms surgery for patients with gastrinoma has been considered controversial and different opinions exist. In certain cases, removal of these tumors can help to decrease hormonal syndrome, alleviate pain, prevent future metastases and increase survival.

The type and extent of the surgery depend on the nature, location, and size of the tumor(s). Depending upon location and metastatic behavior gastrinoma may be removed by pancreatic enucleation, or more invasive pancreaticoduodenectomy. Pancreatic enucleation is an operation when the tumor is removed from the pancreas without removing any pancreatic tissue. Pancreatic-duodectonomy also known as a Whipple Procedure is an extensive surgical operation of the pancreas, duodenum and other organs.

Glucagonoma

Glucagonomas are often large with metastasis to the liver. The type and extent of the surgery depend on the nature, location, and size of the tumor(s). Surgical treatment may require distal pancreatectomy. A distal pancreatectomy is the removal of the body and tail of the pancreas leaving the head intact.

VIPoma

The type and extent of the surgery depend on the nature, location, and size of the tumor(s). Surgical treatment may require distal pancreatectomy. A distal pancreatectomy is removal of the body and tail of the pancreas leaving the head intact.

Non-functioning Pancreatic Neuroendocrine Tumors

These tumors do not cause characteristic hormonal symptoms but surgery may be indicated to prevent obstructive symptoms, manage symptoms of pain, jaundice, and weight loss or inhibit tumor growth. Because non-functioning neuroendocrine tumors are difficult to diagnosis they are usually large at diagnosis and may require pancreatic-duodenectomy. Pancreatic-duodectonomy also known as a Whipple Procedure is an extensive surgical operation of the pancreas, duodenum and other organs.

Liver Metastasis

The liver is the most common site for pancreatic neuroendocrine tumors to metastasize but it is rare for the liver to be the primary site of neuroendocrine tumor development. The type and extent of surgery for liver metastasis is contingent upon tumor type, size, location, disease progression, site of origin and other factors. Liver resection, the surgical removal of part of the liver, is a common treatment protocol for individuals for whom a complete resection is possible.

For individuals for whom a complete resection is not possible, surgery, in combination with other treatment modalities, may be used to debulk (decrease) tumor burden. Resection and debulking (for individuals for whom the majority of tumor burden is removed) have resulted in increased survival and a decrease in disease symptoms.

Presence of liver metastasis is a major prognostic factor with the presence of liver metastasis indicating a worse outcome. In certain cases, a two-stage surgical resection can be done for patients with extensive liver metastases. The first phase of a two-stage resection involves the radical resection of a portion of the left side of the liver with right portal vein ligation to encourage the left side of the liver to regenerate. After the liver is allowed to regenerate, the right side of the liver is then removed.

In a very small group of individuals with neuroendocrine tumor liver metastases, orthotopic liver transplantation has been used. Orthotopic liver transplantation is the process in which the diseased liver is completely removed and replaced with a healthy, donor liver.

Lymph Nodes

Lymph nodes are often the site of neuroendocrine tumor metastases. When an individual is diagnosed with a pancreatic neuroendocrine tumor and is a surgical candidate, the lymph nodes surrounding the affected area should be examined for metastases and removed if affected. A lymphadenectomy is the surgical removal of one or more groups of lymph nodes.

Non-Surgical Therapies

If curative surgery is not possible, other treatment options are available to individuals with pancreatic neuroendocrine tumors. Currently, there is no non-surgical curative treatment, but there are several non-surgical treatment options which can result in decreasing tumor bulk, halting tumor progression, and/or managing tumor symptoms. The type of treatment used is determined by tumor type, size, location, disease progression, as well as many other factors.

While there is currently no non-surgical curative treatment, progress in pancreatic neuroendocrine tumor treatment is being made through clinical trials.

Somatostatin Analogues

The excess of hormones produced and secreted into the body by pancreatic neuroendocrine tumors can cause characteristic syndromes from hormonal hypersecretion. Most neuroendocrine tumors, have five highly specialized receptors for the naturally occurring hormone somatostatin. When somatostatin is bound to these receptors, especially receptors two and five, it inhibits the release of the various hormones that cause many of the symptoms associated with hormonal hypersecretion. Synthetic analogs (man-made versions) of somatostatin can mimic somatostatin by binding to receptors two and five and inhibiting hormone secretion. Currently, there are two synthetic somatostatin analog products available. These somatostatin analogs have been proven to control, decrease and prevent symptoms associated with pancreatic neuroendocrine tumors. Somatostatin analogs can be used for initial management of some patients with glucagonomas, VIPomas, and somatostatinomas.

Somatostatin analogs may be used to manage hormone secretion from pancreatic neuroendocrine tumors and is approved for use in patients with VIPomas. In patients with VIPomas somatostatin analogs can improve diarrhea but dose escalation may be necessary to maintain benefit. Somatostatin analogs may be used to manage patients with insulinoma but patients should be monitored as somatostatin analogs can worsen symptoms of hypoglycemia. Somatostatin analogs can decrease hormone levels and improve skin rash in patients with glucagonoma.

For patients with symptoms that are unresponsive to somatostatin analogs breakthrough medication, increased dosage or more frequent dosage can be considered.

Side effects from somatostatin analogs include diarrhea, nausea, gallstones and glucose intolerance. In a recent study, octreotide also demonstrated possible antitumor effects when compared to a placebo in patients with well-differentiated carcinoid tumors of midgut origin, limited hepatic tumor mass and a resected primary tumor. Similar studies do not yet exist for pancreatic neuroendocrine tumors.

Proton Pump Inhibitors (PPIs)

Gastrinomas secrete excess gastrin causing Zollinger-Ellison Syndrome. Proton Pump Inhibitors can effectively control the clinical symptoms of Zollinger-Ellison Syndrome and is the preferred non-surgical treatment. Proton Pump Inhibitors (PPIs) are a group of drugs used to reduce production of gastric acid by blocking an enzyme in the wall of the stomach. All patients with Zollinger-Ellison Syndrome should work with a physician to manage PPI usage – treating symptoms may not be sufficient to neutralize the gastrin hypersecretion and a physician should follow acid output. PPIs are most commonly given as oral tablets but can be given intravenously in patients who cannot tolerate oral therapy.

In animal studies, long-term exposure to high doses of PPIs has been shown to lead to the development of gastric carcinoid tumors. However, in humans, there is no evidence of increased rates of gastric carcinoid tumors among patients with Zollinger-Ellison Syndrome on chronic PPI treatment.

Diazoxide

Insulinomas can secrete insulin causing hypoglycemia. Diazoxide can be used to treat hypoglycemia associated with insulinomas. Diazoxide is a benzothiadiazide that inhibits insulin release. Side effects include sodium/fluid retention and nausea.

Interferon-α

Interferons are naturally occurring proteins that are secreted by specialized cells in the body to activate the body’s natural protective response to harmful substances including some tumors. There are many types of interferon produced by the body. A synthetic version of one type, interferon-α, can be used to stabilize tumor growth in pancreatic neuroendocrine tumors. However, interferon-α can have severe side effects, such as myelosuppression (the decrease in bone marrow activity resulting in lower blood cell levels), fatigue, depression, and changes in thyroid function.

Cytotoxic Chemotherapy

Cytotoxic chemotherapy is the use of anticancer drugs that target and kill rapidly proliferating (dividing) cells. Evidence has shown that well-differentiated pancreatic neuroendocrine tumors are more responsive to chemotherapeutic drugs than well-differentiated carcinoid tumors. Poorly differentiated neuroendocrine tumors have been shown to respond to chemotherapeutic drugs.

Pancreatic neuroendocrine tumors may respond to chemotherapeutics such as streptozocin. Streptozocin is approved by the Food and Drug Administration (FDA) to treat pancreatic neuroendocrine tumors. Temozolomide has also shown effectiveness in treating pancreatic neuroendocrine tumors; in particular among patients with deficiency of the MGMT gene (0^6 methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapies in patients with neuroendocrine tumors. MGMT is a DNA repair enzyme. Several chemotherapeutics are currently being investigated in combination with other chemotherapeutics and/or targeted agents to determine their effects on neuroendocrine tumors.

Ablative Therapies

Hepatic Artery Embolization

Individuals with liver metastases may be considered candidates for hepatic embolization or hepatic chemoembolization if they have non-resectable liver metastases, uncontrolled growth of liver metastases and/or uncontrolled symptoms. However, other factors such as physical health and the extent of tumor growth must also be taken into consideration. These procedures can have very positive but short-term results of: a decrease in tumor size, a decrease in tumor symptoms, and a halt in tumor progression. Duration of response is highly variable. Individuals who are candidates may undergo more than one embolization.

Common side-effects of either procedure can include fever, fatigue, abdominal pain, nausea and vomiting. The severity of these varies for each individual. For liver-directed therapies, the order of treatments may matter and the decision to have one therapy may affect treatment options down the road. Please discuss any limitations that embolizations may place on future treatment options with your physician.

Radioembolization

Radioembolization is a form of selective internal radiation therapy (SIRT). It is a minimally invasive procedure that combines embolization and radiation therapy to target liver metastases. Radioembolization involves the injection of millions of radioactive microspheres (microscopic beads) into a branch of the hepatic artery which supplies blood to the tumor. From there, the microspheres travel to the tumor site where they inhibit the blood supply to the tumor and emit radiation effectively killing tumor cells.

Currently, there are two radioactive microsphere products available for patients with metastatic tumors to the liver, one made of glass and the other resin. Both products use Yttrium-90 (90Y), a beta-emitting radionuclide. Individuals with liver metastases may be considered candidates for hepatic embolization or hepatic chemoembolization if they have non-resectable liver metastases, uncontrolled growth of liver metastases and/ or uncontrolled symptoms. Other factors such as physical health, extent of tumor burden and prior treatment therapies must also be taken into consideration. These procedures can have very positive but short-term results of: a decrease in tumor size, a decrease in tumor symptoms, and a halt in tumor progression. Currently, the role of radioembolization in combination with other therapies is not well understood.

Common side-effects of radioembolization can include fever, abdominal pain, fatigue, nausea, and vomiting. The severity of these varies for each individual. For liver-directed therapies the order of treatments may matter and the decision to have one therapy may affect treatment options down the road. Please discuss any limitations that these procedures may place on future treatment options with your physician.

Radiofrequency Ablation

Radiofrequency ablation is a minimally invasive procedure that uses a high-frequency electrical current to destroy tumor cells. Radiofrequency ablation involves placing a small probe into a tumor. Electrical currents (which are at the same range of radiofrequency) are sent through the probe. This effectively raises the temperature of the tumor tissue and destroys it. Radiofrequency ablation can be done laparoscopically but is more commonly done in combination with liver resection.

Individuals with inoperable neuroendocrine tumors may be candidates for radiofrequency ablation . Radiofrequency ablation has been shown to temporarily decrease tumor burden, stall tumor progression and temporarily relieve tumor symptoms. There are many limitations to radiofrequency ablation , including tumor size and tumor location. Tumors that are greater in diameter than 3 cm are difficult to eradicate and radiofrequency ablation cannot be used in tumors that are greater in diameter than 5 cm.

Peptide Receptor Radionuclide Therapy

Most neuroendocrine tumors, including functioning and non-functioning pancreatic neuroendocrine tumors, have five highly specialized receptors that bind to the naturally occurring hormone somatostatin. Octreotide is a synthetic analogue (a man-made version) of somatostatin that is able to attach to two of these five somatostatin receptors.

Peptide receptor radionuclide therapy combines octreotide with a radionuclide (a radioactive substance) to form highly specialized molecules called radiolabeled somatostatin analogues or radiopeptides. These radiopeptides can be injected into a patient and will travel throughout the body binding to carcinoid tumor cells that have receptors for them. Once bound, these radiopeptides emit radiation and kill the tumor cells they are bound to.

There are three radionuclides that are attached to octreotide to create radiopeptides: indium 111 (111In), yttrium 90 (90Y) and lutetium 177 (177Lu). These radiopeptides differ in the type of radiation they emit as well as the depth of tissue into which they penetrate. Tissue penetration is an important factor since a certain range of radiation is necessary to kill tumor cells but not damage surrounding, healthy tissues.111In emits both Auger electrons and γ-radiation and has the shortest range of tissue penetration (10 µm), 90Y emits β-radiation and has a range of 12 mm, and 177Lu emits both β-radiation and γ-radiation and has a range of 2 mm.

Common side effects of radiopeptide therapy are nausea, vomiting, and abdominal pain. Other less common side-effects are bone, liver and kidney toxicity, and mild hair loss.

Individuals whose tumors can be visualized by somatostatin receptor scintigraphy or 68 GA –DOTATE PET/ CT and have inoperable neuroendocrine tumors that are growing or individuals whose symptoms are not well managed by somatostatin analogs may be candidates for PRRT. However, the extent of tumor growth, kidney function, liver function, prior treatments, and many other factors must also be considered.

Molecular Targeted Therapies to Treat Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors are formed by an abnormal growth of cells within the body. Normally, the growth and replication of all cells within the body is strictly regulated at a molecular and genetic level. However, tumors are made up of cells that have undergone multiple mutations in their genetic code, which allow them to grow and replicate without the normal controls. By understanding what molecular and genetic mutations have occurred, scientists can develop drug therapies that target these mutations (targeted therapies) effectively stopping tumor cell growth and even promoting tumor cell death. At this time, there are two molecular pathways for which novel targeted therapies are being developed.

Vascular Endothelial Growth Factor (VEGF) Inhibitors

All cells require an adequate blood supply to survive. Cancer cells, since they tend to replicate faster than normal cells, require an even greater blood supply. In order to achieve this, many tumors, including pancreatic neuroendocrine tumors, undergo angiogenesis, the development of new blood vessels. Vascular endothelial growth factor (VEGF) is a highly specialized chemical signal that cells produce in order to stimulate new blood vessel growth. In pancreatic neuroendocrine tumors, this signal is overexpressed. Several targeted therapies called angiogenic inhibitors are currently being investigated to see if they can effectively suppress VEGF in pancreatic neuroendocrine tumors or inhibit pathways that would disrupt its production or effects.

One angiogenic inhibitor, Sunitinib malate is approved by the US FDA for patients with progressive, well-differentiated pancreatic neuroendocrine tumors that are unresectable locally advanced, or metastatic. The approval was based on a double-blind, randomized, placebo-controlled, phase III trial with progression-free survival as the primary endpoint. This phase III trial was conducted at institutions worldwide and the results were published in the New England Journal of Medicine. Common side effects included diarrhea, nausea, asthenia (weakness), vomiting and fatigue.

Mammalian Target of Rapamycin (mTOR) Inhibitors

Normally, cells that have unfixable mutations in the genetic code will undergo apoptosis (programmed cell death). Neuroendocrine tumors cells, like other cancer cells, do not do this. Instead, their growth and death is unregulated. The mammalian target of rapamycin (mTOR) is a protein that is involved in many cellular pathways including cell growth and death. In neuroendocrine tumors, mTOR is not regulated and consequently promotes tumor cell growth. Targeted therapies called mTOR inhibitors deactivate mTOR and prevent cellular growth and replication.

The US FDA approved a mTOR inhibitor to treat patients with progressive pancreatic neuroendocrine tumors that are unresectable, locally advanced or metastatic. The approval was based on a double-blind, randomized, placebo-controlled, phase III trial with progression-free survival as the primary endpoint. This phase III trial was conducted at institutions worldwide and the results were published in the New England Journal of Medicine ². Common side effects included stomatitis (inflammation in the mouth), rash, diarrhea, fatigue, and infections.

Neuroendocrine tumor prognosis

Prognosis is different for different types of neuroendocrine tumor. For example:

For insulinoma, long term survival following surgical removal in this patient population exceeds 90%;
For carcinoid tumor, the survival rate at 5 years following diagnosis (5-year survival rate) for all carcinoid tumors, regardless of the site of tumor, is 67%.

Grading of the tumor based on findings under the microscope is difficult for neuroendocrine tumors. Recent research showed that in malignant neuroendocrine tumors, a few factors confer poor survival:

A high expression of a protein called the Ki 67 protein;
The presence of aneuploidy (abnormal amount of genetic material).

Based on these tests, neuroendocrine tumors are divided into 2 main groups:

Well-differentiated neuroendocrine tumors (which include low-grade [G1] and intermediate-grade [G2] tumors) have 20 or fewer mitoses and a Ki-67 index of 20% or lower.
Poorly differentiated tumors (high-grade [G3] tumors) have more than 20 mitoses or a Ki-67 index of more than 20%. These are also called neuroendocrine carcinomas and they often grow and spread quickly.

Neuroendocrine tumor causes

The exact cause of neuroendocrine tumor is unknown. Neuroendocrine tumors can arise spontaneously in a random fashion or as a result of genetic changes. Neuroendocrine tumors may associated with the following conditions inherited genetically:

Multiple endocrine neoplasia (MEN) types 1 and 2;
von Hippel-Lindau disease/syndrome;
von Recklinghausens neurofibromatosis (neurofibromatosis type 1);
Tuberculous sclerosis.

Neuroendocrine tumor symptoms

Neuroendocrine tumors can be termed functionally active if they produce excessive hormones and lead to a specific clinical syndrome; and functionally inactive if they do not. Insulinoma, gastrinoma, VIPoma, glucagonoma and carcinoid tumor can be functionally active and give rise to various symptoms. Some of the clinical features produced by different neuroendocrine tumors include:

Insulinoma: Symptoms of low blood sugar (intermittent confusion, sweating, weakness, nausea);
Glucagonoma: Redness of the skin (necrotising migratory erythema), excessive weight loss and wasting, diabetes;
VIPoma: Watery diarrhoea, disturbances of water balance;
Gastrinoma: Excessive secretion of acid, peptic ulcer disease, gastro-esophageal reflux disease (GERD), diarrhea;
Somatostatinoma: Diabetes, diarrhoea, gallstones.

On the other hand, functionally inactive neuroendocrine tumors, because of the lack of clinical symptoms, are usually diagnosed the following ways:

By chance during routine ultrasound testing performed for other reasons (e.g. investigation of unexplained complaints of the upper abdomen);
Jaundice (yellow discoloration of the skin and the eyes), in the case of large tumors at the head of the pancreas;
Repeated abdominal cramping, in the case of apparent blockage (pseudo-obstruction) of the bowel by a functionally inactive neuroendocrine tumor in the small bowel (lower jejunum and ileum);
Symptoms produced by the tumor (e.g. bleeding from the digestive tract).

Neuroendocrine tumor diagnosis

Apart from taking a thorough history, a general physical examination will also be conducted by your doctor. The focus of the examination is largely dependent upon the nature of the history and the site of tumor suspected, for example the bowels, pancreas, stomach, adrenal glands (hormonal glands above the kidneys). The lymph nodes around the affected region and the liver will be felt for abnormalities from distant spread.

Many tests can be used to diagnose neuroendocrine tumors, including blood tests, urine tests, scans and a biopsy (where a small tissue sample is taken for closer examination).

Types of scans used include:

ultrasound
CT (computerised tomography)
MRI (magnetic resonance imaging)
PET (positron emission tomography)
octreotide scans – where mildly radioactive liquid is injected into your veins and a special camera is used to highlight any cancerous cells

Neuroendocrine tumor treatment

How a neuroendocrine tumour is treated will depend on your individual circumstances, such as:

where the tumor is
how advanced your condition is
your overall health

Unfortunately, many people are only diagnosed after the tumor has spread to other parts of the body.

The aim of treatment is to control tumor growth and the symptoms caused by hormone release.

Surgery

Surgical removal is always attempted for benign tumors;
In more extensive diseases, surgery is also considered to reduce the bulk of tumor.

Medical treatment

Somatostatin analog: Mimics the hormone somatostatin, and is the drug of first choice to control symptoms. Octreotide and lanreotide is efficient in the control of watery diarrhoea in VIPoma, skin reddening in glucanogoma syndrome, and flushing & diarrhoea in carcinoid syndrome. Somatostatin analog also has effect on tumor growth control.
Alfa-interferon: Since its use in 1982, alfa-interferon has been shown to be comparable to long-acting somatostain analog in the control of hormone release and tumor growth.
Proton-pump inhibitors: At higher doses, this group of drugs can control excessive secretion of acid from the stomach in the case of gastrinoma.
Chemotherapy: Neuroendocrine tumors in the pancreas respond well to chemotherapy. Tumours e.g. carcinoid tumor generally do not show good response to chemotherapy.

Other

Other treatment options include nutritional modification, radiofrequency ablation (the use of electrodes to heat and destroy abnormal tissue), cryoablation (the use of extreme cold to freeze abnormal tissue), chemoembolisation (blocking the blood supply to the tumor).

Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2010 Mar;40(2):78-88. doi: 10.1053/j.semnuclmed.2009.10.004. https://www.ncbi.nlm.nih.gov/pubmed/20113677[↩]
Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N Engl J Med 2011; 364:501-513. http://www.nejm.org/doi/full/10.1056/NEJMoa1003825[↩]

Neuroendocrine tumor

What is a neuroendocrine tumor

Neuroendocrine carcinoid tumor

Neuroendocrine carcinoid tumor classifications

Embryonic Gut Derivation

Presence of Clinical Syndrome

Inherited Versus Sporadic

Histological Features

Neuroendocrine carcinoid tumor symptoms

Obstructive Symptoms

Carcinoid Syndrome

Neuroendocrine carcinoid tumor diagnosis

Biochemical Testing for Carcinoid

Chromogranin A (CgA) in Carcinoid

5-hydroxyindoleacetic acid (5-HIAA) Testing in Carcinoid

Cardinoid Tumor Imaging

Endoscopy

Neuroendocrine carcinoid tumor treatment

Surgery for Carcinoid Tumors

Non-Surgical Therapies for Carcinoid Tumors

Ablative Therapies

Molecular Targeted Therapies

Pancreatic neuroendocrine tumor

Pancreatic neuroendocrine tumor classifications

Presence of Clinical Syndrome

Functioning Pancreatic Neuroendocrine Tumors

Non-Functioning Pancreatic Neuroendocrine Tumors

Inherited Versus Sporadic

Pancreatic neuroendocrine tumor symptoms

Obstructive Symptoms

Carcinoid Syndrome

Typical Carcinoid Syndrome

Carcinoid Crisis

Carcinoid Heart Disease

Cushing’s Syndrome

Zollinger-Ellison Syndrome

Verner Morrison Syndrome

Insulinoma Syndrome

Glucagonoma Syndrome

Pancreatic neuroendocrine tumor diagnosis

Pancreatic neuroendocrine tumor treatment

Pancreatic Neuroendocrine Tumor Surgery

Non-Surgical Therapies

Ablative Therapies

Neuroendocrine tumor prognosis

Neuroendocrine tumor causes

Neuroendocrine tumor symptoms

Neuroendocrine tumor diagnosis

Neuroendocrine tumor treatment

Surgery

Medical treatment

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