Neuroendocrine tumors
Encyclopedia
Neuroendocrine tumors are neoplasms that arise from cells of the endocrine (hormonal) and nervous system
s. Many are benign
, while some are cancer
s. They most commonly occur in the intestine, but are also found in the lung and the rest of the body.
Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, such as looking similar, having special secretory granules, and often producing biogenic amines and polypeptide hormone
s.
s whose normal function is to serve at the neuroendocrine
interface. Neuroendocrine cells are present not only in endocrine glands throughout the body that produce hormone
s, but also diffusely in all body tissues.
However, in 1929 it was recognized that some of these small bowel tumors could be malignant. Despite the differences between these two original categories, and further complexities due to subsequent inclusion of other NETs of pancreas and pulmonary origin, all NETs are sometimes (incorrectly) subsumed into the term "carcinoid."
Enterochromaffin
cells, which give rise to carcinoid tumors, were identified in 1897 by Kulchitsky and their secretion of serotonin
was established in 1953 when the “flushing” effect of serotonin had become clinically recognized. Carcinoid heart disease was identified in 1952 and carcinoid fibrosis in 1961.
Neuroendocrine tumors were sometimes called APUDomas
because these cells often show amine
precursor (L-DOPA and 5-hydroxytryptophan
) uptake and decarboxylation to produce biogenic amines such as catecholamine
s and serotonin
. Although this behavior was also part of the disproven hypothesis that these cells might all embryologically
arise from the neural crest
, neuroendocrine cells sometimes produce various types of hormones and amines, and they can also have strong receptors for other hormones to which they respond.
There have been multiple nomenclature systems for these tumors, and the differences between these schema have often been confusing. Nonetheless, these systems all distinguish between well-differentiated
(low and intermediate-grade
) and poorly differentiated (high-grade) NETs. Cellular proliferative rate is of considerable significance in this prognostic assessment
.
of clinically significant neuroendocrine tumors is approximately 2.5-5 per 100,000; two thirds are carcinoid tumors and one third are other NETs.
The prevalence
has been estimated as 35 per 100,000, and may be considerably higher if clinically silent tumors are included. An autopsy
study of the pancreas in people who died from unrelated causes discovered a remarkably high incidence of tiny asymptomatic NETs. Routine microscopic study of three random sections of the pancreas found NETs in 1.6%, and multiple sections identified NETs in 10%. As diagnostic imaging increases in sensitivity, such as endoscopic
ultrasonography, very small, clinically insignificant NETs may be coincidentally discovered; being unrelated to symptoms, such neoplasms may not require surgical excision.
Additionally, the WHO scheme recognizes mixed tumors with both neuroendocrine and epithelial carcinoma features, such as goblet cell cancer
, a rare gastrointestinal tract
tumor
.
Placing a given tumor into one of categories depends on well-defined histological
features: size, lympho
vascular
invasion, mitotic
counts, Ki-67 labelling index, invasion of adjacent organs, presence of metastases
and whether they produce hormone
s.
The various kinds of cells that can give rise to NETs are present in endocrine glands and are also diffusely distributed throughout the body, most commonly Kulchitsky cells or similar enterochromaffin-like cells, that are relatively more common in the gastrointestinal and pulmonary systems.
NETs include certain tumors of the gastrointestinal tract and of the pancreatic islet cells, certain thymus and lung tumors, and medullary carcinoma
of the parafollicular cells of the thyroid
. Tumors with similar cellular characteristics in the pituitary, parathyroid, and adrenomedullary glands are sometimes included or excluded.
Within the broad category of neuroendocrine tumors there are many different tumor types: this outline is presented to facilitate retrieving information. It is quite clear that neuroendocrine tumors are uncommon in many of these areas, and frequently represent only a very small proportion of the tumors or cancers at these locations.
origin, have
common phenotypic characteristics.
NETs show tissue
immunoreactivity for markers of neuroendocrine differentiation
(pan-neuroendocrine tissue markers) and may secrete various peptides and hormones. There is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers. Widely used neuroendocrine tissue markers are various chromogranin
s, synaptophysin
and PGP9.5. Neuron-specific enolase (NSE) is less specific
.
NETs are often small, yellow or tan masses, often located in the submucosa
or more deeply intramurally, and they can be very firm due to an accompanying intense desmoplastic reaction. The overlying mucosa may be either intact or ulcerated. Some GEP-NETs invade deeply to involve the mesentery
.
Histologically, NETs are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal pleomorphism
but less commonly there can be anaplasia
, mitotic
activity, and necrosis
.
Some neuroendocrine tumor cells possess especially strong hormone
receptor
s, such as somatostatin
receptors and uptake hormones strongly. This avidity
can assist in diagnosis and may make some tumors vulnerable to hormone targeted therapies.
(which conceptually includes pancreas, and even thymus, airway and lung NETs), midgut
and hindgut
; individual tumors within these sites can differ from these group benchmarks:
Carcinoids most commonly affect the small bowel, particularly the ileum, and are the most common malignancy of the appendix
. Many carcinoids are asymptomatic and are discovered only upon surgery for unrelated causes. These coincidental carcinoids are common; one study found that one person in ten has them. Many tumors do not cause symptoms even when they have metastasized. Other tumors even if very small can produce adverse effects by secreting hormones.
10% or less of carcinoids, primarily some midgut carcinoids, secrete excessive levels of a range of hormone
s, most notably serotonin
(5-HT) or substance P
, causing a constellation of symptoms called carcinoid syndrome
:
A carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure can occur if large amounts of hormone are acutely secreted, which is occasionally triggered by factors such as diet, alcohol, surgery chemotherapy, embolization therapy or radiofrequency ablation.
Chronic exposure to high levels of serotonin causes thickening of the heart valves, particularly the tricuspid and the pulmonic valves, and over a long period can lead to congestive heart failure
. However, valve replacement is rarely needed. The excessive outflow of serotonin can cause a depletion of tryptophan
leading to niacin
deficiency, and thus pellagra
, which is associated with dermatitis, dementia, and diarrhea.
Many other hormones can be secreted by some of these tumors, most commonly growth hormone
that can cause acromegaly
, or cortisol, that can cause Cushing's syndrome
.
Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. Bowel obstruction
can occur, sometimes due to fibrosing
effects of NET secretory products with an intense desmoplastic reaction at the tumor site, or of the mesentery
.
Pancreatic neuroendocrine tumors (PETs or PNETs; not to be confused with the primitive neuroectodermal PNET
) can originate within the pancreas or from similar neuroendocrine cells outside of the pancreas. It is unclear whether pancreatic tumors originate from the usual cells of the islet of Langerhans or from diffuse neuroendocrine pluripotent cells. PNETs are quite distinct from the usual form of pancreatic cancer
, adenocarcinoma, which arises in the exocrine pancreas. About 95 percent of pancreatic tumors are adenocarcinoma; only 1 or 2% of clinically significant pancreas neoplasms are GEP-NETs.
Well or intermediately differentiated PNETs are sometimes called islet cell tumors; neuroendocrine cancer (NEC) is more aggressive.
About 70-85% PNETs are functional, secreting hormones that cause symptoms. About 15 to 30 percent of PETs are nonsecretory or nonfunctional, which either don’t secrete, or the quantity or type of products do not cause a clinical syndrome, such as pancreatic polypeptide
(PPoma), chromogranin
A, and neurotensin
although blood levels may be elevated. Functional tumors are often classified by the hormone most strongly secreted, for example:
rash
, sore mouth, altered bowel habits, venous thrombosis
, and high blood glucose levels
In these functional tumors, the frequency of malignancy and the survival prognosis
have been estimated dissimilarly, but a pertinent accessible summary is available.
Bronchial carcinoid can cause airway obstruction, pneumonia
, pleurisy
, difficulty with breathing, cough, and hemoptysis
, or may be associated with weakness, nausea, weight loss, night sweats, neuralgia, and Cushing’s syndrome. Some are asymptomatic.
Animal neuroendocrine tumors include neuroendocrine cancer of the liver in dogs, and Devil facial tumor disease in Tasmanian Devil
s.
Given the diverse secretory activity of NETs there are many other potential markers, but a limited panel is usually sufficient for clinical purposes.
Aside from the hormones of secretory tumors, the most important markers are :
Newer markers include N-terminally truncated variant of Hsp70
is present in NETs but absent in normal pancreatic islets. High levels of CDX2
, a homeobox
gene product essential for intestinal development and differentiation, are seen in intestinal NETs. Neuroendocrine secretory protein-55, a member of the chromogranin
family, is seen in pancreatic endocrine tumors but not intestinal NETs.
CT-scans, MRIs, sonography (ultrasound), and endoscopy
(including endoscopic ultrasound) are common diagnostic tools. CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, but generally not tumors under 1 cm.
The half-life of somatostatin
in circulation is less than three minutes, too short for diagnosis or targeted therapies. Synthetic modifications of somatostatin with longer half-lives, called somatostatin analogs or congeners, are used instead. The earliest was octreotide
, marketed by Sandoz
as Sandostatin, in 1988. OctreoScan, also called somatostatin receptor scintigraphy
(SRS or SSRS), utilizes intravenously administered octreotide that is chemically bound to a radioactive substance, often indium
-111, to detect larger lesions with tumor cells that are avid for octreotide.
Standard PET
scans using fluorodeoxyglucose
(FDG) are not useful in diagnosis of NETs Gallium
-68 receptor PET
-CT is much more sensitive than an OctreoScan. C-5-hydroxy-L-tryptophan
PET has very high sensitivity.
mutation
analysis in well-differentiated pancreatic neuroendocrine tumors identified four important findings:
Recommendations in NET include family history evaluation, evaluation for second tumors, and in selected circumstances testing for germline mutations such as for MEN1.
Observation may be feasible for non-functioning low grade neuroendocrine tumors.
If the tumor is locally advanced or has metastasized, but is nonetheless slowly growing, treatment that relieves symptoms may often be preferred over immediate challenging surgeries.
Intermediate and high grade tumors (noncarcinoids) are usually best treated by various early interventions (active therapy) rather than observation (wait-and-see approach).
Treatments have improved over the past several decades, and outcomes are improving. In malignant carcinoid tumors with carcinoid syndrome, the median
survival has improved from two years to more than eight years.
Detailed guidelines for managing neuroendocrine tumors are available from ESMO
, NCCN
and a UK panel. The NCI
has guidelines for several categories of NET: islet cell tumors of the pancreas, gastrointestinal carcinoids, Merkel cell
tumors and pheochromocytoma
and paraganglioma
.
Even if the tumor has advanced and metastasized, making curative surgery infeasible, surgery often has a role in neuroendocrine cancers for palliation of symptoms and possibly improved survival.
analogs given subcutaneously or intramuscularly alleviate symptoms by blocking hormone release. A consensus review has reported on the use of somatostatin analogs for GEP-NETs.
These medications may also anatomically stabilize or shrink tumors, as suggested by the PROMID study (Placebo-controlled prospective randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors): at least in this subset of NETs, average tumor stabilization was 14.3 months compared to 6 months for placebo
.
Other medications that block particular secretory effects can sometimes relieve symptoms.
is sometimes used to treat GEP-NETs. Its effectiveness is somewhat uncertain, but low doses can be titrated
within each person, often considering the effect on the blood leukocyte count; interferon is often used in combination with other agents, especially somatostatin analogs such as octreotide.
(high-grade
or anaplastic) metastatic disease, where cisplatin
with etoposide
may be used and SSRS
negative tumors which had a response rate in excess of 70% compared to 10% in strongly positive SRSS carcinoid tumors.
with streptozocin, is often more effective. Although marginally effective in well-differentiated PETs, cisplatin
with etoposide
is active in poorly-differentiated neuroendocrine cancers (PDNECs).
Targeted chemotherapy agents have been approved in PETs by the FDA
based on improved progression-free survival (PFS):
and etoposide
combination.
or radioligand
, the peptide or neuroamine hormone previously having shown good uptake of a tracer dose. This kind of RIT may be called peptide receptor radionuclide therapy (PRRT), or hormone-delivered radiotherapy, and can attack all lesions in the body, not just liver metastases. This is typically by radiolabeling octreotate to lutetium-177, ytrium-90 or indium-111. This is a highly targeted and effective therapy with minimal side effects in tumours with high levels of cell surface somatostatin cell surface expression. This is because of the radiation is taken up at sites of tumour or excreted in the urine. The radioactively labelled hormones enter the tumor cells, and these and nearby cells are damaged by the attached radiation. Not all cells are immediately killed; cell death can go on for up to two years. Early referral to a nuclear medicine physician is suggested to assess suitability for this new treatment modality.
Hepatic artery embolization (HAE) occludes the blood flow to the tumors, achieving significant tumor shrinkage in over 80%.
In hepatic artery chemotherapy, the chemotherapy agents are given into the hepatic artery, often by steady infusion over hours or even days. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.
Hepatic artery chemoembolization (HACE), sometimes called transarterial chemoembolization (TACE), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides.
Selective internal radiation therapy (SIRT) for neuroendocrine metastases to the liver delivers radioactive microsphere therapy (RMT) by injection into the hepatic artery, lodging (as with HAE and HACE) in downstream capillaries. In contrast to hormone-delivered radiotherapy, the lesions need not overexpress peptide receptors. The mechanical targeting delivers the radiation from the yttrium-labeled microspheres selectively to the tumors without unduly affecting the normal liver. This type of treatment is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, including neuroendocrine malignancies.
(RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and current is applied to generate heat; the tumor cells are killed by cooking.
Cryoablation
is similar to RFA; an endothermic substance is injected into the tumors to kill by freezing. Cryoablation has been considerably less successful for GEP-NETs than RFA.
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
s. Many are benign
Benign
A benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...
, while some are cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s. They most commonly occur in the intestine, but are also found in the lung and the rest of the body.
Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, such as looking similar, having special secretory granules, and often producing biogenic amines and polypeptide hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s.
Neuroendocrine system
NETs are believed to arise from various neuroendocrine cellNeuroendocrine cell
Neuroendocrine cells are cells that receive neuronal input and, as a consequence of this input, release message molecules to the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration...
s whose normal function is to serve at the neuroendocrine
Neuroendocrinology
Neuroendocrinology is the study of the extensive interactions between the nervous system and the endocrine system, including the biological features of the cells that participate, and how they functionally communicate...
interface. Neuroendocrine cells are present not only in endocrine glands throughout the body that produce hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, but also diffusely in all body tissues.
History
Small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907. They were named carcinoid tumors because their slow growth was considered to be "cancer-like" rather than truly cancerous.However, in 1929 it was recognized that some of these small bowel tumors could be malignant. Despite the differences between these two original categories, and further complexities due to subsequent inclusion of other NETs of pancreas and pulmonary origin, all NETs are sometimes (incorrectly) subsumed into the term "carcinoid."
Enterochromaffin
Enterochromaffin
Enterochromaffin cells are a type of enteroendocrine cell occurring in the epithelia lining the lumen of the digestive tract and the respiratory tract.-Function:They contain about 90% of the body's store of serotonin ....
cells, which give rise to carcinoid tumors, were identified in 1897 by Kulchitsky and their secretion of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
was established in 1953 when the “flushing” effect of serotonin had become clinically recognized. Carcinoid heart disease was identified in 1952 and carcinoid fibrosis in 1961.
Neuroendocrine tumors were sometimes called APUDomas
Apudoma
In pathology, an apudoma is an endocrine tumour that arises from an APUD cell from structures such as the ampulla of Vater, pancreas, and prostate.They are derived from neural crest cells.The term dates back to at least 1975....
because these cells often show amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
precursor (L-DOPA and 5-hydroxytryptophan
5-Hydroxytryptophan
5-Hydroxytryptophan , also known as oxitriptan , is a naturally occurring amino acid and chemical precursor as well as metabolic intermediate in the biosynthesis of the neurotransmitters serotonin and melatonin from tryptophan....
) uptake and decarboxylation to produce biogenic amines such as catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
. Although this behavior was also part of the disproven hypothesis that these cells might all embryologically
Embryology
Embryology is a science which is about the development of an embryo from the fertilization of the ovum to the fetus stage...
arise from the neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
, neuroendocrine cells sometimes produce various types of hormones and amines, and they can also have strong receptors for other hormones to which they respond.
There have been multiple nomenclature systems for these tumors, and the differences between these schema have often been confusing. Nonetheless, these systems all distinguish between well-differentiated
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
(low and intermediate-grade
Grading (tumors)
In pathology, grading is a measure of the cell appearance in tumors and other neoplasms. Some pathology grading systems apply only to malignant neoplasms ; others apply also to benign neoplasms. The neoplastic grading is a measure of cell anaplasia in the sampled tumors arising from the...
) and poorly differentiated (high-grade) NETs. Cellular proliferative rate is of considerable significance in this prognostic assessment
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
.
Incidence
Although estimates vary, the annual incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of clinically significant neuroendocrine tumors is approximately 2.5-5 per 100,000; two thirds are carcinoid tumors and one third are other NETs.
The prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
has been estimated as 35 per 100,000, and may be considerably higher if clinically silent tumors are included. An autopsy
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
study of the pancreas in people who died from unrelated causes discovered a remarkably high incidence of tiny asymptomatic NETs. Routine microscopic study of three random sections of the pancreas found NETs in 1.6%, and multiple sections identified NETs in 10%. As diagnostic imaging increases in sensitivity, such as endoscopic
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
ultrasonography, very small, clinically insignificant NETs may be coincidentally discovered; being unrelated to symptoms, such neoplasms may not require surgical excision.
WHO classification
The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories:- well-differentiated neuroendocrine tumours, further subdivided into tumors with benign and those with uncertain behavior
- well-differentiated (low grade) neuroendocrine carcinomas with low-grade malignant behavior
- poorly differentiated (high grade) neuroendocrine carcinomas, which are the large cell neuroendocrine and small cell carcinomas.
Additionally, the WHO scheme recognizes mixed tumors with both neuroendocrine and epithelial carcinoma features, such as goblet cell cancer
Goblet cell carcinoid
The goblet cell carcinoid, abbreviated GCC and also known as crypt cell carcinoma and neuroendocrine tumour with goblet cell differentiation, is a rare biphasic gastrointestinal tract tumour that consists of a neuroendocrine component and a conventional carcinoma.-Diagnosis:GCCs are diagnosed by...
, a rare gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
.
Placing a given tumor into one of categories depends on well-defined histological
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
features: size, lympho
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...
vascular
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
invasion, mitotic
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
counts, Ki-67 labelling index, invasion of adjacent organs, presence of metastases
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
and whether they produce hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s.
Anatomic distribution
NETs can arise in many different areas of the body, and are most often located in the intestine or the lungs.The various kinds of cells that can give rise to NETs are present in endocrine glands and are also diffusely distributed throughout the body, most commonly Kulchitsky cells or similar enterochromaffin-like cells, that are relatively more common in the gastrointestinal and pulmonary systems.
NETs include certain tumors of the gastrointestinal tract and of the pancreatic islet cells, certain thymus and lung tumors, and medullary carcinoma
Medullary thyroid cancer
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells , which produce the hormone calcitonin....
of the parafollicular cells of the thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
. Tumors with similar cellular characteristics in the pituitary, parathyroid, and adrenomedullary glands are sometimes included or excluded.
Within the broad category of neuroendocrine tumors there are many different tumor types: this outline is presented to facilitate retrieving information. It is quite clear that neuroendocrine tumors are uncommon in many of these areas, and frequently represent only a very small proportion of the tumors or cancers at these locations.
- Pituitary
- neuroendocrine tumor of the anterior pituitary
- Thyroid tumors, particularly medullary carcinomaMedullary thyroid cancerMedullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells , which produce the hormone calcitonin....
- Parathyroid tumors
- Thymus and mediastinal carcinoid tumors
- Pulmonary neuroendocrine tumors
- bronchus
- pulmonary carcinoid tumors: typical carcinoid (TC; low-grade); atypical carcinoid (AC; intermediate-grade)
- small-cell lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
(SCLC) - large-cell neuroendocrine carcinoma (LCNEC of the lung)
- Extrapulmonary small cell carcinomas (ESCC or EPSCC)
- Gastroenteropancreatic neuroendocrine tumors (GEP-NET)
- ForegutForegutThe foregut is the anterior part of the alimentary canal, from the mouth to the duodenum at the entrance of the bile duct. At this point it is continuous with the midgut...
GEP-NET (foregut tumors can conceptually encompasses not only NETs of the stomach and proximal duodenum, but also the pancreas, and even thymus, lung and bronchus)- Pancreatic endocrine tumors (if considered separately from foregut GEP-NET)
- MidgutMidgutThe midgut is the portion of the embryo from which most of the intestines develop. After it bends around the superior mesenteric artery, it is called the "midgut loop"...
GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon)- appendix, including well differentiated NETs (benign); well differentiated NETs (uncertain malignant potential); well differentiated neuroendocrine carcinoma (with low malignant potential); mixed exocrine-neuroendocrine carcinoma (goblet cell carcinoma, also called adenocarcinoid and mucous adenocarcinoid)
- HindgutHindgutThe hindgut is the posterior part of the alimentary canal. In mammals, it includes the distal third of the transverse colon and the splenic flexure, the descending colon, sigmoid colon and rectum.-Blood flow:...
GEP-NET
- Foregut
- Liver and gallbladder
- Adrenal tumors, particularly adrenomedullary tumors
- PheochromocytomaPheochromocytomaA pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
- Peripheral nervous systemPeripheral nervous systemThe peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
tumors, such as:- SchwannomaSchwannomaA schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
- paragangliomaParagangliomaA paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites . About 97% are benign and cured by surgical removal; the remaining 3% are malignant because they are able to produce distant metastases...
- neuroblastomaNeuroblastomaNeuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
- Schwannoma
- Breast
- Genitourinary tract
- urinary tract carcinoid tumor and neuroendocrine carcinoma
- ovary
- neuroendocrine tumor of the cervix
- testes
- Merkel cellMerkel cellMerkel cells or Merkel-Ranvier cells are oval receptor cells found in the skin of vertebrates that have synaptic contacts with somatosensory afferents. They are associated with the sense of light touch discrimination of shapes and textures. They can turn malignant and form the skin tumor known as...
carcinomaMerkel cell carcinomaMerkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...
of skin (trabecular cancer) - Several inherited conditions:
- multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...
(MEN1) - multiple endocrine neoplasia type 2Multiple endocrine neoplasia type 2Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant . They generally occur in endocrine organs Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary...
(MEN2) - von Hippel-Lindau (VHL) disease
- neurofibromatosisNeurofibromatosisNeurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
type 1 - tuberous sclerosisTuberous sclerosisTuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
- Carney complex
- multiple endocrine neoplasia type 1
TNM stage
A TNM scheme has been proposed for NETs by the European Neuroendocrine Tumor Society.Histopathology
Features in common
Neuroendocrine tumors, despite differing embryologicalEmbryology
Embryology is a science which is about the development of an embryo from the fertilization of the ovum to the fetus stage...
origin, have
common phenotypic characteristics.
NETs show tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
immunoreactivity for markers of neuroendocrine differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
(pan-neuroendocrine tissue markers) and may secrete various peptides and hormones. There is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers. Widely used neuroendocrine tissue markers are various chromogranin
Chromogranin
Granin is a protein family of regulated secretory proteins ubiquitously found in the cores of amine and peptide hormone and neurotransmitter dense-core secretory vesicles.- Function :...
s, synaptophysin
Synaptophysin
Synaptophysin also known as the major synaptic vesicle protein p38 is a protein that in humans is encoded by the SYP gene.-Genomics:...
and PGP9.5. Neuron-specific enolase (NSE) is less specific
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
.
NETs are often small, yellow or tan masses, often located in the submucosa
Submucosa
In the gastrointestinal tract, the submucosa is the layer of dense irregular connective tissue or loose connective tissue that supports the mucosa, as well as joins the mucosa to the bulk of underlying smooth muscle .-Contents:Blood vessels, lymphatic vessels, and nerves will run through...
or more deeply intramurally, and they can be very firm due to an accompanying intense desmoplastic reaction. The overlying mucosa may be either intact or ulcerated. Some GEP-NETs invade deeply to involve the mesentery
Mesentery
In anatomy, the mesentery is the double layer of peritoneum that suspends the jejunum and ileum from the posterior wall of the abdomen. Its meaning, however, is frequently extended to include double layers of peritoneum connecting various components of the abdominal cavity.-Mesentery :The...
.
Histologically, NETs are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal pleomorphism
Pleomorphism (cytology)
Pleomorphism is a term used in histology and cytopathology to describe variability in the size and shape of cells and/or their nuclei. It is a feature characteristic of malignant neoplasms....
but less commonly there can be anaplasia
Anaplasia
Anaplasia refers to a reversion of differentiation in cells and is characteristic of malignant neoplasms . Sometimes, the term also includes an increased capacity for multiplication. Lack of differentiation is considered a hallmark of aggressive malignancies. The term anaplasia literally means "to...
, mitotic
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
activity, and necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
.
Some neuroendocrine tumor cells possess especially strong hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s, such as somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
receptors and uptake hormones strongly. This avidity
Avidity
In proteins, avidity is a term used to describe the combined strength of multiple bond interactions. Avidity is distinct from affinity, which is a term used to describe the strength of a single bond...
can assist in diagnosis and may make some tumors vulnerable to hormone targeted therapies.
Argentaffin and hormone secretion
NETs from a particular anatomical origin often show similar behavior as a group, such as the foregutForegut
The foregut is the anterior part of the alimentary canal, from the mouth to the duodenum at the entrance of the bile duct. At this point it is continuous with the midgut...
(which conceptually includes pancreas, and even thymus, airway and lung NETs), midgut
Midgut
The midgut is the portion of the embryo from which most of the intestines develop. After it bends around the superior mesenteric artery, it is called the "midgut loop"...
and hindgut
Hindgut
The hindgut is the posterior part of the alimentary canal. In mammals, it includes the distal third of the transverse colon and the splenic flexure, the descending colon, sigmoid colon and rectum.-Blood flow:...
; individual tumors within these sites can differ from these group benchmarks:
- Foregut NETs are argentaffinArgentaffinArgentaffin refers to cells which take up silver stain. Enteroendocrine cells are sometimes called "argentaffins", because they take up this stain....
negative. Despite low serotonin content, they often secrete 5-hydroxytryptophan5-Hydroxytryptophan5-Hydroxytryptophan , also known as oxitriptan , is a naturally occurring amino acid and chemical precursor as well as metabolic intermediate in the biosynthesis of the neurotransmitters serotonin and melatonin from tryptophan....
(5-HTP), histamine, and several polypeptide hormones. There may be associated atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck. These tumors can metastasize to bone. - Midgut NETs are argentaffin positive, can produce high levels of serotonin 5-hydroxytryptamine (5-HT), kinins, prostaglandins, substance P (SP), and other vasoactive peptides, and sometimes produce corticotropic hormone (previously adrenocorticotropic hormone [ACTH]). Bone metastasis is uncommon.
- Hindgut NETs are argentaffin negative and rarely secrete 5-HT, 5-HTP, or any other vasoactive peptides. Bone metastases are not uncommon.
Carcinoid tumors
(about two thirds of GEP-NETs)Carcinoids most commonly affect the small bowel, particularly the ileum, and are the most common malignancy of the appendix
Vermiform appendix
The appendix is a blind-ended tube connected to the cecum , from which it develops embryologically. The cecum is a pouchlike structure of the colon...
. Many carcinoids are asymptomatic and are discovered only upon surgery for unrelated causes. These coincidental carcinoids are common; one study found that one person in ten has them. Many tumors do not cause symptoms even when they have metastasized. Other tumors even if very small can produce adverse effects by secreting hormones.
10% or less of carcinoids, primarily some midgut carcinoids, secrete excessive levels of a range of hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, most notably serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-HT) or substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
, causing a constellation of symptoms called carcinoid syndrome
Carcinoid syndrome
Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and, less frequently, heart failure and bronchoconstriction...
:
- flushingFlushing (physiology)For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
- diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
- asthmaAsthmaAsthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
or wheezing - congestive heart failureCongestive heart failureHeart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
(CHF) - abdominal cramping
- peripheral edemaPeripheral edemaPeripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids.The condition is commonly associated with aging, but can be caused by many other conditions, including congestive heart failure, trauma, alcoholism, altitude sickness, pregnancy,...
- heart palpitations
A carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure can occur if large amounts of hormone are acutely secreted, which is occasionally triggered by factors such as diet, alcohol, surgery chemotherapy, embolization therapy or radiofrequency ablation.
Chronic exposure to high levels of serotonin causes thickening of the heart valves, particularly the tricuspid and the pulmonic valves, and over a long period can lead to congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
. However, valve replacement is rarely needed. The excessive outflow of serotonin can cause a depletion of tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
leading to niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
deficiency, and thus pellagra
Pellagra
Pellagra is a vitamin deficiency disease most commonly caused by a chronic lack of niacin in the diet. It can be caused by decreased intake of niacin or tryptophan, and possibly by excessive intake of leucine. It may also result from alterations in protein metabolism in disorders such as carcinoid...
, which is associated with dermatitis, dementia, and diarrhea.
Many other hormones can be secreted by some of these tumors, most commonly growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
that can cause acromegaly
Acromegaly
Acromegaly is a syndrome that results when the anterior pituitary gland produces excess growth hormone after epiphyseal plate closure at puberty...
, or cortisol, that can cause Cushing's syndrome
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...
.
Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. Bowel obstruction
Bowel obstruction
Bowel obstruction is a mechanical or functional obstruction of the intestines, preventing the normal transit of the products of digestion. It can occur at any level distal to the duodenum of the small intestine and is a medical emergency...
can occur, sometimes due to fibrosing
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
effects of NET secretory products with an intense desmoplastic reaction at the tumor site, or of the mesentery
Mesentery
In anatomy, the mesentery is the double layer of peritoneum that suspends the jejunum and ileum from the posterior wall of the abdomen. Its meaning, however, is frequently extended to include double layers of peritoneum connecting various components of the abdominal cavity.-Mesentery :The...
.
Pancreatic endocrine tumors (PETs)
(about one third of GEP-NETs)Pancreatic neuroendocrine tumors (PETs or PNETs; not to be confused with the primitive neuroectodermal PNET
Primitive neuroectodermal tumor
Primitive neuroectodermal tumor is a neural crest tumor. It is a rare tumor, usually occurring in children and young adults under 25 years of age...
) can originate within the pancreas or from similar neuroendocrine cells outside of the pancreas. It is unclear whether pancreatic tumors originate from the usual cells of the islet of Langerhans or from diffuse neuroendocrine pluripotent cells. PNETs are quite distinct from the usual form of pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, adenocarcinoma, which arises in the exocrine pancreas. About 95 percent of pancreatic tumors are adenocarcinoma; only 1 or 2% of clinically significant pancreas neoplasms are GEP-NETs.
Well or intermediately differentiated PNETs are sometimes called islet cell tumors; neuroendocrine cancer (NEC) is more aggressive.
About 70-85% PNETs are functional, secreting hormones that cause symptoms. About 15 to 30 percent of PETs are nonsecretory or nonfunctional, which either don’t secrete, or the quantity or type of products do not cause a clinical syndrome, such as pancreatic polypeptide
Pancreatic polypeptide
Pancreatic polypeptide is a polypeptide secreted by PP cells in the endocrine pancreas predominantly in the head of the pancreas. It consists of 36 amino acids and has molecular weight about 4200 Da....
(PPoma), chromogranin
Chromogranin
Granin is a protein family of regulated secretory proteins ubiquitously found in the cores of amine and peptide hormone and neurotransmitter dense-core secretory vesicles.- Function :...
A, and neurotensin
Neurotensin
Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system...
although blood levels may be elevated. Functional tumors are often classified by the hormone most strongly secreted, for example:
- gastrinomaGastrinomaA gastrinoma is a tumor in the pancreas or duodenum that secretes excess of gastrin leading to ulceration in the duodenum, stomach and the small intestine. There is hypersecretion of the HCl in the duodenum which causes the ulcers...
: the excessive gastrinGastrinIn humans, gastrin is a peptide hormone that stimulates secretion of gastric acid by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the antrum of the stomach, duodenum, and the pancreas...
causes Zollinger-Ellison SyndromeZollinger-Ellison syndromeZollinger–Ellison syndrome is a triad of gastric acid hypersecretion, severe peptic ulceration, and non-beta cell islet tumor of pancreas . In this syndrome increased levels of the hormone gastrin are produced, causing the stomach to produce excess hydrochloric acid. Often the cause is a tumor of...
(ZES) with peptic ulcerPeptic ulcerA peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
s and diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and... - insulinomaInsulinomaAn insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin.Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is...
: hypoglycemiaHypoglycemiaHypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
occurs with concurrent elevations of insulinInsulinInsulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, proinsulinProinsulinProinsulin is the prohormone precursor to insulin made in the beta cells of the islets of Langerhans, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene.- Synthesis and post-translational modification :...
and C peptide - glucagonomaGlucagonomaA glucagonoma is a rare tumor of the alpha cells of the pancreas that results in up to a 1000-fold overproduction of the hormone glucagon. Alpha cell tumors are commonly associated with glucagonoma syndrome, though similar symptoms are present in cases of pseudoglucagonoma syndrome in the absence...
: the symptoms are not all due to glucagon elevations, and include a
rash
Necrolytic migratory erythema
Necrolytic migratory erythema is a red, blistering rash that spreads across the skin, particularly the lower abdomen, buttocks, perineum, and groin...
, sore mouth, altered bowel habits, venous thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
, and high blood glucose levels
- VIPomaVIPomaA VIPoma is a rare endocrine tumor, usually originating in the pancreas, that produces vasoactive intestinal peptide ....
, producing excessive vasoactive intestinal peptideVasoactive intestinal peptideVasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 29 amino acid residues that is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain...
, which may cause profound chronic watery diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
and resultant dehydrationDehydrationIn physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, hypokalemiaHypokalemiaHypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
, and achlorhydriaAchlorhydriaAchlorhydria or hypochlorhydria refers to states where the production of gastric acid in the stomach is absent or low, respectively. It is associated with various other medical problems.-Signs and symptoms:...
(WDHA or pancreatic cholera syndrome) - somatostatinomaSomatostatinomaSomatostatinoma is a tumor of the delta cells of the endocrine pancreas that produces somatostatin.It is associated with diabetes mellitus and abnormal glucose tolerance.Triad of : Mild Diabetes mellitus, Steatorrhoea, Gall stones...
: these rare tumors are associated with elevated blood glucose levels, achlorhydriaAchlorhydriaAchlorhydria or hypochlorhydria refers to states where the production of gastric acid in the stomach is absent or low, respectively. It is associated with various other medical problems.-Signs and symptoms:...
, cholelithiasis, and diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and... - less common types include ACTHomaAdrenocorticotropic hormoneAdrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
, CRHCorticotropin-releasing hormoneCorticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
oma, calcitoninCalcitoninCalcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
oma, GHRHoma, GRFoma, and parathyroid hormone–related peptide tumor
In these functional tumors, the frequency of malignancy and the survival prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
have been estimated dissimilarly, but a pertinent accessible summary is available.
Other
In addition to the two main categories, there are rarer forms of GEP-NETs, including neuroendocrine lung, thymus and parathyroid tumors.Bronchial carcinoid can cause airway obstruction, pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, pleurisy
Pleurisy
Pleurisy is an inflammation of the pleura, the lining of the pleural cavity surrounding the lungs. Among other things, infections are the most common cause of pleurisy....
, difficulty with breathing, cough, and hemoptysis
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
, or may be associated with weakness, nausea, weight loss, night sweats, neuralgia, and Cushing’s syndrome. Some are asymptomatic.
Animal neuroendocrine tumors include neuroendocrine cancer of the liver in dogs, and Devil facial tumor disease in Tasmanian Devil
Tasmanian Devil
The Tasmanian devil is a carnivorous marsupial of the family Dasyuridae, now found in the wild only on the Australian island state of Tasmania. The size of a small dog, it became the largest carnivorous marsupial in the world following the extinction of the thylacine in 1936...
s.
Markers
Symptoms from secreted hormones may prompt measurement of the corresponding hormones in the blood or their associated urinary products, for initial diagnosis or to assess the interval change in the tumor. Secretory activity of the tumor cells is sometimes dissimilar to the tissue immunoreactivity to particular hormones.Given the diverse secretory activity of NETs there are many other potential markers, but a limited panel is usually sufficient for clinical purposes.
Aside from the hormones of secretory tumors, the most important markers are :
- chromograninChromograninGranin is a protein family of regulated secretory proteins ubiquitously found in the cores of amine and peptide hormone and neurotransmitter dense-core secretory vesicles.- Function :...
A (CgA) - urine 5-hydroxyindoleacetic acid5-Hydroxyindoleacetic acid5-Hydroxyindoleacetic acid is the main metabolite of serotonin in the human body. In chemical analysis of urine samples, 5-HIAA is used to determine the body's levels of serotonin.- Clinical significance :...
(5-HIAA) - neuron-specific enolase (NSE, gamma-gamma dimer)
- synaptophysinSynaptophysinSynaptophysin also known as the major synaptic vesicle protein p38 is a protein that in humans is encoded by the SYP gene.-Genomics:...
(P38)
Newer markers include N-terminally truncated variant of Hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
is present in NETs but absent in normal pancreatic islets. High levels of CDX2
CDX2
Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. The protein encoded by this gene is a homeobox transcription factor.-Function:...
, a homeobox
Homeobox
A homeobox is a DNA sequence found within genes that are involved in the regulation of patterns of anatomical development in animals, fungi and plants.- Discovery :...
gene product essential for intestinal development and differentiation, are seen in intestinal NETs. Neuroendocrine secretory protein-55, a member of the chromogranin
Chromogranin
Granin is a protein family of regulated secretory proteins ubiquitously found in the cores of amine and peptide hormone and neurotransmitter dense-core secretory vesicles.- Function :...
family, is seen in pancreatic endocrine tumors but not intestinal NETs.
Imaging
Imaging modalities in NETs have been reviewed.CT-scans, MRIs, sonography (ultrasound), and endoscopy
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
(including endoscopic ultrasound) are common diagnostic tools. CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, but generally not tumors under 1 cm.
The half-life of somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
in circulation is less than three minutes, too short for diagnosis or targeted therapies. Synthetic modifications of somatostatin with longer half-lives, called somatostatin analogs or congeners, are used instead. The earliest was octreotide
Octreotide
Octreotide is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone...
, marketed by Sandoz
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....
as Sandostatin, in 1988. OctreoScan, also called somatostatin receptor scintigraphy
Scintigraphy
Scintigraphy is a form of diagnostic test used in nuclear medicine, wherein radioisotopes are taken internally, and the emitted radiation is captured by external detectors to form two-dimensional images...
(SRS or SSRS), utilizes intravenously administered octreotide that is chemically bound to a radioactive substance, often indium
Indium
Indium is a chemical element with the symbol In and atomic number 49. This rare, very soft, malleable and easily fusible post-transition metal is chemically similar to gallium and thallium, and shows the intermediate properties between these two...
-111, to detect larger lesions with tumor cells that are avid for octreotide.
Standard PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
scans using fluorodeoxyglucose
Fluorodeoxyglucose
Fludeoxyglucose or fluorodeoxyglucose , commonly abbreviated 18F-FDG or FDG, is a radiopharmaceutical used in the medical imaging modality positron emission tomography...
(FDG) are not useful in diagnosis of NETs Gallium
Gallium
Gallium is a chemical element that has the symbol Ga and atomic number 31. Elemental gallium does not occur in nature, but as the gallium salt in trace amounts in bauxite and zinc ores. A soft silvery metallic poor metal, elemental gallium is a brittle solid at low temperatures. As it liquefies...
-68 receptor PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
-CT is much more sensitive than an OctreoScan. C-5-hydroxy-L-tryptophan
5-Hydroxytryptophan
5-Hydroxytryptophan , also known as oxitriptan , is a naturally occurring amino acid and chemical precursor as well as metabolic intermediate in the biosynthesis of the neurotransmitters serotonin and melatonin from tryptophan....
PET has very high sensitivity.
Pancreatic neuroendocrine tumors
DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
analysis in well-differentiated pancreatic neuroendocrine tumors identified four important findings:
- as expected, the geneGeneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s mutated in NETs, MEN1MEN1Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
, ATRXATRXTranscriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein is a protein that in humans is encoded by the ATRX gene.- Function :...
, DAXX, TSC2TSC2Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
, PTENPTEN (gene)Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
and PIK3CA, are different from the mutated genes previously found in pancreaticPancreatic cancerPancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
adenocarcinomaAdenocarcinomaAdenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
.
- one in six well-differentiated pancreatic NETs have mutations in mTOR pathway genes, such as TSC2TSC2Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
, PTENPTEN (gene)Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
and PIK3CA. The sequencing discovery might allow selection of which NETs would benefit from mTOR inhibition such as with everolimusEverolimusEverolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
, but this awaits validation in a clinical trialClinical trialClinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
.
- mutations affecting a new cancer pathway involving ATRXATRXTranscriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein is a protein that in humans is encoded by the ATRX gene.- Function :...
and DAXX genes were found in about 40% of pancreatic NETs. The proteins encoded by ATRX and DAXX participate in chromatinChromatinChromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
remodeling of telomereTelomereA telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
s; these mutations are associated with a telomeraseTelomeraseTelomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
-independent maintenance mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric ends of chromosomes.
- ATRXATRXTranscriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein is a protein that in humans is encoded by the ATRX gene.- Function :...
/DAXX and MEN1MEN1Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
mutations were associated with a better prognosisPrognosisPrognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
.
Familial syndromes
Neuroendocrine tumors can be seen in several inherited familial syndromes, including:- multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...
(MEN1) - multiple endocrine neoplasia type 2Multiple endocrine neoplasia type 2Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant . They generally occur in endocrine organs Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary...
(MEN2) - von Hippel-Lindau (VHL) disease
- neurofibromatosisNeurofibromatosisNeurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
type 1 - tuberous sclerosisTuberous sclerosisTuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
- Carney complex
Recommendations in NET include family history evaluation, evaluation for second tumors, and in selected circumstances testing for germline mutations such as for MEN1.
Overview
Several issues help define appropriate treatment of a neuroendocrine tumor, including its location, invasiveness, hormone secretion, and metastasis. Treatments may be aimed at curing the disease or at relieving symptoms (palliation).Observation may be feasible for non-functioning low grade neuroendocrine tumors.
If the tumor is locally advanced or has metastasized, but is nonetheless slowly growing, treatment that relieves symptoms may often be preferred over immediate challenging surgeries.
Intermediate and high grade tumors (noncarcinoids) are usually best treated by various early interventions (active therapy) rather than observation (wait-and-see approach).
Treatments have improved over the past several decades, and outcomes are improving. In malignant carcinoid tumors with carcinoid syndrome, the median
Median
In probability theory and statistics, a median is described as the numerical value separating the higher half of a sample, a population, or a probability distribution, from the lower half. The median of a finite list of numbers can be found by arranging all the observations from lowest value to...
survival has improved from two years to more than eight years.
Detailed guidelines for managing neuroendocrine tumors are available from ESMO
European Society for Medical Oncology
-About ESMO:The European Society for Medical Oncology is a non-profit professional medical oncology society in Europe.ESMO offers post-graduate education and training in clinical cancer care and research, and produces evidence-based recommendations for basic standards of cancer care...
, NCCN
National Comprehensive Cancer Network
National Comprehensive Cancer Network is an alliance of twenty-one cancer centers in the United States, most of which are designated by the National Cancer Institute as comprehensive cancer centers...
and a UK panel. The NCI
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
has guidelines for several categories of NET: islet cell tumors of the pancreas, gastrointestinal carcinoids, Merkel cell
Merkel cell
Merkel cells or Merkel-Ranvier cells are oval receptor cells found in the skin of vertebrates that have synaptic contacts with somatosensory afferents. They are associated with the sense of light touch discrimination of shapes and textures. They can turn malignant and form the skin tumor known as...
tumors and pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
and paraganglioma
Paraganglioma
A paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites . About 97% are benign and cured by surgical removal; the remaining 3% are malignant because they are able to produce distant metastases...
.
Surgery
Surgery is a curative treatment for some neuroendocrine tumors.Even if the tumor has advanced and metastasized, making curative surgery infeasible, surgery often has a role in neuroendocrine cancers for palliation of symptoms and possibly improved survival.
Symptomatic relief
In secretory tumors, somatostatinSomatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
analogs given subcutaneously or intramuscularly alleviate symptoms by blocking hormone release. A consensus review has reported on the use of somatostatin analogs for GEP-NETs.
These medications may also anatomically stabilize or shrink tumors, as suggested by the PROMID study (Placebo-controlled prospective randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors): at least in this subset of NETs, average tumor stabilization was 14.3 months compared to 6 months for placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
.
Other medications that block particular secretory effects can sometimes relieve symptoms.
Chemotherapy
InterferonInterferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
is sometimes used to treat GEP-NETs. Its effectiveness is somewhat uncertain, but low doses can be titrated
Titration
Titration, also known as titrimetry, is a common laboratory method of quantitative chemical analysis that is used to determine the unknown concentration of an identified analyte. Because volume measurements play a key role in titration, it is also known as volumetric analysis. A reagent, called the...
within each person, often considering the effect on the blood leukocyte count; interferon is often used in combination with other agents, especially somatostatin analogs such as octreotide.
Gastrointestinal neuroendocrine tumors
Most gastrointestinal carcinoid tumors tend not to respond to chemotherapy agents, showing 10 to 20% response rates that are typically less than 6 months. Combining chemotherapy medications has not usually been of significant improvement showing 25 to 35% response rates that are typically less than 9 months. The exceptions are poorly-differentiatedCellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
(high-grade
Grading (tumors)
In pathology, grading is a measure of the cell appearance in tumors and other neoplasms. Some pathology grading systems apply only to malignant neoplasms ; others apply also to benign neoplasms. The neoplastic grading is a measure of cell anaplasia in the sampled tumors arising from the...
or anaplastic) metastatic disease, where cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
with etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
may be used and SSRS
SSRS
SSRS may refer to:* Savez Sindikata Republike Srpske, the Confederation of Trade Unions of the Republika Srpska* Ship Security Reporting System, a counter piracy system* SQL Server Reporting Services, a server-based report generation software system...
negative tumors which had a response rate in excess of 70% compared to 10% in strongly positive SRSS carcinoid tumors.
Pancreatic endocrine tumors
PETs are more responsive to chemotherapy than are gastroenteric carcinoid tumors. Several agents can shown activity and combining several medicines, particularly doxorubicinDoxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
with streptozocin, is often more effective. Although marginally effective in well-differentiated PETs, cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
with etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
is active in poorly-differentiated neuroendocrine cancers (PDNECs).
Targeted chemotherapy agents have been approved in PETs by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
based on improved progression-free survival (PFS):
- everolimusEverolimusEverolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
(Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of everolimus in carcinoid tumors have not been established. - sunitinibSunitinibSunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that was approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor on January 26, 2006...
(Sutent) is labeled for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease. Sutent also has approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'.
Bronchial carcinoids
Pulmonary carcinoids are sometimes given a platinumPlatinum
Platinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...
and etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
combination.
Hormone-delivered radiotherapy
In this type of radioisotope therapy (RIT) the tumor is treated intravenously with a peptide or hormone conjugated to a radionuclideRadionuclide
A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron. The radionuclide, in this process, undergoes radioactive decay, and emits gamma...
or radioligand
Radioligand
A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
, the peptide or neuroamine hormone previously having shown good uptake of a tracer dose. This kind of RIT may be called peptide receptor radionuclide therapy (PRRT), or hormone-delivered radiotherapy, and can attack all lesions in the body, not just liver metastases. This is typically by radiolabeling octreotate to lutetium-177, ytrium-90 or indium-111. This is a highly targeted and effective therapy with minimal side effects in tumours with high levels of cell surface somatostatin cell surface expression. This is because of the radiation is taken up at sites of tumour or excreted in the urine. The radioactively labelled hormones enter the tumor cells, and these and nearby cells are damaged by the attached radiation. Not all cells are immediately killed; cell death can go on for up to two years. Early referral to a nuclear medicine physician is suggested to assess suitability for this new treatment modality.
Hepatic artery
Metastases to the liver can be treated by several types of hepatic artery treatments based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 70-80 percent of their nutrients and 50% their oxygen supply from the portal vein, and thus can survive with the hepatic artery effectively blocked.Hepatic artery embolization (HAE) occludes the blood flow to the tumors, achieving significant tumor shrinkage in over 80%.
In hepatic artery chemotherapy, the chemotherapy agents are given into the hepatic artery, often by steady infusion over hours or even days. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.
Hepatic artery chemoembolization (HACE), sometimes called transarterial chemoembolization (TACE), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides.
Selective internal radiation therapy (SIRT) for neuroendocrine metastases to the liver delivers radioactive microsphere therapy (RMT) by injection into the hepatic artery, lodging (as with HAE and HACE) in downstream capillaries. In contrast to hormone-delivered radiotherapy, the lesions need not overexpress peptide receptors. The mechanical targeting delivers the radiation from the yttrium-labeled microspheres selectively to the tumors without unduly affecting the normal liver. This type of treatment is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, including neuroendocrine malignancies.
Other therapies
Radiofrequency ablationRadiofrequency ablation
Radio frequency ablation is a medical procedure where part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from the high frequency alternating current to treat a medical disorder...
(RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and current is applied to generate heat; the tumor cells are killed by cooking.
Cryoablation
Cryoablation
Cryoablation is a process that uses extreme cold to remove tissue .Cryoablation is used in a variety of clinical applications using hollow needles through which cooled, thermally conductive, fluids are circulated...
is similar to RFA; an endothermic substance is injected into the tumors to kill by freezing. Cryoablation has been considerably less successful for GEP-NETs than RFA.
External links
- http://www.netipedia.org
- http://www.carcinoid.org
- Johns Hopkins University School of Medicine Pancreatic Neuroendocrine Tumor Page
- http://unicornfoundation.org.au
- The Caring for Carcinoid Foundation
- Cancer.Net: Neuroendocrine Tumor