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Neuroendocrine tumors:

Neuroendocrine tumors arise from the neuroendocrine system, which are composed of cells that have
features of both nerve cells and endocrine cells and are found though out the body. These cells share
certain biochemical functions such as "amine precursor uptake and decarboxylation (or APUD), hence an
earlier classification referred to these tumors as APUDomas. The term "carcinoid" tumor remains in
common use today and refers to a tumor arising from enterochromaffin cells, which are neuroendocrine
cells in the gastrointestinal tract. Carcinoids usually secrete serotonin, histamine and other vasoactive
substances, which can occasionally cause symptoms of flushing and diarrhea (Carcinoid Syndrome). The
other major category of neuroendocrine tumors encompass pancreatic neuroendocrine tumors also
sometimes referred to as islet cell tumors, which often secrete any number of pancreatic hormones
including gastrin, insulin, VIP, somatostatin, or glucagon whereas about 20-50% of pancreatic
neuroendocrine tumors are non-functional. Neuroendocrine tumors can be noncancerous (benign) or
cancerous (malignant.
Where can these tumors be found:

Neuroendocrine tumors are uncommon in many of these areas, and frequently represent only a
very small proportion of the tumors or cancers at these locations.
Pituitary gland: Neuroendocrine tumor of the anterior pituitary
Thyroid gland: Neuroendocrine thyroid tumors, particularly medullary carcinoma
Parathyroid tumors
Thymus and mediastinal carcinoid tumors
Pulmonary neuroendocrine tumors
Bronchus
Pulmonary carcinoid tumors: typical carcinoid (TC; low-grade); atypical carcinoid (AC;
intermediate-grade)
Small-cell lung cancer (SCLC)
Large cell neuroendocrine carcinoma of the lung (LCNEC)
Extra pulmonary small cell carcinomas (ESCC or EPSCC)
Gastroenteropancreatic neuroendocrine tumors (GEP-NET)
Foregut GEP-NET (foregut tumors can conceptually encompasses not only NETs of the stomach
and proximal duodenum, but also the pancreas, and even thymus, lung and bronchus) [citation
needed]
Pancreatic endocrine tumors (if considered separately from foregut GEP-NET) [22]
Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the
transverse colon) appendix, including well differentiated NETs (benign); well differentiated NETs
(uncertain malignant potential); well differentiated neuroendocrine carcinoma (with low malignant
potential); mixed exocrine-neuroendocrine carcinoma (goblet cell carcinoma, also called
adenocarcinoid and mucous adenocarcinoid)
Hindgut GEP-NET
Liver and gallbladder
Adrenal tumors, particularly adrenomedullary tumors
Pheochromocytoma
Peripheral nervous system tumors, such as:
Schwannoma
Paraganglioma
Neuroblastoma
Genitourinary tract
Urinary tract carcinoid tumor and neuroendocrine carcinoma

Ovary
Neuroendocrine tumor of the cervix
Testes
Merkel cell carcinoma of skin (trabecular cancer)

Can these tumors be inherited?


Specific genetic disorders and chromosomal abnormalities are associated with a predisposition for
developing neuroendocrine/carcinoid tumors. While the majority of neuroendocrine/carcinoid tumors are
not associated with a genetic syndrome (sporadic), about 10% are associated with one of the following:

multiple endocrine neoplasia type 1 (MEN1)

multiple endocrine neoplasia type 2 (MEN2)

von Hippel-Lindau (VHL) disease

neurofibromatosis type 1

tuberous sclerosis

Given these associations, recommendations in NET include family history evaluation, evaluation for
second tumors, and in selected circumstances testing for germline mutations such as for MEN1.
Clinical presentation:

Gastroenteropancreatic neuroendocrine tumors (GEP-NET)


Conceptually, there are two main types of NET within this category: those which arise from
the gastrointestinal (GI) system and those that arise from the pancreas. In usage, the term
"carcinoid" has often been applied to both, although sometimes it is restrictively applied to NETs of
GI origin (as herein), or alternatively to those tumors which secrete
functional hormones or polypeptides associated with clinical symptoms.Ten per cent (10%)[46] or less
of carcinoids, primarily some midgut carcinoids, secrete excessive levels of a range of hormones,
most notably serotonin (5-HT) or substance P,[47] causing a constellation of symptoms
called carcinoid syndrome:

flushing

diarrhea

asthma or wheezing

congestive heart failure (CHF)

abdominal cramping

peripheral edema

heart palpitations

A carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly
fluctuating blood pressure[1] can occur if large amounts of hormone are acutely secreted,[47which is
occasionally triggered by factors such as diet,[47] alcohol,[47] surgery[1][47] chemotherapy,[47] embolization
therapy[1] or radiofrequency ablation.[1] 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.[47] However, valve replacement is rarely needed.[48] The excessive
outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency, and
thus pellagra, [1] 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, hemorrhage or the effects of tumor bulk are the presenting symptoms. Bowel
obstruction can occur, sometimes due to fibrosing effects of NET secretory products [45] with an
intense desmoplastic reaction at the tumor site, or of the mesentery.
Pancreatic neuroendocrine tumors (PanNET)
(About one third of GEP-NETs)
Pancreatic neuroendocrine tumors (PanNETs) are often referred to as "islet cell tumors",

[43] [49]

or

"pancreatic endocrine tumors"[7] originate within the pancreas. Well or intermediately differentiated
PanNETs are sometimes called islet cell tumors; neuroendocrine cancer (NEC) (synonymous with
islet cell carcinoma) is more aggressive. Up to 60% of PanNETs are nonsecretory or nonfunctional,
which either dont secrete, or the quantity or type of products such as pancreatic
polypeptide (PPoma), chromogranin A, and neurotensin do not cause a clinical syndrome, although

blood levels may be elevated. Functional tumors are often classified by the hormone most strongly
secreted, for example:

gastrinoma: the excessive gastrin causes ZollingerEllison syndrome (ZES) with peptic
ulcers and diarrhea

insulinoma:[8] hypoglycemia occurs with concurrent elevations of insulin, proinsulin and C


peptide[9]

glucagonoma: the symptoms are not all due to glucagon elevations,[9] and include a rash,
sore mouth, altered bowel habits, venous thrombosis, and high blood glucose levels[9]

VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound
chronic watery diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA or
pancreatic cholera syndrome)

somatostatinoma: these rare tumors are associated with elevated blood glucose
levels, achlorhydria, cholelithiasis, and diarrhea[9]

less common types include ACTHoma, CRHoma, calcitoninoma, GHRHoma, GRFoma,


and parathyroid hormonerelated peptide tumor

Pheochromocytoma: The signs and symptoms of a pheochromocytoma are those of sympathetic


nervous system hyperactivity, including:

Skin sensations

Flank pain

Elevated heart rate

Elevated blood pressure, including paroxysmal (sporadic, episodic) high blood pressure,
which sometimes can be more difficult to detect; another clue to the presence of
pheochromocytoma is orthostatic hypotension (a fall in systolic blood pressure greater than
20 mmHg or a fall in diastolic blood pressure greater than 10 mmHg upon standing)

Palpitations

Anxiety often resembling that of a panic attack

Diaphoresis (excessive sweating)

Headaches most common symptom

Pallor

Weight loss

Localized amyloid deposits found microscopically

Elevated blood glucose level (due primarily to catecholamine stimulation


of lipolysis (breakdown of stored fat) leading to high levels of free fatty acids and the subsequent
inhibition of glucose uptake by muscle cells. Further, stimulation of beta-adrenergic receptors
leads to glycogenolysis and gluconeogenesis and thus elevation of blood glucose levels).

A pheochromocytoma can also cause resistant arterial hypertension. A pheochromocytoma can be


fatal if it causes malignant hypertension, or severely high blood pressure. This hypertension is not
well controlled with standard blood pressure medications.

What are the pathological features of neuroendocrine tumors?


Neuroendocrine tumors appear as solid masses that often have a yellowish appearance. Under the
microscope, neuroendocrine tumors are composed of round or ovoid cells with a granular cytoplasm and
nuclei that have a "salt and pepper" appearance. The cells often form nests or may form small follicles or
gland-like structures. By electron microscopy, the tumor cells have dense secretory granules, which store
substances that are often secreted by the tumor.

WHO Classification:
Well differentiated NET (non-invasive, benign behaving or uncertain
malignant potential)
Well-differentiated NE carcinomas (low grade malignant and has
invasion or muscularis propria or metastasis)
Poorly differentiated endocrine carcinomas (high grade, malignant)

Diagnosis:
Markers
Symptoms from secreted hormones may prompt measurement of the corresponding hormones in
the blood or their associated urinary products, for initial diagnosis or to assess the interval change in
the tumor. Secretory activity of the tumor cells is sometimes dissimilar to the tissue immunoreactivity
to particular hormones. Some useful markers:

chromogranin A (CgA)

urine 5-hydroxyindoleacetic acid (5-HIAA)

neuron-specific enolase (NSE, gamma-gamma dimer)

synaptophysin (P38)

Newer markers include N-terminally truncated variant of Hsp70 is present in NETs but absent in
normal pancreatic islets.[53] High levels of CDX2, a homeobox gene product essential for intestinal
development and differentiation, are seen in intestinal NETs.[53] Neuroendocrine secretory protein-55,
a member of the chromogranin family, is seen in pancreatic endocrine tumors but not intestinal
NETs.[53]

Imaging
CT-scans, MRIs, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are
common diagnostic tools. CT-scans using contrast medium can detect 95 percent of tumors over
3 cm in size, but generally not tumors under 1 cm.[10]
. Neuronedocrine tumours express somatostatin receptors providing a unique target for imaging.
Octreotide is a synthetic modifications of somatostatin with a longer half-life. OctreoScan, also called
somatostatin receptor scintigraphy (SRS or SSRS), utilizes intravenously administered octreotide
that is chemically bound to a radioactive substance, often indium-111, to detect larger lesions with
tumor cells that are avid for octreotide.
Somatostatin receptor imaging can now be performed with positron emission tomography (PET)
which offers higher resolution, three-dimensional and more rapid imaging. Gallium-68 receptor PETCT is much more accurate than an OctreoScan.[54]

Imaging with fluorine-18 fluorodeoxyglucose (FDG) PET may be valuable to image some
neuroendocrine tumors.[55] This scan is performed by injected radioactive sugar intravenously.
Tumors that grow more quickly use more sugar. Using this scan, the aggressiveness of the tumor
can be assessed.

Treatment:
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.[5]
Cholecystectomy is recommended if there is a consideration of long-term treatment
with somatostatin analogs.[62]:46

Symptomatic relief: secretory tumors, somatostatin analogs given subcutaneously or


intramuscularly alleviate symptoms by blocking hormone release. A consensus review has reported
on the use of somatostatin analogs for GEP-NETs.[63]
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.[64]
Other medications that block particular secretory effects can sometimes relieve symptoms. [48]

Chemotherapy:
Interferon is sometimes used to treat GEP-NETs.[65] Its effectiveness is somewhat uncertain, but low
doses can be titrated within each person, often considering the effect on the blood leukocyte count;
[65]

interferon is often used in combination with other agents, especially somatostatin analogs such as

octreotide.
Targeted therapy with everolimus (Afinitor) and sunitinib (Sutent) is approved by the FDA in
unresectable, locally advanced or metastatic PanNETs. Some PanNETs are more responsive
to chemotherapy than gastroenteric carcinoid tumors. Several agents have shown activity[48] and
combining several medicines, particularly doxorubicin with streptozocin and fluorouracil (5-FU or

f5U), is often more effective.[48] Although marginally effective in well-differentiated


PETs, cisplatin with etoposide is active in poorly differentiated neuroendocrine cancers (PDNECs).[48]

Radioisotope therapy:
Peptide receptor radionuclide therapy (PRRT) is a type of radioisotope therapy (RIT)[13] in which a
peptide or hormone conjugated to a radionuclide or radioligand is given intravenously, the peptide or
neuroamine hormone previously having shown good uptake of a tracer dose, using Somatostatin
receptor imaging as detailed above. This type of radiotherapy can attack all lesions in the body, not
just liver metastases. The peptide receptor may be bound to lutetium-177, yttrium-90 or indium-111.
This is a highly targeted and effective therapy with minimal side effects in tumors with high levels of
somatostatin cell surface expression, because the radiation is absorbed at the sites of the tumor, or
excreted in the urine. The radioactively labelled hormones enter the tumor cells which, together with
nearby cells, are damaged by the attached radiation. Not all cells are immediately killed; cell death
can go on for up to two years.

Other therapies:
Radiofrequency ablation (RFA) is used when a patient has relatively few metastases] In RFA, a
needle is inserted into the center of the lesion and current is applied to generate heat; the tumor
cells are killed by cooking.
Cryoablation is similar to RFA; an endothermic substance] is injected into the tumors to kill by
freezing. Cryoablation has been less successful for GEP-NETs than RFA. [