GEP-Tumor, neuroendokrine Tumoren, NET

Neuroendocrine Tumors (GEP-NET)

Classification of GEP-NET

("Peptid-")OMA ; ("Peptid-")OMA - Syndrome

describes a tumor or a clinical syndrome, characterised by a hormone secreted from the tumor. The tumor consists mostly of functionally active cells originating from neuroendocrine tissues.

Formerly these tumors had been classified as APUDOMAS, today referred to as NET or GEP-NET.

"APUD" denotes "Amin-Precursor Uptake and Decarboxylation" decribing features of these tumors to take up biogenous amines, which are altered chemically or newly synthesized in the tumor cells.

Dating back to Pearse (1967) the APUD-concept of tumorigenesis helped explain the phylogenetical (ontogenic) common features of the tumors. Due to numerous exceptions, though, this term has been abandoned. According to the APUD-theory neuroendocrine tumors may occur whereever neuroendocrine cells are physiologically distributed.

Originating from pluripotent tumor cells NETs may
1. synthesize and secrete / release a variety of different hormones (the basis of a clinical syndrome),
2. synthesize and secrete / release ineffective or less effective precursors of peptide hormones (Prohormones),
3. synthesize and secrete / release several hormones or change the type of hormone during the disease.

WHO - Classification of GEP - NET
© www.gep-net.com / www.gep-net.de
A new classification taking into account the variability of patho-histological features in tumor biology of NET has been proposed in 2000 (see li.link): the histological characteristics of carcinoids as well as the clinical dignity of pancreatic tumors, e.g. non-functioning tumors, is covered including those tumors not representing classical apudomas.
NET of pancreas (PNET)	NET of digestive GI-tract (dNET)
well-differentiated endocrine tumor (WDET) 1. hormone active : typ. clin. syndrome 2. hormone inactive : no clin. syndrome a. benign b. uncertain	- well differentiated endocrine tumor ( WDET) - classical carcinoids - clin. Carcinoid-Syndrome - no Carcinoid-Syndrome - neuroendocrine gut tumors - e.g. intestinal Gastrinoma, Vipoma, Somatostatinoma, Bombesinoma, ACTHoma
*well-differentiated (neuro-)* endocrine carcinoma (WDEC) 1. hormone active : typ. clin. syndrome 2. hormone inactive : no clin. syndrom**e	well-differentiated malignant dNEC (malignant carcinoid)
*poorly-differentiated (neuro-)* endocrine carcinoma (PDEC)**	- poorly differentiated endocrine carcinoma (PDEC) highly malignant dNEC, neuroendocrine carcinoma

most frequent GEP-NET

INSULINOMA : neuroendocrine tumor of the pancreas causing hypoglycemia as a consequence of inadequate insulin secretion.
This is an entopic tumor, originating from the pancreas where there is abundancy of insulin producing B-cells. Ectopic localisation (extrapancreatic insulinoma) has been claimed, but typically is unexisting

INSULINOMA is associated with primary hyperinsulinemia exceeding 100 µU/ml only occasionally. Hypersecretion in the range of just some µU/ml (e.g. 5-10 µU/ml) may be found, which however is too much in the presence of hypoglycemia. Physiological postprandial insulin secretion may exceed this range daily after each meal. Secondary hyperinsulinemia (insulin resistance due to obesity, diabetes mellitus) may reach a range of several hundred µU/ml (150 - > 400 µU/ml).

Further entopic tumor-entities :
GLUCAGONOMA - SOMATOSTATINOMA - PPOMA (pancreatic polypeptidoma).
Ectopic occurence with declining frequency (>>): PPoma > Somatostatinoma > Glucagonoma, has been observed.

GLUCAGONOMA is associated with primary hyperglucagonemia usually exceeding > 1000 pg/ml, often several thousand pg/ml. Physiological secondary hyperglucagonemia in poorly controlled diabetes coinciding with ketoacidosis and during hypoglycemia usually is found in the range of some hundred pg/ml. Extreme hyperglucagonemia similar to glucagonoma is found in very ill patients needing intensive care, e.g.sepsis, liver coma, uremia, myocardial infarction.In other entopic and ectopic GEP-NET - VIPOMA, SOMATOSTATINOMA, PPOMA, NtOMA - primary sometimes extreme hypersecretion of specific hormones / peptides is detected, occasionally exceeding the ng/ml or even the µg/ml range. Causes of secondary hypervipemia, hypersomatostatinemia, hyperPPemia, hyperneurotensinemia are not known.

GASTRINOMA and VIPOMA are ectopic pancreatic tumors but may occur entopically in the GI-tract (duodenal gastrinomas - and extraintestinal Vipomas).

GASTRINOMA is associated with primary hypergastrinemia often ~ 1000 pg/ml . Secondary hypergastrinemia (e.g. atrophic type A gastritis and pernicious anemia; therapy with proton pump blockers (omeprazol) only rarely exceeds 1000 pg/ml. BOMBESINOMA (primary hyper-secretion of gastrin-releasing peptide / GRP = bombesin) causes secondary hypergastrinemia usually not exceeding 1000 pg/ml.

CARCINOIDS - first described in 1888 and 1907 using the term due to typical pathohistological features - represent the first known GEP-NET, which however may occur extraintestinally. e.g. lung and thymus gland.
Not all carcinoids express / secrete serotonin, sometimes other neurotransmitters (-hormones) / neuropeptides (histamin, kallikrein, bradykinin, tachykinin, substance P), sometimes no secretory product at all.
The term "SEROTONINOMA" is not in clinical use.

CARCINOIDS often but not always are associated with hyperserotoninemia and urinary excretion of its metabolite 5-hydroxy-indol acetic acid (5-HIAA). Levels may be very variable. Serotonin concentrations in plasma vary physiologically to a large extent.

CALCITONINOMA (CToma) has been described rarely as a GEP-NET (e.g. pancreatic calcitoninoma), Calcitonin may be co-produced in somatostatinomas and vipomas.

The classical CALCITONINOMA is represented by medullary thyroid carcinoma (MTC, C-cell carcinoma) of thyroidal C-cells. These clearly extraintestinal non-GEP-cells are accounted for by the APUD-system.

non-functioning GEP tumors

Rare and extremely rare neuroendocrine tumors (mostly pancreatic):

T U M O R	P e p t i d e	T U M O R	P e p t i d e
Neurotensinoma - Ntoma -	Neurotensin	GIPoma	GIP (gastric inhibitory peptide ...... glucose-dependent insulinotropic polypeptide)
Serotoninoma - pancreatic carcinoid -	Serotonin	ACTHoma - Corticotropinoma -	ACTH
Bombesinoma - GRPoma -	Bombesin = GRP (gastrin releasing peptide)	CRFoma	CRF (corticotropin releasing factor)
Cholecystokininoma - CCKoma -	Cholecystokinin (CCK)	GRFoma	GRF / GHRH (growth hormone releasing factor)
Parathyrinoma - PTHoma -	Parathormon (PTH)	Amylinoma - IAPPoma -	Amylin = IAPP (islet amyloid polypeptide)
Calcitoninoma - Ctoma -	Calcitonin (CT)	Enteroglucagonoma - Glicentinoma -	Glicentin(1-69) "Enteroglucagon"

Bombesin and VIP are ubiquitous peptidergic transmitters of the GI-tract also expressed extraintestinally.
ACTH and GRF are typical pituitary and hypothalamic peptides. They cause well defined endocrinological diseases due to an extracerebral lesion (ectopic Cushing's -syndrome, ectopic acromegaly).

These neuroendocrine peptides form the basis of paraneoplastic endocrine syndromes playing a clinical role in oncological disease: cctopic ACTH production in small cell lung cancer / SCLC a a basis of a typical Cushing's syndrome.

Ectopic calcitonin and parathyroid hormone - secretion (PTH) lead to disturbances in calcium metabolism as paraneoplastic symptoms (Hypocalcemia -, Hypercalcemia -Syndrome).
PTH - producing tumor are classified as Parathyrinoma (PTHoma), definitely not an apudoma.

Not described in the context of active endocrine NET's includes the hypersecretion of motilin ("Motilinoma") and Secretin ("Secretinoma") as well as the hypersecretion of a proglucagon : Glucagon-like-peptide-1 / GLP-1, an ubiquitous enteral peptide hormone ("GLP-1oma").

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