Neuroendocrine GEP-Tumors (GEP-NET)

Bombesinoma (GRPoma)
NET secreting bombesin (GRP, gastrin-releasing peptide) , found in various neuroendocrine tissues / tumors - as yet not identified in non-NET
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Pathology - Pathophysiology


Bombesin (27 amino acids) first detected 1971 in amphibious skin (name), 1978 in mammalian stomach
typ. ubiquitous peptidergic neurotransmitter with vagal gastrin stimulation

Bombesinomas are observed in pancreas, as carcinoids of lung-pancreas-intestine, medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), paragangliomas, pituitary adenomas

Bombesin effects: stimulation of gastrin (gastric acid), CCK, release of PP, GIP, glucagon, somatostatin, neurotensin;
gastrointestinal motility: inhibition of gastric emptying; inhibition of gastrointestinal passage through activation of the intestinal motor complex; inhibition of exocrine pancreatic secretion; gall bladder contraction

hypothalamic stimulation of satiety: fullness, obstipation


no typical clinical syndrome !
hemorrhagic gastritis / Zollinger-Ellison-Syndrome
satiety, fullness, obstipation / intestinal and gallbladder colics
mild type II - diabetes (glucagon, somatostatin); flushing (serotonin)

clearly elevated (?) GRP-concentrations in plasma

correct diagnosis frequently made only through direct investigation of tissue: presence of typ. neuroendocrine cells by immunhistochemistry; GRP content in tissue extracts

therapy / surgery of underlying diesease / tumor
symptomatic therapy not available except for prokinetic drugs

ACTHoma - CRFoma

Ectopic ACTH-syndrome; ectopic Cushing's syndrome

extracranial tumor producing CRF - (CRH - corticotropin releasing hormone) or ACTH with elevated adrenal secretion of cortisol

> 100 known ACTHoma' s of gastrointestinal tract

(1) lung cancer (SCLC), (2) bronchial carcinoids, carcinoids of stomach, ileum, ovaries; (3) epithelial cancer of thymic gland; (4) islet cell carcinoma of pancreas; (5) MTC (thyroid), pheochromocytoma (adrenals); (6) adeno carcinoma of colon, esophagus, ovaries, uterus, prostate gland; (7) melanoma

prototype of "paraneoplastic" endocrine activity caused via hormonal secretion

Frequency (ACTHoma): lung (33%), bronchial carcinoid (16%), pancreas (11%) - CRFoma unknown in pancreas

Diagnosis: failure of dexamethasone to suppress elevated ACTH levels in patients with Cushing's syndrome and pancreatic mass

Therapy: pancreatic ACTHoma - surgical, adrenal-blocking agents (mitotane, metapyron, aminogluthetimide)

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GRFoma / Somatotropinoma

Extracranial, ectopic acromegaly / gigantism
- tumor syndromes without acromegaly -

extracranial tumor producing GRF - (GHRH - growth hormone releasing hormone)
coincidence with Zollinger-Ellison-Syndrome (gastrinoma), vipoma, insulinoma, MEN type 1, Cushing's disease, hyperprolactinemia

> 60 known GRFoma' s of gastrointestinal tract

with acromegaly: NET of pancreas (30%), lung (50%), small bowel (~10%), retroperitoneal, adrenal glands

without acromegaly: NET of pancreas, jejunal, MTC, SCLC, endometrial cancer, NET of thymus + appendix

Symptoms: 1. classical acromegaly, 2. symptoms related to action of cosecreted peptides (gastrinoma, Cushing's syndrome, hypoglycemia, hyperprolactinemia - 70%), 3. local tumor symptoms


- PTHoma -

ectopic hypercalcemia syndrome due to pancreatic neuroendocrine tumors (PTHoma) producing PTHrP (PTH related peptide) or "true" PTH

Hypercalcemia syndrome in GEP-NET to be differentiated from hypercalcemia due to:

Hyperparathyroidism in MEN type 1, malignomas of parathyroids, "paraneoplastic" PTH secretion in non-parathyroid, non-neuroendocrine tumors with bone metastases and hyperphosphatemia, e.g. exocrine adenocarcinoma of pancreas

Symptoms: hypercalcemia, hypophosphatemia, lethargy, coma

> 35 known PTHoma' s of gastrointestinal tract
Pancreas: PPHrPoma - pancr. parathyroid hormone related protein

mostly large, frequently metastasized tumors (liver, omentum); frequently associated with vipoma, ZES (gastrinoma), CToma

Therapy: surgical; streptozotocin, 5-FU, somatostatin


- CToma -

- "pure" pancreatic CToma rare but described
- frequent cosecretion of VIP (Vipoma-WDHA-Syndrome), somatostatin, PP, neurotensin
- calcitonin is a potential marker of GEP-NET like PP
- calcitonin diminshes small bowel passage time and increses intestinal water- and electrolyte secretion : pathogenesis of diarrhea
Symptoms: hypercalcitoninemia (procalcitonin), hypercalcemia, diarrhea, steatorrhea; weight loss

calcitonin concentrations > 1000 pg/ml, frequently > 10.000 pg/ml

liver metastases

Therapy: surgical; streptozotocin, somatostatin

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GIP: gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide (typical Incretin hormone
peptide actions (normal in duodenum + proximal jejunum) : insulinotropic action, inhibition of gastric acid secretion, stimulates small bowel secretion, stimulates mesenterial blood flow
GIPoma: rarely described NET;
symptoms: watery diarrhea, hypokalemia, acidosis, hypercalcemia, impaired glucose tolerance



- CCKoma -

CCK-33 (native peptide) in duodenum + jejunum, CCK-8, CCK-4 (truncated)
CCK stimulated via mixed meals: activates gallbladder contractions, stimulates exocrine pancreatic secretion
CCKoma described with multihormonal GEP-NET of pancreas: cosecretion of VIP, bombesin (GRP)
clinical: diarrhea, increased gastric acid secretion with normal gastrin levels and normal secretin stimulation, duodenitis, hypokalemia


- Glicentinoma - GLP-2oma ?

intestinal posttranslational proglucagon processing: N-terminal glucagon = enteroglucagone: glicentin - oxyntomodulin - GLP-1 + GLP-2 (localised in intestinal mucosa, L-cells)
pancreatic enteroglucagonomas were described;

actions: intestinotrophic (GLP- 2 = glucagon-like peptide 2)
villous intestinal epithelial hypertrophy ("giant intestinal villi"), prolonged bowel transit time, malabsorption of fat, mild symptoms of the glucagonoma syndrome (weight loss, diabetes, skinrash)



- IAPPoma -

IAPP (islet amyloid polypeptide, Amylin) cosecreted from the B-cell (insulin)

- actions (homology with CGRP = calcitonin-gene related polypeptide): hypocalcemia; inhibition of glycogen synthesis, inhibition of peripheral glucose uptake (insulin antagonism), stimulation of hepatic glucose production (Lactate-Cycle)
- elevated in insulinomas + Type II diabetes, obesity

IAPPoma-syndrome: hyperglycemia, hypocalcemia, hypotension

first description of amylinoma in 1992


Motilinoma - Secretinoma - GLP-1oma

Ghrelinoma - PYYoma ?

? "putative" so far undescribed GEP-NET ?

Motilin: secretion after meals dependent upon mass + volume, tension of the gastric wall, stimulated by fat content, inhibited by glucose

Sekretin: Sekretion im Duodenum durch sauren Mageninhalt und Neutralisation durch pankreatische Bikarbonatsekretion; gesteigerte biliäre Sekretion

GLP-1 (glucagon- like peptide-1): glucose-abhängige Insulinstimulation ohne Hypoglykämie, Hemmung der pankretaischen Glucagonsekretion, antidiabetogen, Lokalisation im gesamten Dünn-, Dickdarm - vorwiegend distal/Colon

Ghrelin ist ein Releasing-Hormon für Wachstumshormon (GH) aus endokrinen L-Zellen des Magens. Es ist ein natürliches, den Appetit steigerndes "Hunger"-Hormon, welches dem appetit-hemmenden Leptin aus dem Fettgewebe entgegenwirkt.

PYY, das Peptid YY aus der PP-Familie (pankreatisches Polypeptid) ist ein weiterer natürlicher "Gegenspieler" des Ghrelin und wurde in endokrinen Zellen des Dünndarms nachgewiesen.