NET secreting bombesin (GRP, gastrin-releasing peptide) , found in various neuroendocrine tissues / tumors - as yet not identified in non-NET Pathology - Pathophysiology
Bombesin (27 amino acids) first detected 1971 in amphibious skin (name), 1978 in mammalian stomach
typ. ubiquitous peptidergic neurotransmitter with vagal gastrin stimulationBombesin 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 contractionhypothalamic stimulation of satiety: fullness, obstipation
Clinical
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
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therapy / surgery of underlying diesease / tumor symptomatic therapy not available except for prokinetic drugs
ACTHoma - CRFomaEctopic ACTH-syndrome; ectopic Cushing's syndrome
> 100 known ACTHoma' s of gastrointestinal tract
Localisations:
(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) melanomaprototype 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 / SomatotropinomaExtracranial, 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
Localisations:
with acromegaly: NET of pancreas (30%), lung (50%), small bowel (~10%), retroperitoneal, adrenal glandswithout 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
Parathyrinoma
- 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 proteinmostly large, frequently metastasized tumors (liver, omentum); frequently associated with vipoma, ZES (gastrinoma), CToma
Therapy: surgical; streptozotocin, 5-FU, somatostatin
Calcitoninoma
- 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 diarrheaSymptoms: hypercalcitoninemia (procalcitonin), hypercalcemia, diarrhea, steatorrhea; weight loss calcitonin concentrations > 1000 pg/ml, frequently > 10.000 pg/ml
liver metastases
Therapy: surgical; streptozotocin, somatostatin © www.gep-net.com / www.gep-net.de
GIPoma
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
Cholecystokininoma- 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
Enteroglucagonoma
- 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)
symptoms: villous intestinal epithelial hypertrophy ("giant intestinal villi"), prolonged bowel transit time, malabsorption of fat, mild symptoms of the glucagonoma syndrome (weight loss, diabetes, skinrash)
Amylinoma- 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, obesityIAPPoma-syndrome: hyperglycemia, hypocalcemia, hypotension
first description of amylinoma in 1992
