Endocrine tissues Pituitary glandhypothalamus Thyroid gland Parathyroid glands

Endocrine tissues • • Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System

Endocrine cells of the GI tract are scattered (not in discrete glands)

Gastric D (somatostatin) cells Immunofluorescence (SLI) Immunohistochemistry (SLI)

Gastric ECL (enterochromaffin like) cells Silver stain of gastric mucosa ECL cells are argyrophilic; they produce histamine.

Endocrine Cells of the Stomach PROXIMAL DISTAL

Gastric G (gastrin) cells Immunohistochemistry (gastrin)

Pancreatic endocrine cells are concentrated in islets scattered through the organ α: Glucagon β: Insulin δ: Somatostatin

(e. g. , gastrin, secretin) (e. g. , somatostatin, histamine)

Physiology of selected GI hormones (Endocrine actions) Gastrin: ↑ gastric acid secretion (target: ECL cell) Secretin: ↑ pancreatic HCO 3 - secretion (target: duct cell) CCK: ↑ pancreatic enzyme secretion and gallbladder contraction (target: neurons with CCK receptors) GIP, GLP-1 (incretins): ↑ glucose-mediated insulin secretion, improving oral glucose tolerance (target: β cells) GLP-2: stimulates growth of intestinal epithelial cells (target: intestinal stem cells? )

Proglucagon Processing in the Pancreas and the Intestine

Gastrin-17 is a hormone controlling gastric acid in humans. Feldman et al, J. Clin Invest 1977 *

Negative Feedback Loop Food + Gastrin + Acid ↑Protonation of AAs ↑Somatotostatin (antrum) ↑Secretin (duodenum)

Clinical Corollary: Gastric Carcinoid Pernicious anemia/chronic atrophic gastritis, with chronic achlorhydria/hypochlohydria (low acid)→ Loss of negative feedback of acid on gastrin Chronic, persistent hypergastrinemia → ECL cell hyperplasia → Increased risk of Type 1 gastric carcinoid tumors (carcinoidosis)

Negative Feedback Loop Food + CCK + Pancreatic trypsin ↓CCK-RF (duodenum) ↓Monitor peptide (pancreas)

Clinical Corollary: Chronic Pancreatitis • • Pancreatic insufficiency (low trypsin) Chronically high plasma CCK → Chronic pancreatic stimulation→ Chronic pain • • • Therapy: Pancreatic enzymes between and with meals Trypsin digests CCK-RF and monitor peptide Lowers plasma CCK levels Less pancreatic stimulation Less pain

Products of GI/Pancreatic Endocrine Cells Polypeptides (N>30) • Half-lives usually in minutes (e. g. , somatostatin, insulin, G-17) • Peptide analogs (agonists) may have half lives of hours (e. g. , octreotide, insulin analogs) • Peptide antagonists are difficult to develop

Products of GI/Pancreatic Endocrine Cells Non-Peptide Products § Half-lives usually in seconds § Analogs (agonists) may have half lives of hours § Antagonists are easier to develop and in common use AMINE PRODUCTS Histamine, 5 -HT, GABA, Dopamine, Norepinephrine, Epinephrine NON-AMINE PRODUCTS Acetylcholine (cholinergic), ATP (purinergic), Nitric oxide (nitrergic)

Amine Precursor Uptake and Decarboxylation Chromaffin cell EC cell Tyrosine + OH DOPA Tryptophan ECL cell Histidine (AP) + OH 5 -OH Tryptophan dopamine Rs norepi Rs 5 -HT epi Rs (serotonin) Rs histamine Rs Rs, receptors

Excessive amine production by NETs • Chromaffin cells (stain with chromium salts) – Adrenal medulla and sympathetic ganglia – Amine Products: epinephrine, norepinephrine, dopamine – Tumors: pheochromocytoma • Enterochromaffin (EC) cell (stain with chromium salts) – GI mucosal endocrine cells (also stain with silver salts) – Amine Product: 5 -hydroxytryptamine (5 -HT; serotonin) – Tumors: carcinoids (NETs) carcinoid syndrome • Enterochromaffin-like (ECL) cell – Gastric/ bronchial mucosal endocrine cells (stain with silver salts) – Amine Product: histamine – Tumors: carcinoids (NETs) atypical carcinoid syndrome

Terminology and ENETS Classification OLD NEW Carcinoid GI-NET Islet cell tumor Pancreatic NET (p. NET) ENETS Grade Ki 67 Index Mitotic count Differentiation Low (G 1) <3% <2/ HPF Well-differ entiated NET Intermediate (G 2) 3 -20% 2 -20/ HPF Well-differ entiated NET >20/ HPF Poorly differentiated neuroendocrine carcinoma High (G 3) >20%

Insulinoma • • • Annual Incidence: 1 -2/million Pancreatic >>>> Nonpancreatic Incidence of malignancy: <10% Incidence in MEN-1: 18% (7%-31%) Clinical Features: fasting hypoglycemia – Neuroglycopenic symptoms (e. g. , visual, confusional) – Adrenergic symptoms (e. g. , sweating, tremulousness)

Insulinoma in a patient with MEN-I and fasting hyperinsulinemic hypoglycemia

Gastrinoma (ZE Syndrome) • • • Annual incidence: 0. 5 -1. 5/million Duodenum > Pancreas >>> other Incidence of malignancy: 60%-90% Incidence in MEN-1: 54% (20%-61%) Clinical Features: – Abdominal pain/ Peptic Ulcer Disease, often with GI bleeding • GI perforation: 5% – Diarrhea/ Steatorrhea – GERD • Esophageal stricture: 4% – Nausea/Vomiting – MEN-1: 22%

Gastrinoma: Pathology Pancreas 2 -3 cm Duodenum

VIPoma (Verner-Morrison; WDHA; Pancreatic cholera) • Annual incidence: 0. 05 -0. 2/million • Pancreatic > nonpancreatic in adults (intestinal, bronchial, pheo) • Ganglioneuroma or ganglioneuroblatoma in young kids (< age 10) • Incidence of malignancy: > 60% in adults • 10% in young kids and rare adults with this tumor • Incidence in MEN-1: 1% (1%-12%) • Clinical Features: – – – Secretory diarrhea Volume depletion Weight loss Abdominal cramps, colic Flushing Hypokalemia, Hypochlorhydria, Hypercalcemia, Hyperglycemia

Glucagonoma • • • Annual incidence: 0. 01 -0. 1/million Pancreatic >> non-pancreatic Incidence of malignancy: 50%-80% Incidence in MEN-1: 3% (1%-6%) Clinical Features: – Dermatitis (NME) – Diabetes/glucose intolerance – Weight loss – Glossitis/cheilitis/stomatitis – Diarrhea – Abdominal pain – VTE – Hypoaminoacidemia – Hypocholesterolemia

Somatostatinoma • • • Annual incidence: very rare Pancreatic> Duodenal>> other sites Incidence of Malignancy: > 70% Incidence in MEN-1: <1% Clinical Features (can be due to tumor per se or ectopic production of somatostatin) – Diabetes mellitus – Gallbladder disease – Diarrhea/steatorrhea – Weight loss

GH-RFoma (GRFoma) • • • Annual incidence: very rare Lung> Pancreas > Small Intestine> Other sites Incidence of malignancy: > 30% Incidence in MEN-1: < 1% Clinical Features: – Acromegaly due to ectopic production of GH-RF – GH and somatomedin-A levels elevated – Pituitary enlargement MEN-1

Other Reported Functional NETs (? significance) • ACTHoma – may occur with gastrinoma • • • CCKoma Neurotensinoma Erythropoietinoma with polycythemia LHoma with masculinization (F) or loss of libido (M) Reninoma with hypertension PTHr. Poma with hypercalcemia

Carcinoid tumors (GI-NETs) • MORE COMMON – Small intestinal (ileal, duodenal, jejunal) – Gastric (Types 1 -3) – 1: achlorhydric – 2: Gastrinoma with MEN-1 – 3. Sporadic – Bronchial/Pulmonary • LESS COMMON • • • Appendiceal Rectal Colonic Esophageal Pancreatic

Carcinoid syndrome • Occurs when sufficient concentration of hormonal products (amines and polypeptides) released by the tumor enter the systemic circulation. • Occurrence of carcinoid syndrome, and its severity, are related to the tumor size in areas that drain into the systemic circulation. – – Hepatic veins (in liver mets), the most common (>90%) Ovarian/Testicular veins (in gonadal carcinoids) Pulmonary veins (in bronchopulmonary carcinoids) Retroperitoneal veins (in GI/pancreatic tumors with local spread)

Clinical Features: Carcinoid Syndrome • Flushing: 70 -80% (probably from tachykinins [SP, NKA, etc. ] • Diarrhea: 70 -80% (probably from 5 -HT in many patients) • Carcinoid valvular heart disease: 26 -30% • R>>L heart; probably from 5 -HT in most patients • Wheezing/asthma: 11 -12% (probably from 5 -HT/histamine) • Pellagra: 1 -2% (from diversion of dietary niacin to 5 -HT synthesis, leading to niacin deficiency)

Somatostatin and GI-Carcinoid/p. NETs • Many GI carcinoids/p. NETs express receptors for somatostatin. • Such somatostatin receptors can be used in the diagnosis & therapy of patients with carcinoids/NETS, using radiolabeled analogs of somatostatin, such as octreotide and lanreotide. • When GI endocrine tumors produce somatostatin, they are called somatostatinomas. • Somatostatinomas may or may not cause the somatostatinoma syndrome (diarrhea, steatorrhea, diabetes, and gallstones). This humoral syndrome has been questioned. Octreotide scans. Note uptake in bladder, kidneys, and spleen, and metastases to the liver and to para-aortic nodes (arrows).

PPomas and Nonfunctional (NF) p. NETS • PPomas (no clinical syndrome) • NF-p. NETs – – Present as asymptomatic lesions detected by imaging Present as mass lesions with local symptoms Presentation similar to pancreatic adenocarcinoma Stain + for chromogranin A and neuron specific enolase

Approach to a Patient with a GI or Pancreatic NET • • Step 1: Is the Tumor Functional? – Clinical assessment – Measurement of plasma/urinary hormones, amines or metabolites – Control hormonal hypersecretion if present and possible to prevent morbidity and mortality Step 2: Tumor Localization and Staging (TMN) – CT/MRI, Endoscopy/EUS±FNA, Somatostatin Receptor Scintigraphy – Hepatic vein sampling after intraarterial calcium or secretin in hard-tolocalize, functional tumors 7 mm gastrinoma in head of pancreas

Therapeutic Approach to NETS • Surgery is the only curative option, but may have adverse effects (e. g. , Whipple for small, well-differentiated, G 1 p. NET) • Incidentalomas without hormonal overproduction and local symptoms: – role of watchful waiting , especially in higher risk surgery patients • Metastases-directed therapies may reduce tumor burden and prolong survival and quality of life, but have adverse effects – Hepatic embolization – Hepatic chemoembolization – Radionuclide receptor targeted therapy (somatostatin analogs) • Systemic chemotherapy with m. TOR inhibitors, interferon, or cytotoxic agents in patients with advanced disease

GI-NETs and p. NETS • Sporadic tumors (more common) • Autosomal dominant inherited syndromes – MEN-1 – Tuberous sclerosis – NF-1 – VHL

Inherited Syndromes: GI-NETs and p. NETs SYNDROME PREVALENCE PER MILLION GENE/PROTEIN FREQ. of NETs TYPE OF NETs 200 -300 17 q 11. 2/ neurofibromin 0 -10% Duodenal somatostatinomas 100 9 q 34 (TSC 1) and 16 p 13 (TSC 2)/ hamartin and tuberin Uncommon Usu. NF p. NETs MEN-1 (PPP) 10 -100 11 q 13/menin 80 -100% • Microscopic> large. • NF>Functional. • Gastrinoma>Insulinoma>>others VHL 20 -30 3 p 25/ p. VHL 10 -17% p. NETS NF 98%; Functional 2% NF-1 Tuberous sclerosis NF, nonfunctional