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

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

Immunohistochemistry (SLI)Immunofluorescence (SLI)

Gastric ECL (enterochromaffin like) cells

Silver stain of gastric mucosaECL 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: Glucagonβ: Insulinδ: 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 HCO3

- 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 PRODUCTSHistamine, 5-HT, GABA, Dopamine,Norepinephrine, EpinephrineNON-AMINE PRODUCTSAcetylcholine (cholinergic), ATP (purinergic), Nitric oxide (nitrergic)

Amine Precursor Uptake and Decarboxylation

Tyrosine

DOPA

dopamine

norepi

epi

Tryptophan

5-OH Tryptophan

5-HT(serotonin)

Histidine (AP)

histamine

+ OH + OH

Rs

Rs

Rs

RsRs

EC cell ECL cellChromaffin cell

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 (pNET)

ENETS Grade

Ki 67 Index

Mitotic count

Differ-entiation

Low (G1) <3% <2/ HPF Well-differ- entiated NET

Inter-mediate (G2)

3-20% 2-20/ HPF

Well-differ- entiated NET

High (G3) >20% >20/ HPF

Poorly differ- entiated neuro-endocrine carcinoma

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

Duodenum

2-3 cm

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• PTHrPoma 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/pNETs

• Many GI carcinoids/pNETs 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) pNETS

• PPomas (no clinical syndrome)• NF-pNETs

– 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 intra-

arterial calcium or secretin in hard-to- localize, 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, G1 pNET)• 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 mTOR inhibitors, interferon, or cytotoxic agents in patients with advanced disease

GI-NETs and pNETS

• Sporadic tumors (more common)• Autosomal dominant inherited syndromes

– MEN-1– Tuberous sclerosis– NF-1– VHL

Inherited Syndromes: GI-NETs and pNETsSYNDROME PREVALENCE PER

MILLIONGENE/PROTEIN FREQ. of NETs TYPE OF NETs

NF-1 200-300 17q11.2/ neurofibromin

0-10% Duodenal somatostatinomas

Tuberous sclerosis 100 9q34 (TSC1) and 16p13 (TSC2)/

hamartin and tuberin

Uncommon Usu. NF pNETs

MEN-1 (PPP) 10-100 11q13/menin 80-100% •Microscopic> large.• NF>Functional.

•Gastrinoma>Insul-inoma>>others

VHL 20-30 3p25/ pVHL 10-17% pNETS NF 98%;Functional 2%

NF, nonfunctional