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

Dec 17, 2015

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Page 1: 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

Page 2: 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)

Page 3: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

Gastric D (somatostatin) cells

Immunohistochemistry (SLI)Immunofluorescence (SLI)

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

Gastric ECL (enterochromaffin like) cells

Silver stain of gastric mucosaECL cells are argyrophilic; they produce histamine.

Page 5: 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 Stomach

PROXIMAL DISTAL

Page 6: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

Gastric G (gastrin) cells

Immunohistochemistry (gastrin)

Page 7: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

Pancreatic endocrine cells are concentrated in islets scattered through the organ

α: Glucagonβ: Insulinδ: Somatostatin

Page 8: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 9: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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?)

Page 10: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

Proglucagon Processing in the Pancreas and the Intestine

Page 11: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

*

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

Page 12: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

Negative Feedback Loop

Food Gastrin Acid+ +

↑Protonation of AAs↑Somatotostatin (antrum)↑Secretin (duodenum)

Page 13: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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)

Page 14: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

Negative Feedback Loop

Food+

CCK Pancreatic trypsin+

↓CCK-RF (duodenum)↓Monitor peptide (pancreas)

Page 15: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 16: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 17: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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)

Page 18: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 19: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 20: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 21: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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)

Page 22: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 23: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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%

Page 24: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

Gastrinoma: Pathology

Pancreas

Duodenum

2-3 cm

Page 25: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 26: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 27: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 28: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 29: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 30: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 31: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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)

Page 32: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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)

Page 33: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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).

Page 34: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 35: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 36: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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

Page 37: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

GI-NETs and pNETS

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

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

Page 38: Endocrine tissues Pituitary gland/hypothalamus Thyroid gland Parathyroid glands (4) Adrenal glands (2) Ovaries (2) Testes (2) GI/Pancreatic Endocrine System.

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