Endocrine tissues

1
Endocrine tissues

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

2
Endocrine cells of the GI tract are scattered
(not in discrete glands)
3
Gastric D (somatostatin) cells
Immunohistochemistry (SLI)
Immunofluorescence (SLI)
4
Gastric ECL (enterochromaffin like) cells
Silver stain of gastric mucosa ECL cells are
argyrophilic they produce histamine.
5
Endocrine Cells of the Stomach
PROXIMAL
DISTAL
6
Gastric G (gastrin) cells
Immunohistochemistry (gastrin)
7
Pancreatic endocrine cells are concentrated in
islets scattered through the organ
a Glucagon ß Insulin d Somatostatin
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(e.g., gastrin, secretin)
(e.g., somatostatin, histamine)
9
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 ß cells)
• GLP-2 stimulates growth of intestinal epithelial
  cells (target intestinal stem cells?)

10
Proglucagon Processing in the Pancreas and the
Intestine
11
Gastrin-17 is a hormone controlling gastric acid
in humans. Feldman et al, J. Clin Invest 1977

12
Negative Feedback Loop

• Food Gastrin Acid

?
?Protonation of AAs ?Somatotostatin
(antrum) ?Secretin (duodenum)
13
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)

14
Negative Feedback Loop

• Food

CCK
Pancreatic trypsin
?
?CCK-RF (duodenum) ?Monitor peptide (pancreas)
15
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

16
Products of GI/Pancreatic Endocrine Cells

• Polypeptides (Ngt30)
• 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

17
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)

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Amine Precursor Uptake and Decarboxylation
EC cell
ECL cell
Chromaffin cell
Tyrosine
Histidine (AP)
Tryptophan
OH
OH
DOPA
5-OH Tryptophan
dopamine
Rs
histamine
Rs
norepi
Rs
5-HT (serotonin)
Rs
Rs
epi
Rs,receptors
19
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

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Terminology and ENETS Classification
ENETS Grade Ki 67 Index Mitotic count Differ-entiation
Low (G1) lt3 lt2/ HPF Well-differ- entiated NET
Inter-mediate (G2) 3-20 2-20/ HPF Well-differ- entiated NET
High (G3) gt20 gt20/ HPF Poorly differ- entiated neuro-endocrine carcinoma
OLD NEW
Carcinoid GI-NET
Islet cell tumor Pancreatic NET (pNET)
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Insulinoma

• Annual Incidence 1-2/million
• Pancreatic gtgtgtgt Nonpancreatic
• Incidence of malignancy lt10
• Incidence in MEN-1 18 (7-31)
• Clinical Features fasting hypoglycemia
• Neuroglycopenic symptoms (e.g., visual,
  confusional)
• Adrenergic symptoms (e.g., sweating,
  tremulousness)

22
Insulinoma in a patient with MEN-I and fasting
hyperinsulinemic hypoglycemia
23
Gastrinoma (ZE Syndrome)

• Annual incidence 0.5-1.5/million
• Duodenum gt Pancreas gtgtgt 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

24
Gastrinoma Pathology
Pancreas
2-3 cm
Duodenum
25
VIPoma (Verner-Morrison WDHA Pancreatic
cholera)

• Annual incidence 0.05-0.2/million
• Pancreatic gt nonpancreatic in adults (intestinal,
  bronchial, pheo)
• Ganglioneuroma or ganglioneuroblatoma in young
  kids (lt age 10)
• Incidence of malignancy gt 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

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Glucagonoma

• Annual incidence 0.01-0.1/million
• Pancreatic gtgt 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

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Somatostatinoma

• Annual incidence very rare
• Pancreaticgt Duodenalgtgt other sites
• Incidence of Malignancy gt 70
• Incidence in MEN-1 lt1
• Clinical Features (can be due to tumor per se or
  ectopic production of somatostatin)
• Diabetes mellitus
• Gallbladder disease
• Diarrhea/steatorrhea
• Weight loss

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GH-RFoma (GRFoma)

• Annual incidence very rare
• Lunggt Pancreas gt Small Intestinegt Other sites
• Incidence of malignancy gt 30
• Incidence in MEN-1 lt 1
• Clinical Features
• Acromegaly due to ectopic production of GH-RF
• GH and somatomedin-A levels elevated
• Pituitary enlargement ? MEN-1

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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

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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

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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
  (gt90)
• Ovarian/Testicular veins (in gonadal carcinoids)
• Pulmonary veins (in bronchopulmonary carcinoids)
• Retroperitoneal veins (in GI/pancreatic tumors
  with local spread)

32
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
• RgtgtL 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)

33
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).
34
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

35
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/EUSFNA, 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
36
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

37
GI-NETs and pNETS

• Sporadic tumors (more common)
• Autosomal dominant inherited syndromes
• MEN-1
• Tuberous sclerosis
• NF-1
• VHL

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Inherited Syndromes GI-NETs and pNETs
SYNDROME PREVALENCE PER MILLION GENE/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 Microscopicgt large. NFgtFunctional. GastrinomagtInsul-inomagtgtothers
VHL 20-30 3p25/ pVHL 10-17 pNETS NF 98Functional 2
NF, nonfunctional