Neuroendocrine Gut and Pancreatic Tumours

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Neuroendocrine Gut and Pancreatic Tumours
Tumour Biology, Diagnosis and Treatment

• Prof. Kjell Öberg MD, Ph.D.
• Head Endocrine Oncology Unit
• Dept of Internal Medicine
• University Hospital
• S-751 85 Uppsala, Sweden

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The Gut and Pancreatic Neuroendocrine Cell System

• Gut

• ECL-cells (Histamine, CgA, gastrocalcin?)
• G-cells (Gastrin)
• S-cells (Somatostatin)
• P-cells (unknown secretory product)
• EC-cells (Serotonin, Tachykinins, CgA)
• Other neuroendocrine cells and peptidergic
  neurons
• Common stem-cell in the pancreatic ducts
• ß-cell (Insulin)
• a-cell (Glucagon)
• D-cell (Somatostatin)
• PP-cell (Pancreatic polypeptide)
• D1 (unknown secretory product)

Pancreas
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Modes of Regulation

• Endocrine

Autocrine

• Neurocrine

Paracrine
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Genes Involved in Neuroendocrine Tumour
Development

• Menin (MEN I)
• PLC- ß3
• Ret-Proto Oncogen (MEN II, MTC)
• Prad
• BRCA I?

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Tumour Biology

• Growth Factors/Receptors

• ICF-1
• TGF-a1, EGF-R
• TGF- ß, family
• PDGF family

Adhesion Molecules
cd44 (exon v6, v10)
b-FGF VEGF
Angiogenetic Factors
Seven Transmembrane Receptor (G-Protein Coupled)
Cell-Growth Signals
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Clinical Syndrome
Secretory Products Causing the Syndrome
Tumour Location

• Carcinoid syndrome
• Zollinger Ellison syndrome
• Hypoglycemic (Insulinoma)
• Verner-Morrison (WDHA)
• syndrome
• Glucagonoma syndrome
• Somatostatinoma syndrome

Serotonin, Histamine, Tachykinins,
Bradykinin Serotonin, Tachykinins Bradykinin Gast
rin Insulin, proinsulin IGF-I/II VIP,
PHM Glucagon, (Glicentin) Somatostatin CgA,
HCG-a/ß, PP, PYY (no endocrine related symptoms)
Lung, Stomach and Pancreas Foregut Ileum and
Jejunum Midgut Pancreas Duodenum Pancreas
(Sareomas) Pancreas, Ganglioneuro-mas,
Paraganglioma, Lung Pancreas Pacreas,
Duodenum Pancreas, Colon
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Carcinoid Tumours
Frequency Secretory Products
Foregut (10-15) Thymus ACTH, CRF, GHRH,
ADH Lung
Serotonin, Histamine, Gastrin,
Calcitonin, Tachykinis, CgA, HCGa/ß
Stomach CgA, Histamine, Gastrin,
Serotonin, Gastrocalcin? Duodenum
Gastrin, Somatostatin, CgA Midgut (20-60)
Appendix No known secretory product Ileum
Caecum Serotonin,
Tachykinins, CgA Colon ascendence
Hindgut (25-30) Colon CgA, PP, HCGa
Rectum PYY, Somatostatin

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Carcinoid Syndrome
Causal Agent

• Flushing
• Diarrhea
• Right Heart Failure
• Broncho Constriction

• Tachykinins, Bradykinins
• Serotonin , Prostaglandins?
• Unknown (TGFß ?)
• Tachykinins, Bradykinins?

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Carcinoid Tumour Diagnosis

• Histopathology
• Tumour Markers
• Other Markers
• Stimulatory Tests
• Radiology
• Other Investigations

• Argyrophil/argentaffin staining CgA, Serotonin
• CgA, u-5-HIAA, p-NPK, p-Subst-P
• P-ACTH, pCRF, PGHRH, s-calcito-
• nin, p-ADH, s-PP, s-HCGa/ß, u-
• Histamine
• Flush provocation Pentagastrin 0,6
• ug/kg bw i.v., measuring p-NKP every 5 min for
  30 min
• Octreoscan (111Ind-DTPA-octreotide)
• CT, US, MRI, (CT-angiography)
• Endoscopy (endoscopic ultrasound)

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Zollinger Ellison Syndrome

• Tumour Location
• Symptoms

• Pancreas 50-60
• Duodenum 40-50
• (sometimes both, MEN-I)
• 20-25 Related to MEN-1
• 50-70 Malignant (lymphnode metastases)
• Gastrinoma Triangle 80
• Gastritis
• Recurrent ulcers

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Zollinger-EllisonSyndrome/Diagnosis

• Histopathology
• Tumour Markers
• Stimulatory Test
• Radiology
• Other Investigations

• Argyrophil staining/CgA/Gastrin
• S-Gastrin, p-CgA
• Secretin infusion 2-3 CU/kg b.w. Secretin
• i.v. measuring gastrin every 5 min for
• 30 min (Protein stimulatory test)
• Meal stimulatory test (MEN-I)
• Endoscopic US
• Octreoscan
• CT, MRI
• Gastroscopy

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Hypoglycemic (Insulinoma)Syndrome
Tumour Location Symptoms
Pancreas 85 Benign tumours Neuroglycopenic
symptoms Catecholamine related symptoms
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Hypoglycemic (Insulinoma) Syndrome/Diagnosis

• Histopathology
• Tumour Markers
• Stimulatory Test
• Other Diag. Tests
• Radiology

• Argyrophil staining/Synaptophysin/Insulin/proinsul
  in, CgB
• s-insulin, s-proinsulin, p-CgB
• (Malignant tumours may also produce gastrin and
  glucagon)
• 48-72 hrs fasting measuring s-insulin/proinsulin,
  b-glucose
• Fasting b-glucose
• Fasting b-glucose lt2.8 mmol/l suggest an
  insulinoma
• CT-angiography
• US (liver metastases)
• Endoscopic ultrasonography

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Glucagonoma Syndrome

• Tumour Location
• Symptoms

• Pancreas
• gt90 malignant
• Necrolytic migratory erythema
• Weight loss
• Anemia
• Trombosis
• Impaired glucose tolerance
• Diarrhoea

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Glucagonoma Syndrome/Diagnosis

• Histopathology
• Tumour Markers
• Radiology

• Agyrophil staining, CgA, glucagon,
• glicentin
• p-CgA, p-glucagon
• Octreoscan, Endoscopic ultrasound,
• CT-angiography, MRI

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Verner-Morrison Syndrome (WDHAs)

• Pancreas
• Lung
• Ganglioneuromas
• gt80 Malignant
• (Pancreatic nesidioblastosis)
• Watery diarrhea (secretory) 3-20 litres/day
• Hypokalemia, Hypomagnesemia,
• Hypercalcemia
• Acidosis
• Flushing
• Flaccid distended gallbladder
• Ileus/subileus

• Tumour Location
• Symptoms

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Verner-Morrison Syndrome/Diagnosis

• Histopathology
• Tumour Markers
• Radiology

• Argyrophil staining, CgA, VIP
• p-VIP, p-PHM, s-Calcitonin
• Octreoscan
• CT-angiography, MRI
• Endoscopic ultrasonography

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Somatostatinoma Syndrome

• Tumour Location
• Symptoms

• Duodenum
• Pancreas
• Colon/Rectum
• gt80 mixed tumours
• Gallstones
• Steatorrhea
• Impaired glucose tolerance
• Often non-functioning tumours!

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Somatostatinoma Syndrome/Diagnosis

• Histopathology
• Tumour Markers
• Radiology

• Argyrophil staining, CgA
• Somatostatin
• p-CgA, p-Somatostatin
• (s-Gastrin, p-Glucagonom, mixed tumour)
• Endoscopic ultrasonography
• CT-angiography, MRI
• Colonoscopy
• US (liver metastases)

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Non-Functioning Tumours/Diagnosis

• Tumour Location
• Symptoms

• Pancreas
• Colon/Rectum
• gt80 malignant
• Sometimes part of MEN-I
• Large abdominal mass
• Intestinal obstruction
• Gastrointestinal bleeding
• Fever
• Abdominal pain

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Non-Functioning Tumours/Diagnosis

• Histopathology
• Tumour Markers
• Stimulatory Test
• Radiology

• Argyrophil staining, CgA
• PP, Somatostatin
• p-CgA, s-PP, s-HCGa/ß
• p-somatostatin
• Meal stimulatory test (MEN-I)
• Octreoscan
• CT-angiography, MRI
• US (liver met. biopsy)
• Colonoscopy

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Multiple Endocrine Neo-Plasia Type I (MEN-I)

• Autosomal dominantly inherited
• Mutations of the MENIN-gene on Chr 11q13
• Parathyroid adenoma 95-100
• Endocrine pancreatic tumours 80
• Pituitary tumours (Prolactin, GH)
  30-50
• Carcinoids (lungs, thymus, gastric, duodenal)
  20-50
• Lipomas 10-20
• Thyroid Nodules 10-15
• Lymphomas lt5

• Genetics
• Tumours

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Pedigree MEN-I
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Neuroendocrine PancreaticTumours (MEN-I)

• Multiple tumours/mixed hormone production
• Gastrinomas (gt45 Duodenal tumours)
• Non-functioning tumours
• Insulinomas
• Glucagonomas
• VIP-omas

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MEN-I Diagnosis

• Genetic Diagnosis
• Biochemical Diagnosis
• Stimulatory Test
• Radiology

• Mutation in MENIN-gene
• s-prolactin
• s-IGF-1
• s-Ca (albumin modified)
• s-PTH
• p-CgA
• s-PP, Gastrin, Insulin
• p-VIP, Glucagon
• Meal stimulatory test
• Endoscopic ultrasonography
• Octreoscan
• CT-angiography, MRI
• Intraoperative US

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Diagnosis General Considerations

• Histopathology

• Argyrophil staining
• Argentaffin staining (carcinoids)
• CgA
• Synaptophysin
• NSE
• Specific peptides (e.g. gastrin, glucagon)

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Tumours Markers
Elevated In Circulation

• Chromogranin A 90-100
• Pancreatic Polypeptide 40-60
• HCG a/ß 15-30

General Markers
General Stim. Test for Neuroendocrine Pancreatic
Tumours Meal stimulation test with Measurement
of PP every 10 for 1.5 hrs.
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Chromogranins (Cg)

• The Cg Family
• Function

• Chromogranin A (CgA)
• Chromogranin B (CgB)
• Chromogranin C (CgC)
• (Seretogranin II)
• (Largely unknown)
• Storage protein in secretory granules
• Precursor molecule for other active peptides
• (Vasostatins, Pancreastatin, Parastatin)
• Antibacterial effects
• Growth regulatory effect
• Tumour marker for Neuroendocrine Tumours

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Radiology of Neuroendocrine Tumours

• Total BodyScreening and Staging
• Disclosure of Endocrine Pancreatic Tumours
• Newer Techniques
• Traditional Techniques (always a complement)

• Octreoscan (111Ind-DTPA-octreotide) (SRI)
• Sensitivity lt10 mm 40
• gt10 mm 90
• Liver metastases 90
• Endoscopic ultrasonography
• (EUS) sensitivity lt10 mm 50
• SRI EUS sensitivity lt10 mm 90
• Positron emission tomography with
• C11-5 HTP or C11-L-dopa (PET)
• CT ( angiography), MRI
• US sensitivity small tumours 10-30
• Liver metastases 90

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The Ultimate Goals for the Treatment of
Neuorendocrine Tumours

• Total erradication by surgery (not possible in
  most cases)
• Abrogation of tumour growth and/or amelioration
  of clinical symptoms
• Improving and maintaining a good quality of life

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Therapy of Neuroendocrine Gut and Pancreatic
Tumours

• Surgery
• (even palliative and tumour reduction)
• Embolisation Chemotherapy
• Irradiation
• ?conventional for bone metastases
• ?experimental 111Ind-DTPA-octreotide 45-60 Gy
• (local) 90
  Y-DOTA-octreotide
• Medical Treatment
• ? Somatostatin analogues
• ? a-interferons
• ? chemotherapy

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Embolisation of Liver Metastases
Biochemcial Tumour Resp
Resp

• Embolisation
• (Spongostan,
• Gel-Foam)
• Chemoembolisation
• (Doxorubicin)

30-50
20-30 median duration 7-10 months
50 80 40-50 median
duration 10-20 months
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Chemotherapy of Neuro-Endocrine Gut and
Pancreatic Tumours
Response Rate

• Endocrine Pancreatic Tumours
• Midgut CarcinoidTumours

Streptozocin 5 FU 40-60 Streptozocin
doxorubicin 60 Cisplatinum Etoposide
50 (low differentiated tumours) Taxol
doxorubicin 40-50 Streptozocin 5
FU 10-30 Cisplatinum Etoposide
10-15
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Treatment with a-Interferons (a-IFNs)

• Types of a-IFNS
• Recommended doses for classical midgut
  carcinoids

Human leukocyte IFN Lymphoblastoid IFN
(Welferon) Recombinant IFNa 2a (Roferon) Recombina
nt IFNa 2b (Intron-A) IFNa 2b
3-5 MU x III-V/week s.c.
NB! Individual dosing according to tolerance and
leukocyte count (lt3.0 x 109/l) is recommended
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a-IFN Treatment

• Subjective Responses
• Biochemical Responses
• Tumour Responses

50-70 30-70 10-15
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Somatostatin Receptors

• Five subtypes cloned SSTR 1-5
• SOM.14 and 28 bind to all receptor subtypes
• All receptor subtypes are 7 TM receptors and
• G-Protein coupled
• Effector mediators are C-AMP, CA2 /K FLUX,
• TYROSINPHOSPHATASES
• Octreotide binds to SSTR2 and SSTR5
• SSTR2 mediates biochemical and tumour responses
• SSTR3 mediates apoptosis
• SSTR5 mediates anti-tumour response different
• from SSTR2 (NOT VIA PTPI-C BUT CA 2 /K FLUX?)

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Treatment With Somatostatin Analogues
(Octreotide)

• Octreotide
• CarcinoidSyndrome
• Carcinoid Crises
• Octreotide LAR

Recommended dosing 100-600 µg/day s.c. given as
2-3 doses Experimental 1,500-3,000 µg/day s.c.
Preoperatively 100 µg
s-c- 30 prior to operation and thereafter 50
µg/hr i.v. infusion during op., continue postop.
either with s.c. or i.v. therapy Octreotide
i.v. 50-100 µg/hr (Foregut carcinoid with
histamine production, continue with H1 and H2
receptor blockers) Long-acting formulation,
dosing 20-30 mg i.m./4 w.
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Octreotide Treatment

• Subjective Response
• Biochemical Response
• Tumour Response

30-75 (Dose dependent) 30-60 (Dose
dependent) 0-15 (Not dose dependent)
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Future Programme Tumour biology based therapy
programme including

• Proliferation markers (KI-67, PCNA)
• Growth factors/receptors
• Adhesion molecules
• Angiogenetic factors
• Somatostatin receptor subtypes
• Induction of IFN sensible genes
• (2-5 A-synthetase, PKR)