1. DIFFUSE HORMONAL SYSTEMS AND ENDOCRINE TUMOR SYNDROMES
Hasan AYDIN, MD; Yeditepe University Medical Faculty; Department of Endocrinology and Metabolism

2. THE ORIGIN OF NEUROENDOCRINE TUMORS
NET originates from APUD (Amine Precursor Uptake and Decarboxylation) cells.
APUD cells constitute the diffuse endocrine system of the body.
Gastrointestinal tractus
Pancreas
Lung
Central nervous system
Skin
Adrenal medulla
Thyroid

3. Neuroendocrine Tumors Frequency
Incidence: 1-2/
Autopsy series 8/
Carcinoid tumors are the most frequent type.
(40% of all NETs)

4. CLASSIFICATION OF NET Well differentiated neuroendocrine tumor
Well differentiated neuroendocrine carcinoma
Poorly differentiated neuroendocrine (small cell) carcinoma
Mixed endocrine tumors
WHO International Histological Classification of Tumours, Springer Verlag 2000

5. Classification of NETs of GEP system
Carcinoid tumors
Foregut
Bronchial carcinoid tumors
Gastric carcinoid tumors
Midgut
Small intestinal carcinoid tumors
Apendix carcinoid tumors
Hindgut
Rectal carcinoid
Pancreatic endocrine tumors
Insulinoma
Gastrinoma
Glucagonoma
VIPoma
Somatostatinoma
PPoma

6. Carcinoid Tumors
Analyses of 13,715 cases of carcinoid between in USA:
75% located in gastrointestinal system
25% located in bronchopulmonary system.

7. Carcinoid Syndrome Carcinoid syndrome:
Vasomotor symptoms
Flushing
Tachycardia
Hypotension
Sweating
Gastrointestinal hypermotility (diarrhea)
Bronchospasm (wheezing, dispne)
Carcinoid syndrome is seen in 10% of all gastrointestinal carcinoid tumors.

8. Gastric Carcinoid Tumors
Constitute 4.1% of all carcinoid tumors and less than 1% of all gastric neoplasms.
Most frequently seen between age
There are 3 distinct types:
Type 1: Associated with Type A chronic atrophic gastritis
Type 2: Associated with Zollinger-Ellison syndrome
Type 3: Sporadic gastric carcinoid tumors

9. Pancreatic Endocrine Tumors
Estimated incidence 1-4 /
Can be a part of MEN-1 syndrome.
Clinical presentation varies according to the hormone(s) secreted.

10. Insulinoma Mostly seen in the 5-6 decades. Symptoms of hypoglycemia
Palpitation, sweating, nervousness, conscious disorders, coma etc
The tumor size usually <1.5 cm.
Usually cannot be detected with CT, MRI and angiography.
EUS is the best method for pre-op localization of the tumor.
Per-operative palpation and IOUS are the best methods to identify the tumor.

11. Gastrinoma
Usually presents with abdominal pain due to peptic ulcer and diarrhea due to hypersecretion.
Ulcers are seen in stamach, duodenum, esophagus and intestines.
Gastrinomas are associated with MEN-1in 25% of the cases.
Fasting gastrin level >100 pg/ml.
Basal acid secretion is >15 mEq/hour.
PPI are effective in supression of acid secretion

12. Somatostatinoma Frequency ( % ) Sign/Symptom Pancreatic (n=27)
Intestinal (n=21)
Diabetes Mellitus 95 21
Gallbladder disease 94 43
Diarrhea 92 38
Steatore 83 12
Hypochlorhydria 86 17
Weight loss 90 69

13. Diagnosis of Neuroendocrine Tumors
Depends on each cellular type
For correct diagnosis:
Clinical symptoms
Humoral biochemical tumor markers
Stimulant (Provacative) tests
Imaging techniques
Histopathology (CgA, sinaptofizin, NSE)

14. Biochemical Tumor Markers
Biochemical markers for NET:
Nonspecific marker:
Plazma Chromogranin A (CgA)
Specific marker(for carcinoid):
24-hour urine 5-HIAA

15. Provocation Tests for GEP/NET
Tumor Provacation tests
Carcinoid Pentagastrin test
Gastrinoma Secretin test
Insulinoma Extended fasting glucose test
VIPoma None
Glucagonoma None
Somatostatinoma None

16. Octreotide Scintigraphy
Advantages
High sensitivity.
Whole body imaging.
Predicts response to octreotide therapy.
Disadvantages
Cannot detect tumors not expressing somatostatin receptors
-Somatostatin receptors including subtype 2 (sst-2) are present in
88-100% of carcinoid tumors.
-Lower tumor size limit 0.5 cm.
-Sensivity is around 90%.

17. Imaging of Neuroendocrine Tumours
Ultrasound: low sensitivity for primary ~30%; metastases ~70%
Spiral CT vs MRI: primary up to 70%; metastases 90%
Octreotide scan: primary up to 80%; 95% metastases
Endoscopic Ultrasound: ~95% pancreatic primary tumour gastric carcinoid; rectal carcinoid

18. Symptom Control– General Measures
Insulinoma
Potassium replacement
IV dextrose administration
Diazoxide
Gastrinoma
Correction of performance status
Control of bleeding
Control of hyperasidity (proton pump inhibitors)
VIPoma
Fluid replacement
Acid- base and electrolyte correction
Glucagonoma
Correction of the nutritional status
Blood transfusion
Control of hyperglycemia
Somatostatinoma

19. Systemic Treatment Chemotherapy Interferon alpha
Somatostatin analogues
Radioactive labelled
MIBG

20. Combination Chemotherapy
Streptozocin-5-fluorouracil
Streptozocin-Doxorubicin
Streptozocin-5-fluorouracil-Doxorubicin
Cisplatinum-Etoposide
5-Fluorouracil-Doxorubicin-Cisplatinum
5-fluorouracil-leucovorin-Interferon

21. Chemoembolisation Indicated in unresectable liver mets
May provide symptom and clinical syndrome control
May result in tumor proliferation control
Contraindications:
Liver failure
Ascites
Renal failure
Portal vein obstruction

22. Biological Treatment Somatostatin analogues Interferon Octreotide
Lanreotide
SOM230
Interferon
Interferon alfa-2a (Roferon-A)
Interferon alfa-2b (Intron A)

23. INTERFERON TREATMENT: Controversies:
No concensus on the dose and regimen to be used
No randomized trial showing improvenment of survival with interferon

24. SOMATOSTATIN ANALOGUES
Octreotide – Sandostatin
Lanreotid-
Somatuline-BIM
SOM230
Octastatin- RC-160
Somatostatin analogues are used in the treatment of carcinoid tumors and functional islet cell tumors of the pancreas

25. OCTREOTIDE FOR TREATMENT OF NET
Somatostatin analogues provide:
Symptomatic response : % 70
Biochemical response : % 30-50
Tumor control : % 3
Di Bartolomeo, Cancer, 1996.

26. TUMOR TARGETED RADIOACTIVE TREATMENT

27. MIBG - META-IODOBENZYLGUANIDINE
Is an catecolamine analog used in localization of adrenal medulla and nonmeduller NET
123I labelled MIBG is used for diagnostic purposes
Kaltas et al, J Clin Endocrinol Metab, 2001
12 pts
11/12 111In-pentetreotide positive
1/12’si 123I-MIBG (+)
123I-MIBG may be done to select patients for 131I-MIBG radionuclide therapy

28. TUMOR TARGETED RADIOACTIVE SOMATOSTATIN TREATMENT
Alpha-emitting radioligands
Short acting auger electrons are used
111 In-pentetreotide
Beta-emitting radioligands
High energy beta particules
90Y-DOTA0 Tyr3-octreotide (OctreoTher)
177Lu-DOTA0 Tyr3-octreotate
90Y-lanreotide
Can only be used in sst2 and sst5 (+) NET
de Herder et al, Curr Opin Oncol, 2002

29. Bortezomib(PS-341): Endostatin Thalidomide Bevacizumab: Imatinib
May increase progression free survival
Endostatin
Thalidomide
Bevacizumab:
Increased progression free survival, however biochemical control was better in the interferon arm
Imatinib
PFS survival was significantly better in patients with concurrent octreotite
SU11248
showed clinical activity in NETs
Gefinitib
Produced prolonged disease stabilization
Temsirolismus
Stabilization of diesase was observed in patients with progressive diease under various medical treatments.

30. Multiple Endocrine Neoplasia
MEN 1
Pituitary adenoma
Pancreatic endocrine tumor
Parathyroid neoplasia (90%)
MEN 2a
Medullary thyroid cancer (100%)
Pheochromocytoma (50%)
Parathyroid neoplasia (10-40%)
MEN 2b
Neuromas (100%)

31. Multiple Endocrine Neoplasia Type 1
Primary hyperparathyroidism 90%
Pituitary tumours 20-40% (90% at autopsy)
Pancreatic endocrine tumours 30-70%; (carcinoid 10%)
Chromosome identified 11q13 (LOH)
MEN-1 gene cloned 1997
Makes protein MENIN which affects speed of cell growth/replication

32. Von Hippel Lindau
phaeochromocytoma, retinal/cerebellar haemangioblastoma, renal and pancreatic tumours, middle ear tumours
pancreatic NETs 15-20% - especially non-functional and PP, SST positive tumours
chromosome 3 short arm
VHL protein involved in regulation of cell replication
NETs also described in Recklinghausen disease, Tuberous Sclerosis