1. Pancreatic endocrine tumors

2. INTRODUCTION One million islets of Langerhans
Several types of cells “Immunohistochemistery”
ß (beta) -> 70% insulin
А (alpha)-> 20% glucagons
D (delta) -> 5-10% somatostatin
P.P Cell -> % pancreatic polypeptide
Other rare cells:
- D1 cells
- VIP ( vasoactive intestinal polypeptide )
- Enterochromaffin cells
- 5 HT-(serotonin)

3. Terminology and NETS Classification
NETS Grade
Ki 67 Index
Mitotic count
Differ-entiation
Low (G1)
<3%
<2/ HPF
Well-differentiated NET
Inter-mediate (G2)
3-20%
2-20/ HPF
High (G3)
>20%
>20/ HPF
Poorly differentiated neuro-endocrine carcinoma

4. INSULINOMA Epidemiology Pathophysiology & Symptoms
Dignosis & Locallization
Management

5. Epidemiology First described by Harris in JAMA 1924
Commonest hormone producing NET of GIT
99% of pancreatic origin
90% solitary, 90% < 2cm, 90% benign
8% ass. with MEN I (multiple, malignant in 25%)
Median age at presentation is 47yrs
F to M ratio 1.4:1

6. Pathophysiology Hypoglycemia ↑glucagon(glycemic threshold 65-70mg/dl)
↑catecholamines
↑cortisol & GH
Neuroglucopenic symptoms(<50mg/dl)

7. Symptoms - Wt gain in 20-30% Adrenergic symptoms Anxiety, nervousness
Tremors
Tachycardia, palpitations
Hypertension
- Wt gain in 20-30%

8. Symptoms Neuroglucopenic symptoms Headache Visual disurbances
Lethargy,lassitude,confusion
Difficulty in speech, thinking
Personality changes
Convulsions, coma

9. Diagnosis Whipples triad ↑ C peptide level ↑ plasma insulin
Hypoglycemic symptoms brought about by fasting or exercise
↓BS during symptoms
Relief on administration of glucose
↑ C peptide level
↑ plasma insulin
Absence of sulfonylurea

10. Diagnostic testing 72 hrs fast(gold standard)
Plasma glucose ≤2.5 mmol/l
Plasma insulin ≥6 μunits/ml (43 pmol/l)
Plasma C-peptide ≥0.2 nmol/l
Plasma proinsulin ≥0.5 nmol/l
Plasma sulphonylurea Negative
Plasma β-hydroxybutyrate <2.7 mmol/l
Change in glucose with 1 mg glucagon ≥25 mg/dl at 30 min
symptoms develop in 35 %of patients within 12 h, 75 % within 24 h, 92 % within 48 h and 99 % within 72 h
C peptide suppression test
Stimulation tests with glucagon, Ca, tolbutamide

11. Locallization CT, MRI Transabd USG, EUS Intraop US
Somatostatin receptor scintigraphy
Angiography
Selective intra-arterial Ca. stimulation with splenic venous sampling

13. Management Surgical Resection is the treatment of choice
Specialized units
Enecluation in most cases
Distal pacreatectomy/ whipples’s procedure in a few
Blind resection shouldn’t be performed

14. Management Medical When awaiting surgery Metastatic disease
Failed surgery
Dietary
Diazoxide (with hydrochlorthiazide)
CCBs, Verapamil, Nifedipine
Somatostatin analogues, Octeotride
CT- Streptozocin, 5FU, Doxarubicin
Hepatic art. embolization

15. Management of Unresectable/Metastatic Disease
Systemic therapy
Somatostatin analogues
Chemotherapy
“Targeted” Agents
Peptide receptor therapy
Regional Therapies
Hepatic arterial embolization (± chemotherapy) or radioembolization
Ablative therapy (RFA, cryo, microwave)
Radiation
Surgical Intervention
Resection
Hepatic arterial ligation
Liver Transplant

16. Zollinger-Ellison Syndrome
“Islet cell” tumor of the pancreas [or of the duodenum] 
Hypergastrinemia 
Gastric acid hypersecretion 
Consequences of acid hypersecretion :
PUD, GERD [ with or without complications]
Diarrhea, malabsorption

17. Epidemiology of Z-E syndrome
Any age group ( mean age  50 years)
Male : Female  3:2
Annual incidence  per million
MEN-1 in approximately 25% of cases

18. Classification of Z-E syndrome
Sporadic %
MEN-1(autosomal dominant) 20-25%
Ectopic gastrin- producing tumors < 1%
ovary
lung
cardiac (ventricular septum)

19. The Gastrinoma Triangle

20. Symptoms in patients with the Zollinger-Ellison syndrome
Pain and diarrhea %
Pain without diarrhea 25%
Diarrhea without pain 20%
Heartburn ± dysphagia 30%
MEN-1 features %

21. Locations of peptic ulcers in ZE syndrome
Duodenal bulb
Post-bulbar duodenum
Jejunum
Esophagus
Stomach
Marginal (stomal)

22. Clinical features suspicious for Zollinger-Ellison syndrome (ZES)
PUD in the absence of Helicobacter pylori or
PUD in association with chronic diarrhea
Post-bulbar duodenal ulcer
Multiple duodenal and/or jejunal ulcers
PUD refractory to standard medical therapy
Giant PUD

23. Diagnosis of ZE Syndrome
Begins with clinical suspicion
Fasting serum gastrin measurement
high sensitivity (> 95%)
poor specificity, even at high levels
modest positive predictive value
excellent negative predictive value

24. Other causes of elevated fasting serum gastrin
Achlorhydria / hypochlorhydria, usu. due to chronic gastritis
Medications: antacids, PPIs,
H2 blockers
Postoperative: vagotomy, retained antrum syndrome
Renal failure
Gastric outlet obstruction
Diabetes mellitus
Hypertriglyceridemia

25. Diagnosis of ZE Syndrome
Fasting serum gastrin measurement
high sensitivity (> 95%)
low specificity and modest positive predictive value can be enhanced with provocative testing with secretin (2 IU/kg or 0.4 ug/kg i.v.) or calcium infusion (4 mg/kg calcium gluconate per hour for 3 hours), where likelihood ratios increase fold with a + test result and decrease 10-fold with a - test result

26. Management of ZE syndrome:
Acid control
Tumor search is designed to find tumor and to stage its/their extent
Tumor search and possible resection for cure is only prudent for patients who are surgical candidates

27. Clinical symptoms and laboratory findings in patients with glucagonoma
Clinical Symptoms Frequency (%)
Dermatitis
Diabetes/glucose intolerance
Weight loss
Glossitis/stomatitis/cheilitis
Diarrhea
Abdominal pain
Thromboembolic disease
Venous thrombosis
Pulmonary emboli
Psychiatric disturbance uncommon
Laboratory Abnormality
Anemia
Hypoaminoacidemia
Hypocholesterolemia
Renal glycosuria unknown

28. VIPoma - Verner Morrison syndrome
•  Watery diarrhea, hypokalemia and achlorhydria
•  Very rare tumor
•  Secretory diarrhea of ≥ 10 liters watery tea colored stool per day
•  Serum VIP levels above 200 pg/ml
•  Exclude other endocrine tumors, laxative and celiac sprue
•  Octreotide allows for preoperative resuscitation and preparation
•  40% are malignant and 22% had hyperplasia

29. Clinical symptoms and laboratory findings in patients with the VIPoma syndrome (WDHA)
Symptoms/Signs Frequency (%)
Watery (secretory) diarrhea
Dehydration
Weight loss
Abdominal cramps, colic
Flushing
Laboratory Findings
Hypokalemia
Hypochlorhydria
Hypercalcemia
Hyperglycemia

30. Somatostatinoma Annual incidence: very rare
Pancreatic> Duodenal>> other sites
Incidence of Malignancy: > 70%
Incidence in MEN-1: <1%
Clinical Features
Diabetes mellitus
Gallbladder disease
Diarrhea/steatorrhea
Weight loss

31. Clinical and laboratory findings in patients with somatostatinomas
Clinical Finding(s) Somatostatinoma Somatostatin syndr.
Pancreatic Intestinal Overall
Diabetes mellitus
Gallbladder disease
Diarrhea
Weight loss
Laboratory Finding(s)
Steatorrhea
Hypochlorhydria

32. 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

33. 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