Pancreatic NETs for undergrads - and postgrads may be :)

1. PANCREATIC
ENDOCRINETUMORS

2. Introduction
•Uncommon neoplasms
•Incidence <1/100,000 persons per year
•Incidence higher in autopsy studies (0.8-10%)
•Better prognosis than pancreatic adenocarcinoma
Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM. Pancreatic
endocrine neoplasms: Epidemiology and prognosis of pancreatic endocrine
tumors. Endocrine-related cancer. 2008;15(2):409-427. doi:10.1677/ERC-07-0221.

3. •Associated with 10-20% patients with MEN 1
•Either functional or non-functional

4. Islets of Langerhans:
1-2% of pancreatic
mass
About 1 million islets in
healthy adult pancreas
-cells = Insulin (65-80%)
-cells = Glucagon (15-20%)
-cells = Somatostatin (3-
10%)
PP-cells = Polypeptide (1%)

5. WHO classification of PETs
1. Well differentiated endocrine tumor
1.1 Benign behavior
Confined to the pancreas, < 2 cm in diameter, ≤ 2 mitoses per 10
HPF*, ≤2% Ki-67 positive cells, no angioinvasion or perineural
invasion
1.2 Uncertain behavior
Confined to the pancreas and one or more of the following features: 2
cm in diameter, > 2 mitoses per 10 HPF* , > 2% Ki-67 positive cells,
angioinvasion, perineural invasion

6. 2. Well differentiated endocrine carcinoma
Low grade malignant
Gross local invasion and/or metastases
3. Poorly differentiated carcinoma
High grade malignant
> 10 mitoses per HPF

7. Tumor (Syndrome) Incidence (%) Malignancy (%) Symptoms
Insulinoma 70-80 <10
Weakness, sweating, tremor, tachycardia, anxiety, fatigue,
dizziness, disorientation, seizures
Gastrinoma 20-25 60-80
Intractable or recurrent peptic ulcer disease (haemorrhage,
perforation), complications of peptic ulcer, diarrhoea
Nonfunctional
tumors
30-50 60-90
Obstructive jaundice, pancreatitis, epigastric pain,
duodenal obstruction, weight loss, fatigue
VIPoma 4 80 Profuse watery diarrhoea, hypotension, abdominal pain
Glucagonoma 4 80
Migratory necrolytic skin rash, glossitis, stomatitis, angular
cheilitis, diabetes, severe weight loss, diarrhoea
Somatostatinoma <5 50 Cholelithiasis, diarrhoea, neurofibromatosis
Carcinoid <1 90 Flushing, sweating, diarrhoea, oedema
ACTHoma <1 >90 Cushing’s syndrome
GRFoma <1 30 Acromegaly

8. INSULINOMA

9. Introduction
•Insulin producing tumors of the pancreas
•Most common cause of hypoglycemia resulting
from endogenous hyperinsulinism
•Clinically characterized by Whipple’s triad:
- Symptoms of hypoglycemia after fasting or exercise
- Plasma glucose levels <2.8 mmol/L
- Relief of symptoms after administration of iv glucose

10. Epidemiology
•Most common PET
•2-4 cases per million population per year
•Highest incidence in 4th to 6th decade
•Median age at diagnosis is 47 years (in MEN1, mid
20s)
•M:F = 2:3
https://emedicine.medscape.com/article/283039-overview#a8

11. Pathology
•10% malignant
•10% multiple (half of them have MEN1)
•Benign tumors are encapsulated, usually 1.5 cm or
less
•Malignant tumors show local invasion or metastasis

12. Presentation
•Symptoms of hypoglycemia (85%)
- diplopia, blurred vision, confusion, abnormal behavior and
amnesia (LOC and coma in some cases)
- usually occur several hours after a meal
•May be episodic due to intermittent nature of insulin
secretion
•Adrenergic symptoms due to catecholamine release
- sweating, weakness, hunger, tremor, nausea, anxiety and
palpitations
•Weight gain (20-40%) as patient eats frequently to avoid
symptoms

13. Diagnosis
•Biochemical
- Plasma glucose < 40 mg/dL
- Serum insulin ≥ 10 µU/mL
- Serum proinsulin ≥ 22 pmol/L
- C-peptide ≥ 2.5 ng/mL
A prolonged supervised fasting that may last upto
72 hours will provide the most reliable result
AIM : to demonstrate
inappropriately high
level of insulin in relation
to blood ghlucose

14. •Imaging
- Successful preoperative tumor localization in 60%
- Surgical exploration with/without intraoperative
ultrasonography 90%
- USG (33%)
- CT scan (33%)
- MRI (15%)
- Endoscopic ultrasound (65%)
- Selective arteriography (82%)

15. The 3-cm contrast-
enhancing neoplasm
(arrow) is seen in the
tail of the pancreas
(P) posterior to the
stomach (S)
P
S

16. The hypoechoic
neoplasm (arrows)
is seen in the body
of the pancreas
anterior to the
splenic vein (SV)

17. Management
Positive
biochemical
tests
Exclude
distant
metastasis
Surgical
resection
Medical
treatment
If diffuse
metastasis or
patient unfit for
surgery

18. Surgery
•Benign:
- Enucleation for superficial tumors
- Distal pancreatectomy for tumours located deep in the
body or tail of the pancreas and those in close
proximity to the pancreatic duct
•Malignant:
- Aggressive resection should be attempted

19. •Role of intraoperative ultrasound (IOUS):
- To confirm tumor location
- To find nonpalpable tumors
- to identify the relation of the tumor to the pancreatic
duct

20. •Blood sugar level begins to rise after few hours
•Hyperglycemia may persist for 48-72 hours and
may require SC insulin
chronic down-regulation of insulin-receptors by
the previously high circulating insulin levels
secreted by the tumor and the suppression of
normal pancreatic B cells

21. Medical management
•Diazoxide – suppresses insulin secretion (50%)
•Octreotide
•Frequent oral feeding or enteral feeding
•Chemotherapy – doxorubicin, streptozotocin

22. GASTRINOMA
Zollinger-Ellison syndrome (ZES)

23. Definition
•Gastrinoma – Gastric secreting tumor most
commonly found in the duodenum and also in the
pancreas
•Zollinger-Ellison syndrome (ZES) - The triad of non-
beta islet cell tumors of the pancreas
(gastrinomas), hypergastrinemia, and severe ulcer
disease (first described by Zollinger and Ellison in 1955)

24. Gastrinoma
triangle
Rarely, the body of the stomach, jejunum, peripancreatic lymph
nodes,splenic hilum, omentum, liver, gallbladder, common bile
duct and the ovary

25. Epidemiology
•Incidence = 0.5-4 /million population /year
•M > F
•Mean age = 38 yrs (Range = 7-83 yrs)
•ZES accounts for 0.1% cases of DU

26. Pathology
•> 60% malignant at diagnosis
•Can be sporadic (80%) or part of MEN1 syndrome (20%)
•Most are found in 1st and 2nd part of duodenum
•Also in pancreas (mostly sporadic), peripancreatic soft tissue
and gastric antrum
•ZES tumors are usually solitary, malignant and located in
pancreas
•MEN1 cases are less likely to be malignant, arise in duodenal
wall, often multicentric

27. Pathophysiology
Gastrin
producing
tumor
• Gastrin
Parietal cell
hyperplasia
• Increased
basal acid
secretion
Severe ulcer
disease

28. Presentation
•Severe peptic ulcer disease (>90%)
•Diarrhoea

29. Diagnosis
•Fasting hypergastrinemia (>1000 pg/mL)
•Gastric pH <2.5 (Basal acid output >10 mEq/h)
•Positive secretin test
Reference range for
fasting S. gastrin is
50-60 pg/mL, up to
150 pg/mL
For patients with intermediate gastrin secretion (150-1000 pg/mL),
secretin stimulation test:
Intravenous secretin (2 U/kg) raises serum gastrin levels to higher
than 200 pg/mL within 2 minutes and, virtually always, within 10
minutes in patients with gastrinomas

30. Fasting serum gastrin measurement
•Most sensitive test for the diagnosis of ZES
•Screening test is indicated for patients strongly
considered to have a gastrinoma
•Stop histamine 2 (H2) blockers 1 day or omeprazole 6
days prior to performing the study
•The reference range for fasting serum gastrin usually is
50-60 pg/mL, with an upper limit as high as 150 pg/mL
•Levels higher than 1000 pg/mL with acid
hypersecretion are highly suggestive of ZES

31. •Imaging: (negative in 1/3rd patients)
•Duodenal gastrinomas nearly impossible to
localize by preoperative imaging
•Pancreatic Gastrinoma -
- EUS (80-90%)
- CT scan (39%)
- MRI (46%)
•Somatostatin receptor scintigraphy (SRS) – to detect
primary tumor and metastasis

32. Treatment
•Medical treatment
- PPIs or H2 blocker
- Chemotherapy (combination of streptozocin, 5-
fluorouracil, and doxorubicin)

33. •Surgery
- Indication:
• benign gastrinomas
• malignant gastrinomas without diffuse metastasis
- Pancreatic:
• enucleation with peripancreatic lymph node dissection
• Distal pancreatectomy
• Duodenotomy (to detect additional tumor in MEN1)
- Duodenal:
• Duodenotomy (i. enucleation for <5mm, ii. Full thickness excision
for larger tumors)

35. Prognosis
•Determinant factor
- size of primary tumor
- presence of metastasis
•Surgical resection of localized disease leads to a
complete cure without any recurrence in 20-25%
of patients with gastrinomas

36. •In patients with localized disease or metastasis to
local lymph nodes without liver metastasis, the 5-
year survival rate may be 90%
•Patients with hepatic metastases may have a
remaining life span of less than 1 year; the 5-year
survival rate is 20-30%

37. NON-FUNCTIONAL PANCREATIC
ENDOCRINETUMORS (NF-PET)

38. Introduction
•30-50% of all PETs
•5th -6th decade of life
•Usually large (> 5 cm) and unifocal except in MEN1
•Head-Body-Tail = 7 : 1 : 1.5
•About 70% malignant
•5-year survival 65%, 10-year survival 49%

39. Clinical feature
•Late presentation
•Obstructing jaundice
•Abdominal pain
•Pancreratitis
•Weight loss

40. Diagnosis
•Biochemical :  chromogranin A (69%*)
•Imaging
* Nobels FR, Kwekkeboom BJ, CoopmansW, et al. Chromogranin A as serum marker for
neuroendocrine neoplasia: comparison with neuron-specific enolase and the alfa-subunit of
glycoprotein hormones. J Clin Endocr Metab. 1997;82:2622–8

42. Treatment
•Aggressive surgical approach (curative resection in
upto 62% cases)
•Surgery – partial pancreatoduodenectomy (±
resection of liver metastasis)
•Medical treatment – CT (if surgery not possible)