A brief description of Neuroendocrine tumors of the pancreas. Includes epidemiology, different classification, syndromes produced depending of the secreted hormone, diagnostic considerations and imaging examples.

1. Neuroendocrine tumors
of the pancreas.
MARCO CASTILLO

2. DEFINITION:
Epithelial neoplasms with neuroendocrine
differentiation.
Arise from omnipotent endocrine stem cells.
Sheet of small round cells with uniform nuclei and
cytoplasm.
Chromogranin A +; Neuron specific enolase +;
Synaptophysin +
Neuroendocrine tumors of the pancreas.

3. Epidemiology
 1 case per 100,000 individuals per year.
 Represent 2 – 4% of clinical detected pancreatic tumors.
 Forth to sixth decade of life.
 GENETICS:
 MEN1. 80 – 100%
 Von Hipple Lindau (VHL). 20%
 Neurofibromatosis 1 (NF-1). 10%
 Tuberous sclerosis complex (TSC). 1%

4. WHO Classification of Pancreatic
Endocrine Tumors.
Well-Differentiated Endocrine Tumor
Type 1: Benign Behavior
Confined to the pancreas
<2 cm in diameter
<2 mitoses per high-powered field
<2% Ki-67–positive cells
No vascular or perineural invasion
Well-Differentiated Endocrine Carcinoma
Low-grade malignant
Gross local invasion
Metastases
Type 2: Uncertain Behavior
Confined to the pancreas and one
of the following:
>2 cm in diameter
>2 mitoses per high-powered field
>2% Ki-67–positive cells
Vascular or perineural invasion
Poorly Differentiated Carcinoma
High-grade malignant
>10 mitoses per high-powered field

5. TNM Classification for Pancreatic
Neuroendocrine Tumors
T: Primary Tumor
T0: No evidence of cancer
Tis: Carcinoma in situ
T2: Tumor limited to the pancreas, size >2 cm
T3: Tumor extends beyond the pancreas but does
not involve the celiac axis or superior mesenteric
artery
T4: Tumor involves celiac axis or superior
mesenteric artery (unresectable primary tumor)
N: Regional Lymph Nodes
N0: No regional lymph nodes involved
N1: Regional lymph nodes involved
M: Distant Metastases
M0: No distant metastases
M1: Distant metastases
Stages
0: Tis N0 M0
IA: T1 N0 M0
IB: T2 N0 M0
IIA: T3 N0 M0
IIB: T1 N1 M0, T2 N1 M0,
……..T3 N1 M0
III: T4, any N, M0
IV: Any T, any N, M1

6. Types:
Insulinomas.
Gastrinoma.
Glucagonoma.
Vasoactive intestinal polypeptide–
producing tumor (VIPoma).
Somatostatinoma.
Growth hormone– releasing factor–
producing tumors (GRFomas).
Adrenocorticotropic hormone–
producing tumors (ACTHomas).
Parathyroid hormone–related protein
producing tumors (PTHrpomas).
Neurotensinomas.
Non Functional:
 Pancreatic polypeptide–producing tumor
(PPoma).
 Ghrelinomas.

7. Insulinoma.
Most common type.
Women (2:1) 50 - 60 years old.
Benign. Solitary and small.
Clinical presentation:
 Whipple’s triad:
 Symptoms of hypoglycemia.
 Blood glucose < 45 mg/dL.
 Relief of symptoms with Glucose.
Symptoms of hypoglycemia:
◦ Altered mental state.
◦ Weakness.
◦ Diplopia.
◦ Seizures.
◦ Coma.
◦ Sweating.
◦ Palpitations.
◦ Anxiety.

8. Insulinoma.
DIAGNOSIS:
 Monitored 72 hours fast.
 Glucose < 50 mg/dL in < 48 hours.
 Relief of symptoms with oral glucose.
 Elevated insulin > 5 – 10 µU/mL.
 Increase proinsulin level > 22 pmol.
 Absence of sulfonylureas in plasma or urine.
 Elevated C peptide levels.
LOCALIZATION:
 CT scan.
 Endoscopic ultrasound.
TREATMENT:
 Enucleation of the tumor.
 Dietary modifications.
 Diazoxide or Octreotide.

9. Insulinoma.

10. Gastrinoma (Zollinger-Ellison Syndrome).
0.5 to 3 per million population per year
Peak age of onset is 50 years
Even with metastases: Good prognosis.
Clinical presentation:
 Peptic ulcer disease:
 With diarrhea.
 Ulcers in unusual locations.
 Refractory to medication ulcers.
 Young age ulcer with complications.
 Disease associated with other endocrinopathies.
 Abdominal pain.
Chronic diarrhea.
Heartburn.
Nausea.
Vomiting.
Bleeding.
Esophageal strictures.
Pyloric or duodenal scarring.
Bleeding.
Prominent gastric folds

11. Gastrinoma (Zollinger-Ellison Syndrome).
LOCATION:
 CT.
 Endoscopic ultrasound.
 Somatostatin Receptor Scintigraphy.
 Intraoperative palpation and Ultrasound.
DIAGNOSIS:
 Fasting gastrin level: > 100 pg/mL or >10 times higher
than upper limit.
 Secretin stimulation test: Gastrin > 200 pg/mL.
 Calcium infusion provocative testing: Gastrin > 395 pg/dL.
 Basic acid output level > 15 mEq/L.
TREATMENT:
 Enucleation.

13. Glucagonoma
Male = Female.
Age 50 – 60.
Malignant 60 – 70 %
Clinical presentation:
 Diabetes.
 Necrolytic migratory erythema.
 Deep vein thrombosis.
 Depression.
 Weight loss.
 Stomatitis.

14. Glucagonoma
LOCATION: Body and Tail
CT, MRI, EUS.
DIAGNOSIS:
 Fasting serum glucagon > 1000 pg/dL.
 Increase glucose.
 Decrease plasma amino acids.
 Anemia.
TREATMENT:
Correction of metabolic deficits.
Subtotal pancreatectomy + Splenectomy.
Resection of metastases.
Typically not resectable.

16. Vasointestinal peptide tumor (VIPoma)
Male > Female.
Mean age 48.
Benign 50%
Clinical presentation:
 Severe watery diarrhea.
 Hypokalemia.
 Achlorhydria.
 Metabolic acidosis.
Diagnosis:
VIP > 200 pg/mL
Location: Tail
CT or MRI.
Treatment:
 Correction of electrolyte imbalance.
 Somatostatin.
 Partial pancreatectomy or debulkyng of the
tumor.

18. Somatostatinoma.
Rare, only 1% of the Neuroendocrine tumors.
Mean age: 50 years.
Men = Women.
Malignant: 60 – 70 %
Clinical presentation:
 Hyperglycemia.
 Cholelitiasis.
 Steatorrhea.
 Diarrhea.
 Gastric hypochloridia.
Jaundice.
Diagnosis:
Fasting somatostatin > 30 pg/mL
Location: Head.
CT or MRI.
Endoscopic ultrasound.
Somatostatin receptor scintigraphy
Treatment:
 Pancreatodudenectomy + Hepatic resection.
 Octreotide.
Liver transplantation.

19. Growth hormone–releasing factor tumor (GRFoma).
Usually large > 6 cm.
Malignant.
30% has metastasis.
50% has also Zollinger-Ellison.
Clinical presentation:
 Acromegaly.
Pancreatic mass.
Diagnosis:
Increase GRF by age.
Location: Lung, Pancreas, Jejunum,
retroperitoneum.
CT.
Treatment:
 Surgical resection.
Debulking prolong survival.
Octreotide for symptoms.

21. Represents > 75%.
Women (2:1) Mean age: 45
Lack of hormonal clinical syndrome.
60 – 80% are metastatic at diagnosis.
60% are malignant.
Clinical presentation:
 Asymptomatic.
 Abdominal pain.
 Jaundice.
Diagnosis:
 Serum: Pancreatic polypeptide,
Neurotensin, Neuronspecific
enolase, Chromogramin A.
 CT scan.
Treatment:
 Surgical resection +/- Partial liver
resection.
Non functional neuroendocrine tumor

24. Clinical pearls: Neuroendocrine tumors.
 CT and MRI are highly sensitive for identification of neuroendocrine tumors.
 Endoscopic ultrasonography is highly sensitive for detection of occult, subcentimeter
pancreatic NETs.
Somatostatin-receptor-scintigraphy (OctreoScan) offers whole-body imaging and functional
information.
 It’s ability to detect subcentimeter tumors is limited.
 Chromogranin A is the most common hormone associated with all types of
gastroenteropancreatic NETs.
 CgA or pancreatic polypeptide can be followed as tumor markers if elevated at baseline.

25. References:
Tricia A, Moo-Young and Richard A. Endocrine tumors of the pancreas: clinical picture, diagnosis,
and therapy. In: Blumgart's Surgery of the Liver, Biliary Tract, and Pancreas. 5th edition. Chapter
61. Pp 934 – 944.
Ladner D and Norton J. Neuroendocrine Tumors of the Pancreas. In: Shackelford’s Surgery of the
Alimentary Tract. 7th edition. Pp 1206 – 1216.
UpToDate:
http://www.uptodate.com/contents/classification-epidemiology-clinical-presentation-
localization-and-staging-of-pancreatic-neuroendocrine-tumors-islet-cell-tumors
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