Pancreatic Neuroendocrine Tumor (PNET)

Henry William Taylor, MD, Forest Washington, MD, and Michael D. Smith, MD
The Operative Review of Surgery. 2023; 1:189-196.

Table of Contents
Definitions and Tumors
Functional PNET Comparisons
Staging
Diagnosis
Treatment

Mnemonics
References

Definitions and Tumors

Definitions

• Pancreatic Neuroendocrine Neoplasia (PNEN) – Any Neuroendocrine Neoplasia of the

Pancreas
o Previously Known as “Islet Cell Tumors”
• Pancreatic Neuroendocrine Tumor (PNET) – Well-Differentiated PNEN
• Pancreatic Neuroendocrine Carcinoma (PNEC) – Poorly-Differentiated PNEN with High-
Proliferative Rate

Non-Functional PNET (NF-PNET) 1,2

• The Majority of PNETs are

Nonfunctional (60-90%)
• Can Secrete Substances but Do Not
Present with Hormonal Syndromes
o Ex: Chromogranin, Pancreatic Resection of a Nonfunctional PNET 3
Polypeptide, Ghrelin, etc.
• Generally Present Later with a More Indolent and Protracted Course
• Symptoms are Generally Related to Mass Effect:
o Abdominal Pain
o Weight Loss
o Anorexia
o Nausea and Vomiting
o Obstructive Jaundice

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Functional PNET (F-PNET)

• Insulinoma – *See Insulinoma

• Gastrinoma – *See Gastrinoma and Zollinger-Ellison Syndrome
• Glucagonoma – *See Glucagonoma and Glucagonoma Syndrome
• VIPoma – *See Vasoactive Intestinal Peptide-Secreting Tumor (VIPoma)
• Somatostatinoma – *See Somatostatinoma
• Other Less Common Functional PNETs:
o ACTH-Secreting Tumors (Cushing Syndrome)
o Serotonin-Secreting Pancreatic Neuroendocrine Tumor (Carcinoid Syndrome)
o PTHrp-oma (Mimics Hyperparathyroidism with Hypercalcemia)

Functional PNET Comparisons

PNET Percentage of All General Presentation
Functional PNETs 4
Insulinoma 35-40% Whipple’s Triad
(Most Common) Fasting Hypoglycemia
Symptoms of Hypoglycemia
Symptomatic Relief with Glucose
Gastrinoma 16-30% Peptic Ulcer Disease
Glucagonoma < 10% 4-D Syndrome
Diabetes/Glucose Intolerance
Dermatoses (NME)
DVT
Depression
VIPoma < 10% WDHA Syndrome
Watery Diarrhea
Hypokalemia
Achlorhydria
Somatostatinoma < 5% Diabetes/Glucose Intolerance
Cholelithiasis
Diarrhea/Steatorrhea

Size and Malignancy

• Most are Large (> 3 cm) and Malignant (60-90%) 5-8

o 75% Present as Advanced Disease
• Conversely, Insulinomas are Generally Small (< 3 cm) and Benign (93%) 9,10

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Association with Multiple Endocrine Neoplasia Type 1 (MEN-1)

• Most are Sporadic

• Insulinoma: 6% 11
• Gastrinoma: 20-30% – The Most Common PNET Associated with MEN-1 12
• Glucagonoma: 3-10% 6,13,14
• VIPoma: 5% 15
• Somatostatinoma: 35-45% 16
o Although MEN-1 is Common in Somatostatinoma, Somatostatinoma is Overall One of
the Least Common PNETS in MEN-1 (< 1%) 16

Most Common Location in the Pancreas

• Insulinoma: Even Distribution Throughout the Pancreas 17

• Gastrinoma: Head 18
• Glucagonoma: Body and Tail 19
• VIPoma: Body and Tail 20
• Somatostatinoma: Head 8

Staging
TNM Staging (AJCC 8) 21

T N M
1 Limited to the Pancreas (< 2 cm) Any Regional M1a – Liver
Lymph Node M1b – Extrahepatic
Involvement M1c – Both Liver and Extrahepatic
2 Limited to the Pancreas (2-4 cm)
3 Limited to the Pancreas (> 4 cm)
or Invades the Duodenum/CBD
4 Invades Adjacent Organs or
Large Vessels

• For T Stage – Multiple Tumors are Designated as T(#) (Example: T3(4))

o If Number or Tumors is Too Numerous or Unavailable – T(m)
• *Note: This System Does Not Apply to High-Grade, Poorly Differentiated Neuroendocrine
Carcinoma (PNEC) – These are Staged as an Exocrine Pancreatic Cancer

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TNM Stage 21

Stage T N M
I T1 N0 M0
II T2-3 N0 M0
III T4 N0 M0
Any T N1 M0
IV Any T Any N M1

WHO 2010 Grading 22

Grade Differentiation Ki-67 Index Mitotic Count

(/10 HPF)
G1 (Low) Well ≤ 2% <2
G2 (Intermediate) Well 3-20% 2-20
G3 (High) Poorly > 20% > 20

Diagnosis
Diagnosis

• Insulinoma: High Insulin Levels During an Episode of Hypoglycemia 23

o *See Insulinoma
• Gastrinoma: High Fasting Serum Gastrin (FSG) and Measurement of Gastric pH 24
o Secretin Stimulation Test if Initial Findings are Not Diagnostic
o *See Gastrinoma and Zollinger-Ellison Syndrome
• Glucagonoma: High Fasting Glucagon 25
o *See Glucagonoma and Glucagonoma Syndrome
• VIPoma: High Plasma VIP 26
o *See Vasoactive Intestinal Peptide-Secreting Tumor (VIPoma)
• Somatostatinoma: High Fasting Plasma Somatostatin 27
o May Be Made by Biopsy/Histology if Classic Presentation is Absent
o *See Somatostatinoma

Localization

• Initial Imaging: Noninvasive (CT or MRI)

• Somatostatin Receptor Imaging
o Consider if Initial Imaging Fails to Localize
o Options:
§ Somatostatin (Octreotide) Receptor Scintigraphy (SRS) – Classic Test Used
§ Functional PET Scan (Ga-68 DOTATATE) – Becoming More Prevalent with
Higher Sensitivity

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 o Insulinomas Demonstrate Relatively Low
Somatostatin Receptor Expression (May Be
More Difficult to Detect than Other PNETs) 28,29
• If Noninvasive Imaging Fails: Invasive Imaging
o Endoscopic Ultrasound (EUS) – Generally
Preferred Next Step
o Selective Arterial Stimulation with Hepatic
Venous Sampling
§ Use: Insulinoma (Calcium Stimulation)
or Gastrinoma (Secretin Stimulation)
o Selective Visceral Angiography
• For Gastrinoma, Consider Surgical Exploration with
Palpation or Intraoperative Ultrasound if High PNET on Imaging: (A) CT, (B) EUS,
Suspicion but All Imaging Negative (C) SRS, (D) Functional PET 30

Treatment
Surgical Resection (Treatment of Choice)

• Small (< 2-3 cm): Enucleation

o *Enucleation is Controversial for the More Malignant PNETs (VIPoma,
Somatostatinoma, or Glucagonoma)
• Large (> 2-3 cm): Surgical Resection

See Individual Pages for Specifics on Management

• Insulinoma – *See Insulinoma

• Gastrinoma – *See Gastrinoma and Zollinger-Ellison Syndrome
• Glucagonoma – *See Glucagonoma and Glucagonoma Syndrome
• VIPoma – *See Vasoactive Intestinal Peptide-Secreting Tumor (VIPoma)
• Somatostatinoma – *See Somatostatinoma

Pancreatic Neuroendocrine Carcinoma (PNEC)

• Poor Prognosis with Rapid Disease Progression

• Resectable Disease: Surgical Resection with Adjuvant Chemotherapy
• Unresectable Disease: Palliative Chemotherapy

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Mnemonics
Most Common Site of PNET’s 31

• “6: The Number of the Pancreas”

o Pancreas Looks Like a #6
o *Used in Other Mnemonics: Pseudocyst and Chronic Pancreatitis
• “SIX” Written on Pancreas:
o “S” in Head: gaStrin and SomatoStatin
o “I” Anywhere: Insulin
o “X” in Body/Tail: Glucagon and VIP

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