Pancreas: Pancreatic Neuroendocrine Tumor (PNET)

Pancreatic Neuroendocrine Tumor (PNET)

Definitions

Pancreatic Neuroendocrine Neoplasia (PNEN) – All Neuroendocrine Neoplasias in the Pancreas
- Previously Known as Islet Cell Tumors
Pancreatic Neuroendocrine Tumor (PNET) – Well Differentiated
Pancreatic Neuroendocrine Carcinoma (PNEC) – Poorly Differentiated Histology & High-Proliferative Rate

Non-Functional Endocrine Tumor

Secrete Substances but Do Not Present with Hormonal Syndromes
- Can Secrete Chromogranin, Pancreatic Polypeptide, Ghrelin, etc.
- Present Later with More Indolent & Protracted Course
Most Common PNET (50-85%)
Presentation:
- Abdominal Pain
- Weight Loss
- Anorexia
- Nausea

Insulinoma

Insulin Secreting Tumor
Most Common Functional PNET
Most are Benign (93%)
Evenly Distributed Throughout Pancreas Mn
Presentation:
- Symptoms:
  - Confusion
  - Visual Changes
  - Palpitations
  - Diaphoresis
  - Amnesia
- Whipple’s Triad:
  - Fasting Hypoglycemia
  - Symptoms of Hypoglycemia
  - Relief with Glucose
High C-Peptide – If Low: Consider Exogenous Insulin Administration (Munchausen’s Syndrome)

Glucagonoma

Glucagon Secreting Tumor
Most are Malignant (50-80%)
Most Common in Body & Tail Mn
Presentation:
- Symptoms:
  - Weight Loss (Most Common Presenting Symptom)
  - Stomatitis
  - Diarrhea
  - 4-D’s Syndrome:
    - Diabetes (Glucose Intolerance)
    - DVT
    - Depression
    - Dermatitis (NME)
- Necrolytic Migratory Erythema (NME)
  - Erythematous Papules of Face, Perineum & Extremities
    - Enlarge Over 1-2 Weeks Then Have Central Clearing with Indurated Blisters and Crust
  - From Malnutrition & Amino Acid Deficiency
  - Treatment: Supplementation (Zinc, Amino Acids & Fatty Acids)
    - Resolves with Tumor Resection

Gastrinoma

*See Stomach: Gastrinoma

Somatostatinoma

Somatostatin Secreting Tumor
Most are Malignant (75%)
Most Common in Head Mn
Presentation:
- Most Common Symptoms: Abdominal Pain & Weight Loss
- Somatostatinoma Syndrome
  - Triad:
    - Diabetes
    - Cholelithiasis
    - Diarrhea/Steatorrhea
  - Less Commonly Seen (19% if in Pancreas or 2% if in Duodenum)

VIPoma

VIP Secreting Tumor
Most are Malignant (60-80%)
Most Common in Body & Tail Mn
Presentation:
- VIPoma Syndrome (WDHA Syndrome/Verner-Morrison Syndrome)
  - Profuse Watery Diarrhea (> 700 mL/Day) that Persists with Fasting
  - “WDHA”: Watery Diarrhea, Hypokalemia & Achlorhydria (HCl)
    - Electrolyte Losses Due to Profound Diarrhea
    - Causes Metabolic Acidosis

Insulinoma ¹

Glucagonoma in Pancreatic Tail ²

Necrolytic Migratory Erythema (NME) ³

PNET – Staging & Variation

TNM Staging – AJCC 8

	T	N	M
1	< 2 cm	N+	M1a – Liver M1b – Extrahepatic M1c – Liver & Extrahepatic
2	≥ 2 cm
3	> 4 cm or Invades Duodenum/CBD
4	Invades Adjacent Organs or Large Vessels

- For T Stage – Multiple Tumors are Designated as T(#) (Example: T3(4))
  - If Number or Tumors is Too Numerous or Unavailable – T(m)
Stage

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

Histologic Grading

Well-Differentiated
- PNET-G1 (Low-Grade): Ki-67 < 3% or Mitotic Index < 2
- PNET-G2 (Intermediate-Grade): Ki-67 > 3% or Mitotic Index > 2
- PNET-G3 (High-Grade): Ki-67 > 20% or Mitotic Index > 20
Poorly-Differentiated
- PNEC-G3: Ki-67 > 20% or Mitotic Index > 20

Malignancy

Most are Malignant
- Insulinoma Mostly Benign
- Gastrinoma 50-60%
75% Present as Advanced Disease
Most Common Site of Mets: Liver

Association with MEN-1

Most Commonly Spontaneous
Insulinoma: 6%
Glucagonoma: 20%
Gastrinoma: 20-30%
- Most Common PNET in MEN-1 Syndrome
Somatostatinoma: 35-45%
- Although One of the Least Common Overall
VIPoma: 5%

Location

Most Common in Head: Gastrinoma & Somatostatinoma
Most Common in Body & Tail: Glucagonoma & VIPoma
Even Distribution: Insulinoma

PNET – Management

Diagnosis

Insulinoma: High Insulin & Hypoglycemia
- Produce Hypoglycemia By 72-Hour Fast or Mixed-Meal Test
- Rule Out Exogenous Administration:
  - C-Peptide Level – Low Values Indicate Exogenous Insulin
  - Sulfonylurea Screen & Meglitinide Screen
Glucagonoma: High Fasting Glucagon (> 500 pg/mL)
Gastrinoma: Secretin Stimulation Test (Causes Marked Gastrin Increase)
- *See Stomach: Gastrinoma
Somatostatinoma:
- If Somatostatinoma Syndrome Present: High Fasting Somatostatin (> 30 pg/mL)
- If Not Present (Most Common): Specimen Histology Stain Positive for Somatostatin
VIPoma: High Serum VIP (> 75 pg/mL)

Localization

Initial: CT or MRI
If Fails: Somatostatin Receptor Imaging
- Not Used for Insulinomas (Low Somatostatin Receptor Expression)
- Tests:
  - Somatostatin (Octreotide) Receptor Scintigraphy (SRS)
    - Classically Used
  - Functional PET Scans
    - Becoming More Prevalent with Higher Sensitivity
    - Radiotracer: Ga-68 DOTATATE or Ga-68 DOTATOC
If Imaging Fails: EUS
If EUS Fails: Invasive Testing
- Selective Arterial Stimulation with Hepatic Venous Sampling
  - Use: Insulinoma (Calcium Stimulation) or Gastrinoma (Secretin Stimulation)
- Selective Visceral Angiography
  - Use: Glucagonoma, Somatostatinoma or VIPoma
If High Suspicion of Gastrinoma & All Testing Fails: Surgical Exploration

Treatment

Resectable:
- < 2-3 cm: Enucleate
  - Should Be ≥ 2-3 mm From the Main Pancreatic Duct (Reduce Leak Risk)
  - *May Consider Observation in Select Patients
  - *Enucleation is Controversial for the More Malignant PNETs (VIPoma, Somatostatinoma or Glucagonoma)
- > 2-3 cm, Local Invasion or N+: Resection
  - Head/Neck: Pancreaticoduodenectomy
  - Body/Tail: Distal Pancreatectomy
    - If Malignancy Suspected: Concurrent Splenectomy
  - Entire Pancreas: Total Pancreatectomy
Unresectable or Mets:
- Resect Mets if Able
- Symptomatic Treatment:
  - Insulinoma – Diazoxide (Inhibits Insulin Release)
    - If Fails: Octreotide or Everolimus
  - Gastrinoma – PPI
    - If Fails: Octreotide
  - Others – Octreotide
- If Severe/Enlarging: Chemotherapy
  - Classic Regimen: Streptozocin with/without Doxorubicin (Toxic to Beta Cells)
  - Newer Regimen: Temozolomide with/without Capecitabine (CAPTEM)

PNET on CT ⁴

PNET on SRS ⁴

PNET on Functional PET ⁴

PNET on EUS ⁴

Pancreatic Neuroendocrine Carcinoma (PNEC)

Basics

Poorly Differentiated Histology & High-Proliferative Rate
Almost All are Non-Secretory
Aggressive – Most Are Metastatic at Time of Presentation
Sx: Abdominal Pain, Nausea, Fatigue & Weight Loss

Diagnosis

Requires Bx with Neuroendocrine Markers (Chromogranin & Synaptophysin)
Imaging: CT, MRI or PET
- Somatostatin Receptor Imaging Usually Not Helpful

Treatment

Resect if Able
Chemotherapy for All
- Platinum-Based (Carboplatin or Cisplatin) & Etoposide

Mnemonics

Most Common Site of PNET’s

#6 – The Number of the Pancreas (Used in Other Mnemonics: Pseudocyst and Chronic Pancreatitis)
- Pancreas Looks Like a #6
“SIX” Written on Pancreas:
- “S” in Head: gaStrin & SomatoStatin
- “I” Anywhere: Insulin
- “X” in Body/Tail: Glucagon & VIP

#6 – The Number of the Pancreas

References

Alabraba E, Bramhall S, O’Sullivan B, Mahon B, Taniere P. Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1. World J Surg Oncol. 2009 Feb 13;7:18. (License: CC BY-2.0)
Al-Faouri A, Ajarma K, Alghazawi S, Al-Rawabdeh S, Zayadeen A. Glucagonoma and Glucagonoma Syndrome: A Case Report with Review of Recent Advances in Management. Case Rep Surg. 2016;2016:1484089. (License: CC BY-4.0)
Pakran J, Riyaz N. Necrolytic migratory ulceration. Indian Dermatol Online J. 2013 Jul;4(3):205-7.(License: CC BY-NC-SA-3.0)
Kartalis N, Mucelli RM, Sundin A. Recent developments in imaging of pancreatic neuroendocrine tumors. Ann Gastroenterol. 2015 Apr-Jun;28(2):193-202. (License: CC BY-NC-SA-3.0)