Pancreatic neuroendocrine tumors

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Pancreatic neuroendocrine tumors (PNETs) are hormone-secreting tumors of the pancreas that derive from neuroendocrine cells. The most important types are glucagonomas, VIPomas, somatostatinomas, insulinomas (treated in a separate article), and gastrinomas (treated in a separate article). With the exception of insulinomas, PNETs typically manifest with diarrhea, weight loss, and normal or elevated blood glucose levels; insulinomas do not affect bowel movements and manifest instead with weight gain and hypoglycemia. Diagnosis involves laboratory studies to identify excess hormone levels and imaging to detect the primary tumor and metastases. Surgical resection is the first-line treatment. Octreotide is the treatment of choice for inoperable tumors.

For more information, see “Insulinoma” and “Gastrinoma.”

• Definition: a rare neuroendocrine tumor of the pancreatic α-cells that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis.
• Clinical features
  • Weight loss
  • Impaired glucose tolerance or diabetes mellitus (75–95%)
  • Necrolytic migratory erythema
    • A cutaneous paraneoplastic syndrome that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinoma
    • Occurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities
    • Develop into painful and pruritic crusty patches with central areas of bronze-colored induration
    • Tend to resolve and reappear in a different location
    • Skin biopsy shows epidermal necrosis
  • Chronic diarrhea
  • Deep vein thrombosis
  • Depression
• Diagnostics: requires a high index of suspicion to make the diagnosis
  • Laboratory findings: ↑ glucagon > 500 pg/mL, ↑ blood glucose levels, normocytic normochromic anemia
  • Imaging (CT): to locate the tumor
• Treatment
  • Glycemic control
  • Tumor resection
  • Octreotide (if tumor is inoperable)

“Wait for 6 Days until the GLUe (glucagonoma) is dry:” Decreasing weight, Diabetes, Dermatitis, Diarrhea, DVT, Depression.

Reference:^[3]

• Definition: a rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin.
  • ↑ Somatostatin → ↓ secretion of the following hormones:
    • Secretin
    • Cholecystokinin
    • Glucagon
    • Insulin
    • Gastrin
    • Gastric inhibitory peptide
• Clinical features
  • Abdominal pain
  • Weight loss
  • Classic triad
    • Glucose intolerance/diabetes
    • Cholelithiasis
    • Steatorrhea
  • Achlorhydria
• Diagnostics
  • Laboratory findings: ↑ somatostatin, ↑ blood glucose levels
  • Imaging: locate the tumor
• Treatment
  • Tumor resection: curative if no metastases are present
  • Octreotide (if tumor is inoperable)
  • Chemotherapy

Reference:^[4]

• Definition: : a neuroendocrine tumor that secretes VIP (vasoactive intestinal polypeptide)
• Etiology: associated with MEN1 syndrome (5% of cases)
• Pathophysiology
  • Excess VIP → ↑ relaxation of gastric and intestinal smooth muscles and cAMP activity (similar to cholera toxin) → secretory diarrhea and inhibition of gastric acid production
  • VIP also stimulates vasodilation, bone resorption, and glycogenolysis
• Tumor location: The primary tumor is most frequently found in the pancreas.
• Clinical features
  • WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria): tea-colored watery diarrhea (> 700 mL/day) → dehydration
  • Weight loss
  • Abdominal pain, nausea, vomiting
  • Achlorhydria → ↓ iron and B₁₂ absorption → anemia
• Diagnostics
  • ↑ Serum VIP concentration (> 75 pg/mL)
  • Hypokalemia
  • Hypercalcemia ^[5]
  • Hyperglycemia
  • Gastric achlorhydria or hypochlorhydria
  • CT scan to localize the primary tumor
• Treatment
  • Tumor resection
  • Octreotide (inhibits VIP secretion)

• Definition: a rare PNET that secretes growth hormone-releasing hormone (GHRH), resulting in ectopic acromegaly ^[6]
• Clinical features: clinical features of acromegaly: e.g.,
  • Acral overgrowth
  • Cardiomegaly
• Diagnostics ^[6]
  • IGF-1 > 2× ULN
  • GHRH > 250 mg/L
• Differential diagnosis: benign GH-secreting pituitary adenoma
• Management ^[6]
  • First line: somatostatin analogues (SSA)
  • Pegvisomant can be added to control symptoms if IGF-1 levels remain elevated despite SSA treatment.

• Definition: a rare PNET characterized by the secretion of serotonin (5-HT), leading to elevated levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) and/or 5-HT ^[7]
• Clinical features ^[7][8]
  • Patients may be asymptomatic or present with nonspecific symptoms, e.g.:
    • Abdominal pain
    • Clinical features of acute pancreatitis
    • Weight loss
    • Jaundice
    • Ascites
  • Carcinoid syndrome is uncommon.
• Diagnostics ^[7][8]
  • Contrast-enhanced cross-sectional imaging (CT scan or MRI)
    • Hyperenhanced, well-delineated lesions in the arterial phase
    • Main pancreatic duct stenosis with upstream dilatation
  • Functional imaging (e.g., 111In-scintigraphy, 18F-FDG PET/CT) may also be used.
  • Laboratory studies ^[7]
    • ↑ 24-hour urinary 5-HIAA
    • ↑ Serum 5-HT
  • Histopathology: dense, fibrotic, paucicellular stromal reaction ^[7][8]
  • Immunohistochemistry: positive staining for 5-HT ^[8]
• Differential diagnoses
  • Metastatic ileal neuroendocrine tumor to the pancreas ^[8]
  • Nonfunctional PNET ^[7]
• Management ^[7]
  • A multimodal treatment approach (e.g., chemotherapy, somatostatin analogs, and/or ablation of liver metastases) is typically employed.
  • Most patients are not candidates for curative surgical resection because they present with metastatic disease (typically to the liver).
• Complications ^[7][8]
  • Pancreatic duct obstruction
  • Acute pancreatitis
  • Portal vein thrombosis
• Prognosis: The 5-year disease-related survival is < 50%. ^[7]

• Definition: a PNET that is not associated with a clinical hormonal syndrome, even though it may express hormones on immunohistochemical analysis ^[9][10]
• Epidemiology: 50–85% of all PNETs are nonfunctional PNETs (NF-PNETs). ^[9][10]
• Etiology ^[9]
  • 90% of NF-PNETs are sporadic. ^[9]
  • Genetic syndromes
    • Multiple endocrine neoplasia type 1 (MEN 1)
    • von Hippel-Lindau syndrome
    • Tuberous sclerosis complex
  • DNA damage repair gene mutations are present in up to 10% of apparently sporadic cases. ^[9]
• Clinical features ^[9][10][11]
  • Often asymptomatic and discovered incidentally
  • Symptoms, if present, are typically related to tumor mass effect.
    • Abdominal pain
    • Weight loss
    • Jaundice
    • Duodenal obstruction
  • Rarely, tumors may become functional and manifest as hormonal syndromes.
• Diagnosis ^[9]
  • Laboratory studies
    • Specific markers
      • Assess specific markers (e.g., gastrin, insulin, 5-HT, VIP, glucagon, somatostatin) to rule out a functional PNET.
      • Obtain calcium, PTH, prolactin, and IGF-1 levels if MEN 1 syndrome is suspected.
    • Nonspecific markers
      • Serum chromogranin A: for monitoring treatment response and detecting disease progression or recurrence
      • Serum pancreatic polypeptide: a circulating marker, especially in MEN 1 syndrome
  • Imaging: The sequence of imaging should be individualized. ^[9]
    • Modalities include multiphasic contrast-enhanced CT, contrast-enhanced MRI with DWI, MRCP, and endoscopic ultrasound.
    • Whole-body staging for therapy planning (e.g., somatostatin receptor imaging with PET/CT; CECT of chest, abdomen, and pelvis; F-FDG PET/CET)
  • Biopsy and histopathology (confirmatory)
• Differential diagnoses ^[9]
  • Acinic cell carcinoma
  • Solid pseudopapillary neoplasm of the pancreas
  • Pancreatic paraganglioma
  • Ectopic spleen
  • Pancreatic polypeptide islets
  • Metastasis from other neoplasms
• Management: Decisions should be made by a multidisciplinary team. ^[9][10][11]
  • Localized disease: active surveillance or surgical resection based on tumor size and the presence or absence of pancreatic duct dilatation
  • Locally advanced disease: surgical resection; neoadjuvant chemotherapy may be considered.
  • Advanced or metastatic disease: The choice of treatment depends on multiple factors (e.g., tumor burden, growth rate, somatostatin receptor status, symptoms).
• Prognosis: Patients with NF-PNETs have a significantly worse overall survival rate than those with functional tumors. ^[9]

Genetic counseling is indicated for patients with multiple PNETs or those diagnosed at a young age (30–50 years). ^[9]