Hormones Secreted by Pancreatic Neuroendocrine Tumors
Pancreatic NETs secrete insulin (most common, 70% of functioning tumors), gastrin, glucagon, somatostatin, vasoactive intestinal peptide (VIP), pancreatic polypeptide, and rarely cholecystokinin, with 40-91% being nonfunctional tumors that produce no clinically evident hormonal syndrome. 1
Common Functioning Tumors and Their Hormones
Insulinomas (70% of functioning PNETs)
- Secrete insulin, causing fasting or nocturnal hypoglycemia 1
- Approximately 90% are benign 1
- Insulin levels are often within normal range but inappropriate to blood glucose; measure C-peptide or pro-insulin for confirmation 1
- Chromogranin A is typically NOT elevated unless metastatic 1
Gastrinomas (part of the 10% with gastrin/somatostatin)
- Secrete gastrin, causing Zollinger-Ellison syndrome with recurrent peptic ulcers and diarrhea 1
- 80-90% have high risk for metastases 1
- Most common PNET in MEN1 patients (along with insulinoma) 1
- Fasting serum gastrin >10 times elevated with gastric pH <2 is diagnostic 1
Glucagonomas (approximately 15% of functioning PNETs)
- Secrete glucagon, causing diabetes mellitus and/or migratory necrolytic erythema 1
- Associated with higher tumor grade and worse prognosis 1
VIPomas (rare)
- Secrete vasoactive intestinal polypeptide (VIP), causing watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) 1
- Presents with severe secretory diarrhea 1
Somatostatinomas (part of the 10% with gastrin/somatostatin)
- Secrete somatostatin, causing diabetes mellitus and/or diarrhea/steatorrhea 1
- 80-90% have high risk for metastases 1
- May also present with gallstones 1
Rare Functioning Tumors
- PPomas: Secrete pancreatic polypeptide (PP) 1
- Cholecystokininomas (CCKomas): Recently described, secrete cholecystokinin 1
- ACTH-secreting tumors: Cause Cushing syndrome and indicate poor prognosis 1
- Growth hormone-releasing hormone (GHRH): Causes acromegaly 1
- Calcitonin-secreting tumors: May present as nonfunctioning 1
Nonfunctioning Tumors (40-91% of PNETs)
- Do not produce clinically evident hormonal syndromes 1
- Often secrete pancreatic polypeptide (PP), which can serve as a tumor marker 1
- Chromogranin A elevated in 60% or more of cases 1
- May also produce calcitonin, PTHrP, or growth hormone-releasing hormone without clinical symptoms 1
Critical Clinical Pitfalls
Multiple Hormone Expression
- 30% of PNETs express multiple hormones simultaneously, even when only one causes clinical symptoms 2, 3
- Hormonal expression patterns differ between primary tumors and metastatic sites in 50-89% of cases 3
- Some metastatic lesions show positive hormonal expression when primary tumors were negative 3
Metachronous Hormonal Syndromes
- 3.4% of patients develop new hormonal syndromes after initial diagnosis (median 55 months later) 4
- Most commonly occurs with tumor progression and increased Ki-67 index 4
- Insulin-related metachronous syndromes associated with decreased survival 4
- The original hormone may still be detectable on retrospective immunostaining before clinical syndrome develops 4
Chromogranin A Interpretation
- Elevated in 60% of functioning and nonfunctioning PNETs 1, 5
- Spuriously elevated by proton pump inhibitors, renal failure, liver failure, hypertension, and chronic gastritis 1, 6, 5
- Stop PPIs for at least 1-2 weeks before measuring 1, 6, 5
- Levels >2× normal associated with shorter survival (HR 2.8) 1
Biochemical Testing Algorithm
For suspected functioning PNET:
- Measure specific hormone based on clinical syndrome (insulin with hypoglycemia, gastrin with ulcers, glucagon with rash/diabetes, VIP with watery diarrhea) 1
- Stop PPIs for 1-2 weeks before gastrin or chromogranin A measurement 1, 6
- Obtain fasting specimens for insulin, gastrin, and PP (remain elevated >6 hours postprandially) 1
For nonfunctioning PNET: