Pancreatic Polypeptide (PP) is a 36 amino acid linear oligopeptide, primary secreted by pancreatic islets of Langerhans cells.^3-6 Its specific role is not well clarified,⁷ but it is thought to regulate pancreatic and gastrointestinal secretions⁸ and hepatic glycogen levels.⁹ PP is generally considered a neuroendocrine differentiation marker with good specificity but low and variable sensitivity.^1,2,10 PP can be over-secreted by foregut neuroectodermal tumors as well as other tumors.^11,12 Measurement of PP has been recommended for the diagnosis of pancreatic neuroendocrine tumors (pNETs)¹³ and non-functioning pNETs.¹⁴ A 2012 Endocrine Society clinical practice guideline for multiple endocrine neoplasia type 1 (MEN1) recommended annual screening for emergence of pNETs by measuring levels of several serum tests in a gastrointestinal profile consisting of PP along with chromogranin A (CGA), and vasoactive intestinal polypeptide.¹⁵ However, two subsequent retrospectives found that, singly or in combination, these tests were not effective in early diagnosis of tumors.^16-18 The poor performance of these markers in screening for MEN1 was thought to likely be due to the low amounts of these peptides secreted by small tumors.¹⁸

While PP has been found to be elevated in the majority of patients with metastatic disease,¹⁹ less than half of patients with pNET present with elevated serum PP.²⁰ Detection of high levels of circulating PP, together with CGA is suggestive for pNETs.^3,10 Production of PP and/or CGA is observed in 100% of spontaneous and hereditary gastrinomas.²¹ A decline of PP level during patient monitoring is considered a good prognostic marker.²⁰