Little is known about pancreatic polypeptide and disease. Published reports of pancreatic polypeptide cell hyperplasia (PPCH) will be reviewed and compared with the present case.

Histological examination showed diffuse islet cell hyperplasia and ductulo‐insular complex (DIC) formation (ie, endocrine cells budding from duct epithelium). The islets were increased in number and size, with irregular outlines, replacing parts of the otherwise normal acinar lobules. They showed an abnormal trabecular and pseudoglandular architecture (fig 1​1).). Synaptophysin immunostaining confirmed these findings (fig 2​2).). Whereas most islets, irregular endocrine cell clusters and DICs harboured α, β, δ and pancreatic polypeptide cells, the quantitative and spatial relationship of these cell populations was disrupted in some of the enlarged islets and cell clusters (so‐called islet cell dysplasia). Immunostaining for pancreatic polypeptide showed that between 10% and >50% of all endocrine cells, both in the enlarged islets and DICs, produced pancreatic polypeptide (​(figsfigs 3, 4​4),), a finding that is markedly higher than even that in the pancreatic polypeptide cell‐rich ventral portion of the normal pancreas (<10%). The normal spatial distribution of islet cells was lost as pancreatic polypeptide cells occupied both a central and a peripheral position in the enlarged islets (fig 5​5).). Mitotic figures were not identified, and Ki‐67 immunostaining showed few positive nuclei (<1%) in the endocrine compartment.

A few of the endocrine cell clusters were distinct from the others by their larger size (<0.8 mm), smooth contour, sharp delineation from adjoining parenchyma and monohormonal secretion of pancreatic polypeptide (fig 6​6),), findings that meet the diagnostic criteria of endocrine microadenomas. The endocrine cell population comprised in a focus of ectopic pancreatic tissue in the ampulla and surrounding duodenal wall, showed changes similar to those in the pancreatic head.

These findings were reported as PPCH, with the possible presence of pancreatic polypeptide cell microadenomas. Unfortunately, preoperative serum levels of pancreatic polypeptide were not measured.

The condition described as PPCH is surrounded by confusion due to inconsistencies in histological criteria and terminology. This may be related to the heterogeneous distribution of pancreatic polypeptide cells throughout the pancreas and the ensuing sampling problems. Pancreatic polypeptide cells are mostly confined to the pancreatic region of ventral embryological origin,¹ whereas islets of the tail, body and other parts of the pancreatic head contain only a small number of these cells. Within the islets, pancreatic polypeptide cells often take up a peripheral position, mixed with α and δ cells.

In this case, pancreatic histology was characterised by marked expansion of the endocrine compartment in the form of irregularly enlarged islets or ragged cell clusters and foci of DICs. The normal spatial and quantitative relationship between the four islet cell populations was disrupted (so‐called islet cell dysplasia) and characterised by a marked increase in pancreatic polypeptide cells. Interestingly, similar pancreatic polypeptide cell changes were present in a small focus of ectopic pancreatic tissue in the periampullary duodenal wall, suggesting that the process may be diffuse, affecting the entire pancreas.

The clinical presentation of pancreatic polypeptide hypersecretion is usually silent. In this case it could be speculated that intestinal (pseudo‐) obstruction was effected by the inhibitory action of pancreatic polypeptide on the upper gastrointestinal tract. Of the seven published cases of PPCH (table 1​1),^4,5,6,7 three were associated with and assumed to be the cause of watery diarrhoea syndrome (Verner–Morrison syndrome).^4,5,6 This assumption was not supported by other observations, as highly increased pancreatic polypeptide levels were found in the plasma without concomitant diarrhoea or achlorhydria. PPCH has also been reported in three patients with sporadic pancreatic or duodenal gastrinoma.⁷ In one of these patients, PPCH was seen 15 years after normalisation of gastrin levels by removal of a pancreatic gastrinoma, a finding arguing against a trophic role for hypergastrinaemia in the development of PPCH. Initial studies reported diffuse pancreatic polypeptide cell changes in the context of MEN I syndrome; however, subsequent large MEN I series identified microadenomatosis (ie, multiple well‐circumscribed monohormonal tumours) as the most distinctive feature, while PPCH did not belong to the spectrum of lesions.⁸ Hence, the association of PPCH seems to be limited to sporadic gastrinoma (and possibly other sporadic PETs), whereby the relationship between the two lesions remains unclear.

The morphological changes associated with the pancreatic polypeptide cell population in our case are remarkably similar to those of β cells in persistent hyperinsulinaemic hypoglycaemia, a rare condition in neonates and also in adults.⁹ Interestingly, similar histological changes affecting the α cells have recently been described,¹⁰ indicating that functional and morphological abnormalities may affect all three cell types. With the genetic defects underlying persistent hyperinsulinaemic hypoglycaemia being identified,¹¹ abnormalities of genes controlling pancreatic polypeptide release could in a parallel way lead to similar histological changes. Although diffuse hyperplasia characterises the adaptive process of the affected β, α or pancreatic polypeptide cell population, the presence of a few microadenomas in this case suggests that neoplastic transformation may occur if the underlying cause is longstanding and unabated. As the prognosis of PPCH is unknown, long‐term follow‐up is recommended.