Non-functional pancreatic neuroendocrine neoplasms do not produce active hormones, and are not associated with specific clinical syndromes. They may secrete inactive amine and peptide products, such as neurotensin, neuron-specific enolase, pancreatic polypeptide, and chromogranin A. Most lesions are well-differentiated (G1/G2 according to the 2010 World Health Organization classification), slow-growing, and present at later clinical stages with symptoms attributable to mass effect, such as compression or infiltration of nearby organs. Quite a high proportion of patients (between 35-70%) will have metastases at the time of diagnosis, possibly to the liver. As tumour cells can spread via the bloodstream and lymphatic system, there can be metastases to other areas of the body such as lymph nodes and bones. 

These neoplasms are usually diagnosed at the ages of 40-60 years, and are generally larger than their functional counterpart. However, because of the widespread availability of cross-sectional imaging (CT-scan, magnetic resonance imaging), small and asymptomatic non-functional pancreatic neuroendocrine neoplasms are being identified more frequently during examinations performed for other reasons. Between 20-40% of these neoplasms are associated with MEN1.

The most common symptoms at presentation of non-functional pancreatic neuroendocrine neoplasms are: 

• Abdominal pain
• Weight loss
• Anorexia and nausea
• Gastrointestinal bleeding
• Jaundice
• Palpable mass

If a non-functional pancreatic neuroendocrine neoplasm is suspected on the basis of cross-sectional imaging, blood can be tested for certain tumour markers, particularly chromogranin A. This peptide is expressed by nearly all neuroendocrine neoplasms, with serum levels being associated with tumor burden. It should be kept in mind that chromogranin A levels are affected by proton pump inhibitors, a family of drugs commonly used to treat gastritis or gastro-esophageal reflux (e.g. omeprazole, pantoprazole). Furthermore, the trend of chromogranin A levels over a period of time is a useful to evaluate the response to therapies. Other blood tests may look at pancreatic polypeptide or neuron-specific enolase.

As seen in previous sections, clinical and radiologic staging will determine the appropriate management, which differs according to whether the disease is localized, locally advanced or metastatic. Pancreatic neuroendocrine neoplasms are particularly challenging to treat, and patients should be better referred to a multidisciplinary team with a broad experience in the field.