The correct answer is the third option. PNETs are capable of producing and secreting various biomarkers. Some of these, such as insulin, are active hormones and produce a specific clinical syndrome (i.e. hypoglycemia). Others are inactive, and more useful in diagnosis and monitoring response to therapy. Chromogranin A is a polypeptide that is present in the secretory granules of PNETs. Therefore, it is useful in the diagnosis of PNETs in general, but is not helpful in differentiating the active PNET subtypes. Although there is no uniform consensus, Chromogranin A is found most useful for monitoring response to therapy or looking for tumor relapse, in a patient with a known PNET and elevated baseline serum level. Chromogranin A serum levels may be high in patients with small tumors (such in Case 1), but there are many common clinical situations that can lead to falsely elevated serum levels (decreased renal function, liver and heart failure, PPI use, chronic gastritis, inflammatory bowel disease, physical exercise and eating). This limits its usefulness as a “screening” test for PNETs. It is plausible that in our patient with a small insulinoma, the mild elevation of chromogranin level was due to PPI use. Qiao et al. found that Chromogranin A is a reliable serum diagnostic biomarker for PNETs but not for insulinomas. Insulin levels are helpful in the diagnosis of insulinoma, as a high insulin level in the setting of hypoglycemia proves the presence of excess insulin (should normally be low in the setting of hypoglycemia due to feedback inhibition). Pro-insulin levels are useful in differentiating endogenous from exogenous insulin sources, as only the pancreas secretes insulin in its prohormone form. Similarly, C-peptide is a marker of pancreas insulin secretion and is not elevated in exogenous insulin use. Testing for sulfonylureas is necessary to exclude oral hypoglycemia agent-induced hypoglycemia.
NOTE: Patients with hereditary syndromes can have a different treatment and surveillance protocol due to multi-focal disease or risk of other tumors. For loco-regionally advanced and/or metastatic PNETs, systemic therapy may be used but this approach is often determined following a multidisciplinary review. Options for systemic therapy includes Somatostatin analogues, Everolimus, Sunitinib, or even cytotoxic Therapies (Temezolomide or Streptozocin/doxorubicin with or without 5-FU). There is no panel consensus on a single specific treatment.