Published online Jun 6, 2022. doi: 10.12998/wjcc.v10.i16.5124
Peer-review started: November 13, 2021
First decision: January 9, 2022
Revised: January 17, 2022
Accepted: April 21, 2022
Article in press: April 21, 2022
Published online: June 6, 2022
Processing time: 200 Days and 12.6 Hours
Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and well-defined diagnostic criteria; however, prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge. The comparative studies between benign and malignant cases are limited, suggesting that short clinical history, early hypoglycemia during fasting, high proinsulin, insulin, and C-peptide concentrations raise suspicion of malignancy. Indeed, malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity, but there are no accurate histological criteria to distinguish benign from malignant forms. Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas; however, our knowledge is limited, urging a further understanding of molecular genetics. Therefore, there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma. This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.
Core Tip: Insulinomas are rare but potentially malignant tumors. The only sure sign of malignancy is metastases present at diagnosis. Long-term survival of patients with malignant insulinoma is poor; however, newly available agents and approaches, are reassuring. Nonetheless, it is important to distinguish between benign and malignant insulinomas early, as well as follow the non-functioning pancreatic neuroendocrine tumors and plan the appropriate treatment and follow-up. Important initial parameters include 2-3-fold higher insulin, proinsulin, and C-peptide levels, early-onset hypoglycemia during the 72-h fasting test, and high chromogranin A from the biochemical aspect, earlier recognition of neuroglycopenic symptoms from the clinical aspect, and tumor size exceeding 3 cm and higher tumor grade (G2 or G3) from the pathohistological standpoint. Molecular genetic advances are still insufficient in adding to the individualization of treatment and prognosis, but α-internexin and chromosomal instability, where available, might add to early recognition of malignancy.