Malignant insulinoma: Can we predict the long-term outcomes?

Abstract

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.

Keywords: Liver; Malignant insulinoma; Pancreatic neuroendocrine tumor; Resection; Transplantation.

Figure 1

Schematic representation of signaling pathways involved in insulinoma development. Proteins that are mutated are marked in red, downregulated or with a loss of function are marked in yellow, and those with a gain of function or overexpression are highlighted in green. Proteins whose role is ambiguous are colored grey. Genes and proteins that are differentially expressed only in malignant insulinomas are highlighted in glow.

Figure 2

Pathohistological appearance of malignant insulinoma. One of our own cases, G2 pancreatic neuroendocrine tumor, exhibited small nests of uniform cells showing infiltrative growth pattern (hemalaun and eosin, × 400). A; Brown cytoplasmic staining in tumorous cells (synaptophysin, × 100), B; Low Ki-67 proliferation index of up to 7% (Ki-67, ×200).