Search for new immunohistochemical and circulating markers of insulinoma

BACKGROUND: Insulinoma is a neuroendocrine tumor, the main manifestation of which is hypoglycemia. However, the symptoms of hypoglycemia can be non-specific for a long time, especially outside provocative conditions, and quite often the tumor manifests from a life-threatening condition — hypoglycemic coma. In this regard, timely laboratory diagnosis of insulinoma and determination of its aggressive course is one of the priorities in modern researches.
AIM: Search for new immunohistochemical (IHC) and circulating markers (CM) of insulinoma, including its aggressive course.
MATERIALS AND METHODS: The patients examined at the Endocrinology Research Centre in the period 2017–2022 and operated on for an insulin-producing tumor were included. Before surgery and 2–12 months after it, blood sampling was performed with the determination of targeted marker proteins. Some patients underwent an extended IHC examination of the tumor, surrounding tissue and islets of Langerhans with primary antibodies to target marker proteins with an assessment of the degree of their expression. To determine the aggressive course of the tumor, the degree of malignancy (Grade), the number of tumors and signs of recurrence were characterized.
RESULTS: Based on the analysis of literature and pathogenetic characteristics of insulinoma, the following candidates for targeted marker proteins were selected: cocaine and amphetamine-regulated transcript (CART), chromogranin B (CrB), neuroendocrine secretory protein 55 (NESP55), glucagon-like peptide 1 (GLP1), arylalkylamine-N-acetyltransferase (AA-NAT), melatonin, and, exclusively for IHC research, protein D52 (TPD52), as well as receptors for glucagon-like peptide-1 (rGLP1) and melatonin (MTNR1b). 41 patients were included in the study, of which 10 patients underwent an extended IHC study. In patients with both aggressive and non-aggressive insulinoma after surgical treatment, CM levels did not change significantly and in individual patients they could both increase and decrease, including those patients with the expression of the corresponding marker in tumor tissue. It was shown that CART was expressed only in the tumor (in 4/10 of cases), while MTNR1b and rGLP1 were expressed in the tumor (in 6/10 and 10/10, respectively) and the islets of Langerhans (in 5/9 and 9/9, respectively). The association of marker expression with the aggressiveness of the course of insulinoma has not been revealed.
CONCLUSION. The markers CART, MTNR1b and rGLP1 are of primary interest for further study in a larger sample of patients with insulinoma. Other markers (TPD52, XgB, NESP55, melatonin, AA-NAT) have not been shown to be associated with an insulin-producing tumor, therefore they are not promising for future researches. At the same time, it is necessary to continue research aimed at finding new both circulating and IHC markers in order to early diagnose the manifestation of the disease and its recurrence, and more accurately determine the malignant and proliferative potential of the tumor.

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