Abstract
Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.
Highlights
Insulinomas are the most common functional pancreatic neuroendocrine tumor (PanNET) type and are diagnosed by the triad of hypoglycemic symptoms, low blood glucose concentrations, and relief of symptoms after glucose administration
The metastatic primary insulinomas were larger than the indolent primary insulinomas, but this did not reach statistical significance
None of the insulinomas in these studies metastasized, but remarkably, the ARXexpressing case in the study of Chan et al was ATRX mutated and very large (8 cm), while all the negative cases were small (< 2cm) and ATRX, DAXX, MEN1 wild type [20]. These results are in line with our observation that there is an association between size, alternative lengthening of telomeres (ALT), and ARX expression in insulinomas
Summary
Insulinomas are the most common functional pancreatic neuroendocrine tumor (PanNET) type and are diagnosed by the triad of hypoglycemic symptoms, low blood glucose concentrations, and relief of symptoms after glucose administration. Most insulinomas are indolent tumors: there are few mitoses (low grade) and metastases are very rare [1, 2]. 40–50% of non-functional PanNETs present with liver metastases at time of initial diagnosis [3, 4]. There are no insulinoma-specific international recommendations for follow-up after surgery [5, 7]. About 10% of insulinoma patients develop metastases that are mostly present at time of initial diagnosis, but may sometimes develop years after resection of the primary tumor [8]. Median survival is less than 2 years in patients with
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