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Open Access 01-06-2020 | Fluorescence in Situ Hybridization

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas

Authors: Wenzel M. Hackeng, Willemien Schelhaas, Folkert H. M. Morsink, Charlotte M. Heidsma, Susanne van Eeden, Gerlof D. Valk, Menno R. Vriens, Christopher M. Heaphy, Els J. M. Nieveen van Dijkum, G. Johan A. Offerhaus, Koen M. A. Dreijerink, Lodewijk A. A. Brosens

Published in: Endocrine Pathology | Issue 2/2020

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.

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Title: Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas
Authors: Wenzel M. Hackeng
Willemien Schelhaas
Folkert H. M. Morsink
Charlotte M. Heidsma
Susanne van Eeden
Gerlof D. Valk
Menno R. Vriens
Christopher M. Heaphy
Els J. M. Nieveen van Dijkum
G. Johan A. Offerhaus
Koen M. A. Dreijerink
Lodewijk A. A. Brosens
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Fluorescence in Situ Hybridization
Metastasis
Insulinoma
Insulinoma
Neuroendocrine Tumor
Published in: Endocrine Pathology / Issue 2/2020
Print ISSN: 1046-3976
Electronic ISSN: 1559-0097
DOI: https://doi.org/10.1007/s12022-020-09611-8

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Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas

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