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Review
. 2024 Nov;45(Suppl 1):74-82.
doi: 10.1007/s00292-024-01393-8. Epub 2024 Nov 18.

Diagnostic and prognostic biomarkers for pancreatic neuroendocrine neoplasms

Andreas F-P Sonnen  1 , Anna Vera D Verschuur  1 , Lodewijk A A Brosens  2
Affiliations
Review

Diagnostic and prognostic biomarkers for pancreatic neuroendocrine neoplasms

Andreas F-P Sonnen et al. Pathologie (Heidelb). 2024 Nov.

Abstract
in English, German

This review examines the diagnostic and prognostic biomarkers for pancreatic neuroendocrine neoplasms (PanNENs), a heterogeneous group of tumors with expression of neuroendocrine markers. PanNENs include both well-differentiated pancreatic neuroendocrine tumors (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). The diagnosis is confirmed through markers such as chromogranin A, synaptophysin, and INSM1, which establish neuroendocrine differentiation. The World Health Organization classification categorizes PanNENs based on tumor differentiation and proliferative activity (Ki-67 and/or mitotic index) into well-differentiated PanNETs (grade 1 to grade 3) and poorly differentiated PanNECs. In most cases, the morphology and proliferation index are sufficient to distinguish PanNETs from PanNECs. However, distinguishing grade 3 PanNETs from PanNECs can be challenging on the basis of morphology and proliferative activity alone. Additional key diagnostic markers for distinguishing grade 3 PanNET from PanNEC include SSTR2A expression and molecular immunohistochemical markers such as p53, Rb1, menin, ATRX, and DAXX. PanNECs are by definition high-grade tumors with highly aggressive clinical behavior, while PanNETs have a variable prognosis that is difficult to predict using current biomarkers such as tumor grade and size. Several studies have shown that ATRX or DAXX loss is strongly associated with a higher risk of PanNET metastasis and recurrence. They are therefore key prognostic markers in PanNETs. In addition, chromosomal copy number variations can further help assess PanNET aggressiveness and prognosis. Molecular profiling is increasingly important for improving the diagnosis, treatment, and prognosis of PanNENs.

In diesem Review werden die diagnostischen und prognostischen Biomarker für pankreatische neuroendokrine Neoplasien (PanNEN) skizziert, eine heterogene Gruppe von Tumoren mit Expression neuroendokriner Marker. PanNEN umfassen sowohl gut differenzierte pankreatische neuroendokrine Tumoren (PanNET) als auch schlecht differenzierte pankreatische neuroendokrine Karzinome (PanNEC). Die Diagnose wird durch Marker wie Chromogranin A, Synaptophysin und INSM1 unterstützt, mit welchen sich die neuroendokrine Differenzierung nachweisen lässt. In der Klassifikation gemäß Weltgesundheitsorganisation (WHO) werden PanNEN auf Basis der Tumordifferenzierung und der proliferativen Aktivität (Ki-67 und/oder Mitoseindex) in gut differenzierte PanNET (Grad 1 bis Grad 3) und schlecht differenzierte PanNEC unterteilt. In den meisten Fällen reichen Morphologie und Proliferationsindex aus, um PanNET von PanNEC zu unterscheiden. Allerdings können PanNET Grad 3 und PanNEC allein auf Basis der Morphologie und Proliferationsaktivität schwer zu differenzieren sein. Wichtige zusätzliche Marker zur Unterscheidung von PanNET G3 und PanNEC umfassen die Expression von SSTR2A und molekulare immunhistochemische Marker wie p53, Rb1, Menin, ATRX und DAXX. PanNEC sind per Definition hochgradige Tumoren mit sehr aggressiven klinischen Verläufen. Im Gegensatz dazu ist die Prognose von PanNET sehr variabel und mit den derzeit verwendeten Biomarkern wie Tumorgrad und -größe schwer vorherzusagen. Mehrere Studien haben gezeigt, dass der Verlust von ATRX und DAXX stark mit einem höheren Risiko für Metastasen und Rezidive verbunden ist. Sie sind daher wichtige prognostische Marker bei PanNET. Darüber hinaus können chromosomale Kopienzahlvariationen dazu beitragen, die Aggressivität und Prognose von PanNET besser einzuschätzen. Molekulare Profile gewinnen zunehmend an Bedeutung zur Verbesserung von Diagnose, Behandlung und Prognose von PanNEN.

Keywords: Biomarker; Diagnosis; Pancreatic neuroendocrine carcinoma; Pancreatic neuroendocrine tumor; Prognosis.

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Conflict of interest statement

Declarations. Conflict of interest: A.F.-P. Sonnen, A.V.D. Verschuur and L.A.A. Brosens declare that they have no competing interests. For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case. The supplement containing this article is not sponsored by industry.

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