Moser, Elisa; Ura, Ayako; Vogel, Loreen; Steiger, Katja; Mogler, Carolin; Evert, Matthias; Märkl, Bruno; Scheidhauer, Klemens; Martignoni, Marc; Friess, Helmut; von Werder, Alexander; Marinoni, Ilaria; Perren, Aurel; Klöppel, Günter; Kasajima, Atsuko (2024). ARX, PDX1, ISL1 and CDX2 expression distinguishes five subgroups of PanNETs with correlations to histology, hormone expression and outcome. (In Press). Modern pathology, 37(11), p. 100595. Elsevier 10.1016/j.modpat.2024.100595
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Many pancreatic neuroendocrine tumors (PanNETs) fall into two major prognostic subtypes based on DAXX/ATRX induced ALT phenotype and alpha and beta cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well characterized in terms of their histological and hormonal phenotype. We aimed to identify new subgroups of PanNETs by extending the currently used transcription factor signatures and to investigate their correlation with histological, hormonal molecular and prognostic findings. 185 PanNETs (non-functioning 165, functioning 20) resected between 1996 and 2023 were classified into five subgroups (A1, A2, B, C, D) by cluster analysis based on ARX, PDX1, ISL1 and CDX2 expression and correlated with trabecular vs. solid histology, expression of insulin, glucagon, PP, somatostatin, serotonin, gastrin, calcitonin, ACTH, DAXX/ATRX, MEN1 and ALT status by FISH, and disease-free survival (DFS). A1 (46%, ARX+/ISL1+/PDX1-/CDX2-) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2-) showed trabecular histology and glucagon/ PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX-/CDX2-) showed solid histology, insulin and somatostatin expression (p<0.001). It included all insulinomas and had the best outcome (p<0.01). C (15%, ARX-/PDX1-/ISL1-/CDX2-) showed solid histology and frequent expression of serotonin, calcitonin und ACTH. D (5%, PDX1+/CDX2+/ISL1-/ARX-) showed solid histology, expressed ACTH/serotonin and was an independent poor prognosticator (p<0.01). Differential expression of ARX, PDX1, ISL1 and CDX2 stratified PanNETs into five subgroups with different histology, hormone expression and outcome. Subgroups A1 and A2 resembled the alpha cell-like type, subgroup B the beta cell-like type. Subgroup C with almost a no transcription factor signature was unclear in cell lineage, while the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the subgroups may help to establish the diagnosis, predict the outcome, and guide the treatment.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology 04 Faculty of Medicine > Service Sector > Institute of Pathology |
UniBE Contributor: |
Marinoni, Ilaria, Perren, Aurel |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1530-0285 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
16 Aug 2024 11:06 |
Last Modified: |
09 Sep 2024 00:15 |
Publisher DOI: |
10.1016/j.modpat.2024.100595 |
PubMed ID: |
39147030 |
Uncontrolled Keywords: |
PanNETs hormone expression outcome subgroups transcription factors |
BORIS DOI: |
10.48350/199754 |
URI: |
https://boris.unibe.ch/id/eprint/199754 |
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