Immunophenotypic and molecular characterization of pancreatic neuroendocrine tumors producing serotonin.

Depoilly, Thomas; Leroux, Raffaele; Andrade, Dafne; Nicolle, Remy; Dioguardi Burgio, Marco; Marinoni, Ilaria; Dokmak, Safi; Ruszniewski, Philippe; Hentic, Olivia; Paradis, Valérie; De Mestier, Louis; Perren, Aurel; Couvelard, Anne; Cros, Jérôme (2022). Immunophenotypic and molecular characterization of pancreatic neuroendocrine tumors producing serotonin. Modern pathology, 35(11), pp. 1713-1722. Springer Nature 10.1038/s41379-022-01110-x

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Serotonin producing pancreatic neuroendocrine tumors (SP-PanNET) account for 0.58-1.4% of all pancreatic neuroendocrine tumors (PanNET). They may present with atypical symptoms, such as acute pancreatitis and are often radiologically characterized by main pancreatic duct dilatation. SP-PanNET are well differentiated neuroendocrine tumors (NET) distinct from classical PanNET by atypical serotonin secretion and abundant dense stroma deposition, like serotonin producing ileal NET leading in some cases to difficulties to reliably distinguish SP-PanNET from ileal NET metastases. The biology and molecular profile of SP-PanNET remain poorly characterized and the cell of origin within the pancreas is unclear. To address these questions, we analyzed a large cohort of SP-PanNET by immunohistochemistry (n = 29; ATRX, DAXX, MENIN, Islet1, PAX6, PDX1, ARX, CDX2), whole genome copy number array (Oncoscan™) and a large NGS panel (NovoPM™) (n = 10), FISH (n = 13) and RNA sequencing (n = 24) together with 21 ileal NET and 29 nonfunctioning PanNET (NF-PanNET). These analyses revealed a unique genomic profile with frequent isolated loss of chromosome 1 (14 cases-61%) and few pathogenic mutations (KMT2C in 2 cases, ARID1A in 1 case). Unsupervised RNAseq-based clustering showed that SP-PanNET were closer to NF-PanNET than ileal NET with an exclusive beta cell-like signature. SP-PanNET showed TGF-β pathway activation signatures associated with extracellular matrix remodeling and similar signature were reproduced in vitro when pancreatic stellate cells were exposed to serotonin. SP-PanNET immunohistochemical profile resemble that of ileal NET except for PDX1 and PAX6 expression to a lesser extend suggesting that these two markers may be useful to diagnose SP-PanNET. Taken together, this suggests that SP-PanNET are a very specific PanNET entity with a peculiar biology leading to the characteristic fibrotic aspect.

Item Type:

Journal Article (Original Article)

Division/Institute:

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:

Springer Nature

Language:

English

Submitter:

Pubmed Import

Date Deposited:

27 Jun 2022 08:04

Last Modified:

05 Dec 2022 16:21

Publisher DOI:

10.1038/s41379-022-01110-x

PubMed ID:

35739266

BORIS DOI:

10.48350/170925

URI:

https://boris.unibe.ch/id/eprint/170925

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