Glucagon-Producing Pancreatic Neuroendocrine Tumors (Glucagonomas) are Enriched in Aggressive Neoplasms with ARX and PDX1 Co-expression, DAXX/ATRX Mutations, and ALT (Alternative Lengthening of Telomeres).
ALT
ATRX
DAXX
Functioning
Glucagon
MUTYH
NET
Neuroendocrine
Journal
Endocrine pathology
ISSN: 1559-0097
Titre abrégé: Endocr Pathol
Pays: United States
ID NLM: 9009288
Informations de publication
Date de publication:
27 Sep 2024
27 Sep 2024
Historique:
accepted:
10
09
2024
medline:
27
9
2024
pubmed:
27
9
2024
entrez:
27
9
2024
Statut:
aheadofprint
Résumé
Glucagonomas are functioning pancreatic neuroendocrine tumors (PanNETs) responsible for glucagonoma syndrome. This study aims to shed light on the clinicopathological and molecular features of these neoplasms. Six patients with glucagonomas were identified. All neoplasms were investigated with immunohistochemistry for neuroendocrine markers (Synaptophysin, Chromogranin-A), ATRX, DAXX, ARX, and PDX1 transcription factors. Fluorescent in situ hybridization (FISH) for assessing alternative lengthening of telomeres (ALT), and next-generation sequencing (NGS) for molecular profiling were performed. All cases were large single masses (mean size of 8.2 cm), with necrolytic migratory erythema as the most common symptom (6/6 cases, 100%). All neoplasms were well-differentiated G1 tumors, except one case that was G2. The tumors consistently showed classic/conventional histomorphology, with solid-trabecular and nested architecture. Lymphatic and vascular invasion (6/6, 100%), perineural infiltration (4/6, 66.6%), and nodal metastasis (4/6, 66.6%) were frequently observed. Transcription factors expression showed strong ARX expression in all tumors, and PDX1 expression in 5/6 cases (83.3%), indicating co-occurring alpha- and beta-cell differentiation. NGS showed recurrent somatic MEN1 and ATRX/DAXX biallelic inactivation. Cases with ATRX or DAXX mutations also showed matched loss of ATRX or DAXX protein expression and ALT. One case harbored somatic MUTYH inactivation and showed a high tumor mutational burden (TMB, 41.0 mut/Mb). During follow-up, one patient died of the disease, and four patients developed distant metastasis. Pancreatic glucagonomas are distinct PanNETs with specific clinicopathological and molecular features, including histological aspects of biological aggressiveness, co-occurring alpha- and beta-cell differentiation, MEN1 and DAXX/ATRX mutations enrichment, and the possible presence of high-TMB as an actionable marker.
Identifiants
pubmed: 39331358
doi: 10.1007/s12022-024-09826-z
pii: 10.1007/s12022-024-09826-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : 26343, 28054, 29829
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : 26343, 28054, 29829
Organisme : KWF Kankerbestrijding
ID : 2020-1 12978
Organisme : KWF Kankerbestrijding
ID : 2020-1 12978
Organisme : Fondazione Italiana per la ricerca sulle Malattie del Pancreas
ID : J38D19000690001
Organisme : Fondazione Italiana per la ricerca sulle Malattie del Pancreas
ID : J38D19000690001
Organisme : Ministero della Salute
ID : (RF CO-2019-12369662: CUP: B39C21000370001
Informations de copyright
© 2024. The Author(s).
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