• Antonio Pea, Jun Yu, Luigi Marchionni, Michael Noe, Claudio Luchini, Alessandra Pulvirenti, Roeland F de Wilde, Lodewijk A Brosens, Neda Rezaee, Ammar Javed, Peter Chianchiano, Stefano Gobbo, Paolo Regi, Roberto Salvia, Claudio Bassi, Jin He, Matthew J Weiss, John L Cameron, OfferhausG Johan AGJADepartment of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands., Ralph H Hruban, Rita T Lawlor, Aldo Scarpa, Christopher M Heaphy, Laura D Wood, and Christopher L Wolfgang.
• Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
• Ann. Surg. 2020 Mar 1; 271 (3): 566-573.

ObjectiveThe aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases.BackgroundWell-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver.MethodsA total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation.ResultsIn the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss.ConclusionsWe identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.

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