Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size

Wenzel M. Hackeng, Lodewijk A.A. Brosens, Joo Young Kim, Roderick O'Sullivan, You Na Sung, Ta Chiang Liu, Dengfeng Cao, Michelle Heayn, Jacqueline Brosnan-Cashman, Soyeon An, Folkert H.M. Morsink, Charlotte M. Heidsma, Gerlof D. Valk, Menno R. Vriens, Els Nieveen Van Dijkum, G. Johan A. Offerhaus, Koen M.A. Dreijerink, Herbert Zeh, Amer H. Zureikat, Melissa HoggKenneth Lee, David Geller, J. Wallis Marsh, Alessandro Paniccia, Melanie Ongchin, James F. Pingpank, Nathan Bahary, Muaz Aijazi, Randall Brand, Jennifer Chennat, Rohit Das, Kenneth E. Fasanella, Asif Khalid, Kevin McGrath, Savreet Sarkaria, Harkirat Singh, Adam Slivka, Michael Nalesnik, Xiaoli Han, Marina N. Nikiforova, Rita Teresa Lawlor, Andrea Mafficini, Boris Rusev, Vincenzo Corbo, Claudio Luchini, Samantha Bersani, Antonio Pea, Sara Cingarlini, Luca Landoni, Roberto Salvia, Massimo Milione, Michele Milella, Aldo Scarpa, Seung Mo Hong, Christopher M. Heaphy, Aatur D. Singhi

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Objective: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. Design: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). Results: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). Conclusions: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

Original languageEnglish (US)
StateAccepted/In press - 2021


  • neuroendocrine tumors
  • pancreatic endocrine tumour
  • pancreatic islet cell
  • pancreatic pathology
  • pancreatic surgery

ASJC Scopus subject areas

  • Gastroenterology


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