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.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).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%).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.
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 Hogg, Kenneth 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