• Jun Uemura, Keiichi Okano, Minoru Oshima, Hironobu Suto, Yasuhisa Ando, Kensuke Kumamoto, Kyuichi Kadota, Shuji Ichihara, Yasutaka Kokudo, Takashi Maeba, Yoshihide Nanno, Hirochika Toyama, Yasutsugu Takada, Mitsuo Shimada, Kazuhiro Hanazaki, Tsutomu Masaki, and Yasuyuki Suzuki.
• Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
• Ann. Surg. 2021 Dec 1; 274 (6): e949-e956.

ObjectiveThe goal of this retrospective study was to clarify the clinical implications of immunohistochemically detected protein expression for genes that are frequently mutated in pancreatic neuroendocrine tumors (PNETs).BackgroundThe clinical management of PNETs is hindered by their heterogenous biological behavior. Whole-exome sequencing recently showed that 5 genes (DAXX/ATRX, MEN1, TSC2, and PTEN) are frequently mutated in PNETs. However, the clinical implications of the associated alterations in protein expression remain unclear.MethodsWe collected Grade 1 and 2 (World Health Organization 2017 Classification) primary PNETs samples from 100 patients who underwent surgical resection. ATRX, DAXX, MEN1, TSC2, and PTEN expression were determined immunohistochemically to clarify their relationships with prognosis and clinicopathological findings.ResultsKaplan-Meier analysis indicated that loss of TSC2 (n = 58) or PTEN (n = 37) was associated with significantly shorter overall survival, and that loss of TSC2 or ATRX (n = 41) was associated with significantly shorter recurrence-free survival. Additionally, loss of ATRX or TSC2 was significantly associated with nodal metastasis. In a multivariate analysis, combined loss of TSC2 and ATRX (n = 31) was an independent prognostic factor for shorter recurrence-free survival (hazard ratio 10.1, 95% confidence interval 2.1-66.9, P = 0.003) in G2 PNETs.ConclusionsLoss of ATRX, TSC2, and PTEN expression might be useful as a method of clarifying the behavior and clinical outcomes of Grade 1 and 2 PNETs in routine clinical practice. Combined loss of TSC2 and ATRX had an especially strong, independent association with shorter recurrence-free survival in patients with G2 PNETs. Loss of pairs in ATRX, TSC2, or PTEN would be useful for selecting the candidate for postoperative adjuvant therapy.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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