• Atsushi Kudo, Keiichi Akahoshi, Sakiko Ito, Takumi Akashi, Shu Shimada, Toshiro Ogura, Kosuke Ogawa, Hiroaki Ono, Yusuke Mitsunori, Daisuke Ban, Ukihide Tateishi, Shinji Tanaka, and Minoru Tanabe.
• Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
• Ann. Surg. 2020 Apr 1; 271 (4): 732-739.

ObjectiveTo predict metachronous liver metastasis after pancreatectomy for pancreatic neuroendocrine neoplasms (Pan-NENs).Summary Of Background DataLiver metastasis determines the prognosis of patients with Pan-NENs, but no index exists in the WHO 2017 classification for this prediction.MethodsBetween April 2014 and March 2018, resected primary tumors from 20 patients with or without simultaneous liver metastasis were examined using genome-wide gene expression analysis. For validation analysis, resected primary tumors from 62 patients without simultaneous liver metastasis were examined for PAX6 expression.ResultsGene expression profiling revealed pancreatic beta cell genes (NES, -2.0; P < 0.001) as the most downregulated set in patients with simultaneous liver metastasis. In the test study, PAX6 was the most valuable index for liver metastasis (log FC, -3.683; P = 0.0096). Multivariate analysis identified PAX6 expression (hazard ratio, 0.2; P = 0.03) as an independent risk factor for metachronous liver metastasis-free survival (mLM-FS). The 5-year mLM-FS of patients with high versus low PAX6 expression was significantly better (95% vs 66%, respectively; P < 0.0001). The 5-year overall survival rate of was also better than in those with high versus low PAX6 expression (100% vs 87%, respectively). Patients with low PAX 6 expression were significantly younger and leaner, had a higher Ki-67 index (P = 0.01, 0.007, 0.008, respectively), and showed a higher mitotic rate than patients with high PAX6 expression.ConclusionsDownregulated pancreatic beta cell genes involving PAX6 in primary tumors may predict mLM and poor overall survival after primary tumor resection in Pan-NEN patients.

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