Preventive medicine of von Hippel–Lindau disease-associated pancreatic neuroendocrine tumors
Authors: Krauss Tobias , Ferrara Alfonso Massimiliano , Links Thera P , Wellner Ulrich , Bancos Irina , Kvachenyuk Andrey , Villar Gómez de las Heras Karina , Yukina Marina Y , Petrov Roman , Bullivant Garrett , von Duecker Laura , Jadhav Swati , Ploeckinger Ursula , Welin Staffan , Schalin-Jäntti Camilla , Gimm Oliver , Pfeifer Marija , Ngeow Joanne , Hasse-Lazar Kornelia , Sansó Gabriela , Qi Xiaoping , Ugurlu M Umit , Diaz Rene E , Wohllk Nelson , Peczkowska Mariola , Aberle Jens , Lourenço Delmar M , Pereira Maria A A , Fragoso Maria C B V , Hoff Ana O , Almeida Madson Q , Violante Alice H D , Quidute Ana R P , Zhang Zhewei , Recasens Mònica , Díaz Luis Robles , Kunavisarut Tada , Wannachalee Taweesak , Sirinvaravong Sirinart , Jonasch Eric , Grozinsky-Glasberg Simona , Fraenkel Merav , Beltsevich Dmitry , Egorov Viacheslav I , Bausch Dirk , Schott Matthias , Tiling Nikolaus , Pennelli Gianmaria , Zschiedrich Stefan , Därr Roland , Ruf Juri , Denecke Timm , Link Karl-Heinrich , Zovato Stefania , von Dobschuetz Ernst , Yaremchuk Svetlana , Amthauer Holger , Makay Özer , Patocs Attila , Walz Martin K , Huber Tobias B , Seufert Jochen , Hellman Per , Kim Raymond H , Kuchinskaya Ekaterina , Schiavi Francesca , Malinoc Angelica , Reisch Nicole , Jarzab Barbara , Barontini Marta , Januszewicz Andrzej , Shah Nalini , Young William F , Opocher Giuseppe , Eng Charis , Neumann Hartmut P H , Bausch Birke 
Published: May 2018

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.