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Birke Bausch, Ulrich Wellner, Dirk Bausch, Francesca Schiavi, Marta Barontini, Gabriela Sanso, Martin K Walz, Mariola Peczkowska, Georges Weryha, Patrizia Dall'Igna, Giovanni Cecchetto, Gianni Bisogno, Lars C Moeller, Detlef Bockenhauer, Attila Patocs, Karoly Rácz, Dmitry Zabolotnyi, Svetlana Yaremchuk, Iveta Dzivite-Krisane, Frederic Castinetti, David Taieb, Angelica Malinoc, Ernst von Dobschuetz, Jochen Roessler, Kurt W Schmid, Giuseppe Opocher, Charis Eng, and Hartmut P H Neumann

A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma–Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.

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

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.