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  • Author: Kornelia Hasse-Lazar x
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Ernst von Dobschuetz, Helena Leijon, Camilla Schalin-Jäntti, Francesca Schiavi, Michael Brauckhoff, Mariola Peczkowska, Giovanna Spiazzi, Serena Demattè, Maria Enrica Cecchini, Paola Sartorato, Jolanta Krajewska, Kornelia Hasse-Lazar, Katarzyna Roszkowska-Purska, Elisa Taschin, Angelica Malinoc, Lars A Akslen, Johanna Arola, Dariusz Lange, Ambrogio Fassina, Gianmaria Pennelli, Mattia Barbareschi, Jutta Luettges, Aleksander Prejbisz, Andrzej Januszewicz, Tim Strate, Birke Bausch, Frederic Castinetti, Barbara Jarzab, Giuseppe Opocher, Charis Eng and Hartmut P H Neumann

The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry (IHC), and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, IHC, and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and IHC were re-investigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of the SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, TMEM127, and MAX genes. Analyses included Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for detection of large rearrangements. Of 947 registrants, eight candidates were initially identified. After immunohistochemical analyses of these eight subjects, 5 (0.5%) were confirmed to have thyroid paraganglioma. IHC was positive for chromogranin, synaptophysin, and S-100 and negative for calcitonin in all five thyroid paragangliomas, whereas the three excluded candidate tumors stained positive for pan-cytokeratin, a marker excluding endocrine tumors. Germline variants, probably representing mutations, were found in four of the five confirmed thyroid paraganglioma cases, two each in SDHA and SDHB, whereas the excluded cases had no mutations in the tested genes. Thyroid paraganglioma is a finite entity, which must be differentiated from medullary thyroid carcinoma, because medical, surgical, and genetic management for each is different. Notably, approximately 80% of thyroid paragangliomas are associated with germline variants, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.

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Frederic Castinetti, Ana Luiza Maia, Mariola Peczkowska, Marta Barontini, Kornelia Hasse-Lazar, Thera P Links, Rodrigo A Toledo, Sarka Dvorakova, Caterina Mian, Maria Joao Bugalho, Stefania Zovato, Maria Alevizaki, Andrei Kvachenyuk, Birke Bausch, Paola Loli, Simona R Bergmann, Attila Patocs, Marija Pfeifer, Josefina Biarnes Costa, Ernst von Dobschuetz, Claudio Letizia, Gerlof Valk, Marcin Barczynski, Malgorzata Czetwertynska, John T M Plukker, Paola Sartorato, Tomas Zelinka, Petr Vlcek, Svetlana Yaremchuk, Georges Weryha, Letizia Canu, Nelson Wohllk, Frederic Sebag, Martin K Walz, Charis Eng and Hartmut P H Neumann

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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.