Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

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; 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; Ozer 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; Giuseppe Opocher; Charis Eng; Hartmut P.H. Neumann; Birke Bausch

doi:10.1530/ERC-18-0100

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

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 SansóXiaoping Qi, M. Umit Ugurlu, Rene E. Diaz, Nelson Wohllk, Mariola Peczkowska, Jens Aberle, Delmar M. Lourenço, 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, Ozer 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, Giuseppe Opocher, Charis Eng, Hartmut P.H. Neumann, Birke Bausch

Endocrinology, Diabetes, Metabolism, and Nutrition

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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 2cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8cm. 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 ≥2.8cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8cm (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 2.8cm 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.

Original language	English (US)
Pages (from-to)	783-793
Number of pages	11
Journal	Endocrine-Related Cancer
Volume	25
Issue number	9
DOIs	https://doi.org/10.1530/ERC-18-0100
State	Published - Sep 2018

Keywords

Management recommendations
PanNET
Survival
Von Hippel-Lindau disease

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Oncology
Endocrinology
Cancer Research

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10.1530/ERC-18-0100

Cite this

Krauss, T., Ferrara, A. M., Links, T. P., Wellner, U., Bancos, I., Kvachenyuk, A., De Las Heras, K. V. G., Yukina, M. Y., Petrov, R., Bullivant, G., Von Duecker, L., Jadhav, S., Ploeckinger, U., Welin, S., Schalin-Jäntti, C., Gimm, O., Pfeifer, M., Ngeow, J., Hasse-Lazar, K., ... Bausch, B. (2018). Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. Endocrine-Related Cancer, 25(9), 783-793. https://doi.org/10.1530/ERC-18-0100

Krauss, T, Ferrara, AM, Links, TP, Wellner, U, Bancos, I, Kvachenyuk, A, De Las Heras, KVG, Yukina, MY, Petrov, R, Bullivant, G, Von Duecker, L, Jadhav, S, Ploeckinger, U, Welin, S, Schalin-Jäntti, C, Gimm, O, Pfeifer, M, Ngeow, J, Hasse-Lazar, K, Sansó, G, Qi, X, Umit Ugurlu, M, Diaz, RE, Wohllk, N, Peczkowska, M, Aberle, J, Lourenço, DM, Pereira, MAA, Fragoso, MCBV, Hoff, AO, Almeida, MQ, Violante, AHD, Quidute, ARP, Zhang, Z, Recasens, M, Díaz, LR, Kunavisarut, T, Wannachalee, T, Sirinvaravong, S, Jonasch, E, Grozinsky-Glasberg, S, Fraenkel, M, Beltsevich, D, Egorov, VI, Bausch, D, Schott, M, Tiling, N, Pennelli, G, Zschiedrich, S, Därr, R, Ruf, J, Denecke, T, Link, KH, Zovato, S, Von Dobschuetz, E, Yaremchuk, S, Amthauer, H, Makay, O, Patocs, A, Walz, MK, Huber, TB, Seufert, J, Hellman, P, Kim, RH, Kuchinskaya, E, Schiavi, F, Malinoc, A, Reisch, N, Jarzab, B, Barontini, M, Januszewicz, A, Shah, N, Young, WF, Opocher, G, Eng, C, Neumann, HPH & Bausch, B 2018, 'Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors', Endocrine-Related Cancer, vol. 25, no. 9, pp. 783-793. https://doi.org/10.1530/ERC-18-0100

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title = "Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors",

abstract = "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 2cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8cm. 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 ≥2.8cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8cm (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 2.8cm 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.",

keywords = "Management recommendations, PanNET, Survival, Von Hippel-Lindau disease",

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

note = "Publisher Copyright: {\textcopyright} 2018 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain.",

year = "2018",

month = sep,

doi = "10.1530/ERC-18-0100",

language = "English (US)",

volume = "25",

pages = "783--793",

journal = "Endocrine-Related Cancer",

issn = "1351-0088",

publisher = "Society for Endocrinology",

number = "9",

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TY - JOUR

T1 - Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

AU - Krauss, Tobias

AU - Ferrara, Alfonso Massimiliano

AU - Links, Thera P.

AU - Wellner, Ulrich

AU - Bancos, Irina

AU - Kvachenyuk, Andrey

AU - De Las Heras, Karina Villar Gómez

AU - Yukina, Marina Y.

AU - Petrov, Roman

AU - Bullivant, Garrett

AU - Von Duecker, Laura

AU - Jadhav, Swati

AU - Ploeckinger, Ursula

AU - Welin, Staffan

AU - Schalin-Jäntti, Camilla

AU - Gimm, Oliver

AU - Pfeifer, Marija

AU - Ngeow, Joanne

AU - Hasse-Lazar, Kornelia

AU - Sansó, Gabriela

AU - Qi, Xiaoping

AU - Umit Ugurlu, M.

AU - Diaz, Rene E.

AU - Wohllk, Nelson

AU - Peczkowska, Mariola

AU - Aberle, Jens

AU - Lourenço, Delmar M.

AU - Pereira, Maria A.A.

AU - Fragoso, Maria C.B.V.

AU - Hoff, Ana O.

AU - Almeida, Madson Q.

AU - Violante, Alice H.D.

AU - Quidute, Ana R.P.

AU - Zhang, Zhewei

AU - Recasens, Mònica

AU - Díaz, Luis Robles

AU - Kunavisarut, Tada

AU - Wannachalee, Taweesak

AU - Sirinvaravong, Sirinart

AU - Jonasch, Eric

AU - Grozinsky-Glasberg, Simona

AU - Fraenkel, Merav

AU - Beltsevich, Dmitry

AU - Egorov, Viacheslav I.

AU - Bausch, Dirk

AU - Schott, Matthias

AU - Tiling, Nikolaus

AU - Pennelli, Gianmaria

AU - Zschiedrich, Stefan

AU - Därr, Roland

AU - Ruf, Juri

AU - Denecke, Timm

AU - Link, Karl Heinrich

AU - Zovato, Stefania

AU - Von Dobschuetz, Ernst

AU - Yaremchuk, Svetlana

AU - Amthauer, Holger

AU - Makay, Ozer

AU - Patocs, Attila

AU - Walz, Martin K.

AU - Huber, Tobias B.

AU - Seufert, Jochen

AU - Hellman, Per

AU - Kim, Raymond H.

AU - Kuchinskaya, Ekaterina

AU - Schiavi, Francesca

AU - Malinoc, Angelica

AU - Reisch, Nicole

AU - Jarzab, Barbara

AU - Barontini, Marta

AU - Januszewicz, Andrzej

AU - Shah, Nalini

AU - Young, William F.

AU - Opocher, Giuseppe

AU - Eng, Charis

AU - Neumann, Hartmut P.H.

AU - Bausch, Birke

PY - 2018/9

Y1 - 2018/9

N2 - 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 2cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8cm. 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 ≥2.8cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8cm (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 2.8cm 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.

AB - 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 2cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8cm. 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 ≥2.8cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8cm (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 2.8cm 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.

KW - Management recommendations

KW - PanNET

KW - Survival

KW - Von Hippel-Lindau disease

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U2 - 10.1530/ERC-18-0100

DO - 10.1530/ERC-18-0100

M3 - Article

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AN - SCOPUS:85050883238

SN - 1351-0088

VL - 25

SP - 783

EP - 793

JO - Endocrine-Related Cancer

JF - Endocrine-Related Cancer

IS - 9

ER -

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

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