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

in Endocrine-Related Cancer
Authors:
Tobias Krauss Department of Radiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

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Alfonso Massimiliano Ferrara Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV- IRCCS, Padua, Italy

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Thera P Links Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

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Ulrich Wellner Department of Surgery, University of Luebeck, Luebeck, Germany

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Irina Bancos Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, USA

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Andrey Kvachenyuk Institute of Endocrinology and Metabolism, NAMS of Ukraine, Kiev, Ukraine

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Karina Villar Gómez de las Heras Central Services, Servicio de Salud de Castilla-La Mancha (SESCAM), Toledo, Spain

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Marina Y Yukina Department of Surgery, Endocrinology Research Center, Moscow, Russia

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Roman Petrov Department of Surgery, Bakhrushin Brothers Moscow City Hospital, Moscow, Russia

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Garrett Bullivant Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada

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Laura von Duecker Department of Medicine IV, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany

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Swati Jadhav Department of Endocrinology, KEM Hospital, Mumbai, India

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Ursula Ploeckinger Interdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany

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Staffan Welin Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden

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Camilla Schalin-Jäntti Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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Oliver Gimm Department of Clinical and Experimental Medicine, Department of Surgery, University of Linköping, Linköping, Sweden

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Marija Pfeifer Department of Endocrinology, University Medical Center, Ljubljana, Slovenia

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Joanne Ngeow Cancer Genetics Service, Division of Medical Oncology, National Cancer Center Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

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Kornelia Hasse-Lazar Department of Endocrine Oncology and Nuclear Medicine, Center of Oncology, MSC Memorial Institute, Gliwice, Poland

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Gabriela Sansó Centro de Investigaciones Endocrinológicas “Dr Cesar Bergada” (CEDIE), Hospital de Niños Ricardo Gutiérrez, CABA, Buenos Aires, Argentina

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Xiaoping Qi Department of Oncologic and Urologic Surgery, the 117th PLA Hospital, Wenzhou Medical University, Hangzhou, Peoples Republic of China

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M Umit Ugurlu Department of General Surgery, Breast and Endocrine Surgery Unit, Marmara University School of Medicine, Istanbul, Turkey

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Rene E Diaz Endocrine Section, Hospital del Salvador, Santiago de Chile, Chile

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Nelson Wohllk Department of Medicine, Endocrine Section, Hospital del Salvador, University of Chile, Santiago de Chile, Chile

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Mariola Peczkowska Department of Hypertension, Institute of Cardiology, Warsaw, Poland

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Jens Aberle 3rd Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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Delmar M Lourenço Jr Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria A A Pereira Serviço de Endocrinologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria C B V Fragoso Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Ana O Hoff Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Madson Q Almeida Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Alice H D Violante Department of Internal Medicine-Endocrinology, Faculty of medicine-Hospital Universitario Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Ana R P Quidute Department of Physiology and Pharmacology, Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Brazil

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Zhewei Zhang Department of Urology, 2nd Hospital of Zhejiang University, School of Medicine, Hangzhou, China

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Mònica Recasens Hospital Universitari de Girona, Gerencia Territorial Girona, Institut Català de la Salut, Girona, Spain

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Luis Robles Díaz Unidad de Tumores Digestivos, Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain

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Tada Kunavisarut Division of Endocrinology and metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Taweesak Wannachalee Division of Endocrinology and metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Sirinart Sirinvaravong Division of Endocrinology and metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Eric Jonasch Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Division, Endocrinology & Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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Merav Fraenkel Neuroendocrine Tumor Division, Endocrinology & Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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Dmitry Beltsevich Department of Surgery, Endocrinology Research Center, Moscow, Russia

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Viacheslav I Egorov Department of Surgery, Bakhrushin Brothers Moscow City Hospital, Moscow, Russia

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Dirk Bausch Department of Surgery, University of Luebeck, Luebeck, Germany

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Matthias Schott Department of Endocrinology, Heinrich-Heine-University, Düsseldorf, Germany

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Nikolaus Tiling Interdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany

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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.

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 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.

Introduction

Preventive medicine uses key evidence to exponentially improve the quality of life and life expectancy. Next to environmental and behavioral parameters, heritable factors can result in major morbidity and mortality but also pose opportunities for early detection and prevention. Hereditary neoplasia syndromes such as von Hippel–Lindau disease (VHL) reflect a major challenge and major opportunity. VHL is characterized by specific tumors in different organs. Optimal surveillance and treatment decisions are based on disease-specific parameters. Hereditary diseases offer the possibility that mutation carriers are detected early, often in an asymptomatic stage. For VHL and its tumor spectrum, tumor-specific surveillance programs and long-term management strategies are of paramount importance.

VHL is an autosomal-dominant neoplasia syndrome caused by germline mutations in the VHL tumor suppressor gene (Latif et al. 1993). Disease incidence is ~1/36000 live births (Maher et al. 1991, Neumann & Wiestler 1991, Lonser et al. 2003). Penetrance is high but incomplete (Maher et al. 1990). VHL is characterized by hemangioblastomas of retina and the central nervous system (CNS), clear cell renal carcinomas (RCCs), pheochromocytomas, endolymphatic sac tumors of the inner ear, cystadenomas of the epididymis and broad ligament and cysts and tumors of the pancreas (Maher et al. 1990, Neumann & Wiestler 1991). Hemangioblastomas and RCCs are associated with a high morbidity and mortality due to potential blindness, life-threatening elevation of intracranial pressure, paraplegia and metastases. Quality of life is dramatically decreased and correlates with the number of operations a patient has undergone (Shuin et al. 2006).

Pancreatic neuroendocrine tumors (PanNETs) originate from the islets of the pancreas and may be hormonally active or inactive. PanNETs occur mainly as sporadic tumors, but 9% are also components of three hereditary syndromes, multiple endocrine neoplasia type 1 and 4 (MEN 1 and 4) and VHL; VHL-associated PanNETs represent only a subgroup of about 1% of all PanNETs (Erlic et al. 2010, Thakker 2014). In contrast to MEN 1, a disease with neuroendocrine tumors (NETs) also occurring in extra-pancreatic sites, in VHL, NETs have been observed almost exclusively in the pancreas (Neumann & Wiestler 1991). A subset of VHL-associated PanNETs have metastatic potential and should therefore be optimally operated before metastatic spread (Hammel et al. 2000, Libutti et al. 2000, Blansfield et al. 2007, Igarashi et al. 2014, Keutgen et al. 2016).

Preventive medicine is based on evidence-based guidelines. For VHL, such guidelines have been recently revised (Keutgen et al. 2016). These guidelines recommend surgical resection when PanNETs are >30 mm diameter in the pancreatic body and tail and >20 mm in the pancreatic head and uncinate process. However, current guidelines are based on small numbers of patients and only a few studies on VHL-PanNETs. Therefore, we analyzed an independent large series of PanNETs for clinical data, growth kinetics and morbidity and mortality from the population-based European-American-Asian-VHL-PanNET-Registry in order to critically reassess diagnostic and management criteria and to optimize the outcome of patients with VHL-associated PanNETs.

Patients and methods

This study is based on the registry for patients with VHL, the VHL-Registry, which was founded in 1983 in Freiburg, Germany and continuously updated and finally transformed into the European-American-Asian-VHL-PanNET-Registry. The VHL-Registry included mainly German patients with VHL disease. The European-American-Asian-VHL-PanNET-Registry was founded for this study and included registrants with VHL-PanNET. For this purpose, we contacted all centers worldwide with an interest on VHL-PanNET. The requested data provided by each center were collected into a central registry database platform. Inclusion criteria for this study were (i) a confirmed diagnosis of VHL either by the identification of a pathogenic germline mutation of the VHL gene (which was the case in about 85%) or clinically by the presence of hemangioblastomas of the retina or CNS; (ii) PanNETs must have been documented by contrast-enhanced MRI or CT and (iii) the diagnosis of PanNET was based on diagnostic imaging or histopathology (Neumann 1987, Lonser et al. 2003). PanNET was defined as a solid tumor of the pancreas with early arterial contrast enhancement (Choyke et al. 1995, Rha et al. 2007). Of the criteria for malignancy, we used in this study metastases and/or gross invasion to adjacent tissue, since not all patients were operated (Bosman et al. 2010).

From all registrants, demographic, clinical and molecular genetic data were analyzed, including gender; age at diagnosis; number, size and location of PanNETs; mode of treatment; treatment-associated complications; location of metastases; other manifestations of VHL; clinical outcomes and the specific VHL germline mutation. Data were updated till March 31, 2018.

The study protocol was approved by the Ethical Committee of the Freiburg University Medical Center and accordingly by the cooperating institutions. All patients provided written informed consent. The following are exceptions: in The Netherlands, data were collected anonymously, and according to Dutch law, no further Institutional Review Board approval is required; in Spain, data were obtained anonymously through Alianza-VHL in collaboration with the patients.

Imaging

The patients had state-of-the-art imaging for detection of PanNETs, which included thin-section and multiphase technique with early arterial-phase images for CT or dynamic contrast-enhanced sequences for MRI (Thoeni et al. 2000). Positron-emission tomography/CT (PET/CT) with 68Ga-labeled somatostatin receptor-based tracers (68Ga-DOTANOC/DOTATATE/DOTATOC) and/or 111In-/99mTc-labeled scintigraphy were also performed if considered necessary for further evaluation. For follow-up, most patients had MRI, others endoscopic ultrasonography. For tumor growth measurements, serial imaging with intervals of at least 12 months was used.

Growth kinetics

For calculation of tumor size, each tumor was analyzed on the initial and all follow-up studies. Diameters measured were the longest transverse and its perpendicular diameter on the largest cross-sectional area of the lesion and the cranio-caudal diameter on the coronal plane. Tumor volume was calculated according to the equation V = (4/3)πr(x*y*z) (Therasse et al. 2000). Growth rate was characterized as tumor volume doubling time (TVDT) and specific growth rate (SGR). TVDT was calculated from SGR according to Schwartz’s equation as log(2)/SGR. SGR was calculated as the slope of a linear regression line through the growth curve measurement points defined by natural logarithm of volume on the y-axis and time on the x-axis (Schwartz 1961, Mehrara et al. 2007).

Statistical analysis

Statistical analyses and plots were performed with R software (www.R-project.org). Scale and categorical variables are expressed as median/range and absolute/relative frequencies. Statistical testing included two-sided Fisher’s exact and Kruskal–Wallis tests. Multivariable prediction analysis was performed by least absolute shrinkage and selection operator (LASSO) and covariance test for significance (Lockhart et al. 2014). Survival was analyzed by Kaplan–Meier and Cox proportional hazard methods. P values of <0.05 were defined as significant.

Results

Clinical characteristics of VHL-associated PanNETs

The European-American-Asian-VHL-PanNET-Registry comprises 2330 patients, of whom 273 patients (12%) had PanNETs. Demographic and clinical characteristics are given in Table 1. PanNETs were detected by screening in 248 (91%) patients with asymptomatic presentations; 25 (9%) patients were symptomatic due to abdominal discomfort, large tumor size, bile duct compression with subsequent pancreatitis or due to metastases. The 273 patients had a total of 484 PanNETs. All VHL-PanPNETs were nonfunctioning. Maximum tumor diameter at diagnosis was <1.5 cm in 76, 1.6–3 cm in 108, 3.1–4.5 cm in 40, 4.6–6 cm in 24 and ≥6.1 mm in 25 patients. Metastatic PanNETs were diagnosed in 55 patients (20%) with a minimum diameter of ≥2.8 cm. Metastases occurred in lymph nodes (n = 29), liver (n = 35), lungs (n = 5) and bones (n = 5).

Table 1

Demographics and clinical characteristics of the patients of the European-American-Asian-VHL-PanNET-Registry.

n
Total of patients with VHL-associated PanNETs 273
Index patients 208/273
Related registrants with PanNETs 65/273
Overall number of PanNETs 484
Nationalities
 German 52 (19%)
 Italian 40 (15%)
 US American 28 (10%)
 Ukrainian 21 (8%)
 Spanish 15 (6%)
 Dutch 12 (5%)
 Russian 12 (5%)
 Brazilian 12 (5%)
 Canadian 11 (4%)
 Swedish 18 (7%)
 Indian 8 (3%)
 Chinese 6 (2%)
 Others 38 (15%)
Gender
 Female 171 (63%)
 Male 102 (37%)
Age at diagnosis in years
 Median/range 35/10–75
PanNET location
 Head and uncinate 320 (66%)
 Body and tail 164 (34%)
Number of PanNETs per patient
 Single 167 (61%)
 2 tumors 40 (15%)
 3 tumors 43 (15%)
 >3 tumors 24 (9%)
Metastatic PanNET 55 (20%)
Other VHL lesions
 Hemangioblastoma of the CNS 197 (72%)
 Retinal hemangiomablastoma 142 (52%)
 Pheochromocytoma 144 (53%)
 Renal clear cell carcinoma 63 (23%)
 Pancreatic cysts 79 (29%)
 Endolymphatic sac tumor 9 (3%)

Radiological findings

All 273 patients had an MRI (194, 71%) and/or CT (139, 51%) as initial imaging study. In metastatic PanNETs, both the maximum tumor diameter and the tumor volume were significantly larger than those of non-metastatic tumors (median 5 cm vs 2 cm; P < 0.001; 65.47 cm3 vs 3.05 cm3; P < 0.001) (Table 2). The smallest maximum diameter of metastatic PanNETs was 2.8 cm. Hundred-three patients (40%) received additional somatostatin receptor imaging: PET/CT (68Ga-DOTANOC/DOTATATE/DOTATOC) was positive in 44/45 (98%) patients, scintigraphy (111In-/99mTc-labeled) in 32/53 (60%).

Table 2

Tumor characteristics of patients with non-metastatic and metastatic PanNETs. TVDT, tumor volume doubling time.

Non-metastatic Metastatic P value
Sex
 Female 133 (61%) 38 (69%) 0.46
 Male 85 (39%) 17 (31%)
Age at diagnosis in years
 Median 35 33 0.17
 Range 10–75 11–68
Maximal tumor diameter (cm)
 Median 2 5 <0.001
 Range 0.4–10 2.8–17
Maximal tumor volume (cm3)
 Median 3.05 65.42 <0.001
 Range 0.02–376.8 5.86–2571.14
TVDT overall (months)
 Median 126 22 0.001

Growth kinetics of VHL-associated PanNETs

For 111 patients, including 17 with metastatic PanNETs, the change of tumor size was studied by MRI or CT with intervals of ≥12 months. Only the largest tumor size was used for calculation of TVDT and SGR. Median follow-up time was 48 months. TVDTs of metastatic vs non-metastatic PanNETs differed significantly with median 22 months vs 126 months (P = 0.001) (Table 2).

Germline mutations in patients with VHL-associated PanNETs

The European-American-Asian-VHL-PanNET-Registry comprises 2,330 total registrants, 2,057 without PanNETs and 273 with PanNETs. Of the 2330, 1770 patients had mutation analysis of the VHL gene and VHL germline mutations identified; of the 1770, 1539 did not have PanNETs and 231 had PanNETs. Germline mutation testing was not possible in 518 patients without PanNETs but meeting clinical criteria of VHL, and in 42 patients with PanNETs, meeting clinical criteria for VHL. This is due to either the patients not consenting to provide blood samples or the center not having the facility of germline mutation analysis. The 231 VHL mutation-positive patients with PanNETs included 194 index patients and 37 relatives with 86 different intra-exonic mutations and 32 large deletions of 1–3 exons (Table 3). We compared the genotype and spectra of VHL germline mutations in patients with and without PanNETs. PanNETs were significantly more frequent in patients with intragenic mutations compared to large deletions (191/1249 vs 30/408; P < 0.001). In addition, intragenic mutations were more common in those patients who had metastatic compared to non-metastatic PanNETs (43/1249 vs 5/408, P = 0.017). Also, patients with large deletions involving exon 3 developed significantly more often PanNETs compared to those with deletions involving exons 1 and/or 2 (17/133 vs 14/285; P = 0.008). In contrast, PanNETs and metastatic PanNETs occurred more frequently in patients with intragenic exon 3 mutations compared to those with intragenic mutations in exons 1 and 2 (PanNETs, 107/521 vs 84/728; P < 0.001 and metastatic PanNETs, 30/521 vs 13/728; P < 0.001). Further, mutations of codon 161 and 167 were statistically more frequent in patients with PanNETs as well as metastatic PanNETs compared to mutations in the rest of exon 3 (78/273 vs 29/262; P < 0.001, and metastatic PanNETs 23/273 vs 8/262; P = 0.005). In contrast, patients with mutations in the third most frequently mutated codon 98 showed rarely PanNETs (6/206 vs 58/267; P < 0.001).

Table 3

Germline mutations of the VHL gene in patients with VHL-PanNET. Two-hundred and thirty-one VHL-PanNET patients (194 index patients and 37 relatives) from 27 countries showed 86 different intra-exonic mutations of the VHL gene. The 86 different germline mutations were distributed over the 3 exons of the VHL gene with a hotspot region in exon 3, codon 161/167, the latter with enhanced risk of metastatic PanNET. Additionally, 32 patients had large deletions from 1 to 3 exons.

VHL-PanNET patients n Non-metastatic/metastatic VHL-PanNET patients n Exon Nucleotide change Amino acid change Center n
1 1/0 1 c.167C>T p.Ala56Val 1
1 1/0 1 c.188T>G p.Leu63Arg 1
1 1/0 1 c.191G>C p.Arg64Pro 1
2 2/0 1 c.194C>G p.Ser65Trp 2
1 1/0 1 c.194C>T p.Ser65Leu 1
1 1/0 1 c.202T>C p.Ser68Pro 1
1 0/1 1 c.208G>T p.Glu70* 1
1 1/0 1 c.219T>G p.Val74Gly 1
1 0/1 1 c.221T>A p.Val74Asp 1
3 3/0 1 c.227_229del p.Phe76del 3
4 4/0 1 c.233A>G p.Asn78Ser 3
3 3/0 1 c.233A>C p.Asn78Thr 1
1 1/0 1 c.238A>G p.Ser80Gly 1
1 1/0 1 c.239G>T p.Ser80Ile 1
1 0/1 1 c.340-2GGT>TGA Splice 1
1 1/0 1 c.240T>G p.Ser80Arg 1
1 1/0 1 c.245G>T p.Arg82Leu 1
1 1/0 1 c.250G>T p.Val84Leu 1
5 5/0 1 c.256C>G p.Pro86Ala 1
1 1/0 1 c.256C>T p.Pro86Ser 1
1 1/0 1 c.256C>A p.Pro86Thr 1
1 1/0 1 c.257C>T p.Pro86Leu 1
1 1/0 1 c.266T>C p.Leu89Pro 1
1 1/0 1 c.273del p.Phe91Leufs*68 1
4 4/0 1 c.277G>C p.Gly93Arg 3
1 1/0 1 c.280G>T p.Glu94* 1
1 0/1 1 c.286/287 p.Pro+Val86-87Ser+Leu 1
1 1/0 1 c.287_288AG>CC p.Gln96Pro 1
2 2/0 1 c.292T>C p.Tyr98His 1
4 1/3 1 c.293A>C p.Tyr98Ser 1
1 1/0 1 c.319C>G p.Arg107Gly 1
1 1/0 1 c.333C>G p.Ser111Arg 1
2 1/1 1 c.340+1G>T Splice 2
4 3/1 1 c.340G>A p.Gly114Ser 2
1 0/1 2 c.349dupT p.Trp117Leufs*15 1
2 2/0 2 c.357C>G p.Phe119Leu 2
1 1/0 2 c.362A>G p.Asp121Gly 1
1 1/0 2 c.364_365delinsAT p.Ala122Ile 1
2 1/1 2 c.374A>C p.His125Pro 2
1 1/0 2 c.382C>T p.Leu128Phe 1
1 1/0 2 c.388G>T p.Val130Phe 1
1 0/1 2 c.392A>C p.Asn131Thr 1
1 0/1 2 c.393C>A p.Asn131Lys 1
1 1/0 2 c.394C>T p.Gln132* 1
1 1/0 2 c.395A>C p.Gln132Pro 1
1 1/0 2 c.401T>G p.Leu63Arg 1
3 3/0 2 c.407T>C p.Phe136Ser 2
1 1/0 2 c.407C>G p.Ser65Trp 1
1 1/0 2 c.408delT p.Phe136Leufs*23 1
2 1/1 2 c.412C>A p.Pro138Thr 1
1 1/0 2 c.434T>G p.Val74Gly 1
2 2/0 2 c.440delTCT p.delPhe76 1
1 1/0 2 c.449C>G p.Leu188Val 1
1 1/0 2 c.449_462del p.Asn150Serfs*19 1
3 3/0 2 c.452T>C p.Ile151Thr 2
1 1/0 2 c.453C>G p.Ile151Met 1
1 0/1 2 c.457C>G p.Phe119Leu 1
1 1/0 2 c.461C>T Splice 1
1 1/0 2 c.463G>C Splice 1
1 1/0 2 c.463+3A>T Splice 1
1 1/0 2 c.463+2T>G Splice 1
2 1/1 3 c.464-2A>G Splice 1
1 1/0 3 c.464-1G>A Splice 1
1 1/0 3 c.464T>G p.Val155Gly 1
1 1/0 3 c.467A>G p.Tyr156Cys 1
1 1/0 3 c.472C>G p.Leu158Val 1
2 1/1 3 c.479_480del p.Glu160Alafs*13 2
1 1/0 3 c.481C>G p.Arg161Gly 1
3 3/0 3 c.481C>T p.Arg161X 3
15 8/7 3 c.482G>A p.Arg161Gln 8
2 1/1 3 c.488T>A p.Leu163His 2
1 1/0 3 c.490C>T p.Gln164Ter 1
1 1/0 3 c.491A>G p.Gln164Arg 1
3 1/2 3 c.496G>T p.Val166Phe 1
1 1/0 3 c.497T>C p.Val166Ala 1
2 2/0 3 c.499C>G p.Arg167Gly 2
32 24/8 3 c.499C>T p.Arg167Trp 15
24 16/8 3 c.500G>A p.Arg167Gln 16
2 2/0 3 c.501G>A p.Arg167= 2
1 1/0 3 c.509T>G p.Val170Gly 1
3 2/1 3 c.533T>C p.Leu178Pro 2
1 1/0 3 c.548C>A p.Ser183* 1
2 2/0 3 c.583C>T p.Gln195* 2
2 1/0 3 c.593T>A p.Leu198Gln 1
1 1/0 3 c.599G>C p.Arg200Pro 1
1 1/0 3 c.641G>T p.*214Leuext*14 1

Characteristics of VHL disease in patients with VHL-associated PanNET

Of the 273 VHL-PanNET patients, all had extra-pancreatic VHL-associated tumors. Hemangioblastomas of the retina and CNS occurred in 52% and 72% of the patients, respectively. RCCs and pheochromocytomas were detected in 23% and 53% of the patients, respectively. Patients had an average of 2 (range 0–12) operations for extra-pancreatic VHL tumors.

Severe non-PanNET-related VHL-associated disabilities occurred in 144 (144/215, 67%) living patients. Blindness occurred bilaterally in 2 and unilaterally in 19 patients. Steroid dependency after bilateral adrenalectomy for pheochromocytoma occurred in 26, severe neurological deficits after removal of CNS hemangioblastomas in 24 patients, respectively.

Forty-three patients died of VHL, of whom 26 (60%) were caused by PanNETs (2 due to complications during surgery, 24 due to metastases), 10 of CNS hemangioblastomas, 5 of RCC-related metastases and 2 of adrenal insufficiency. Nine patients died of non-VHL-related reasons, including one each of hepatocellular, rectal and ovarian cancers, three from non-VHL-related cardiac arrest, two from drug abuse and one from sepsis.

Surgical treatment and survival

Indication for surgery were tumor size and metastases diagnosed by MRI, CT and /or nuclear medicine imaging. Removal of PanNETs was performed in 117 (43%) patients; in 80 for non-metastatic and in 37 for metastatic PanNETs. Of the 55 patients with metastatic PanNETs, 16 had tumors in advanced stage, too late for surgery and 2 patients refused operation. Total pancreatectomy with or without removal of adjacent organs was performed in 18 patients, segmental pancreatectomy or enucleation of PanNETs in 99 (69 non-metastatic and 30 metastatic). Perioperative mortality was 2% (2/117). Early postoperative complications like fistula, abscess or cholangitis had 23% (27/117) and long-term complications (diabetes and/or exocrine pancreatic insufficiency) occurred in 41% (48/117) of the patients.

Estimation of survival was performed for four groups (Fig. 1): patients with maximum tumor diameters 1.5–2.7 cm and ≥2.8 cm (groups 1 and 2) not operated and operated (A and B) with a median follow-up of 7 years. Operated patients (groups 1B and 2B) experienced significantly longer survival than non-operated patients (94% (1B) vs 85% (1A) by 10 years; P = 0.020; 80% (2B) vs 50% (2A) at 10 years; P = 0.030). Comparing patients operated for smaller-to-larger tumors, survival was also significantly longer (groups 1B vs 2B, 94% vs 80%; P = 0.030). Finally, both groups together showed longer survival when operated (88% (1B+2B) vs 70% [1A+2A]; P = 0.04). In multivariate modeling, survival was independently reduced by age >35 years (HR 2.5, P = 0.012), by metastatic PanNET (HR 8.7; P = 0.001) or if mutations were present in codons 161 or 167.

Figure 1
Figure 1

Survival of von Hippel–Lindau disease patients with pancreatic neuroendocrine tumors with a maximum tumor diameter 1.5–2.7 cm not operated/operated vs ≥2.8 cm not operated/operated. Survival was analyzed by Kaplan–Meier Cox proportional hazard methods. Group 1A: patients with maximum tumor diameter 1.5–2.7 cm not operated. Group 1B: patients with maximum tumor diameter 1.5–2.7 cm operated. Group 2A: patients with maximum tumor diameter ≥2.8 cm not operated. Group 2B: patients with maximum tumor diameter ≥2.8 cm operated. Survival was significantly longer in operated patients (group 1B + group 2B) compared to not operated patients (group 1A+ group 2A) (94% (1B) vs 85% (1A) by 10 years, P = 0.020; 80% (2B) vs 50% (2A) at 10 years, P = 0.030; 88% (1B+2B) vs 70% (1A+2A) P = 0.040). Survival was also significantly longer in patients operated for smaller tumors compared to patients operated for larger tumors (groups 1B vs 2B, 94% vs 80% P = 0.030).

Citation: Endocrine-Related Cancer 25, 9; 10.1530/ERC-18-0100

Multivariate prediction modeling for metastatic PanNET

Multivariate modeling by LASSO regression incorporating maximum tumor diameter and volume, TVDT, age and hotspot mutations disclosed only maximum tumor diameter and TVDT as significant predictor variables. Positive and negative predictive values for metastatic PanNET were 51% and 100% for maximum tumor diameter at cut-off >2.8 cm, and 44% and 91% for TVDT at cut-off <24 months, respectively.

There were no statistical differences found for gene, age at diagnosis and tumor size in predicting long-term survival in those with metastatic PanNETs. Similarly, center of accrual (for those contributing more than ten registrants) did not confound survival data. Further, there are no gender-specific statistically significant differences.

Discussion

Our current study reassesses clinical management recommendations based on a large, independent, population-based registry of 273 patients with VHL-PanNETs from a total of 2330 patients with VHL from 27 different countries and 3 continents. Recently, revised diagnostic and treatment recommendations for VHL-associated PanNETs have been presented (Keutgen et al. 2016, Tirosh et al. 2018). These guidelines were based on past literature, mainly four smaller referral-based studies from the United States (Blansfield et al. 2007, Tirosh et al. 2018), France (Corcos et al. 2008) and Japan (Igarashi et al. 2014) with a total of 175, 108, 53 and 35 patients with VHL-associated PanNETs, from a total of 1239 VHL patients (Table 4). Patients with VHL and PanNET are confronted with the risks of metastatic spread of PanNETs and the consequences of surgeries. Complementary, but in these studies widely neglected, challenges are morbidity and mortality due to the multiplicity of non-pancreatic VHL-associated tumors.

Table 4

PanNET characteristics and patient information of current study in comparison with those in the literature. All values indicate number of patients; *values based on 111 growth observations (cases) of this study and 63 growth observations (cases) of Blansfield et al. (2007).

This study Blansfield et al. (2007) Corcos et al. (2008) Igarashi et al. (2014) Tirosh et al. (2018)
Patients total with VHL 2330 633 n.a. 377 229
 Patients total with PanNET (%) 273 (11.7) 108 (17.1) 35 53 (14.1) 175
 Age at diagnosis in years range (median) 10–75 (35) 16–68 (38) 21–57 (37) 14–55 (34) n.a.
Non-metastatic PanNETs 218 98 12 49 166
 Diameter mm (median) 4–101 (20) n.a. 10–45 (23) n.a. n.a.
Metastatic PanNETs 55 9 17 4 9
 Diameter mm (median) 28–170 (50) n.a. 15–80 (34) n.a. n.a.
TVDT (months) non-metastatic/metastatic* 126 (22) 88 (11) n.a. n.a. n.a.
Multiple PanNETs (%) 107 (39) 32 (30) 6 (17) n.a. n.a.
Patients’ nationalities 27 1 1 1 1
Operated patients 117 39 23 34 29
 Total pancreatectomy (%) 18 (17) 2 (5) 14 (61) 3 (9) n.a.
 Early postoperative complications 26 (24) 11 (28) n.a. n.a. n.a.
 Long-term complications 46 (43) n.a. n.a. n.a. n.a.
 Perioperative mortality rate (%) 2 (1.8) 1 (3) n.a. n.a. n.a.
Total death (n=) 52 n.a. 7 16 n.a.
 Death associated with VHL 43
 Death associated with PanNET (%) 26 (50) n.a. 2 (29) 0 n.a.
 Death associated with VHL but not PanNET (%) 17 (32) n.a. n.a. n.a. n.a.

Rates of metastatic PanNETs and key characteristics for early diagnosis differ substantially among these studies with prevalence of metastatic VHL-PanNETs of 7.5–20% and case numbers of only 2–17 patients (Yamasaki et al. 2006, Blansfield et al. 2007, Corcos et al. 2008, Charlesworth et al. 2012, Igarashi et al. 2014, Tirosh et al. 2018). In contrast, our study contains 55 patients with metastatic PanNETs, 20% of the total series. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as the only independent predictors of malignancy. And the strongest predictor for metastatic VHL-PanNET shown here is the maximum tumor diameter regardless of location within the pancreas with a cut-off diameter of ≥2.8 cm, a parameter essential for treatment decisions. The key unanswered question has been whether patients with VHL benefit from the operative removal of PanNETs? Our study answers this question based on 117 patients who underwent removal of PanNETs, an operated cohort larger than any previously published study. We found that the 10-year survival was statistically significantly longer in patients operated for PanNETs that measured 1.5–2.7 cm in diameter in contrast to the watch-and-wait approach; the same findings were found for PanNETs ≥2.8 cm. But the improved survival needs to take into account the side effects by the surgical intervention, reported to occur in 28–35% of the patients (Blansfield et al. 2007, de Mestier et al. 2015). Our study demonstrated permanent postoperative complications in 41% of the patients with exocrine and endocrine pancreatic insufficiency, although 85% of the operations were declared as organ sparing. This seemingly high frequency of complications is confounded by 29% of the patients having organ-sparing PanNET removal having multiple pancreatic cysts as an additional manifestation of VHL. The higher complication rate obtained in our multicenter, multicontinental study probably represents the reality of outcomes.

The second important aspect is the complexity of multi-organ tumor involvement of patients with VHL by their non-pancreatic tumors. In our study, this is characterized by tumors in extra-pancreatic organs or organ systems like the CNS with a need of up to 17 (median 2) surgeries and in addition frequent laser coagulation of retinal hemangioblastomas to prevent blindness. Complications were experienced in nearly two-thirds of the patients with permanent neurological deficits, uni- or bilateral blindness or steroid dependency after bilateral adrenalectomy for pheochromocytomas. Non-PanNET-related mortality in our study (eg, related to other VHL-associated tumors) was high, with 39% of deaths due to CNS hemangioblastomas, metastases of RCC or adrenal insufficiency.

Diagnosis and treatment recommendations for the evaluation and treatment of VHL-associated PanNETs should be revised to detect metastatic PanNET <2.8 cm in diameter in order to impact survival (Kruizinga et al. 2014). Screening for PanNETs should be started before age 11 years, the age of our youngest patient with metastatic PanNET. Thus, screening for PanNETs should be a part of the generally recommended screening program for VHL-associated tumors. If a solid pancreatic lesion is detected, functional somatostatin receptor PET-CT using 68Ga-DOTANOC/DOTATATE/DOTATOC (highly sensitive and specific in our and other studies) should be considered to confirm the endocrine nature (Poeppel et al. 2011, Prasad et al. 2016). A maximum tumor diameter ≥2.8 cm (regardless of location within the pancreas) should guide treatment decisions, which differs from current recommendations (Libutti et al. 2000, Blansfield et al. 2007, Keutgen et al. 2016, Tirosh et al. 2018). We recommend yearly monitoring of the pancreas and calculation of TVDT of PanNETs, if a diameter close to 2 cm is documented. Our recommendations differ to those most recently published, since we found metastatic tumors in five patients with diameters 2.8–3.0 cm (Tirosh et al. 2018). Our recommendations do not differentiate between missense mutations and mutations in exon 3 vs other VHL germline mutations, since four of our patients with metastatic PanNETs not exceeding 3.2 cm in diameter carried missense mutations. MRI or endoscopic ultrasonography can be used for imaging surveillance; the latter is contrast medium-free and may become the method of choice (van Asselt et al. 2016). Compared to recently published data our genotype–phenotype correlation based on 1,539 VHL patients without and 231 with PanNETs does not only exceed the existing number of patients, but is important, as VHL-associated PanNETs occurred significantly more often in patients with mutations affecting exon 3 with hotspots in codons 161/167, the latter with enhanced risk for malignancy (Tirosh et al. 2017). But an exclusion of surveillance for PanNETs based on specific mutations cannot be recommended, since PanNETs have been observed in carriers of germline mutations of any type and region of the VHL gene and genotype as a predictor of malignancy did not emerge in our multivariate analysis.

In summary, this worldwide study of PanNETs associated with VHL provides a unique and broad data platform to guide the management of VHL-PanNETs, demonstrating the complex challenges due to pancreatic and extra-pancreatic VHL-associated-tumors. For effective preventive medicine, clinical and molecular evaluation is essential. Maximum tumor diameter and growth of PanNETs, measured as TVDT, germline mutations and associated tumors need to be defined, since hotspot mutations in some codons in particular predispose to metastases. To improve the outcome and survival, patients with PanNETs ≥2.5 cm in diameter, regardless of location within the pancreas, are strong candidates for surgery. This study exemplifies the comprehensive data, which are needed for best-practice counseling of neoplasia syndromes and optimally established by an international consortium.

Strength and limitations of the study

Our current sample size of patients with VHL and PanNET exceeds by far all previous reports. The international research participants provide realistic (i.e., unbiased) data which help avoidance of fatal outcome by PanNET. The limitations of our study include that this is a retrospective-prospective registry study. Because the registry accrues over time, technical advances of imaging and surgical techniques may currently contribute to a better outcome in the latter years.

Declaration of interest

There is no relevant conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

H P H N, B B and C E had access to all the data in the study and are responsible for the conduct and content of the study. H P H N, B B, T K and C E conceptualized, designed and directed the study. T K reassessed radiological data. All authors obtained family histories, collected phenotypic documentation, reviewed all clinical information, ensured regulatory compliance and/or analyzed the data. Statistical analysis of the data was performed by U W, H P H N, C E, T K and B B. H P, H N, B B and C E interpreted the data and drafted the manuscript. All authors reviewed and critically revised the manuscript, and approved the final manuscript.

Acknowledgements

The authors are grateful to our patients and their families in participating in our registries and our studies. They thank for support of this study Fabio Azzolin, Padova, Italy. C Eng is the Sondra J and Stephen R Hardis Endowed Chair in Cancer Genomic Medicine at the Cleveland Clinic, and an American Cancer Society Clinical Research Professor. G Opocher, C Eng, H P H Neumann and B Bausch: shared senior authorship.

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  • Lockhart R, Taylor J, Tibshirani RJ & Tibshirani R 2014 A significance test for the lasso. Annals of Statistics 42 413468. (https://doi.org/10.1214/13-AOS1175)

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  • Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT & Ferguson-Smith MA 1990 Clinical features and natural history of von Hippel-Lindau disease. QJM 77 11511163. (https://doi.org/10.1093/qjmed/77.2.1151)

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    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J, Williams A, Ferguson-Smith MA & Morton N 1991 Von Hippel-Lindau disease: a genetic study. Journal of Medical Genetics 28 443447. (https://doi.org/10.1136/jmg.28.7.443)

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    • PubMed
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    • Export Citation
  • Mehrara E, Forssell-Aronsson E, Ahlman H & Bernhardt P 2007 Specific growth rate versus doubling time for quantitative characterization of tumor growth rate. Cancer Research 67 39703975. (https://doi.org/10.1158/0008-5472.CAN-06-3822)

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    • PubMed
    • Search Google Scholar
    • Export Citation
  • Neumann HP 1987 Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. VASA 16 220226.

  • Neumann HP & Wiestler OD 1991 Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 337 10521054. (https://doi.org/10.1016/0140-6736(91)91705-Y)

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    • PubMed
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  • Poeppel TD, Binse I, Petersenn S, Lahner H, Schott M, Antoch G, Brandau W, Bockisch A & Boy C 2011 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. Journal of Nuclear Medicine 52 18641870. (https://doi.org/10.2967/jnumed.111.091165)

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    • Export Citation
  • Prasad V, Tiling N, Denecke T, Brenner W & Plockinger U 2016 Potential role of (68)Ga-DOTATOC PET/CT in screening for pancreatic neuroendocrine tumour in patients with von Hippel-Lindau disease. European Journal of Nuclear Medicine and Molecular Imaging 43 20142020. (https://doi.org/10.1007/s00259-016-3421-6)

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  • Rha SE, Jung SE, Lee KH, Ku YM, Byun JY & Lee JM 2007 CT and MR imaging findings of endocrine tumor of the pancreas according to WHO classification. European Journal of Radiology 62 371377. (https://doi.org/10.1016/j.ejrad.2007.02.036)

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    • Export Citation
  • Schwartz M 1961 A biomathematical approach to clinical tumor growth. Cancer 14 12721294. (https://doi.org/10.1002/1097-0142(196111/12)14:6<1272::AID-CNCR2820140618>3.0.CO;2-H)

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  • Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M & Ashida S 2006 Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Japanese Journal of Clinical Oncology 36 337343. (https://doi.org/10.1093/jjco/hyl052)

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  • Thakker RV 2014 Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology 386 215. (https://doi.org/10.1016/j.mce.2013.08.002)

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  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. 2000 New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute 92 205216. (https://doi.org/10.1093/jnci/92.3.205)

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  • Thoeni RF, Mueller-Lisse UG, Chan R, Do NK & Shyn PB 2000 Detection of small, functional islet cell tumors in the pancreas: selection of MR imaging sequences for optimal sensitivity. Radiology 214 483490. (https://doi.org/10.1148/radiology.214.2.r00fe32483)

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  • Tirosh A, Lakis ME, Green P, Nockel P, Patel D, Nilubol N, Gara SK, Keutgen XM, Linehan WM & Kebebew E 2017 In-silico VHL gene mutation analysis and prognosis of pancreatic neuroendocrine tumors in von Hippel-Lindau disease. Journal of Clinical Endocrinology and Metabolism [epub]. (https://doi.org/10.1210/jc.2017-02434)

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  • Tirosh A, Sadowski SM, Linehan WM, Libutti SK, Patel D, Nilubol N & Kebebew E 2018 Association of VHL genotype with pancreatic neuroendocrine tumor phenotype in patients with von Hippel-Lindau disease. JAMA Oncology 4 124126. (https://doi.org/10.1001/jamaoncol.2017.3428)

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  • van Asselt SJ, Brouwers AH, van Dullemen HM, van der Jagt EJ, Bongaerts AH, Koopmans KP, Kema IP, Zonnenberg BA, Timmers HJ, de Herder WW, et al. 2016 Potential value of EUS in pancreatic surveillance of VHL patients. European Journal of Endocrinology 174 611620. (https://doi.org/10.1530/EJE-15-1012)

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  • Yamasaki I, Nishimori I, Ashida S, Kohsaki T, Onishi S & Shuin T 2006 Clinical characteristics of pancreatic neuroendocrine tumors in Japanese patients with von Hippel-Lindau disease. Pancreas 33 382385. (https://doi.org/10.1097/01.mpa.0000240604.26312.e4)

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  • Survival of von Hippel–Lindau disease patients with pancreatic neuroendocrine tumors with a maximum tumor diameter 1.5–2.7 cm not operated/operated vs ≥2.8 cm not operated/operated. Survival was analyzed by Kaplan–Meier Cox proportional hazard methods. Group 1A: patients with maximum tumor diameter 1.5–2.7 cm not operated. Group 1B: patients with maximum tumor diameter 1.5–2.7 cm operated. Group 2A: patients with maximum tumor diameter ≥2.8 cm not operated. Group 2B: patients with maximum tumor diameter ≥2.8 cm operated. Survival was significantly longer in operated patients (group 1B + group 2B) compared to not operated patients (group 1A+ group 2A) (94% (1B) vs 85% (1A) by 10 years, P = 0.020; 80% (2B) vs 50% (2A) at 10 years, P = 0.030; 88% (1B+2B) vs 70% (1A+2A) P = 0.040). Survival was also significantly longer in patients operated for smaller tumors compared to patients operated for larger tumors (groups 1B vs 2B, 94% vs 80% P = 0.030).

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  • Lockhart R, Taylor J, Tibshirani RJ & Tibshirani R 2014 A significance test for the lasso. Annals of Statistics 42 413468. (https://doi.org/10.1214/13-AOS1175)

  • Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM & Oldfield EH 2003 von Hippel-Lindau disease. Lancet 361 20592067. (https://doi.org/10.1016/S0140-6736(03)13643-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT & Ferguson-Smith MA 1990 Clinical features and natural history of von Hippel-Lindau disease. QJM 77 11511163. (https://doi.org/10.1093/qjmed/77.2.1151)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J, Williams A, Ferguson-Smith MA & Morton N 1991 Von Hippel-Lindau disease: a genetic study. Journal of Medical Genetics 28 443447. (https://doi.org/10.1136/jmg.28.7.443)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mehrara E, Forssell-Aronsson E, Ahlman H & Bernhardt P 2007 Specific growth rate versus doubling time for quantitative characterization of tumor growth rate. Cancer Research 67 39703975. (https://doi.org/10.1158/0008-5472.CAN-06-3822)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Neumann HP 1987 Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. VASA 16 220226.

  • Neumann HP & Wiestler OD 1991 Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 337 10521054. (https://doi.org/10.1016/0140-6736(91)91705-Y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Poeppel TD, Binse I, Petersenn S, Lahner H, Schott M, Antoch G, Brandau W, Bockisch A & Boy C 2011 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. Journal of Nuclear Medicine 52 18641870. (https://doi.org/10.2967/jnumed.111.091165)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Prasad V, Tiling N, Denecke T, Brenner W & Plockinger U 2016 Potential role of (68)Ga-DOTATOC PET/CT in screening for pancreatic neuroendocrine tumour in patients with von Hippel-Lindau disease. European Journal of Nuclear Medicine and Molecular Imaging 43 20142020. (https://doi.org/10.1007/s00259-016-3421-6)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rha SE, Jung SE, Lee KH, Ku YM, Byun JY & Lee JM 2007 CT and MR imaging findings of endocrine tumor of the pancreas according to WHO classification. European Journal of Radiology 62 371377. (https://doi.org/10.1016/j.ejrad.2007.02.036)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schwartz M 1961 A biomathematical approach to clinical tumor growth. Cancer 14 12721294. (https://doi.org/10.1002/1097-0142(196111/12)14:6<1272::AID-CNCR2820140618>3.0.CO;2-H)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M & Ashida S 2006 Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Japanese Journal of Clinical Oncology 36 337343. (https://doi.org/10.1093/jjco/hyl052)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thakker RV 2014 Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology 386 215. (https://doi.org/10.1016/j.mce.2013.08.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. 2000 New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute 92 205216. (https://doi.org/10.1093/jnci/92.3.205)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thoeni RF, Mueller-Lisse UG, Chan R, Do NK & Shyn PB 2000 Detection of small, functional islet cell tumors in the pancreas: selection of MR imaging sequences for optimal sensitivity. Radiology 214 483490. (https://doi.org/10.1148/radiology.214.2.r00fe32483)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tirosh A, Lakis ME, Green P, Nockel P, Patel D, Nilubol N, Gara SK, Keutgen XM, Linehan WM & Kebebew E 2017 In-silico VHL gene mutation analysis and prognosis of pancreatic neuroendocrine tumors in von Hippel-Lindau disease. Journal of Clinical Endocrinology and Metabolism [epub]. (https://doi.org/10.1210/jc.2017-02434)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tirosh A, Sadowski SM, Linehan WM, Libutti SK, Patel D, Nilubol N & Kebebew E 2018 Association of VHL genotype with pancreatic neuroendocrine tumor phenotype in patients with von Hippel-Lindau disease. JAMA Oncology 4 124126. (https://doi.org/10.1001/jamaoncol.2017.3428)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • van Asselt SJ, Brouwers AH, van Dullemen HM, van der Jagt EJ, Bongaerts AH, Koopmans KP, Kema IP, Zonnenberg BA, Timmers HJ, de Herder WW, et al. 2016 Potential value of EUS in pancreatic surveillance of VHL patients. European Journal of Endocrinology 174 611620. (https://doi.org/10.1530/EJE-15-1012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yamasaki I, Nishimori I, Ashida S, Kohsaki T, Onishi S & Shuin T 2006 Clinical characteristics of pancreatic neuroendocrine tumors in Japanese patients with von Hippel-Lindau disease. Pancreas 33 382385. (https://doi.org/10.1097/01.mpa.0000240604.26312.e4)

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