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Anouk Scholten, Menno R Vriens, Geert Jan E Cromheecke, Inne H M Borel Rinkes and Gerlof D Valk

Objective

Hemodynamic (HD) instability still underlies difficulties during pheochromocytoma resection. Little is known about HD instability in patients with multiple endocrine neoplasia (MEN) type 2-related pheochromocytoma. Our aim was to assess differences in HD during pheochromocytoma resection between MEN2 and non-MEN patients. In addition, we sought to identify risk factors for intraoperative HD instability.

Design

Retrospective cohort study.

Methods

A total of 22 MEN2 and 34 non-MEN patients underwent 61 pheochromocytoma resections at the University Medical Center Utrecht between 2000 and 2010. All MEN2-related pheochromocytomas were diagnosed by annual screening. HD instability was assessed by measuring the frequency of hypotensive (mean arterial blood pressure (MABP) <60 mmHg) and/or hypertensive (systolic arterial blood pressure (SABP) >200 mmHg) episodes.

Results

Compared with non-MEN patients, MEN2 patients were younger at diagnosis, had less symptoms, lower hormone levels, and smaller tumors. Intraoperatively, MEN2 patients had a similar frequency of hypertensive episodes (1.3 vs 1.9, P=0.162, 95% confidence interval (CI): −6.7 to 35.4) and a similar maximum SABP (200 vs 220 mmHg, P=0.180, 95% CI: −9.7 to 50.5). However, MEN2 patients experienced less frequent (1.04 vs 2.6, P=0.003, 95% CI: 0.57 to 2.6) and less severe hypotensive episodes after tumor resection (lowest MABP: 52.5 vs 45.6 mmHg, P=0.015, 95% CI: −12.6 to 1.16). Tumor size was an independent risk factor for HD instability for the total group after multivariate analysis.

Conclusion

MEN2 patients with pheochromocytoma, despite their smaller tumors, do not distinguish themselves from non-MEN patients in terms of hypertensive episodes during pheochromocytoma resection. Therefore, pretreatment with α- and β-blockade remains the standard of care in MEN2-related as well as in non-MEN-related pheochromocytomas.

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Joanne M de Laat, Emma Tham, Carolina R C Pieterman, Menno R Vriens, Johannes A N Dorresteijn, Michiel L Bots, Magnus Nordenskjöld, Rob B van der Luijt and Gerlof D Valk

Objective

Endocrine diseases that can be part of the rare inheritable syndrome multiple endocrine neoplasia type 1 (MEN1) commonly occur in the general population. Patients at risk for MEN1, and consequently their families, must be identified to prevent morbidity through periodic screening for the detection and treatment of manifestations in an early stage. The aim of the study was to develop a model for predicting MEN1 in individual patients with sporadically occurring endocrine tumors.

Design

Cross-sectional study.

Methods

In a nationwide study in The Netherlands, patients with sporadically occurring endocrine tumors in whom the referring physician suspected the MEN1 syndrome were identified between 1998 and 2011 (n=365). Logistic regression analysis with internal validation using bootstrapping and external validation with a cohort from Sweden was used.

Results

A MEN1 mutation was found in 15.9% of 365 patients. Recurrent primary hyperparathyroidism (pHPT; odds ratio (OR) 162.40); nonrecurrent pHPT (OR 25.78); pancreatic neuroendocrine tumors (pNETs) and duodenal NETs (OR 17.94); pituitary tumor (OR 4.71); NET of stomach, thymus, or bronchus (OR 25.84); positive family history of NET (OR 4.53); and age (OR 0.96) predicted MEN1. The c-statistic of the prediction model was 0.86 (95% confidence interval (95% CI) 0.81–0.90) in the derivation cohort and 0.77 (95% CI 0.66–0.88) in the validation cohort.

Conclusion

With the prediction model, the risk of MEN1 can be calculated in patients suspected for MEN1 with sporadically occurring endocrine tumors.

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Lutske Lodewijk, Pim J Bongers, Jakob W Kist, Elfi B Conemans, Joanne M de Laat, Carla R C Pieterman, Anouk N A van der Horst-Schrivers, Ciska Jorna, Ad R Hermus, Olaf M Dekkers, Wouter W de Herder, Madeleine L Drent, Peter H Bisschop, Bas Havekes, Inne H M Borel Rinkes, Menno R Vriens and Gerlof D Valk

Objective

Currently, little is known about the prevalence of thyroid tumors in multiple endocrine neoplasia type 1 (MEN1) patients and it is unclear whether tumorigenesis of these thyroid tumors is MEN1-related. The aim of the study was to assess the prevalence of thyroid incidentalomas in MEN1 patients compared with nonMEN1 patients and to verify whether thyroid tumorigenesis is MEN1-related.

Design

A cross-sectional study.

Methods

The study included two groups: patients with MEN1 and a matched non-MEN1 control group without known thyroid disease, who underwent an ultrasound of the neck for the localization of parathyroid adenoma. Ninety-five MEN1 patients underwent ultrasound of the neck and were matched on gender and age with non-MEN1 patients. The prevalence of thyroid incidentalomas described in the ultrasound report was scored. Multinodular goiters, solitary nodes, and cysts were scored as incidentalomas. Presence of nuclear menin expression was evaluated by menin immunostaining of the thyroid tumors.

Results

In the MEN1 group, 43 (45%) patients had a thyroid incidentaloma compared with 48 (51%) in the non-MEN1 group, of which 14 (15%) and 16 (17%), respectively, were solitary nodes. Menin was expressed in the nuclei of all evaluated thyroid tumors.

Conclusions

MEN1 patients do not have a higher prevalence of thyroid incidentalomas compared with primary hyperparathyroidism patients without the diagnosis of MEN1. Menin was expressed in the thyroid tumors of MEN1 patients.

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T M A Kerkhofs, R H A Verhoeven, H J Bonjer, E J Nieveen van Dijkum, M R Vriens, J De Vries, C H Van Eijck, B A Bonsing, L V Van de Poll-Franse, H R Haak and on behalf of the Dutch Adrenal Network

Objective

Adrenocortical carcinoma (ACC) is a rare disease with an estimated incidence of one to two cases per 1 million inhabitants. The Dutch Adrenal Network (DAN) was initiated with the aim to improve patient care and to stimulate scientific research on ACC. Currently, not all patients with ACC are treated in specialized DAN hospitals. The objective of the current investigation was to determine whether there are differences in survival between patients operated on in DAN hospitals and those operated on in non-DAN hospitals.

Design

The study was set up as a retrospective and population-based survival analysis.

Methods

Data on all adult ACC patients diagnosed between 1999 and 2009 were obtained from The Netherlands Cancer Registry (NCR). Overall survival was calculated and a comparison was made between DAN and non-DAN hospitals.

Results

The NCR contained data of 189 patients. The median survival of patients with European Network for the Study of Adrenal Tumors stages I–III disease was significantly longer for patients operated on in a DAN hospital (n=46) than for those operated on in a non-DAN hospital (n=37, 5-year survival 63 vs 42%). Survival remained significantly different after correction for sex, age, year of diagnosis, and stage of disease in the multivariate analysis (hazard ratio 1.96 (95% CI 1.01–3.81), P=0.047).

Conclusion

The results associate surgery in a DAN center with a survival benefit for patients with local or locally advanced ACC. We hypothesize that a multidisciplinary approach for these patients explains the observed survival benefit. These findings should be carefully considered in view of the aim for further centralization of ACC treatment.

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E B Conemans, L Lodewijk, C B Moelans, G J A Offerhaus, C R C Pieterman, F H Morsink, O M Dekkers, W W de Herder, A R Hermus, A N van der Horst-Schrivers, M L Drent, P H Bisschop, B Havekes, L A A Brosens, K M A Dreijerink, I H M Borel Rinkes, H Th M Timmers, G D Valk and M R Vriens

Objective

Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.

Design and methods

Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed.

Results

We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel–Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression.

Conclusion

Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.