Microadenomatosis of the Endocrine Pancreas in Patients With and Without the Multiple Endocrine Neoplasia Type 1 Syndrome

Self Cite

Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (PZ0.01), multifocal ICTs (PZ0.0029), and lower malignancy rate (P!0.001) in VHL-ICTs compared to sporadic cases. VHL was prevalent in !0.5% of NETs, while NETs occur in w10% of VHL, virtually exclusively as ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

Section: Discussionmentioning

confidence: 83%

Systematic comparison of sporadic and syndromic pancreatic islet cell tumors

Erlic

Ploeckinger

Cascón

et al. 2010

Self Cite

“…Moreover, histopathological analysis of resected MEN1-pancreases has shown numerous micro-tumors that were not identified using imaging studies (Anlauf et al 2006), further emphasizing the diffuse involvement of the pancreas in patients with MEN1. Historically, NF tumors were diagnosed late because of local symptoms and were associated with a high lethality early in life (Wilkinson et al 1993, Doherty et al 1998, Goudet et al 2010, Ito et al 2013).…”

Section: Non-functional Pancreatic Netsmentioning

confidence: 99%

The future: surgical advances in MEN1 therapeutic approaches and management strategies

Sadowski¹,

Cadiot²,

Dansin³

et al. 2017

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary autosomal dominant disorder associated with numerous neuroendocrine tumors (NETs). Recent advances in the management of MEN1 have led to a decrease in mortality due to excess hormones; however, they have also led to an increase in mortality from malignancy, particularly NETs. The main challenges are to localize these tumors, to select those that need therapy because of the risk of aggressive behavior and to select the appropriate therapy associated with minimal morbidity. This must be applied to a hereditary disease with a high risk of recurrence. The overall aim of management in MEN1 is to ensure that the patient remains disease-and symptom-free for as long as possible and maintains a good quality of life. Herein, we review the changes that occurred in the last 20 years in the surgical management of MEN1-associated functional and non-functional pancreaticoduodenal NETs and thymic and bronchial NETs.

“…The Men1 Δ3/+ model showed islet cell hyperplasia in 65% of cases at the age of 8-12 months, but also adenomas (5%) and carcinomas (9%), whereas gastrinomas occurred in 19% of the analyzed mice. All pancreatic NET subtypes could be detected, with the occasional simultaneous overexpression of two hormones, a feature also observed in microadenomas of MEN1 patients (Anlauf et al 2006). In this model (i.e.…”

Section: :10mentioning

confidence: 87%

Animal models of MEN1

Mohr¹,

Pellegata²

2017

Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the human MEN1 gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation in Cdkn1b (p27) and not in Men1. Both Men1-knockout mice and MENX rats have been exploited for therapy-response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors.