Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies

Abstract

Pancreatic endocrine tumors (PETs) can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and surgical treatment of PETs in such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed.

Figure 1

Location and frequency of tumors/hyperplasia in patients with MEN1. Location and frequency are graphed from the data for the 130 MEN1 patients reported in . Percentage refers to percent of the total 130 patients with the tumor in the indicated location.

Figure 2

Representation of the genomic organization of the MEN 1 gene, its encoded protein, menin, and the menin regions that interact with different proteins grouped according to their main functional activity. The 10-exon gene has a 1.8-kb coding region (shaded) from 9 exons, which encode for the 610 amino acid protein, menin. Menin has 3 nuclear recognition signals (NLS) and five putative guanosine triphosphatase (GTPase) sites indicated by the bars. Regions which have been implicated in binding to different interacting proteins are shown and they are divided by their main intracellular function. Abbreviations are explained in text and individual menin interactions discussed. Figure drawn form data in – and references in text.

Figure 3

Age of diagnosis or onset of various PETs and other manifestations of MEN1 in all MEN1 patients (A, top) or MEN1/ZES patients (B, Middle) and comparison of age onset of ZES in MEN1 patients and patients with sporadic ZES. Panel A is drawn form data in , panel B from and panel C from .

Figure 4

Characteristic multiplicity of duodenal gastrinomas PETs in MEN1/ZES patients and its appearance on CT scan. Panels A (gross specimen) and B (IHC-gastrin stain) show multiple small and larger duodenal gastrinomas (T=tumors) which limits the ability to cure patients MEN1/ZES patients with tumor enucleation (see Figure 2B). Panel 1C shows the appearance of a duodenal gastrinoma which is projecting into the lumen but arises submucosally ,,.

Figure 5

Characteristic multiplicity of pancreatic PETs in MEN1 patients and the ability to image them. Panel 1A show an anterior somatostatin receptor scintigraphy (SRS) SPECT image demonstrating 4 tumors in this patient with MEN1/ZES. The tumor in the lower right was not in the pancreas but a gastric carcinoid, demonstrating the importance of not assuming all positive abdominal lesions are PETs in MEN1 patients. Panels 1B (SRS), 1C (CT) and 1D (histology) from a different patient show the multiple, intrapancreatic PETs (T=tumor) that are frequently seen in MEN1 patients.

Figure 6

Effect of various factors on survival in patients with PETs with MEN1 (1A, 1B, 2B, 3A, 3B) or without MEN1 (2A, 2B). Panels 1A, 3A show the effect of type of PET or lack of size of NF-PET on survival in MEN1 patients and are drawn from data in ,. Panels 1B, shows survival in patients with MEN1/ZES with (15%) or without (85%) aggressive tumors and is drawn from data in . Panel 2A shows the effect presence or extent of liver metastases in patients with sporadic ZES and is drawn form data in ,. Panel 2B compares the disease-free survival rate in patients with ZES with sporadic ZES or MEN1/ZES and is drawn from . Panel 3B shows the difference in survival for MEN1/ZES patients with no surgery with tumors <2 cm, (Group 1); group 2 with surgery with no liver metastases with a single (group 1A) or >2 PETs (2B) prior to surgery and group 3 with diffuse liver metastases and no surgery (drawn from data in .