Angiogenic markers endoglin and vascular endothelial growth factor in gastroenteropancreatic neuroendocrine tumors.

AIM: To investigate the expression and potential prognostic role of vascular endothelial growth factor (VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: Microvessel density (MVD) in GEP-NETs was evaluated using endoglin and CD31 immunohistochemistry. In addition, tissue levels of endoglin and VEGF were determined in homogenates by ELISA. RESULTS: Endoglin was highly expressed on tumor endothelial cells. CD31 MVD in GEP-NETs was significantly higher compared to endoglin MVD (P < 0.01). Two- to four-fold higher tissue levels of endoglin and VEGF were seen in tumors compared to associated normal tissue. This increased endoglin tissue expression in tumors was significantly related to tumor size (P < 0.01), presence of metastases (P = 0.04), and a more advanced tumor stage (P = 0.02), whereas expression of VEGF was not. CONCLUSION: We suggest that endoglin is a potential marker to indicate and predict metastases, which might be useful in the post-resection therapeutic approach of patients with GEP-NETs.

Pathological incidence of duodenopancreatic neuroendocrine tumors in the Netherlands: a Pathologisch Anatomisch Landelijk Geautomatiseerd Archief study.

OBJECTIVES: Duodenopancreatic neuroendocrine tumors are rare, although current epidemiological studies worldwide suggest an incidence rate increase. We assessed the pathological incidence of duodenopancreatic neuroendocrine tumors for 18 years in The Netherlands. METHODS: Standardized excerpts from pathological reports of all patients who had a diagnosis of duodenopancreatic neuroendocrine tumors from 1991 until 2009 were collected from the Pathologisch Anatomisch Landelijk Geautomatiseerd Archief and reviewed. This nationwide network and registry of histopathological and cytopathological data covers 100% of the pathological reports in The Netherlands. RESULTS: We identified 905 patients with pancreatic (n = 692) or duodenal (n = 213) neuroendocrine tumors. Most of these patients (69.4%) had a nonfunctional tumor. Functional tumors were diagnosed at a younger age compared with nonfunctional tumors (mean [SD] age, 52.3 [17.7] years vs 60.0 [14.6] years, respectively; P < 0.0001). The mean annual incidence rates per 1,000,000 persons over 1991 to 2009 were 2.54 for pancreatic and 0.81 for duodenal neuroendocrine tumors. The highest incidence was found in patients 65 to 79 years of age. The incidence of nonfunctional neuroendocrine tumors had increased significantly for 2 decades (P < 0.0001). CONCLUSIONS: The incidence of duodenopancreatic nonfunctional neuroendocrine tumors in The Netherlands increased over 1991 to 2009. The etiology for this change includes improved diagnostic techniques and clinical awareness, as discussed.

Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis.

Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane.In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment.

Diagnostic efficacy of the secretin stimulation test for the Zollinger-Ellison syndrome: an intra-individual comparison using different dosages in patients and controls.

BACKGROUND/AIMS: The secretin stimulation test is the principal diagnostic tool to identify Zollinger-Ellison syndrome (ZES). We investigated, by intra-individual comparison, which dose of secretin results in the highest diagnostic efficacy to identify the ZES. METHODS: Fifty-seven paired secretin stimulation tests, using both 0.26 microg/kg and 0.78 microg/kg secretin, performed in 13 ZES patients and 12 controls, were analyzed and the findings confirmed in a validation cohort. RESULTS: A gastrin increase of >100 ng/l was found to be the most sensitive and specific criterion for a positive test. Higher gastrin increases after 0.78 microg/kg compared to 0.26 microg/kg secretin contributed to a slightly more sensitive (82.9 vs. 80.5%) but less specific (68.8 vs. 81.3%) test. A validation cohort, with 98 tests using 0.26 microg/kg secretin in 21 ZES patients and 39 controls, provided similar results. In ZES patients with normal fasting serum gastrin levels (<100 ng/l), there was no diagnostic benefit from the use of a higher secretin dose. CONCLUSIONS: The 0.26 microg/kg secretin stimulation test has the best diagnostic efficacy for the ZES. and IAP.

A case of recurrent gastrinoma in the liver with a review of "primary" hepatic gastrinomas.

The present report concerns a patient with a malignant gastrin-producing neuroendocrine tumour (ie, Zollinger-Ellison syndrome) with recurrent hepatic gastrinomas, in whom no gastrinoma in the duodenum, pancreas or other extrahepatic sites could be identified despite the use of multiple, repeatedly performed imaging and exploration techniques over the past 20 years. A short review on primary liver gastrinomas published since 1981 is also given. Interestingly, our patient is the only case with documented recurrent gastrinoma in the liver. None of the cases in the literature had liver gastrinomas as part of the multiple endocrine neoplasia type I syndrome. The interpretation of hepatic gastrinomas as primary lesions is questionable unless comprehensive investigation and well documented long-term follow-up is performed.