Low microvessel density is an unfavorable histoprognostic factor in pancreatic endocrine tumors

Marion-Audibert, Anne-Marie; Barel, Cécile; Gouysse, Géraldine; Dumortier, Jérôme; Pilleul, F.; Pourreyron, Céline; Hervieu, Valérie; Poncet, Gilles; Lombard‐Bohas, Catherine; Chayvialle, Jean‐Alain; Partensky, Christian; Scoazec, Jean‐Yves

doi:10.1016/s0016-5085(03)01198-3

Cited by 135 publications

(70 citation statements)

References 41 publications

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“…However, we found a wide range of MVD values according to the malignant potential, undifferentiated carcinomas showing a 10 times lower MVD than benign tumours. A negative correlation has previously been described between MVD and advanced pituitary adenomas and carcinomas (Erroi et al, 1986;Jugenburg et al, 1995;Bernini et al, 2002), and a recent study demonstrates comparable results in PETs (Marion-Audibert et al, 2003). In our series, a high MVD was found to correlate with previously established markers of good prognosis (small tumour size, welldifferentiated tumours, low mitotic count and low proliferation index) (Solcia et al, 2000;Hochwald et al, 2002).…”

Section: Discussionsupporting

confidence: 86%

Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression

et al. 2004

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Tumour-associated angiogenesis is partly regulated by the hypoxia-inducible factor (HIF) pathway. Endocrine tumours are highly vascularised and the molecular mechanisms of their angiogenesis are not fully delineated. The aim of this study is to evaluate angiogenesis and expression of HIF-related molecules in a series of patients with pancreatic endocrine tumours (PETs). The expression of vascular endothelial growth factor (VEGF), HIF-1a, HIF-2a and carbonic anhydrase 9 (CA9) was examined by immunohistochemistry in 45 patients with PETs and compared to microvascular density (MVD), endothelial proliferation, tumour stage and survival. Microvascular density was very high in PETs and associated with a low endothelial index of proliferation. Microvascular density was significantly higher in benign PETs than in PETs of uncertain prognosis, well-differentiated and poorly differentiated carcinomas (mean values: 535, 436, 252 and 45 vessels mm À2, respectively, Po0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1a expression. Poorly differentiated carcinomas were associated with nuclear HIF-1a and membranous CA9 expression. Low MVD (P ¼ 0.0001) and membranous CA9 expression (P ¼ 0.0004) were associated with a poorer survival. Contrary to other types of cancer, PETs are highly vascularised, but poorly angiogenic tumours. As they progress, VEGF expression is lost and MVD significantly decreases. The regulation of HIF signalling appears to be specific in pancreatic endocrine tumours.

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Section: Discussionsupporting

confidence: 86%

Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression

et al. 2004

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“…Expression of Vascular endothelial growth factor (VEGF) has been associated with more aggressive tumor growth, the presence of metastases, and shorter progression-free survival in patients with low-grade neuroendocrine tumors when compared with tumors not expressing VEGF (Hansel et al Phan et al 2006). Microvessel density (MVD) in PETs has also received attention recently and decreased MVD may be an adverse prognostic factor according to some studies but not others (Marion-Audibert et al 2003, La Rosa et al 2003, Tan et al 2004, Couvelard et al 2005, Takahashi et al 2007). …”

Section: Other Prognostic Factorsmentioning

confidence: 99%

Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors

Halfdanarson¹,

Rubin²,

Farnell³

et al. 2008

Endocrine Related Cancer

343

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Pancreatic endocrine tumors (PETs) are uncommon tumors with an annual incidence !1 per 100 000 person-years in the general population. The PETs that produce hormones resulting in symptoms are designated as functional. The majority of PETs are non-functional. Of the functional tumors, insulinomas are the most common, followed by gastrinomas. The clinical course of patients with PETs is variable and depends on the extent of the disease and the treatment rendered. Patients with completely resected tumors generally have a good prognosis, and aggressive surgical therapy in patients with advanced disease may also prolong survival. The epidemiology, prognosis, and established and novel prognostic markers of PETs are reviewed.

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“…11 Microvascular density is correlated with prognosis in many tumor types, including pancreatic endocrine tumors. 12,13 Its quantification is heterogeneous in most cancer types and it is therefore mostly analyzed in hot spots, which correspond to areas with the highest vascular density. [14][15][16][17][18] Moreover, microvascular density reflects tumor angiogenesis, which is a therapeutic target shared by many types of tumors.…”

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confidence: 99%

Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors

et al. 2009

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Liver biopsy of metastatic pancreatic endocrine tumors allows confirmation of the diagnosis and assessment of prognosis. However, sampling variability is a potential limitation. Our aim was to use the tissue microarray technique to assess the heterogeneity of three prognostic markers, ie, MIB-1 proliferation index, microvascular density and somatostatin receptor type 2, inside single or between synchronous or metachronous liver metastases of pancreatic endocrine tumors. Tissue microarrays were constructed, which included core biopsies taken from surgically resected liver metastases in 29 patients. MIB-1, microvascular density and somatostatin receptor type 2 were evaluated after immunostaining. The heterogeneity was highlighted by the calculation of the reproducibility of the values of two cores randomly selected among all the cores studied. For quantitative variables, it was assessed by the intraclass correlation coefficient and by a Bland-Altman approach. For qualitative variables, observed agreement and weighted j were given. A total of 184 liver metastases were analyzed. For MIB-1, the intraclass correlation coefficients were 0.63, 0.69 and 0.67 and for microvascular density, the intraclass correlation coefficients were 0.48, 0.60 and 0.00, respectively, in single, synchronous and metachronous liver metastases. The variability increased for higher mean values of microvascular density. For somatostatin receptor type 2, the observed agreements were 91% (j ¼ 0.81), 69% (j ¼ 0.49) and 79% (j ¼ 0.68) in single, synchronous and metachronous liver metastases, respectively. In conclusion, tissue microarray analysis identifies heterogeneity of protein expression in pancreatic endocrine metastases, which depends on the marker tested. The reproducibility is better for MIB-1 and somatostatin receptor type 2 than for microvascular density. Sampling variability should be taken into consideration as a potential limitation to the assessment of prognostic and therapeutic markers in biopsy samples from metastatic pancreatic endocrine tumors.

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Low microvessel density is an unfavorable histoprognostic factor in pancreatic endocrine tumors

Cited by 135 publications

References 41 publications

Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression

Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression

Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors

Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors

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