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Comparative Study
. 2010 Jun 17:10:299.
doi: 10.1186/1471-2407-10-299.

Different significance between intratumoral and peritumoral lymphatic vessel density in gastric cancer: a retrospective study of 123 cases

Xiao-Lei Wang  1 , Jian-Ping Fang, Ru-Yong Tang, Xi-Mei Chen
Affiliations
Comparative Study

Different significance between intratumoral and peritumoral lymphatic vessel density in gastric cancer: a retrospective study of 123 cases

Xiao-Lei Wang et al. BMC Cancer. .

Abstract

Background: Patients with gastric cancer in China have worse outcome and poorer prognosis. Tumor-induced lymphangiogenesis plays a crucial role in metastasis and tumor progression. The intratumoral and peritumoral lymphatics were supposed to have different biological effects. Three major growth factors, vascular endothelial growth factor- (VEGF)-A, VEGF-C and VEGF-D, are involved in the activation process via their receptors (VEGFRs). The purpose of current study is to investigate the significant difference between intratumoral and peritumoral lymphatic vessel density (LVD) in gastric cancer and their correlations with lymphangiogenetic growth factors.

Methods: Intratumoral LVD (I-LVD) and peritumoral LVD (P-LVD) of 123 patients with primary gastric cancer were assessed after staining with D2-40, and confirmed by double staining with D2-40/CD34. Proliferative activity of lymphatics endothelium was evaluated by double staining with D2-40/Ki-67. The associations were analyzed between I-LVD/P-LVD and the expression level of VEGF-A, VEGF-C, VEGF-D and the receptor VEGFR-3, which was measured by immunohistochemistry (IHC). The correlations of I-LVD and P-LVD with patient prognosis were also valued.

Results: (1) The peritumoral lymphatics (PTLs) were relatively enlarged with dilated lumen compared with the intratumoral lymphatics (ITLs). Increased P-LVD was significantly higher than I-LVD (P < 0.05). (2) P-LVD was found significantly associated with lymph node metastasis (LNM) (P < 0.001), lymphatic vessel invasion (LVI) (P < 0.001), VEGF-C (P = 0.003), VEGF-D expression level (P = 0.005) and VEGFR-3 expression level (P < 0.001) in peritumoral tissues, despite no significant association was found between above variants with I-LVD. However, increased I-LVD was demonstrated to be associated with decreased tumor volume (P < 0.001). Neither I-LVD nor P-LVD was correlated with VEGF-A expression (P > 0.05). (3) Proliferative activity of lymphatics endothelium was observed in PTLs, in spite of ITLs. (4) Increased P-LVD, but not I-LVD, was indicated to be an independent risk factor for lymph node metastasis by multivariate logistic regression analysis, and was related to worse disease-free survival and overall survival.

Conclusions: PTLs play roles in gastric cancer progression. Increased P-LVD, but not I-LVD, was significantly associated with VEGF-C/-D/VEGFR-3 system, and could be an independent risk factor for lymph node metastasis and a prognostic factor in gastric cancer.

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Figures

Figure 1
Figure 1
The D2-40-positive lymphantics mainly located at the layer of submucosa in gastric tissue (arrows). IHC, magnification: ×200.
Figure 2
Figure 2
The double immunohistochemical staining for D2-40 and CD34 clearly distinguished the lymphatic vessels (black arrow) from blood vessels (red arrow). IHC, magnification: ×400.
Figure 3
Figure 3
The intratumoral lymphatic vessels in gastric cancer were collapsed (arrow); Double immunohistochemical staining, magnification: ×200.
Figure 4
Figure 4
The invading cancer cells cluster were present in lymphatic vessel invasion (LVI). Double immunohistochemical staining for D2-40/CD34, magnification: ×400.
Figure 5
Figure 5
The peritumoral lymphatic vessels in gastric cancer were enlarged with dilated lumen located at the superficial submucosa. IHC, magnification: ×200.
Figure 6
Figure 6
The peritumoral lymphatic vessels in gastric cancer were enlarged with dilated lumen located at deep part of submucosa. IHC, magnification: ×200.
Figure 7
Figure 7
VEGF-A expression in the cytoplasm in gastric cancer. IHC, magnification: ×400.
Figure 8
Figure 8
VEGF-C expression in the cytoplasm in gastric cancer. IHC, magnification: ×400.
Figure 9
Figure 9
VEGF-D expression in the cytoplasm in gastric cancer. IHC, magnification: ×200.
Figure 10
Figure 10
Ki-67-positive lymphatic vessel nuclei (arrows) were detected in the tumor periphery. Double staining for D2-40/Ki-67, magnification: ×400.
Figure 11
Figure 11
No Ki-67 positive expression in the intratumoral lymphatics nuclei. Double staining for D2-40/Ki-67, magnification: ×400.
Figure 12
Figure 12
Lymphatic vessels invasion was detected in the peritumoral tissue (arrows). Double staining for D2-40/Ki-67, magnification: ×400.
Figure 13
Figure 13
The VEGFR-3-positive expression in the endothelial cells cytoplasm in tumor periphery (P-VEGFR-3), occasionally with cancer cell clusters invading (arrows). IHC, magnification: ×400.
Figure 14
Figure 14
The VEGFR-3-positive expressions were located at tumor center (arrows). IHC, magnification: ×200.
Figure 15
Figure 15
Relationship between P-LVD with overall survival (P < 0.001).
Figure 16
Figure 16
Relationship between P-LVD with disease-free survival (P < 0.001).
Figure 17
Figure 17
Relationship between P-LVD with cancer-specific survival (P < 0.001).
Figure 18
Figure 18
Relationship between I-LVD with overall survival (P = 0.5825).
Figure 19
Figure 19
Relationship between I-LVD with disease-free survival (P = 0.2844).
Figure 20
Figure 20
Relationship between I-LVD with cancer-specific survival (P = 0.6246).
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