Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix.

Lymphatic invasion and nodal metastasis plays a major role in the spread of cervical cancer; however, little is known about the mechanisms whereby tumor cells enter the lymphatic system. We examined the intra- and peritumoral lymphatic vessel density (LVD) using D2-40 immunohistochemistry in 111 cervical squamous cell carcinomas and correlated them with vascular endothelial growth factor (VEGF)-C expression, clinicopathologic tumor features, and outcome. Compared with benign cervix, intratumoral and peritumoral LVD was significantly increased (P < 0.0001). Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.009). High peritumoral, but not intratumoral, LVD showed significant correlation with high tumor stage, lymphatic invasion, and nodal metastasis. VEGF-C showed increased expression at the invasive edge compared with the center of tumors (P < 0.0001) and correlated with high peritumoral LVD, lymphatic invasion, and nodal metastasis. High peritumoral LVD and VEGF-C expression at the invasive edge of tumors were associated with poor overall and recurrence-free survival in univariate analysis. In multivariate analysis, peritumoral LVD was the only independent term predictive of overall survival. Our findings suggest a potential role for VEGF-C in tumor-induced lymphangiogenesis represented by high peritumoral LVD, which may be one of the mechanisms leading to lymphatic invasion and metastatic spread. High peritumoral LVD may be an independent prognostic factor in early-stage cervical cancer.

Gombos Z ，Xu X ，Chu CS ，Zhang PJ ，Acs G ... -  《CLINICAL CANCER RESEARCH》

Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma.

Lymphatic vessel density (LVD) and microvessel density (MVD) are important parameters for assessing the malignant potential of tumors and patient survival. In this report, the authors defined LVD as the density of D2-40-positive lymphatic vessels and MVD as the density of CD105-positive microvessels per unit area of tissue. It was reported previously that vascular endothelial growth factor C (VEGF-C) is a major modulator of LVD and MVD. The objectives of this study were to clarify the clinical and prognostic significance of both LVD and MVD in oral squamous cell carcinoma (OSCC) and to elucidate the lymphangiogenic and angiogenic activities of VEGF-C in cancer tissues. In total, 110 OSCC tissue samples were evaluated for LVD, MVD, and expression of VEGF-C using immunohistochemistry. Correlations among these parameters and clinicopathologic factors were examined. LVD was significantly higher in tumors that had very high expression of VEGF-C compared with tumors that had no/weak expression of VEGF-C. LVD correlated well with lymph node metastasis (P < .001). MVD was correlated significantly with positive lymph node metastasis (P < .001) but not with VEGF-C expression. In contrast, high expression of VEGF-C was correlated significantly with advanced tumor status (P = .041). Survival rates were lower in patients who had higher LVD (P < .001), higher MVD (P = .0028), and strong VEGF-C expression (P = .048). Lymphangiogenesis predominantly influenced metastasis-free survival. The current results suggested that LVD is a more useful tool than MVD and VEGF-C for deciding on therapeutic strategies in patients with OSCC.

Miyahara M ，Tanuma J ，Sugihara K ，Semba I ... -  《CANCER》

Lymphangiogenesis in gastric carcinoma correlates with prognosis.

Gao P ，Zhou GY ，Zhang QH ，Su ZX ，Zhang TG ，Xiang L ，Wang Y ，Zhang SL ，Mu K ... -  《-》

Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer.

Metastasis to the regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer and an important prognostic factor in many types of cancer. Recent evidence suggests that VEGF-C promotes lymphangiogenesis, and that tumor lymphangiogenesis in turn promotes lymphatic metastasis. We have studied the role of LVD in breast cancer, and examined whether LVD is associated with lymph node metastasis, VEGF-C expression, or prognosis. In addition, we examined whether VEGF-C mRNA transcript levels were associated with lymph node metastasis and LVD. We began by investigating the lymphatics in primary human breast carcinoma with long-term follow-up (113 cases of invasive ductal and other breast cancers) by quantitative immunohistochemical staining for podoplanin. We then analyzed the relationship between LVD and lymph node status as well as VEGF-C immunoreactivity and other established clinicopathological parameters. The relationship between LVD and prognosis was also studied. VEGF-C mRNA transcript levels were examined by quantitative real-time RT-PCR, in 55 invasive ductal breast carcinomas. This was followed by an analysis of the relationship between VEGF-C mRNA transcript levels and lymph node metastasis as well as LVD. Mean LVD of 'hot spots' was 10.2 +/- 7.4/each case. LVD was significantly correlated with lymph node metastasis (p < 0.0001), VEGF-C immunoreactivity (p = 0.0084), and podoplanin positive lymphatic invasion (p < 0.0001). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that high LVD was associated with both worse disease free survival (p = 0.0033) and overall survival (p = 0.0391). VEGF-C mRNA transcript levels were also correlated with lymph node metastasis (p = 0.0074) and LVD (p = 0.0409). Increased LVD was correlated with lymph node metastasis and VEGF-C expression. High LVD may be a significant unfavorable prognostic factor for long-term survival in breast cancer.

Nakamura Y ，Yasuoka H ，Tsujimoto M ，Imabun S ，Nakahara M ，Nakao K ，Nakamura M ，Mori I ，Kakudo K ... -  《BREAST CANCER RESEARCH AND TREATMENT》

[Clinical significance of detection on lymphatic microvessel, lymphatic microvessel density and vascular endothelial growth factor-C in patients with colorectal carcinoma].

To evaluate the clinical significance of detection on lymphatic microvessel, lymphatic microvessel density (LMVD) and vascular endothelial growth factor-C (VEGF-C) in patients with colorectal carcinoma. Eighty tissue specimens of the colorectal carcinoma and the peritumoral tissue and thirty of adjacent normal bowel tissue were collected. The lymphatic microvessel and LMVD were determined by 5'-nucleotidase histochemical staining. The expression of VEGF-C protein and VEGF-C mRNA in specimens of colorectal carcinoma and normal colorectal tissues were studied by RT-PCR and immunohistochemical methods utilizing strept-avidin-biotin complex. Clinicopathological data and survival of each patient were obtained and analyzed. (1) The brown or filemot stained lymphatic microvessels were observed in specimens from the colorectal carcinoma, the peritumoral tissue and the normal bowel. Collapsed, nonfunctional lymphatic vessels were observed in the intratumoral tissue, and plenty of lymphatic vessels with large lumen referred as functional lymphatic vessels were observed in the peritumoral tissue. (2) The mean value of LMVD in the peritumoral tissue was significantly higher than that in the normal bowel tissue (9.76+/-2.85 vs. 5.49+/-1.43, t=8.220, P<0.01) and tumor tissue (9.76+/-2.85 vs. 2.13+/-0.96, t=15.118, P<0.001). (3) The positive rate (48.8% vs. 0, P<0.01) and mean value (1.09+/-1.20 vs. 0, P<0.01) of the VEGF-C protein expression in colorectal carcinoma specimens were significantly higher than that of the normal bowel tissue. The expression of VEGF-C protein was consistent with the expression of VEGF-C mRNA. The VEGF-C expression in intratumoral tissue demonstrated significant correlation with LMVD in the peritumoral tissue of colorectal carcinoma. (4) Both LMVD in the peritumoral tissue and the expression of VEGF-C in the intratumoral tissue correlated significantly with Dukes' stage (P<0.0001 and P=0.0234), lymph node metastasis (P<0.0001 and P=0.0059), and survival (P<0.0001 and P<0.0001), but not with age, sex, location and dimension of lesion, gross and histological type. Also, there was a positive significant correlation of LMVD in the peritumoral tissue with degree of differentiation (P=0.0168) and metastasis to the liver or the lung (P=0.0088). Lymphatic microvessels in the peritumoral tissue are functional. The functional lymphatic microvessels, increased LMVD in the peritumoral tissue and the expression of VEGF-C in the intratumoral tissue may act as the morphological features and the molecular phenotype of lymphangiogenesis in colorectal carcinoma, and also as important predictive markers for evaluating lymphatic metastasis and prognosis in patients with colorectal carcinoma.

Fan YZ ，Li GM ，Huang GP ，Li XP ... -  《-》