High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer.

PURPOSE: The clinical significance of intratumoral or peritumoral lymph vessel density is not known. LYVE-1, a lymphatic endothelium-specific hyaluronan receptor, is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells of both normal and neoplastic tissues. EXPERIMENTAL DESIGN: We investigated expression of LYVE-1 by immunohistochemistry in 180 unilateral, invasive ductal breast carcinomas and assessed the presence and density of lymph vessels within the tumor and at the tumor periphery. RESULTS: A minority (12%) of breast carcinomas had intratumoral lymph vessels, whereas peritumoral lymph vessels were identified in almost all cases (94%). No substantial association was found between the number of LYVE-1-positive vessels and the number of CD31 or vascular endothelial growth factor receptor-3-positive vessels, or vascular endothelial growth factor-C expression. The number of metastatic axillary lymph nodes increased in parallel with increasing lymph vessel counts (P = 0.033). A higher than the median lymph vessel count at the tumor periphery was significantly associated with unfavorable distant disease-free survival and overall survival. Women with high peritumoral lymph vessel density had only 58% (95% confidence interval, 46-70%) 5-year distant disease-free survival as compared with 74% (66-83%) among those with a low peritumoral lymph vessel density (P = 0.0088). In contrast, the presence of intratumoral lymph vessels was associated with neither axillary nodal status nor survival. Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis. CONCLUSIONS: A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer.     

Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients

The type of tumor-infiltrating macrophages may be decisive in tumor immunity, lymphangiogenesis and in the clinical outcome of cancer. Here, we elucidated the prognostic significance of lymphatic vessels, different types of macrophages and the balance between different macrophage types in colorectal cancer. We analyzed the impact of density, type and location of macrophages on the clinical behavior of 159 primary colorectal carcinomas using CD68 as a pan-macrophage marker and CLEVER-1/Stabilin-1 as a marker for regulatory/suppressive macrophages. Podoplanin was used as a pan-lymphatic vessel marker. A high number of CLEVER-1/Stabilin-1(+) peritumoral macrophages positively correlated with survival (p = 0.04). However, in more advanced disease (Stage IV), the patients with a high number of peritumoral or intratumoral CLEVER-1/Stabilin-1(+) macrophages had a shorter disease-specific survival (p = 0.05, and p = 0.008, respectively). Moreover, a low number of suppressive intratumoral CLEVER-1/Stabilin-1(+) macrophages among high numbers of CD68(+) macrophages correlated with a low number of distant recurrences (p = 0.01) and to fewer disease relapses exclusively in the liver as well (p = 0.006). A high number of intratumoral lymphatics correlated with poor survival (p = 0.03). The results of this work suggest that the type of macrophages, number of lymphatic vessels and their location contribute to the clinical behavior of colorectal cancer in a disease stage-specific manner.     

Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer

How tumors access and spread via the lymphatics is not understood. Although it is clear that dissemination via the blood system involves hemangiogenesis, it is uncertain whether tumors also induce lymphangiogenesis or simply invade existing peritumoral vessels. To address the issue we quantitated tumor lymph vessels in archival specimens of head and neck cancer by immunostaining for the recently described lymphatic endothelial marker LYVE-1, the vascular endothelial marker CD34, and the pKi67 proliferation marker, correlating lymph vessel density and proliferation index with clinical and pathological variables. Discrete "hotspots" of intratumoral small proliferating lymphatics were observed in all carcinomas, and a high intratumoral lymph vessel density was associated with neck node metastases (n = 23; P = 0.027) and an infiltrating margin of tumor invasion (P = 0.046) in the oropharyngeal subgroup. Quantitation of the lymphangiogenic growth factor vascular endothelial growth factor C by real-time PCR and immunohistochemistry revealed higher levels of mRNA in tumor tissue than in normal samples (n = 8; P = 0.017), but no obvious correlation with intratumoral lymphatics. Our results provide new evidence that proliferating lymphatics can occur in human cancers and may in some cases contribute to lymph node metastasis.     

Clinicopathological Significance of Tumor Lymphatic Vessel Density in Head and Neck Squamous Cell Carcinoma

Various studies have demonstrated that the lymphatic system is the additional route for solid tumor metastasis. Lymph nodes metastasis in Head and neck squamous cell carcinoma (HNSCC) is a major prognostic indicator for disease progression and a guide for therapeutic strategies. We conducted a study to compare intratumoral (IT) and peritumoral (PT) lymphatic vessel density (LVD) in HNSCC using lymphatic marker D2-40 and its correlation with lymph node metastasis, histological grading and other clinicopathological parameters. Fifty specimen of HNSCC with modified radical neck dissection tissue were included in the study group. Tissue from tumor, peritumoral tissue, tumor margin and all the lymph nodes were processed for paraffin wax blocks and histopathological diagnosis. Immunohistochemical profile of lymphatic vessels in intratumoral and peritumoral tissue was assessed by subjecting one section each from the tumor and peritumoral tissue to D2-40 immunostain. To determine LVD, four fields with the highest LVD (hot spots) were identified. The mean values were calculated by taking an average of all the measurements. The comparison of LVD between peritumoral and intratumoral area revealed significantly higher PT-LVD (P = 0.001). No significant association was seen between LVD, IT-LVD and PT-LVD and different age groups, gender, site of tumor, risk factors, size of tumor, tumor inflammation, pushing/infiltrating margin and stage of tumors. Significantly higher LVD, IT-LVD and PT-LVD was seen in association with lymph node metastasis. Both high intratumoral and peritumoral LVD were found significantly associated with the presence of lymph node metastasis, however lymphatic vessels were found to be significantly more numerous and larger in peritumoral areas as compared to intratumoral lymphatics. The specificity of D2-40 as a lymphatic endothelial marker was also confirmed. The results of our study support the possibility of using the determination of tumor lymphangiogenesis to identify patients of HNSCC who are at risk of developing the lymph node metastasis.     

Tumor lymphangiogenesis in head and neck squamous cell carcinoma: a morphometric study with clinical correlations

BACKGROUND: Tumor metastasis to regional lymph nodes via the lymphatic system represents the first step of dissemination in head and neck squamous cell carcinoma (HNSCC) and serves as a major prognostic indicator for disease progression and as a guide for therapeutic strategies. In the current study, the authors investigated whether tumor lymphangiogenesis may be related to the risk of lymph node metastasis and to clinical outcome in patients with HNSCC. METHODS: Immunostaining for the lymphatic marker D2-40 was used, and lymphangiogenesis was quantified within the tumor and in the peritumoral area in 52 HNSCC specimens using computer-assisted morphometric analysis. RESULTS: Lymphatic vessels were found to be significantly more numerous and larger in the peritumoral area compared with within the tumor, and the number and relative area of intratumoral and peritumoral lymphatics was significantly higher in HNSCC cases with lymph node metastasis. Multivariate analysis demonstrated that high peritumoral lymphangiogenesis (above the median value) was associated with an increased risk of developing lymph node metastasis. No correlation was found between tumor lymphangiogenesis and the disease-free or overall survival in the current series. CONCLUSIONS: The results indicate that peritumoral lymphangiogenesis may be an indicator of the risk of lymph node metastasis in patients with HNSCC.     

Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection

Tumor-infiltrating lymphocytes (TILs) represent the host immune response to cancer. CD8(+) cytotoxic T cells (CTLs) have a central role in the elimination of tumors, while regulatory T cells (Tregs) can suppress the immune reaction. The aim of this study was to investigate the prognostic value of TILs, especially Tregs and CTLs, in hepatocellular carcinoma (HCC) patients after resection. CD3(+), CD4(+), CD8(+), and FoxP3(+) TILs were assessed by immunohistochemistry in tumor tissue from 141 randomly selected HCC patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Kaplan-Meier and Cox regression analysis using the median values as cutoff. The density of intratumoral Tregs (P = 0.040) and peritumoral CTLs (P = 0.004) were an independent factor for overall survival (OS), but not for disease-free survival (DFS). The density of CD3(+) and CD4(+) TILs, and the prevalence of Tregs and CTLs were associated with neither OS nor DFS. The presence of low intratumoral Tregs with high intratumoral CTLs was a negative independent prognostic factor for OS (P = 0.001), while that of low intratumoral Tregs and low peritumoral CTLs independently correlated with improved DFS (P = 0.008). Moreover, the combined analysis of Tregs and CTLs displayed better prognostic performances than any of them alone. Additionally, higher density of intratumoral Tregs correlated with both the presence of liver cirrhosis (P = 0.025) and increased tumor size (P = 0.050). Tregs within tumor environment are promising prognostic parameters for HCC patients, and their combination with CTLs can predict prognosis more effectively.     

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

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.     

VEGF-C及癌周淋巴管密度与头颈鳞癌颈部淋巴结转移的关系

目的探讨血管内皮细胞生长因子-C（VEGF-C）表达及癌周淋巴管密度（P-LVD）与头颈鳞癌（HNSCC）颈部淋巴结转移的关系。方法采用免疫组化法,检测104例HNSCC组织中VEGF-C及癌周LYVE-1的表达,幷计算P-LVD,分析P-LVD及VEGF-C表达与其临床病理因素的关系。结果 104例HNSCC组织中,VEGF-C阳性表达率显著高于正常头颈部黏膜组织（74.04%vs 0,P〈0.05）。淋巴结转移组VEGF-C阳性表达率高于无淋巴结转移组（P〈0.05）。对LYVE-1标记的淋巴管密度（LVD）分析显示,癌周组织P-LVD高于癌内及正常组织（P〈0.05）,而VEGF-C阳性表达者及颈部淋巴结转移者P-LVD分别显著高于VEGF-C阴性表达者和无颈部淋巴结转移者（P〈0.05）。结论 HNSCC中VEGF-C表达及P-LVD与肿瘤淋巴结转移密切相关,对判断肿瘤侵袭、转移具有一定参考价值。     

Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: New insights into intratumoral and peritumoral lymphatics

Lymphatic metastasis of tumor cells represents a series of extremely complex and sequential processes that include dissemination and invasion into surrounding stromal tissues from primary tumors, penetration into lymphatic walls and implantation in regional lymph nodes, and extravasation or proliferation in parenchyma of target organs. Recent developments in lymphatic biology and research, especially the application of unique molecular markers specific for lymphatic endothelial cells (LECs), LYVE-1, Prox-1 and podoplanin have provided exciting new insights into the tumor microenvironment and LEC–tumor cell interface. To date, established factors for determining the behavior and prognosis of primary tumors have been emphasized morphologically and physiologically, i.e., lymphatic impairment and vessel density, dysfunction of lymphatic valves, interstitial fluid pressure, as well as a series of lymphangiogenic growth factors including VEGF-C/-D, and other cytokines and chemokines. Increasing knowledge of the tumor biological significance in lymphatics within the tumors (intratumoral lymphatics, ITLs) and at the tumor periphery (peritumoral lymphatics, PTLs) has greatly promoted understanding of tumor access into the lymphatic system by inducing lymphangiogenesis or by co-opting preexisting lymphatics. Therefore, the targeting PTLs and ITLs, which have been proposed as an important route for antimetastatic approach, are deemed worthy of further study in various animal tumor models and human tumors.     

Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study.

PURPOSE: At the time of diagnosis, metastatic dissemination of tumor cells via the lymphatic system has occurred in nearly all patients with inflammatory breast cancer (IBC). The objective of this study was twofold: (a) to determine which is the most suitable marker of lymph vessels in primary breast tumors and (b) to compare histomorphometric lymph vessel variables in IBC and non-IBC. EXPERIMENTAL DESIGN: Serial sections of 10 IBCs and 10 non-IBCs were immunostained for D2-40, LYVE-1, podoplanin, and PROX-1. Relative lymph vessel area, lymph vessel perimeters, and counts and lymphatic endothelial cell proliferation (LECP) were then measured in D2-40/Ki-67 double-immunostained sections of 10 normal breast tissues, 29 IBCs, and 56 non-IBCs. RESULTS: D2-40 was the most suitable antibody for staining peritumoral and intratumoral lymph vessels. D2-40-stained intratumoral lymph vessels were present in 80% of non-IBCs and 82.8% of IBCs (P = 0.76). In non-IBC, lymph vessels located in the tumor parenchyma were smaller and less numerous than those at the tumor periphery (P < 0.0001) whereas in IBC, intratumoral and peritumoral variables were not significantly different. The mean relative tumor area occupied by lymph vessels was larger in IBC than in non-IBC (P = 0.01). LECP at the tumor periphery was higher in IBC than in non-IBC: median LECP was 5.74% in IBC versus 1.83% in non-IBC (P = 0.005). CONCLUSIONS: The high LECP in IBC suggests that lymphangiogenesis contributes to the extensive lymphatic spread of IBC.     

Vascular endothelial growth factor-D induces lymphangiogenesis and lymphatic metastasis in models of ductal pancreatic cancer

The presence of lymphatic metastases is a strong indicator for poor prognosis in patients with ductal pancreatic cancer. In order to better understand the mechanisms controlling lymphatic growth and lymph node metastasis in human ductal pancreatic cancer, we analyzed the expression pattern of the vascular endothelial growth factor-D (VEGF-D), its receptor VEGF-receptor-3 (VEGFR-3) and the lymphatic endothelium-specific hyaluronan receptor LYVE-1 in a panel of 19 primary human ductal pancreatic tumors and 10 normal pancreas specimens. We further addressed the biological function of VEGF-D for induction of lymphatic metastasis in a nude mouse xenograft model using two human ductal pancreatic cancer cell lines with overexpression of VEGF-D. Compared to normal human pancreas, pancreatic cancer tissue showed overexpression of VEGF-D and VEGFR-3 in conjunction with a high lymphatic vascularization as determined by immunohistochemistry and in situ hybridization. Tumors derived from VEGF-D-overexpressing cells had a higher microvessel density compared to their mock-controls, as determined based on CD31 immunohistochemistry. Importantly, these tumors also revealed a significant induction of intra- and peritumoral lymphatics, as judged from immunohistochemical detection of LYVE-1 expression. This was associated with a significant increase in lymphatic vessel invasion by tumor cells and an increased rate of lymphatic metastases, as indicated by pan-cytokeratin reactive cells in lymph nodes. Our results suggest that VEGF-D plays a pivotal role in stimulating lymphangiogenesis and lymphatic metastasis in human ductal pancreatic cancer, and therefore represents a novel therapeutic target for this devastating disease.     

LYVE-1与血管内皮生长因子-C在喉鳞状细胞癌中的表达和意义

目的通过测定喉鳞状细胞癌组织内LYVE-1和血管内皮生长因子-C（VEGF-C）的表达情况,为喉鳞状细胞癌转移和预后的判定以及治疗提供一定的理论依据。方法通过免疫病理学方法检测LYVE-1的表达并计数喉鳞状细胞癌组织中淋巴管密度（LVD）,RT-PCR法检测喉鳞状细胞癌中VEGF-C的表达,使用统计学方法对LVD和VEGF-C表达进行分析。结果喉癌组织内存在LYVE-1（＋）的管腔样结构,LYVE-1在喉癌组织和癌旁正常组织之间表达差异有统计学意义（P〈0．05）,喉癌组织中VEGF-C mRNA的平均水平与正常组织之间差异有统计学意义（P〈0．05）,瘤组织比正常组织高4-5倍,而且喉癌组织内VEGF-C表达与LVD之间存在相关性。结论喉鳞状细胞癌瘤组织中存在淋巴管;VEGF-C mRNA在喉鳞状细胞癌组织中的表达要比正常对照组织高,且VEGF-C mRNA的高表达可能会通过促进瘤内淋巴管的增生来促进喉癌的淋巴结转移。     

Lymphatic vessel density in vocal cord carcinomas assessed with LYVE-1 receptor expression.

BACKGROUND AND PURPOSE: Early stage vocal cord carcinomas are usually cured by radiation therapy despite the use of portals that exclude the cervical lymph nodes. We investigated whether the lymphatic vessel density (LVD) of vocal cord carcinomas differs from that of other head and neck carcinomas. PATIENTS AND METHODS: Deparaffinized tissue from tumors of 60 patients diagnosed with head and neck squamous cell carcinoma (HNSCC) were immunostained for LYVE-1, a novel lymphatic vessel marker. Twenty-two had vocal cord carcinoma. Tumor blood vessel density (BVD) was assessed using immunostaining for CD31. RESULTS: Tumor overall LVD, including both intra- and peritumoral lymph vessels, was 10-fold lower than the BVD (5 counts/mm2 vs. 52 mm(-2), respectively). A high LVD was associated with a high BVD (P = .002), but neither was associated with the tumor size. Both tumor LVD and BVD were lower in vocal cord carcinomas than in HNSCCs arising at other sites (median, 0 vs. 7 mm(-2), P=.016; and median, 36 vs. 52 mm(-2), P = .006, respectively). Only one vocal cord carcinoma was associated with a regional metastasis at the time of the diagnosis. Among the rest of the cases tumor size was a better predictor for the presence of regional metastases than tumor BVD or LVD in a logistic regression model (odds ratio 2.2, 95% CI 1.1-4.5). CONCLUSION: Vocal cord carcinomas have a low lymph vessel density as compared with HNSCCs arising at other sites.     

VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma

Lymphatic spread is an important clinical determinant for the prognosis of hepatocellular carcinoma (HCC), but little is known about the control of lymphangiogenesis in HCC. We addressed expression and biological role of the pro-(lymph), angiogenic protein VEGF-D in this tumor entity. Using immunohistochemistry and in situ hybridization on specimens of HCC, cirrhotic and normal liver we found abundant expression of VEGF-D exclusively in the tumor cells. The cognate receptor VEGFR-3 was detected on blood and lymphatic vessels. By clinicopathological analysis VEGF-D expression was correlated with pT-stage of the primary, lymph node metastasis and lymphangiosis carcinomatosa. Three out of 4 human HCC cell lines expressed and secreted VEGF-D. To approach its biological function, VEGF-D deficient SKHep-1 cells were stably transfected with VEGF-D cDNA and effects on tumor progression were determined in vivo. Compared to mock-transfected controls, subcutaneous tumors derived from VEGF-D expressing cells were larger and more frequently metastasized to regional lymph nodes. VEGF-D expressing tumors exhibited increased microvessel density and increased abundance of peri- and intratumoral lymphatics, as assessed by immunostaining for CD31 and for LYVE-1 and/or podoplanin, respectively. Furthermore, coexpression of the soluble extracellular VEGFR-3 domain blocked VEGF-D-induced tumor growth and lymphatic spread via reduction of angiogenesis and lymphangiogenesis. In the orthotopic approach, VEGF-D expression resulted in an increased rate of intra- and extrahepatic as well as lymph node metastasis. In conclusion, our study suggests that expression of VEGF-D is involved in growth and lymphatic spread of HCC. Therefore, VEGF-D might represent a therapeutic target in HCC.     

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

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.     

肺腺癌瘤周微淋巴管密度的检测及其预后意义

目的　检测肺腺癌瘤周微淋巴管密度（ＬＭＶＤ）,探讨其与患者预后之间的关系。方法　应用免疫组化ＳＰ法检测６５例肺腺癌Ｄ２-４０蛋白表达并计数Ｄ２-４０表达阳性瘤内、瘤周的ＬＭＶＤ,分析其与患者临床病理特征的关系;观察患者总生存时间。结果　肺腺癌Ｄ２-４０表达阳性瘤周的ＬＭＶＤ为１１.５６±１０.７３,明显高于瘤内的３.９６±１.１５（Ｐ＜０.００１）。Ｄ２-４０表达阳性瘤周的ＬＭＶＤ与淋巴结转移密切相关（Ｐ＝０.００３）。瘤周高ＬＭＶＤ组（＞１０）中位生存时间为１３个月（９５％ＣＩ：１１.４～１４.６个月）,瘤周低ＬＭＶＤ组（≤１０）中位生存时间为３１个月（９５％ＣＩ：１７.８～４４.２个月）,两组间差异有统计学意义（Ｐ＝０.００５）。多因素分析显示,瘤周ＬＭＶＤ、有无淋巴结转移和ｐＴＮＭ分期是独立的预后因素。结论　Ｄ２-４０表达阳性的瘤周ＬＭＶＤ可以用于预测肺腺癌的预后。     

乳腺癌患者新辅助化疗前后淋巴管密度检测

背景与目的:淋巴管生成在肿瘤经淋巴途径转移中所起的作用已成为近几年里新的研究热点,但目前的研究结果仍存在很多争议。本研究拟检测乳腺癌患者新辅助化疗前后的淋巴管密度(lymphatic vessel density,LVD)并与乳腺良性病变进行比较,以进一步明确淋巴管生成的意义及其在化疗过程中的变化。方法:45例原发性乳腺癌患者给予3个周期新辅助化疗并手术,免疫组化法标记肿瘤及26例纤维腺瘤标本中特异性淋巴管内皮标志物Podop lan in并计数LVD。结果:乳腺癌瘤周、瘤内的淋巴管阳性率分别为70.9%、19.8%。化疗前瘤周平均LVD为9.6,纤维腺瘤瘤周平均LVD为5.4,两者间差异有显著性(P=0.012)。化疗后瘤周平均LVD为3.3,与化疗前相比显著降低(P<0.001),化疗前、后瘤内平均LVD分别为1.9、0.9(P=0.055)。淋巴结转移阳性和阴性组的平均瘤周LVD分别为11.8、7.0(P=0.048)。化疗后客观缓解组化疗前后平均瘤周LVD值分别为9.8、2.0(P<0.001)。结论:与良性病变相比,乳腺癌瘤周LVD显著增高;有瘤内淋巴管存在;瘤周LVD与HER-2、腋淋巴结转移状态相关;化疗后瘤周LVD明显降低,而瘤内LVD无显著变化;化疗后瘤周LVD的降低程度与化疗疗效相关。     

胃癌淋巴管密度、微血管密度水平及其临床意义

目的 探讨胃癌组织中淋巴管密度（LVD）和微血管密度（MVD）水平及两者与胃癌临床病理特征的关系。方法 收集本院2004年2月至2007年2月手术切除的68例胃癌患者肿瘤组织,分别采用D2-40和CD31标记胃癌组织中淋巴管和血管,采用免疫组化法检测瘤周及瘤内D2 40、CD31表达情况并计算LVD和MVD,分析瘤周及瘤内LVD、MVD水平与临床病理参数（肿瘤大小、淋巴结转移、脏器转移、TNM分期、性别、年龄、分化程度、Lauren分型及病理类型）和预后的关系。结果 68例患者瘤内和瘤周LVD分别为（4.6±2.0）个和（8.2±3.5）个,瘤内和瘤周MVD分别为（46.3±16.5）个和（47.6±15.3）个;瘤周LVD与肿瘤大小、淋巴结转移、脏器转移及TNM分期有关（P＜0.05）,与性别、年龄、分化程度、Lauren分型及病理类型均无关（P＞0.05）;瘤内LVD、瘤内及瘤周MVD与以上参数均无关（P＞0.05）;全组中位总生存期（OS）为48.6个月,其中瘤周低LVD者的中位OS为31.0个月,低于瘤周高LVD的43.0个月（P＜0.05）;瘤周高MVD者的中位OS为46.0个月,而瘤周低MVD者为48.0个月,差异无统计学意义（P＞0.05）。结论 瘤周LVD与胃癌的临床病理特征及预后密切相关,可能成为胃癌发展及预后的预测指标。     

Lymphatic vessel density and vascular endothelial growth factor-C expression correlate with malignant behavior in human pancreatic endocrine tumors.

Metastatic dissemination of tumor cells to regional lymph nodes is a common early feature of many human cancers including pancreatic adenocarcinoma. In contrast, lymph node metastasis is more variably observed in pancreatic endocrine tumors. The objective of this study was to assess the lymphatic system of human pancreatic endocrine tumors and correlate this to clinical behavior. Immunohistochemistry was performed using antibodies to two recently identified markers of lymphatic endothelium, namely, LYVE-1 and podoplanin, and to the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. As has been reported previously, we observed that in the normal pancreas, islets of Langerhans are devoid of intra-islet lymphatics, but that lymphatics are present in connective tissue in association with ducts and blood vessels. We found that both benign and malignant pancreatic endocrine tumors contain intratumoral lymphatic vessels. Lymphatic vessel density was related to the size of the tumor in benign tumors and to the presence of liver metastasis but not to lymph node metastasis in malignant tumors. VEGF-C was expressed in tumor cells: 4 of 19 (21%) benign tumors were positive, whereas 6 of 9 (67%) borderline tumors and 9 of 11 (82%) carcinomas were positive. These findings strongly suggest that lymphangiogenesis occurs in pancreatic endocrine tumors and that lymphatic invasion and the development of metastases are associated with VEGF-C expression.