Similarities and differences of human and experimental mouse lymphangiomas.

Lymphangioma is a disfiguring malformation of early childhood. A mouse lymphangioma model has been established by injecting Freund's incomplete adjuvant (FIA) intraperitoneally, but has not been compared with the human disease. We show that, in accordance with studies from the 1960s, the mouse model represents an oil-granuloma, made up of CD45-positive leukocytes and invaded by blood and lymph vessels. Several markers of lymphatic endothelial cells are expressed in both mouse and human, like CD31, Prox1, podoplanin, and Lyve-1. However, the human disease affects all parts of the lymphovascular tree. We observed convolutes of lymphatic capillaries, irregularly formed collectors with signs of disintegration, and large lymph cysts. We observed VEGFR-2 and -3 expression in both blood vessels and lymphatics of the patients, whereas in mouse VEGFR-2 was confined to activated blood vessels. The experimental mouse FIA model represents a vascularized oil-granuloma rather than a lymphangioma and reflects the complexity of human lymphangioma only partially.     

钙离子依赖型凝集素样受体2 (CLEC-2)研究进展

 钙离子依赖型凝集素样受体2(calcium dependent lectin like receptor 2,CLEC-2)是近年发现的血小板表面受体,相对分子质量(Mr)约32 000,是一种Ⅱ型跨膜受体。蛇毒蛋白Rhodocytin和唾液酸样糖蛋白Podoplanin是目前被分别鉴定出的CLEC-2的外源性和内源性配体。配体与受体相互作用后,通过Src及Syk依赖的酪氨酸激酶途径活化下游分子,最终激活PLCγ2,产生第二信使的生理效应,引起血小板活化聚集。研究表明CLEC-2与配体的相互作用和血栓性疾病、肿瘤转移和进展以及血小板捕获HIV 1并呈递给靶细胞等过程密切相关。因此,阻断两者相互作用可能成为治疗上述疾病的新靶点。     

Podoplanin在口腔鳞状细胞癌中的表达及与淋巴结转移的关系

目的:采用淋巴管特异性标志物podoplanin标记口腔鳞癌组织和正常口腔组织中的淋巴管,并计数淋巴管密度(lymphatic vessel density,LVD)值,探讨口腔鳞癌及癌周淋巴管密度与淋巴结转移的相关性及可能机制。方法:采用免疫组织化学方法检测21例正常口腔黏膜组织和88例口腔鳞癌患者组织的podoplanin表达;用podoplanin标记淋巴管,并计数口腔鳞癌和癌周组织的淋巴管密度。采用SPSS13.0软件包对数据进行t检验,分析正常组织和癌组织、淋巴结转移组和未转移组的淋巴管密度(癌周、癌内)。结果:口腔鳞癌及癌周组织的淋巴管密度均高于正常口腔黏膜组织,有显著差异(P<0.05)。癌组织内淋巴管小而闭锁,癌组织周围的淋巴管大而扩张;淋巴结转移组的癌周淋巴管密度(14.270±4.610)显著高于无转移组(9.450±2.411),差异具有显著性(P<0.05),癌组织淋巴管密度在2组间无显著差异。结论:口腔鳞癌患者癌周淋巴管的生成可能是影响区域淋巴结转移的重要因素。     

胃癌组织中微淋巴管的生成特点及临床病理意义

目的:探讨胃癌组织中微淋巴管的生成特点及与临床病理特征之间的关系.方法:对胃癌56例及相应正常胃组织12例进行双重免疫组织化学染色,采用微淋巴管特异标记物Podoplanin标记微淋巴管,同时采用Ki-67来检测微淋巴管内皮细胞的增殖活性,并观察微淋巴管分布特点,分析其与临床病理特征之间的关系.结果:胃癌组织中存在微淋巴管,但分布不一致.癌内微淋巴管数目少,并且多呈闭锁条索状,癌周微淋巴管数目多且多扩张,呈管腔样,有时可在其中发现癌栓.胃癌癌周微淋巴管密度(11.89±3.95)与癌内微淋巴管密度(5.83±3.26)相比较,差别有显著统计学意义(P<0.01),与相应正常组织微淋巴管密度(6.93±1.32)相比较,差别亦有统计学意义(P<0.05).胃癌癌周微淋巴管内皮细胞Ki-67指数(0.04±0.02)分别与癌内微淋巴管内皮细胞Ki-67指数(0)及相应正常胃组织微淋巴管内皮细胞Ki-67指数(0)相比较,差别均有统计学意义(P<0.05).胃癌癌周微淋巴管密度与肿瘤的分化程度、淋巴结转移以及淋巴管受累相关(P<0.05).胃癌癌周微淋巴管内皮细胞Ki-67指数仅与淋巴管受累相关(P<0.05).结论:胃癌组织中存在新生淋巴管,且主要存在于癌周,癌周淋巴管是发生淋巴结转移的主要途径.     

Prognostic Significance of Immunohistochemically Detected Blood and Lymphatic Vessel Invasion in Colorectal Carcinoma: Its Impact on Prognosis

Background The prognostic significance of blood vessel invasion (BVI) and lymphatic vessel invasion (LVI) is unclear. Because of the absence of specific markers for venous and lymphatic vessels, earlier studies could not reliably distinguish between BVI and LVI. Methods By immunostaining for podoplanin and CD34 antigen, we retrospectively investigated LVI and BVI in 419 tissue specimens of colorectal carcinoma. We performed univariate and multivariate analysis of the clinicopathologic features, frequency of recurrence, and outcome of patients with or without LVI and BVI. Results The use of hematoxylin and eosin (H&E) staining to identify BVI and LVI yielded a false positive rate of 9.1% and false negative rate of 12.6%. The incidence of BVI was significantly higher among tumors with LVI than tumors without LVI (P <.001). In logistic multivariate analysis, only LVI (P < .001) was associated with lymph node metastasis and BVI (P = .015) was associated with distant recurrence. Calculating the prognostic relevance, both two invasion types correlated with decreased survival in univariate analysis (both P <.001). In multivariate analysis, BVI (P =.024), lymph node status (P =.003) and tumor stage (P <.001) remained statistically significant factors for survival. Conclusions Our results suggest that immunohistologic evaluation of BVI and LVI could be useful in colorectal carcinoma indicating the risk of lymph node metastasis and recurrence, thereby contributing to prognostic evaluation.     

小鼠肝癌移植瘤及其淋巴管的研究

目的为探讨癌细胞淋巴道转移的机制,观察小鼠肝癌移植瘤淋巴管Podoplanin免疫组化及酶组化表达。方法取(H22)肝癌细胞株,接种于小鼠腹股沟部皮下,第20 d后处死动物,取肿瘤及瘤周组织。应用5’-核苷酸酶(5’-Nase)和碱性磷酸酶(ALPase)双重染色及podoplanin免疫组化染色法,观察肿瘤及瘤周组织淋巴管的分布。结果动物模型在接种20 d时可见明显肿块;癌周边区可见较多棕色的毛细淋巴管和淋巴管。淋巴管腔较大且饱满,管壁薄,形态不规则。结论移植瘤周边区淋巴管增多,推测癌细胞淋巴道转移与癌周淋巴管的密度和扩张相关。     

Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer

Purpose Although lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer. Methods We examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis. Results A significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114). Conclusions Our data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal cancer. *Deceased. The Poster presentation at the meeting of the Japanese Society of Gastroenterology, Sapporo, Japan, October 11 to 14, 2006. Reprints are not available.     

Peritumoural vascular invasion: a major determinant of triple-negative breast cancer outcome

Purpose

Triple-negative breast cancers (TNBC) have the worst outcome of all breast cancer subtypes. Nevertheless TNBC are heterogeneous in terms of pathological, biological and prognostic behaviours. We explored clinical and pathological factors correlated with outcome in this phenotype.

Methods

We retrospectively studied clinical and pathological factors correlated with prognosis in a series of 344 early TNBC. Staining for blood (CD31) and lymphatic (Podoplanin) vascular endothelium markers was performed to best characterise peritumoural vascular invasion (PVI) in 108 cases available for pathological reviewing.

Results

Univariate and multivariate analyses performed on our whole cohort underlined PVI as an independent predictive factor of distant metastasis (p = 0.00012, HR = 2.72 [1.63-4.52]). Standardised pathological reviewing of 101 histologically confirmed TNBC showed that PVI, observed in 41% (28% by haematoxylin and eosin staining plus 13% by immunohistochemistry), was confirmed as the first prognostic factor in TNBC, particularly in node-negative tumours. Five-year metastasis-free survival in this subset was 87.5% and 50.8% without and with PVI, respectively (p = 0.003).

Conclusions

Vascular invasion diagnosis is improved by the combination of HES and IHC. Moreover it is a major prognostic feature and must take a greater part in therapeutic management of early TNBC with the possibility to adapt the adjuvant treatment according to the predicted relapse risk.