Serum vascular endothelial growth factor-C and lymphoangiogenesis are associated with the lymph node metastasis and prognosis of patients with colorectal cancer

Background: The study aims to investigate the relationship among serum vascular endothelial growth factor (SVEGF‐C), VEGF‐C expression and lymph vessel density (LVD) in tumour tissue, and their influence to colorectal carcinoma (CRC). Methods: The SVEGF‐C concentration of 110 patients with CRC and 40 healthy donors was examined by ELISA. The 110 tumour tissues and 40 normal colorectal specimens were examined by immunohistochemical staining (SP method) with VEGF‐C and podoplanin (lymphatic vessel specific antibody). Kaplan–Meier survival analysis determined the influence on CRC prognosis. Results: CRC SVEGF‐C level (889.0 ± 264.0 pg/mL) significantly exceeded (P= 0.000) the control level (373.2 ± 97.3 ng/L), and was significantly higher in T3, lymph node metastasis (LNM), distant metastasis, and pTNM groups III and IV. LNM prediction sensitivity, specificity, and accuracy of SVEGF‐C were 85.7, 80.0 and 83.6%, respectively (875 pg/mL cut‐off). VEGF‐C expression was elevated in CRC versus control patients (P= 0.000), and was significantly related to LNM and pTNM stages III and IV. Mean LVD in CRC (6.3 ± 0.7/200 HP) significantly exceeded control mean (3.0 ± 0.7/200 HP) (P= 0.000). LVD was significantly higher in LNM and pTNM stages III and IV. SVEGF‐C level was significantly higher in VEGF‐C positive versus negative patients (P= 0.000), and was related to LVD (P= 0.009). Kaplan–Meier ranking of prognostic factors was SVEGF‐C level (P= 0.000), VEGF‐C expression (P= 0.001) and LVD (P= 0.012). Conclusion: SVEGF‐C level, VEGF‐C and LVD are related to LNM and poor prognosis in patients with CRC. SVEGF‐C may be a biomarker for LNM in CRC.     

Vascular endothelial growth factor-C (VEGF-C) expression predicts lymph node metastasis of transitional cell carcinoma of the bladder

PURPOSE: It has been found that expression of vascular endothelial growth factor-C (VEGF-C) in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis. However, VEGF-C expression in bladder transitional cell carcinoma (TCC) has not yet been reported. To elucidate the role of VEGF-C in bladder TCC, we examined VEGF-C expression in bladder TCC and pelvic lymph node metastasis specimens obtained from patients who underwent radical cystectomy. METHODS: Eighty-seven patients who underwent radical cystectomy for clinically organ-confined TCC of the bladder were enrolled in the present study. No neoadjuvant treatments, except transurethral resection of the tumor, were given to these patients. The VEGF-C expressions of 87 bladder tumors and 20 pelvic lymph node metastasis specimens were examined immunohistochemically and the association between VEGF-C expression and clinicopathological factors, including angiogenesis as evaluated by microvessel density (MVD), was also examined. RESULTS: Vascular endothelial growth factor-C expression was found in the cytoplasm of tumor cells, but not in the normal transitional epithelium. Vascular endothelial growth factor-C expression was significantly associated with the pathological T stage (P = 0.0289), pelvic lymph node metastasis (P < 0.0001), lymphatic involvement (P = 0.0008), venous involvement (P = 0.0002) and high MVD (P = 0.0043). The multivariate analysis demonstrated that VEGF-C expression and high MVD in bladder TCC were independent risk factors influencing the pelvic lymph node metastasis. Moreover, the patients with VEGF-C-positive tumors had significantly poorer prognoses than those with the VEGF-C-negative tumors (P = 0.0087) in the univariate analysis. The multivariate analysis based on Cox proportional hazard model showed that the independent prognostic factors were patient age (P = 0.0132) and pelvic lymph node metastasis (P = 0.0333). CONCLUSION: The present study suggests that VEGF-C expression is an important predictive factor of pelvic lymph node metastasis in bladder cancer patients.     

血管内皮生长因子-C与乳腺癌淋巴结转移关系的研究

目的 探讨血管内皮生长因子-C(vascular endothelial growth factor-C, VEGF-C)的表达与乳腺癌淋巴结转移的关系.方法 应用免疫组化法观察78例乳腺浸润性导管癌组织中VEGF-C的表达情况,评价VEGF-C表达与淋巴结转移及其他临床病理因素的关系.取20例乳腺纤维腺瘤标本做对照.结果 78例乳腺浸润性导管癌中52例VEGF-C呈阳性表达,阳性率为67%;对照组仅3例可见VEGF-C弱表达,阳性率为15%.乳腺癌组VEGF-C表达阳性率明显高于对照组,差异有统计学意义(P<0.01);乳腺癌腋淋巴结转移组VEGF-C表达阳性者阳性率(78%)明显高于腋淋巴结无转移组(48%),差异有统计学意义(P<0.05);VEGF-C表达与患者年龄、肿瘤大小、激素受体、及临床分期之间差异无统计学意义(P>0.05).结论 VEGF-C与乳腺癌淋巴结转移呈正相关,是乳腺癌重要预后因子.     

趋化因子受体7蛋白与膀胱尿路上皮癌淋巴结转移的相关性

目的观察趋化因子受体7蛋白(CCR7)在膀胱尿路上皮的表达量,分析CCR7蛋白表达与膀胱尿路上皮癌相关临床参数的相关性。方法对28例膀胱尿路上皮癌患者的标本和5例正常膀胱组织标本,采用免疫组化法检测组织中的CCR7蛋白含量,分析CCR7含量与膀胱尿路上皮癌淋巴结转移发生率、CCR7与肿瘤的分期、分级等临床参数之间的关系。结果膀胱尿路上皮癌组织CCR7阳性率为85.71%,显著高于正常膀胱组织(20.00%);在膀胱尿路上皮癌组织中,淋巴结转移组的CCR7阳性率为90.91%,淋巴结未转移组为41.18%,两组差异有显著性意义(P0.05)。高分期膀胱尿路上皮癌(T3~T4)中CCR7的阳性率也显著高于低分期(T1~T2)(93.75%vs.75.00%),高分级膀胱尿路上皮癌(G3)中的阳性率也显著高于低分级(G1~G2)(93.34%vs.38.46%)。CCR7蛋白表达与肿瘤分期、病理分级以及淋巴结是否转移均有相关性,CCR7蛋白表达是淋巴结转移的独立影响因子(P=0.017,OR=3.152)。结论膀胱尿路上皮癌中CCR7蛋白与淋巴结转移成正相关,是淋巴结转移的独立影响因素。     

Diagnosis and treatment of pelvic lymph node metastasis in bladder cancer

BACKGROUND AND METHODS: Bipedal lymphography and percutaneous fine needle aspiration biopsy (FNAB) of pelvic lymph node was done in 200 patients with bladder cancer. RESULTS: A diagnosis of metastasis to the pelvic lymph node was obtained by this method in 34 patients. Of these 34 patients, only 12 (35%) were positive or suspected of having pelvic lymph node metastasis by computed tomography. Sixteen patients (47%) had unequivocally positive or highly suspicious lymphogram and 18 patients (53%) had normal lymphogram. Seventy-eight cases, including eight FNAB-positive cases, were treated by radical cystectomy and regional lymph node dissection. Sensitivity, specificity, positive predictive value and negative predictive value of FNAB were 57, 100, 100 and 91%, respectively. Thirteen FNAB-positive M0 patients could be treated by multimodality therapy and evaluated after neoadjuvant therapy by repeated lymphography and FNAB. All were changed to N0 by FNAB after neoadjuvant therapy. In eight patients treated by total cystectomy and lymph node dissection, four had down staged to pN0 but four had one positive node. In five follow-up cases without surgery, one had recurrent pelvic lymph node metastasis 35 months later. Cause-specific survival of these patients was 76% at 5 years and 57% at 8 years. CONCLUSIONS: Pretreatment diagnosis of pelvic lymph node metastasis and multimodality therapy may improve the prognosis of regional lymph node-positive bladder cancer. Because it is difficult to diagnose pN1 using FNAB, radical operation should be performed even if neoadjuvant therapy is effective and down staging is obtained.     

胃癌单个淋巴结转移规律及临床意义

目的分析胃癌淋巴结转移的规律以指导临床规范化治疗。方法对天津医科大学附属肿瘤医院1999年7月至2004年6月间经手术治疗、清扫淋巴结数大于或等于10枚、术后病理证实仅有1枚淋巴结转移的胃癌患者临床资料进行回顾性分析．并对淋巴结跳跃与非跳跃转移、横向与非横向转移患者的资料进行对比。结果全组65例患者共检出淋巴结1415枚．平均21．8枚／例;单个淋巴结转移率的分布从多到少依次为N0．3（30．8％）、No．4（21．5％）、No．6（15．4％）、No．7和No．8（均为6．2％）、No．1和No．2及N0．5（均为4．6％）、No．12（3．1％）和No．14及No．16（均为1．5％）;其中跳跃转移20．0％（13／65）,横向转移42．2％（19／45）。单因素分析显示．淋巴结跳跃性转移仅与肿瘤大小有关（X2=4．447,P=0．035）：淋巴结横向转移与各临床病理因素均无关。但淋巴结跳跃与非跳跃转移、横向与非横向转移间患者的生存曲线差异有统计学意义（P=0．000．P=0．000）。结论胃癌淋巴结转移规律总体遵循由远及近的转移顺序．但跳跃转移和横向转移方式也占有一定比例．对于胃癌淋巴结跳跃转移和横向转移的高危患者．术中应加强相应区域淋巴结清扫以提高患者生存率。     

The prognostic impact of pelvic lymph node metastasis and lymphovascular invasion on bladder cancer

Objectives:   To present long-term results of a single-center series of patients undergoing bilateral pelvic lymphadenectomy and radical cystectomy for bladder cancer and to analyze the impact of pelvic lymph node metastasis and lymphovascular invasion on clinical outcome.
Methods:   Between 1986 and 2005 833 patients were treated with bilateral pelvic lymphadenectomy and radical cystectomy at our institution. 614 of them with valid clinical follow-up information and no neoadjuvant therapy could be evaluated.
Results:   Disease-free and overall survival in the entire cohort was 56.7% and 49.5% at 5 years and 52.4% and 38.2% at 10 years, respectively. 28.1% of all patients had pelvic lymph node metastasis. We found organ-confined tumor stages (≤pT2) in 43.8%. Patients with non-organ-confined tumor stages (≥pT3) and positive pelvic lymph nodes had a significantly shorter overall survival than those without lymph node metastasis ( P  < 0.0001). In the subgroup of ≤pT2, the presence of pelvic lymph node metastasis did not show a statistically significant effect on overall survival ( P  = 0.618). The presence of lymphovascular invasion was associated with an impaired survival ( P  < 0.0001). In multivariate analysis, pathological tumor stage ( P  < 0.0001), lymph node stage (≥pT3) ( P  = 0.004) and lymphovascular invasion ( P  = 0.001) were independent prognostic parameters.
Conclusions:   According to the present series, survival for patients with ≤pT2 does not depend on the lymph node stage. Lymphovascular invasion is an independent parameter of impaired survival and should be determined routinely in cystectomy specimens to identify patients, who may benefit from adjuvant systemic therapy.     

浸润性膀胱癌组织中肿瘤血管形成与淋巴结转移间的关系

目的 通过对浸润性膀胱移行细胞癌(TCCB,T2～T4 NXMO)组织中血管形成的定量研究,探讨微血管密度(Microvessel Density,MVD)与淋巴结转移之间的关系。方法 应用免疫组织化学SP法对23例淋巴结阴性及15例淋巴结阳性浸润性膀胱移行细胞癌组织中的血管进行染色,用微血管密度(MVD)表示血管形成的程度。结果 有淋巴结转移的病例TCCB肿瘤组织中MVD明显高于无转移组(p<0.01)。结论 肿瘤血管形成在TCCB的生长转移过程中起到重要作用,在浸润性ICCB中MVD可推测淋巴结转移状况。     

Role of lymph node density in predicting survival of patients with lymph node metastases after radical cystectomy: A multi-institutional study

Objectives:   To evaluate the prognostic role of different clinico-pathological parameters in node-positive patients treated by radical cystectomy.
Methods:   A retrospective multi-institutional study of 435 patients who underwent radical cystectomy between 1990 and 2005 was carried out. Of them, pathological lymph node (LN) metastases were found in 83 patients. Sixty of these 83 patients, whose clinical information and follow-up data were available, were included in the analysis. Twenty-five patients had undergone adjuvant chemotherapy, whereas 35 had not. A Cox proportional hazards model was used to determine the impact of the following clinico-pathological parameters on patient survival: number of resected LNs, number of positive LNs, LN density (defined as the ratio of the number of positive LNs divided by the total number of resected LNs) and adjuvant chemotherapy.
Results:   Median follow-up for surviving patients was 41 months (range 4–138) after surgery. The median survival time for all patients was 22 months (95% confidence interval, 15–42 months). At multivariate analysis, LN density of 25% or less, adjuvant chemotherapy and pure urothelial carcinoma were independently significant predictors of survival.
Conclusions:   Lymph node density predicts survival in patients with node-positive bladder cancer.     

Overexpression of vascular endothelial growth factor-C correlates with lymph node micrometastasis in submucosal esophageal cancer

Lymph node metastasis, including lymph node micrometastasis (LMM), is one of the most important prognostic factors in esophageal squamous cell carcinoma (ESCC). Vascular endothelial growth factor C (VEGF-C) plays a key role in the process of lymphangiogenesis. We examined VEGF-C expression and tumor microvessel density of the primary tumors in ESCC and analyzed relationships between VEGF-C expression and clinicopathologic findings including LMM in submucosal ESCC. The subjects were 87 patients with submucosal ESCC. Immunohistochemical staining of VEGF-C and CD34 was performed with primary tumors, and staining of cytokeratin was performed with dissected lymph nodes. Microvessel density was calculated from CD34 expression, and LMM was detected by cytokeratin staining. VEGF-C overexpression significantly correlated with depth of tumor invasion, lymphatic invasion, and lymph node metastasis (P<0.05, P<0.0001, and P<0.0001, respectively). High microvessel density also correlated with lymphatic invasion and lymph node metastasis (P<0.005 and P<0.05, respectively). LMM was detected in 8 cases and 14 lymph nodes by cytokeratin staining. VEGF-C overexpression and high microvessel density were found in tumors with lymph node metastasis and/or LMM, compared with tumors without nodal metastasis or LMM (P<0.0001 and P<0.01, respectively). The present findings indicate that in ESCC with submucosal invasion, VEGF-C overexpression of the primary tumor is a strong high risk factor for lymph node metastasis, including LMM. Supported in Grant No. 17390373 part by grants-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture, Japan. (Shoji Natsugoe, M.D., Ph.D.)     

环氧化酶-2表达与胃癌淋巴管生成及淋巴结转移的关系

目的研究环氧化酶-2(COX-2)与血管内皮生长因子C(VEGF-C)在胃癌中的表达及其与胃癌临床病理因素间的关系,并评价上述两指标与肿瘤新生淋巴管和淋巴结转移之间的相关性。方法采用免疫组织化学(免疫组化)染色法,检测63例胃癌原发灶标本COX-2与VEGF-C蛋白的表达情况,并用淋巴管内皮细胞特异性抗体LYVE-1行免疫组化染色,观察肿瘤组织淋巴管生成状况。结果所测63例胃癌组织中,COX-2及VEGF-C的表达阳性率分别为66.7%(42/63)和52.4%(33/63),35例标本(55.6%)中可检测到LYVE-1阳性的肿瘤新生淋巴管。COX-2表达与VEGF-C表达、肿瘤新生淋巴管形成及淋巴结转移等临床病理指标间呈明显相关关系(P<0.05);但与患者性别、肿瘤大小、肿瘤部位、Lauren分型及有无浆膜浸润等无明显相关。结论胃癌组织中,COX-2表达与VEGF-C表达状态、肿瘤淋巴管生成和淋巴结转移均呈明显相关。COX-2可能通过上调VEGF-C表达,促进胃癌淋巴管生成,并顺次导致淋巴结转移的发生。     

乳腺癌前哨淋巴结活检对腋窝淋巴结转移的预警价值研究

目的探讨乳腺癌前哨淋巴结(sentinel lymph node,SLN)预警腋窝淋巴结转移的价值. 方法对56例乳腺癌行亚甲蓝前哨淋巴结定位、活检和腋窝淋巴结清扫术,标本常规行HE染色、免疫组化病理检查. 结果 SLN成功检出52例(52/56,92.8%),常规病理检查证实SLN转移22例;SLN无转移,但非SLN发现转移者1例,假阴性率为4.3%(1/23).常规病理检查无转移的29例患者,免疫组化检测发现1例CK-19( )、EMA( ),另1例CK-19( ),CEA( ),而所属非前哨淋巴结无肿瘤转移. 结论乳腺癌亚甲蓝前哨淋巴结定位、活检可以预示腋窝淋巴结转移.     

Oncological issues in staging mediastinal lymph node metastasis for left lung cancer

ObjectiveWe aimed to discuss the underlying oncological issues in staging of mediastinal lymph node metastasis in patients with left lung cancer who underwent extended radical lymphadenectomy (ERL).MethodsThis multi-institutional retrospective study analyzed 116 patients with left non-small-cell lung cancer who underwent bilateral paratracheal lymph node dissection (ERL) via median sternotomy. The clinicopathological records of patients with mediastinal lymph node metastasis were examined for prognostic factors, including age, sex, histology, tumor size, cN number, preoperative data, metastatic stations (number and distribution), pT, and adjuvant chemotherapy.ResultsMediastinal lymph node metastases were found in 43 patients, and right paratracheal lymph node metastases (pN3) were found in 13 patients. The 5-year overall survival rate was 25.2% in patients with pN3 tumors (n = 13) and 23.1% in patients with pN2 tumors (n = 30). The prognosis did not differ between patients with pN3 and pN2. Univariate analyses showed that histology, cN, and adjuvant chemotherapy were significant prognostic factors in patients with mediastinal lymph node metastasis. In these 43 patients, cN and adjuvant chemotherapy were significant independent prognostic factors in multivariate analysis.ConclusionsThe prognostic factors for left lung cancer with mediastinal lymph node metastasis were cN status and adjuvant chemotherapy, and not pN status (pN2 or pN3). We hope that the study results, which suggest that there may be no difference in prognosis between pN2 and pN3, would broaden the discussion of oncological issues in the staging of mediastinal lymph node metastasis of left lung cancer.     

Predictors of nonsentinel lymph node metastasis in breast cancer patients

BACKGROUND: In order to define a future subset of breast cancer patients in whom the axilla may be staged by sentinel lymph node biopsy alone, the conditions under which nonsentinel axillary lymph node metastases occur must be delineated. METHODS: A prospective database including 212 breast cancer patients who underwent sentinel lymph node biopsy followed by completion axillary dissection at our institution was reviewed. A multivariate, logistic, stepwise regression was performed to evaluate the relationship between nonsentinel lymph node metastasis and patient age, primary tumor size, presence of lymphatic invasion, use of radioisotope to identify the sentinel node and degree of metastasis in the sentinel node. RESULTS: Tumor size greater than 2 cm, lymphatic invasion of the primary tumor, macrometastasis in the sentinel node, and use of radioisotope all positively correlated independently with metastasis in the nonsentinel lymph node (P = 0.0001, P = 0.0483, P = 0.0008, P = 0.0271, respectively). CONCLUSIONS: Predictors of nonsentinel axillary node metastasis exist and are important in defining those patients in whom a sentinel lymph node biopsy alone may not be adequate.     

Lymph flow and lymph node metastasis in esophageal cancer

This paper delineates which lymph nodes should be dissected due to the high frequency of metastasis associated with different types of primary lesions of the thoracic esophagus. In cancer involving the upper third of the esophagus (Iu), lymph flow was found to be primarily from the superior mediastinal area to the cervical area; in that involving the middle third (Im), it was broadly distributed from the superior, middle, and inferior mediastinal region to the cervical and abdominal regions; and in that involving the lower third (Ei), it tended to extend from the inferior mediastinal region to the abdominal region, with single primary metastatic nodes also being noted in this area. The significance of the top nodes, namely, the nodes located along the right recurrent laryngeal nerve in the upper portion of the thorax, was also investigated, and it was confirmed that the prognosis for patients with metastases to both the top nodes and other nodes was unfavorable. An immunohistochemical study on mediastinal lymph flow using the anti-Su-Ps antibody demonstrated interactions between top nodes and cervical and/or thoracic nodes.Part of this paper was presented at the UICC Kyoto International Symposium on Recent Advances in Management of Digestive Cancers held in Kyoto, Japan, in April 1993.     

CXCL5在膀胱癌组织中的表达及其临床意义

目的研究CXCL5在膀胱正常组织和膀胱癌组织中的表达及与临床病理及预后的关系。方法应用免疫组化方法检测136例膀胱癌和30例膀胱正常组织石蜡标本中CXCL5表达情况,并进行相关临床病理及5年生存率分析。结果在正常膀胱组织和膀胱癌组织中CXCL5表达有显著性差异(P0.05);CXCL5的阳性表达与膀胱癌病理分级、临床分期、淋巴结转移之间有显著性差异(P0.05)。Kaplan-Meier分析结果显示CXCL5的表达与预后呈负相关。用Log-Rank统计方法判断其中有显著性差异(P0.05),且CXCL5强阳性组、弱阳性表达组和阴性组三者之间的5年生存率的差异有统计学意义(P0.05)。结论CXCL5在膀胱癌中表达增高,与膀胱癌的病理分级、临床分期及淋巴结转移呈正相关,其高表达是膀胱癌的独立预后危险因子之一。