| Part one, The expressions of LYVE-1, VEGFR-3, Podoplanin, Prox-1 in cancer tissues and paracancer tissues[Background and Purpose] The function of lymphatic system markers in the process of lymph node metastasis was known gradually, whereas there were few studies about the relationship between lymphatic system markers and lymph node metastasis in colorectal cancer. Lymphatic system markers included the lymphatic endothelial markers and lymphatic endothelial growth factors. This study was designed to analyze the expressions of lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), vascular endothelial growth factor receptor 3 (VEGFR-3), Podoplanin and Prox-1 in cancer tissues and paracancer tissues, and to analyze the relationship between lymphatic endothelial markers and lymph node metastasis in colorectal cancer.[Materials and Methods] 47 paired cancer and paracancer fresh specimens were collected from patients who received surgical treatment between August 2013 and March 2014 in Cancer Hospital, Chinese Academy of Medical Sciences. The number of specimens with NO, N1a, N1b, N2a and N2b lymphatic staging was 20,7,5,8 and 7; the number of specimens with Ⅱa, Ⅱb, Ⅲb and Ⅲc was 18,2,18 and 9. Fluorescence real-time quantitative PCR was used to detect the expression of LYVE-1, VEGFR-3, Podoplanin and Prox-1 in cancer tissues and paracancer tissues. The differences of expression between cancer tissues and paracancer tissues were analyzed, the differences of expression in cancer tissues between N+ and N-,among N1a, N1b, N2a and N2b, among Ⅱa, Ⅱb, Ⅲb and Ⅲc were analyzed, and the differences in paracancer were also analyzed.[Results] The positive expression rates of LYVE-1, VEGFR-3, Podoplanin and Prox-1 were 100%,93.6%,100% and 91.4% in cancer tissues, and 100%,100%,100% and 87.2% in paracancer tissues.The expression level of LYVE-1 and VEGFR-3 was higher in paracancer tissues than in cancer tissues (8.393±10.248 vs.0.498±0.794, P< 0.001; 5.028±8.253 vs. 1.741±3.065, P=0.013, respectively), whereas the expression level of Podoplanin was higher in cancer tissue than in paracancer tissues (3.365±4.552 vs.1.634±1.421, P=0.016). There was no significant difference in expression of Prox-1 between cancer tissues and paracancer tissues (53.729±161.664 vs.11.323±20.637, P=0.078).There were no significant differences in the expression level of LYVE-1, VEGFR-3, Podoplanin and Prox-1 in cancer tissues between N(+) and N(-) (0.592±0.953 vs. 0.372±0.504, P=0.354; 1.926±3.275 vs.1.478±2.805,P=0.631; 2.965±2.405 vs. 3.904±6.459, P=0.490; 72.350±233.542 vs.39.936±76.925, P=0.503) and similarly in paracancer tissues (9.046±11.375 vs.7.511±8.706, P=0.617; 4.68±15.345 vs. 5.521±11.339, P=0.738; 1.565±1.230 vs.1.773±1.670, P=0.625; 16.110±30.777 vs. 7.776±5.529, P=0.174), no significant differences in cancer tissues among N1a, N1b, N2a and N2b staging (0.383±0.420 vs.0.586±1.013 vs.0.630±0.871 vs.0.762±1.452, P=0.914; 0.868±0.928 vs.3.501±5.929 vs.1.116±1.052 vs.2.786±3.973, P=0.493; 1.719±1.545 vs.2.716±2.507 vs.3.379±1.163 vs.3.914±3.710, P=0.370; 20.585±25.348 vs.43.801±48.398 vs.61.697±133.726 vs.31.658±37.608, P=0.780) and similarly in paracancer tissues (6.628±.827 vs.7.645±9.339 vs.12.526±17.303 vs.8.487±8.186, P=0.784; 4.093±4.136 vs.2.747±.386 vs.4.975±.504 vs.6.316±3.428, P=0.955; 1.156±0.759 vs.0.958±0.642 vs.1.640±1.527 vs.2.322±1.346, P=0.199; 9.230±6.486 vs. 3.238±2.558 vs.9.090±4.263 vs.8.061±6.542, P=0.234), no significant differences in cancer tissues among Ⅱa, Ⅱb, Ⅲb and Ⅲc staging (0.346±0.491 vs.0.609±.774 vs. 0.400±0.570 vs.0.975±1.420, P=0.242; 1.306±2.814 vs.2.940±3.182 vs.1.522±3.207 vs. 2.735±3.451, P=0.654; 3.321±6.361 vs.9.155±6.612 vs.2.459±1.780 vs.3.975±3.215, P=0.254; 78.362±246.080 vs.18.240±18.577 vs.25.867±33.432 vs.68.075±124.580, P=0.784) and similarly in paracancer tissues (6.833±7.620 vs.13.612±19.239 vs. 9.315±13.150 vs.8.508±.250, P=0.793; 5.011±11.570 vs.9.854±11.435 vs. 4.399±6.096 vs.5.246±3.651, P=0.860; 1.788±1.731 vs.1.637±.404 vs.1.352±1.153 vs. 1.992±1.338, P=0.699; 16.754±.445 vs.10.315±5.205 vs.7.685±5.501 vs. 7.958±5.914,P=0.576).[Conclusions] Highly positive expression rates of LYVE-1, VEGFR-3, Podoplanin and Prox-1 were detected both in cancer tissues and paracancer tissues. The expression levels of LYVE-1 and VEGFR-3 were higher in paracancer tissues than in cancer tissues, whereas the expression level of Podoplanin was higher in cancer tissue than in paracancer tissues. Expression levels of the four markers in cancer tissues were not correlated with lymphatic metastasis and TNM staging, similarly in paracancer tissues. The value of LYVE-1, VEGFR-3, Podoplanin and Prox-1 in predicting metastasis of colorectal cancer was not revealed in this study. Whether LYVE-1, VEGFR-3, Podoplanin and Prox-1 could be used as powerful predictors for detecting lymph node metastasis of colorectal cancer or not needed to be verified by large sample trial.Part two, Relationship between number of lymph node retrieved and prognosis for colorectal cancer[Background and Purpose] The incidence and mortality rate of colorectal cancer stay at the high level. Both of the doctor and patient are paying a attention to the way to improve prognosis of colorectal cancer after operation. The prognosis of colorectal cancer is influenced by various factors including the number of lymph node retrieved which is focused on by several studies. This study was designed to explore the relationship between number of lymph node retrieved and prognosis and to analyze the influence factors of number of lymph node retrieved.[Materials and Methods] Clinicopathological data of 867 patients who received radical colorectal resection in Cancer Hospital, Chinese Academy of Medical Sciences between July,2006 and February,2010 were reviewed. Number of lymph node retrieved between patients with and without recurrence, and between deaths and survivals were calculated and compared; Based on 5-year survival rate, the minimum number of lymph node retrieved (N) was confirmed; The recurrence rate and 5-year survival rate in all patients were calculated and the impact of influence factors including patients themselves, tumor itself, operation types etc. on prognosis were analyzed, meanwhile the role of number of lymph node retrieved was observed especially; all patients were divided into two groups named <N group and ≥N group according to the N we confirmed, and the different survival rates and recurrence rates between the two groups for each influence factor were compared; the influence factors for number of lymph node retrieved were also analyzed.[Results] The recurrence rate and 5-year overall survival rate in all patients were 10.9% and 70.8%. The mean number of lymph node retrieved was 13.7±11.6 and 9.0±12.0 in patients with and without recurrence (P<0.001), and 16.2±10.5 and 19.3±12.6 in deaths and survivals (P=0.001), respectively.The minimum number of lymph node retrieved was 12 based on our results. All patients were divided into the<12 group and ≥group, and the 5-year survival rate was 58.8% and 76.1% in<12 group and ≥12 group (P<0.001), the recurrence rate was 22.3% and 5.2% (P<0.001), respectively. Multiple factors analysis showed that number of lymph node retrieved was one of the independent factors by which the survival rate of patients was influenced (P<0.001).Patients based on each parameter were divided into two groups (<12 group and ≥12) group according to the minimum number of lymph node retrieved. The results showed that the survival rates were 59.6% and 74.0% in<12 group and ≥12 group in male patients (P<0.001),68.0% and 73.4% in female patients (P=0.022),67.1% and 73.5% in patients aged<50 years (P=0.024),62.4% and 73.4% in patients aged ≥50 years (P<0.001),66.4% and 74.2% in patients with the size of tumor <5cm (P<0.001), 54.2% and 71.1% in patients with the size of tumor ≥5cm (P<0.001),66.5% and 74.1% in moderately differentiated carcinoma (P< 0.001),50.0% and 73.2% in poorly differentiated carcinoma (P<0.001),63.9% and 75.1% in adenocarcinoma (P<0.001), 65.7% and 74.2% in patients without vessel carcinoma embolus (P<0.001),65.4% and 73.5% in patients without neural invasion (P<0.001),52.6% and 84.6% in pT2 staging tumors (P<0.001),64.5% and 74.4% in pT3 staging tumors (P<0.001),68.2% and 78.9% in stage Ⅱ tumors (P<0.001),54.8% and 69.0% in stage Ⅲ tumors (P<0.001). Recurrence rates were 23.2% and 7.0% in<12 group and ≥12 group in male patients (P<0.001),15.0% and 6.9% in female patients (P=0.015),15.1% and 6.5% in patients aged<50 years (P=0.032),20.2% and 7.1% in patients aged ≥50 years (P<0.001), 18.1% and 6.2% in patients with the size of tumor<5cm (P<0.001),22.0% and 9.2% in patients with the size of tumor ≥5cm (P=0.013),18.0% and 7.3% in moderately differentiated carcinoma (P<0.001),21.7% and 4.7% in poorly differentiated carcinoma (P=0.002),18.0% and 6.2% in adenocarcinoma (P<0.001),17.9% and 6.4% in patients without vessel carcinoma embolus (P<0.001),18.0% and 6.1% in patients without neural invasion (P<0.001),26.3% and 13.6% in pT2 staging tumors (P=0.013),18.4% and 6.6% in pT3 staging tumors (P<0.001),14.7% and 4.7% in stage Ⅱ tumors (P< 0.001),24.2% and 9.3% in stage Ⅲ tumors (P<0.001).According to the lymph node ratio (LNR), all patients with stage Ⅲ carcinoma were divided into the LNR<0.125 group,0.125≤LNR<0.25 group,0.25≤LNR<0.375 group and LNR ≥0.375 group. The recurrence rates in these four groups were 9.8%, 12.1%,20.3% and 32.5%(P=0.001), and the 5-year survival rates were 73.8%,65.7%, 57.4% and 38.5% (P<0.001), respectively.The number of lymph node retrieved was obviously more in patients with stage Ⅲ carcinoma than that in stage Ⅱ carcinoma (21.7±12.9 vs.15.4±10.4, P<0.001); number of lymph node retrieved was 21.7±12.9 in patients with the size of tumor<5cm, and 20.2±14.3 in patients with the size of tumor ≥5cm (P=0.020); the number was 15.6±9.3, 19.1±12.7 and 18.1±10.9 in well, moderated and poor differentiated carcinomas (P=0.007), and the number of lymph node retrieved was 17.4±8.9,18.2±11.8 and 21.3±16.1 in patients with pT2, pT3 and pT4 stage, respectively (P=0.031).[Conclusions] Number of lymph node retrieved was one of influence factors which had impact on the recurrence rate and survival rate of colorectal cancer after operation. The minimum number of lymph node retrieved should be 12 based on our results, and patients with number of lymph node retrieved ≥12 had the better prognosis compared with patients with <12 lymph node retrieved. LNR was one of factors correlated with prognosis for stage Ⅲ colorectal cancer patients, the survival rate reduced and the recurrence rate increased as the increasing of LNR. Tumor size, degree of differentiation, depth of invasion and pathological stage were correlated with the number of lymph node retrieved. |
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