下咽癌瘤内淋巴管生成及颈淋巴转移关系的研究

发布时间：2018-08-17 17:25

【摘要】：研究背景：下咽癌发生部位隐蔽不易早期发现,且生物学特征恶劣易发生淋巴结转移。转移是影响患者预后的重要因素。据文献报道,下咽癌5年生存率为28.6%-59.1%,其中出现颈淋巴结转移者较无转移者5年生存率下降约50%。长期以来,大量的研究集中在肿瘤的血管生成及血行转移,一些抗肿瘤血管生成的药也已进入临床。由于缺乏特异的淋巴管内皮标志物,对淋巴管的生成及转移机制的研究进展缓慢,对肿瘤组织内是否存在新生淋巴管,肿瘤淋巴转移的途径等问题仍有争论。近年来研究发现多种淋巴管内皮标志物,如血管内皮细胞生长因子C、D(VEGF-C/D)及其受体VEGFR-3,和淋巴管内皮特异性标志物,如同源异型盒转录因子Prox-1、透明质酸受体LYVE-1、肾小球足突膜蛋白podoplanin和D2-40。不同于VEGFR-3同时表达于淋巴管内皮和某些肿瘤的微血管内皮、肿瘤细胞,D2-40只在淋巴管内皮表达,在血管内皮不表达。国外学者研究发现D2-40是一种高选择性与podoplanin结合的抗体,和其它淋巴管内皮标志物如：LYVE-1、podoplanin和Prox-1相比,D2-40有更高的特异性。因此,D2-40可常规用于观察淋巴管形态、分布,便于研究淋巴管生成、淋巴管转移。已有研究表明碱性成纤维细胞生长因子b-FGF、VEGF-C、VEGF-D、COX-2参与肿瘤淋巴管生成,并在肿瘤淋巴结转移中发挥重要作用。抗肿瘤淋巴管生成有望成为抗肿瘤治疗的新方式。目的：观察D2-40标记的淋巴管的形态,分别比较下咽癌患者肿瘤组织中和癌旁正常黏膜中b-FGF、D2-40的表达情况,检测淋巴管密度(LVD),并与淋巴转移情况进行分析,探讨D2-40的临床病理意义,下咽癌可能的淋巴转移途径,分析探讨下咽癌淋巴管生成机制,为下咽癌治疗和判断预后提供理论依据。方法：材料取自2007年10月～2009年9月间山东大学齐鲁医院耳鼻咽喉头颈外科行手术切除的下咽癌47例及癌旁正常下咽黏膜组织。应用免疫组织化学方法分别检测这47例患者瘤内和癌旁正常黏膜组织b-FGF、D2-40的表达,观察瘤内和癌旁正常黏膜组织中淋巴管形态有无差别,同时采用Greespan半定量法对细胞染色强度及阳性细胞百分率进行评分, Weidner法对淋巴管进行计数,并与临床病理参数进行分析。应用SPSS16.0统计学软件,对结果用t检验、秩和检验、X2检验或Fisher确切概率法进行分析,检验水准取0.05。结果： 1.b-FGF在下咽癌瘤内阳性表达率为82.98%,在正常组织中的阳性表达率为8.51%,两者差异显著(P=0.000)。b-FGF在不同年龄、性别、T分期、高-中分化和低分化间差异无统计学意义(P0.05)。有淋巴结转移者b-FGF阳性表达率高于无淋巴结转移者(P0.05)。 2.下咽癌肿瘤组织中可观察到新生淋巴管：淋巴管形态幼稚,并且部分管腔内可见肿瘤细胞。而在正常组织中淋巴管多呈扩张状。 3.下咽癌瘤内LVD值高于癌旁正常粘膜组织LVD值,差异有统计学意义(P0.05)。肿瘤淋巴管密度和患者的年龄、性别、肿瘤的T分期和分化程度差别均无统计学意义(P0.05),而与N分期之间差别有统计学意义(P0.05)。 4.下咽癌组织中b-FGF阳性表达的LVD值高于b-FGF阴性表达的LVD值,差别有统计学意义(P0.05)。结论：本研究发现,在下咽癌肿瘤组织内与癌旁正常黏膜组织中D2-40标记的淋巴管形态不同,属于未发育成熟的淋巴管,这与国外学者研究发现的新生淋巴管形态一致,证明其为新生淋巴管。肿瘤内高表达的淋巴管密度和淋巴结转移相关(P0.05)提示新生淋巴管是有功能的,瘤内淋巴管生成增多肿瘤转移亦增加,即肿瘤可能是通过这些淋巴管转移到淋巴结。b-FGF阳性表达和阴性表达在瘤内和正常组织间、淋巴管密度间存在差异,提示高表达b-FGF会诱导肿瘤内淋巴管生成。因此,我们认为下咽癌内存在新生淋巴管,b-FGF可促进其生成,从而促进淋巴结转移。随着对肿瘤淋巴管生成、调控机制研究的不断深入,抑制肿瘤淋巴管生成将成为治疗肿瘤患者的一种方式。
[Abstract]:Research background:
Metastasis is an important factor affecting the prognosis of hypopharyngeal carcinoma. According to the literature, the 5-year survival rate of hypopharyngeal carcinoma is 28.6% - 59.1%. The 5-year survival rate of cervical lymph node metastasis is about 50% lower than that of non-metastasis. Some anti-angiogenesis drugs have also been used in tumor angiogenesis and hematogenous metastasis. Due to the lack of specific markers of lymphatic endothelium, the progress in the study of lymphatic angiogenesis and metastasis is slow. There are still controversies about the existence of new lymphatic vessels in tumor tissues and the pathway of lymphatic metastasis. To study and identify a variety of lymphatic endothelial markers, such as vascular endothelial growth factor C, D (VEGF-C/D) and its receptor, VEGFR-3, and lymphatic endothelial specific markers, such as homeobox transcription factor Prox-1, hyaluronic acid receptor LYVE-1, glomerular Podoplanin and D2-40. D2-40 is a highly selective antibody binding to podoplanin. Compared with other lymphatic endothelial markers such as LYVE-1, Podoplanin and Prox-1, D2-40 has higher specificity. Basic fibroblast growth factor b-FGF, VEGF-C, VEGF-D, COX-2 have been shown to be involved in tumor lymphangiogenesis and play an important role in tumor lymph node metastasis. Way.
Objective:
To observe the morphology of lymphatic vessels labeled with D2-40, compare the expression of b-FGF and D2-40 in tumor tissues and normal mucosa adjacent to hypopharyngeal carcinoma, detect lymphatic vessel density (LVD) and analyze lymphatic metastasis, explore the clinicopathological significance of D2-40, the possible lymphatic metastasis pathway of hypopharyngeal carcinoma, and lymphangiogenesis of hypopharyngeal carcinoma. The mechanism provides a theoretical basis for the treatment and prognosis of hypopharyngeal carcinoma.
Method:
Materials 47 cases of hypopharyngeal carcinoma and normal hypopharyngeal mucosa adjacent to the tumor underwent surgical excision from October 2007 to September 2009 in Qilu Hospital of Shandong University. The lymphatic vessels were counted by Weidner method and analyzed with clinicopathological parameters. The results were evaluated by t test, rank sum test, X2 test or Fisher's exact probability method. Line analysis, test level 0.05.
Result:
1. The positive expression rate of b-FGF was 82.98% in hypopharyngeal carcinoma and 8.51% in normal tissues. The difference was significant (P = 0.000). There was no significant difference in age, sex, T stage, high-middle differentiation and low differentiation of b-FGF (P 0.05). The positive expression rate of b-FGF in patients with lymph node metastasis was higher than that in patients without lymph node metastasis (P 0.05).
2. Neogenetic lymphatic vessels were observed in hypopharyngeal carcinoma: lymphatic vessels were immature in shape and tumor cells could be seen in some lumens, while lymphatic vessels were usually dilated in normal tissues.
3. The LVD value of hypopharyngeal carcinoma was higher than that of normal mucosal tissue (P 0.05). There was no significant difference in lymphatic vessel density, age, sex, T stage and differentiation degree of tumor between hypopharyngeal carcinoma and normal mucosal tissue (P 0.05), but there was significant difference between tumor and N stage (P 0.05).
4. The LVD value of positive expression of b-FGF in hypopharyngeal carcinoma was higher than that of negative expression of b-FGF (P 0.05).
Conclusion:
In this study, D2-40 labeled lymphatic vessels in hypopharyngeal carcinoma and normal mucosa adjacent to hypopharyngeal carcinoma were found to be immature lymphatic vessels, which were consistent with the morphology of new lymphatic vessels found by foreign scholars, and proved to be new lymphatic vessels. These results suggest that neonatal lymphatics are functional and that the lymphangiogenesis and metastasis of tumors are increased. The positive and negative expression of b-FGF may be in lymph nodes through these lymphatics. There are differences in lymphatic vessel density between tumors and normal tissues, suggesting that high expression of b-FGF may induce lymphangiogenesis in tumors. It is believed that there are new lymphatic vessels in hypopharyngeal carcinoma, and b-FGF can promote its production and lymph node metastasis.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R739.63

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