調強放療技術下鼻咽癌侵襲性標志物表達對其療效預測的意義
發(fā)布時間：2018-09-12 13:59
【摘要】：研究背景與目的：上皮-間質轉化(EMT)是惡性腫瘤浸潤和轉移的重要機制,腫瘤內新生血管和淋巴管的形成與腫瘤浸潤轉移密切相關,腫瘤細胞通過EMT獲得侵襲與轉移的能力,侵入腫瘤新生血管與淋巴管內,完成內侵襲過程。本研究觀察上皮-間質轉化相關標志物E-cad, N-cad及CD34標記的微血管和D2-40標記的淋巴管在鼻咽癌組織中的表達情況及其相互關系,分析其與鼻咽癌臨床病理特征的關系及與轉移復發(fā)和預后的關系,進一步研究這些侵襲性標志物與放療局控率的關系及調強放療對這些標志物高危表達的逆轉趨勢,初步探討它們在鼻咽癌發(fā)展中的作用及其臨床應用價值。 方法：對160例鼻咽癌組織標本采用免疫組織化學方法同期檢測E-cad、N-cad、CD34和D2-40表達,通過計算機輔助圖像分析系統(tǒng)定量分析其表達情況,與臨床病理資料作對照,研究其與鼻咽癌臨床病理特征的關系,通過Spearman秩相關分析這些指標在鼻咽癌中表達的相關性。對接受常規(guī)放射治療的77例患者進行治療后隨訪,通過單因素和Logistic多因素回歸分析篩選鼻咽癌復發(fā)轉移的獨立風險因素,Kaplan-Meier法和Log-rank檢驗上皮-間質轉化相關標志物與鼻咽癌的預后關系。對接受調強放射治療的83例患者,通過精確概率法分析E-cad、N-cad, D2-40與CD34表達與鼻咽部腫瘤體積退縮情況的關系。 結果： 1、侵襲性標志物檢測結果：E-cad蛋白主要表達于細胞膜和細胞漿,呈棕黃或棕褐色,陽性細胞彌漫或局灶性分布,在鼻咽癌組織中表達的免疫組化陽性指數(IHCPI)為1.250±0.454(95%區(qū)間1.182～1.315)；N-cad蛋白主要在細胞膜和細胞質表達,呈棕黃色至深褐色彌散性分布,IHCPI為0.735±0.338(95%區(qū)間0.684～0.785)；D2-40標記的淋巴管呈一致性的管腔結構,呈棕黃色染色,表現為一層薄壁,管腔內很少有淋巴細胞,無紅細胞,IHCPI為0.122±0.127(95%區(qū)間0.102-0.141)；CD34標記的微血管可見染色清晰的血管內皮細胞,呈棕黃色至深褐色彌散性分布,管腔大小不一,IHCPI為0.116±0.061(95%區(qū)間0.106～0.125)。E-cad表達下調、N-cad表達上調與鼻咽癌的淋巴結轉移、腫瘤分期和復發(fā)轉移具有密切關系,CD34表達與腫瘤分期有關,D2-40表達與淋巴管轉移有關；這些指標表達與患者的年齡和性別均無顯著意義(P0.05)。Spearman秩相關檢驗顯示E-cad與N-cad,以及E-cad與D2-40表達呈明顯負相關,CD34和D2-40表達旱明顯正相關。 2、侵襲性標志物表達與鼻咽癌復發(fā)轉移相關性分析：單因素分析顯示E-cad,N-cad, CD34和D2-40表達與鼻咽癌復發(fā)轉移相關(P0.05)。多因素分析顯示E-cad和C934是影響鼻咽癌復發(fā)轉移的獨立風險因素。E-cad下調,N-cad、CD34和D2-40上調的鼻咽癌病人預后差,反之亦然。 3、侵襲性標志物表達與鼻咽癌放療結果分析：精確概率法分析顯示70Gy時鼻咽癌原發(fā)灶和頸淋巴結退縮均高于50Gy時；調強放療組腫瘤體積退縮率高于常規(guī)放療組,差異有統(tǒng)計學意義(P0.05)；E-cad高表達較E-cad1(?)表達、V-cad低表達較N-cad高表達組鼻咽部腫瘤退縮好,差異有統(tǒng)計學意義(P0.05)。在CD34高表達組中,常規(guī)放療與調強放療對腫瘤的退縮率無明顯差異(P0.05)；在CD34低表達組中,調強放療組對腫瘤退縮率高于與常規(guī)放療組(P0.05)。在D2-40高表達組中,常規(guī)放療與調強放療對腫瘤的退縮率無明顯差異(P0.05)；在D2-40低表達組中,調強放療組對腫瘤退縮率高于與常規(guī)放療組(P0.05)。 結論：鼻咽癌組織中存在EMT現象,E-cad蛋白在鼻咽癌中低表達,而N-cad蛋白在鼻咽癌中高表達,可能存在E-cad向N-cad轉化；鼻咽癌基質內存在新生淋巴管和微血管,新生淋巴管與淋巴結轉移相關,新生微血管與腫瘤T分期和臨床分期相關。聯(lián)合檢測E-cad、N-cad、CD34和D2-40對于鼻咽癌侵襲轉移和預后有一定的預測價值。在早期鼻咽癌患者中調強放療技術對腫瘤的局控率與常規(guī)放療技術相仿,提示是否可適當下調每次分割劑量,有利進一步保護腫瘤周圍正常組織；在局部晚期鼻咽癌患者中,調強放療技術對腫瘤的局控率高于常規(guī)放療技術。調強放療技術增加了局部晚期鼻咽癌患者中CD34和D2-40低表達組的腫瘤退縮率,考慮是調強放療技術可能因為增加了每次分割劑量,從而提高了腫瘤殺傷效率。在鼻咽癌侵襲性標志物不同表達的患者中,調強放療技術對腫瘤的局控率均高于常規(guī)放療技術,因此推測調強放療技術可能存在逆轉相關侵襲性過程。
[Abstract]:BACKGROUND AND OBJECTIVE: Epithelial-mesenchymal transition (EMT) is an important mechanism of invasion and metastasis of malignant tumors. The formation of neovascularization and lymphatic vessels in tumors is closely related to tumor invasion and metastasis. Tumor cells acquire the ability of invasion and metastasis through EMT, invade tumor neovascularization and lymphatic vessels, and complete the process of internal invasion. Expression of E-cad, N-cad, CD34-labeled microvessels and D2-40-labeled lymphatics in nasopharyngeal carcinoma tissues and their relationship with clinicopathological features, metastasis, recurrence and prognosis were analyzed. The relationship between these invasive markers and local control rate of radiotherapy was further studied. The reversal trend of high-risk expression of these markers by relational and intensity-modulated radiotherapy (IMRT) was studied. The role of IMRT in the development of nasopharyngeal carcinoma and its clinical value were discussed.
Methods: The expression of E-cad, N-cad, CD34 and D2-40 in 160 nasopharyngeal carcinoma tissues was detected by immunohistochemistry. The expression of E-cad, N-cad, CD34 and D2-40 was quantitatively analyzed by computer-aided image analysis system. The relationship between E-cad, N-cad, CD34 and D2-40 expression and clinicopathological features of nasopharyngeal carcinoma was studied by comparing with clinicopathological data. The independent risk factors for recurrence and metastasis of nasopharyngeal carcinoma were screened by univariate and logistic multivariate regression analysis. Kaplan-Meier method and Log-rank method were used to examine the relationship between epithelial-mesenchymal transition-related markers and the prognosis of nasopharyngeal carcinoma. The relationship between the expression of E-cad, N-cad, D2-40 and CD34 and the volume regression of nasopharyngeal tumors was analyzed by exact probability method in 83 patients with IMRT.
Result:
1. Invasive markers: E-cad protein was mainly expressed in the cell membrane and cytoplasm, brown or brown, positive cells were diffuse or focal distribution, the expression of immunohistochemical positive index (IHCPI) in nasopharyngeal carcinoma tissue was 1.250 (+ 0.454) (95% range 1.182-1.315); N-cad protein was mainly expressed in the cell membrane and cytoplasm, showing brown. Yellow to dark brown diffuse distribution, IHCPI 0.735 (+ 0.338) (95% range 0.684 ~0.785); D2-40 labeled lymphatic vessels were uniform lumen structure, showing a brown-yellow staining, a thin wall, few lymphocytes in the lumen, no red blood cells, IHCPI 0.122 (+ 0.127) (95% range 0.102-0.141); CD34 labeled microvessels showed clear staining. The clear vascular endothelial cells were brown-yellow to dark-brown diffusely distributed with different lumen sizes. IHCPI was 0.116 (+ 0.061) (95% range 0.106-0.125). E-cad expression was down-regulated, N-cad expression was up-regulated and closely related to lymph node metastasis, tumor stage and recurrence and metastasis, CD34 expression was related to tumor stage, D2-40 expression was related to lymphatic metastasis. Spearman rank correlation test showed that E-cad was negatively correlated with N-cad, E-cad was negatively correlated with D2-40 expression, and CD34 and D2-40 were positively correlated with drought.
2. Correlation between expression of invasive markers and recurrence and metastasis of nasopharyngeal carcinoma: Univariate analysis showed that expression of E-cad, N-cad, CD34 and D2-40 was associated with recurrence and metastasis of nasopharyngeal carcinoma (P 0.05). Multivariate analysis showed that E-cad and C934 were independent risk factors for recurrence and metastasis of nasopharyngeal carcinoma. The prognosis is poor, and vice versa.
3. Expression of invasive markers and results of radiotherapy for nasopharyngeal carcinoma: Precise probability analysis showed that the primary lesion and cervical lymph node shrinkage of nasopharyngeal carcinoma at 70 Gy was higher than that at 50 Gy; the tumor volume shrinkage rate of IMRT group was higher than that of conventional radiotherapy group, the difference was statistically significant (P 0.05); E-cad expression was higher than that of E-cad1 (?), V-cad expression was lower than that of N-cad. There was no significant difference between conventional radiotherapy and intensity modulated radiotherapy (P 0.05). In the low expression group, intensity modulated radiotherapy had a higher rate of tumor regression than conventional radiotherapy (P 0.05). In the high expression group, conventional radiotherapy and intensity modulated radiotherapy had a higher rate of tumor regression than conventional radiotherapy (P 0.05). There was no significant difference in tumor shrinkage rate between the two groups (P 0.05), but in the low expression group of D2-40, the rate of tumor shrinkage in IMRT group was higher than that in conventional radiotherapy group (P 0.05).
Conclusion: EMT exists in nasopharyngeal carcinoma tissues, E-cad protein is low expressed in nasopharyngeal carcinoma, and N-cad protein is high expressed in nasopharyngeal carcinoma, which may lead to the transformation from E-cad to N-cad. Combined detection of E-cad, N-cad, CD34 and D2-40 has certain predictive value for invasion, metastasis and prognosis of nasopharyngeal carcinoma. In early stage nasopharyngeal carcinoma patients, the local control rate of IMRT is similar to that of conventional radiotherapy, suggesting whether proper dose reduction of each dose is beneficial to protect the surrounding normal tissues. Intensity modulated radiation therapy (IMRT) can increase the tumor regression rate in locally advanced nasopharyngeal carcinoma (NPC) patients with low expression of CD34 and D2-40. In patients with different expression of invasive markers, intensity modulated radiation therapy (IMRT) has a higher tumor control rate than conventional radiotherapy, so IMRT may reverse the invasive process.
【學位授予單位】：復旦大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R739.63
[Abstract]:BACKGROUND AND OBJECTIVE: Epithelial-mesenchymal transition (EMT) is an important mechanism of invasion and metastasis of malignant tumors. The formation of neovascularization and lymphatic vessels in tumors is closely related to tumor invasion and metastasis. Tumor cells acquire the ability of invasion and metastasis through EMT, invade tumor neovascularization and lymphatic vessels, and complete the process of internal invasion. Expression of E-cad, N-cad, CD34-labeled microvessels and D2-40-labeled lymphatics in nasopharyngeal carcinoma tissues and their relationship with clinicopathological features, metastasis, recurrence and prognosis were analyzed. The relationship between these invasive markers and local control rate of radiotherapy was further studied. The reversal trend of high-risk expression of these markers by relational and intensity-modulated radiotherapy (IMRT) was studied. The role of IMRT in the development of nasopharyngeal carcinoma and its clinical value were discussed.
Methods: The expression of E-cad, N-cad, CD34 and D2-40 in 160 nasopharyngeal carcinoma tissues was detected by immunohistochemistry. The expression of E-cad, N-cad, CD34 and D2-40 was quantitatively analyzed by computer-aided image analysis system. The relationship between E-cad, N-cad, CD34 and D2-40 expression and clinicopathological features of nasopharyngeal carcinoma was studied by comparing with clinicopathological data. The independent risk factors for recurrence and metastasis of nasopharyngeal carcinoma were screened by univariate and logistic multivariate regression analysis. Kaplan-Meier method and Log-rank method were used to examine the relationship between epithelial-mesenchymal transition-related markers and the prognosis of nasopharyngeal carcinoma. The relationship between the expression of E-cad, N-cad, D2-40 and CD34 and the volume regression of nasopharyngeal tumors was analyzed by exact probability method in 83 patients with IMRT.
Result:
1. Invasive markers: E-cad protein was mainly expressed in the cell membrane and cytoplasm, brown or brown, positive cells were diffuse or focal distribution, the expression of immunohistochemical positive index (IHCPI) in nasopharyngeal carcinoma tissue was 1.250 (+ 0.454) (95% range 1.182-1.315); N-cad protein was mainly expressed in the cell membrane and cytoplasm, showing brown. Yellow to dark brown diffuse distribution, IHCPI 0.735 (+ 0.338) (95% range 0.684 ~0.785); D2-40 labeled lymphatic vessels were uniform lumen structure, showing a brown-yellow staining, a thin wall, few lymphocytes in the lumen, no red blood cells, IHCPI 0.122 (+ 0.127) (95% range 0.102-0.141); CD34 labeled microvessels showed clear staining. The clear vascular endothelial cells were brown-yellow to dark-brown diffusely distributed with different lumen sizes. IHCPI was 0.116 (+ 0.061) (95% range 0.106-0.125). E-cad expression was down-regulated, N-cad expression was up-regulated and closely related to lymph node metastasis, tumor stage and recurrence and metastasis, CD34 expression was related to tumor stage, D2-40 expression was related to lymphatic metastasis. Spearman rank correlation test showed that E-cad was negatively correlated with N-cad, E-cad was negatively correlated with D2-40 expression, and CD34 and D2-40 were positively correlated with drought.
2. Correlation between expression of invasive markers and recurrence and metastasis of nasopharyngeal carcinoma: Univariate analysis showed that expression of E-cad, N-cad, CD34 and D2-40 was associated with recurrence and metastasis of nasopharyngeal carcinoma (P 0.05). Multivariate analysis showed that E-cad and C934 were independent risk factors for recurrence and metastasis of nasopharyngeal carcinoma. The prognosis is poor, and vice versa.
3. Expression of invasive markers and results of radiotherapy for nasopharyngeal carcinoma: Precise probability analysis showed that the primary lesion and cervical lymph node shrinkage of nasopharyngeal carcinoma at 70 Gy was higher than that at 50 Gy; the tumor volume shrinkage rate of IMRT group was higher than that of conventional radiotherapy group, the difference was statistically significant (P 0.05); E-cad expression was higher than that of E-cad1 (?), V-cad expression was lower than that of N-cad. There was no significant difference between conventional radiotherapy and intensity modulated radiotherapy (P 0.05). In the low expression group, intensity modulated radiotherapy had a higher rate of tumor regression than conventional radiotherapy (P 0.05). In the high expression group, conventional radiotherapy and intensity modulated radiotherapy had a higher rate of tumor regression than conventional radiotherapy (P 0.05). There was no significant difference in tumor shrinkage rate between the two groups (P 0.05), but in the low expression group of D2-40, the rate of tumor shrinkage in IMRT group was higher than that in conventional radiotherapy group (P 0.05).
Conclusion: EMT exists in nasopharyngeal carcinoma tissues, E-cad protein is low expressed in nasopharyngeal carcinoma, and N-cad protein is high expressed in nasopharyngeal carcinoma, which may lead to the transformation from E-cad to N-cad. Combined detection of E-cad, N-cad, CD34 and D2-40 has certain predictive value for invasion, metastasis and prognosis of nasopharyngeal carcinoma. In early stage nasopharyngeal carcinoma patients, the local control rate of IMRT is similar to that of conventional radiotherapy, suggesting whether proper dose reduction of each dose is beneficial to protect the surrounding normal tissues. Intensity modulated radiation therapy (IMRT) can increase the tumor regression rate in locally advanced nasopharyngeal carcinoma (NPC) patients with low expression of CD34 and D2-40. In patients with different expression of invasive markers, intensity modulated radiation therapy (IMRT) has a higher tumor control rate than conventional radiotherapy, so IMRT may reverse the invasive process.
【學位授予單位】：復旦大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R739.63
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