臺灣博碩士論文加值系統

本研究收集1992年至1997年初，在臺大醫院牙科部口腔病理及診斷科檔案中，曾在實施外科手術之前施以輔助性化學治療的口腔鱗狀細胞癌33例，利用蘇木紫與伊紅染色法及免疫組織化學染色方式，研究口腔鱗狀細胞癌經輔助性化學治療後原發及轉移部位腫瘤之組織學形態特徵差異及p53、p21、MDM2和PCNA蛋白之表現。
腫瘤在化學治療後的組織學表現，初期主要表現腫瘤壞死現象，而後期則主要表現腫瘤細胞的角化增加與分化增加現象，然而存活著且具增殖能力的殘餘腫瘤細胞仍然存在，因此化學治療後的手術治療仍應儘快進行，並慎重評估手術方法。
經化學治療後p53於原發部位腫瘤的表現明顯高於化學治療前的表現(p=0.002)，p53的表現變化僅與患者之腫瘤臨床分期有統計學上具邊緣意義之相關(p=0.063)。p21的表現變化與患者之淋巴結狀況(p=0.047)、檳榔之總消耗量(p=0.026)、吸菸之總時間(p=0.011)、菸之總消耗量(p=0.013)、復發狀況(p=0.034)和預後(p=0.015)有統計學上有意義之相關。經化學治療後MDM2及PCNA於原發部位(p<0.001)及轉移部位(p<0.05)腫瘤的表現皆明顯低於化學治療前原發部位腫瘤的表現。
我們認為於我們口腔癌標本中之p53蛋白應為野生型p53蛋白，因為p53基因突變很少發生於嚼檳榔和吸菸相關之臺灣口腔癌。於口腔癌細胞中之p21主要經由p53依賴途徑誘導產生，而於口腔癌細胞中之MDM2可能經由非p53依賴途徑誘導產生。
化學治療導致口腔癌細胞壞死、角化和分化，因此導致p53、p21和MDM2陽性和陰性染色細胞比率之改變。此種改變進一步造成化學治療後原發口腔癌中p53和p21標記指數之增加及MDM2標記指數之降低。而化學治療前後原發口腔癌中PCNA標記指數之改變，直接反映化學治療前後各別口腔癌細胞之增殖活性。

Thirty-three cases of oral squamous cell carcinoma (SCC), which had been treated with adjuvant chemotherapy (C/T) before surgical excision, were collected from the file of Department of Oral Pathology and Oral Diagnosis from 1992 to 1997. The changes of histology and expression of p53, p21, MDM2 and PCNA proteins in primary oral SCCs and their metastatic counterparts after adjuvant chemotherapy were studied using hematoxylin and eosin as well as immunohistochemical staining techniques.
Prominent necrosis and degeneration of tumor cells with pseudocyst formation were found in oral SCCs resected soon after the cessation of C/T. Increased keratinization and differentiation of tumors was also found in those oral SCCs resected 2 weeks after the cessation of C/T. However, we also observed cancer cells with proliferating activity in the primary tumor sites. Thus, for patients receiving pre-operative C/T, a radical operation should still be performed soon after the patients recovered from the immunosupressive effects of the cytotoxic drugs.
The labeling index of p53 in primary tumors after C/T was significantly greater than that in primary tumors before C/T (p=0.002). A marginally significant correlation was found between the change of p53 expression in primary tumors after C/T and the clinical staging of the cancer (p=0.063). The change of p21 expression in primary tumors after C/T was significantly correlated with the N status (p=0.047), total consumption of betel quids (p=0.026), duration of smoking cigarettes (p=0.011), total consumption of cigarettes (p=0.013), recurrence (p=0.034) and prognosis (p=0.015). The MDM2 and PCNA labeling indices in primary tumors after C/T (p<0.001) and in metastatic lymph nodes after C/T (p<0.05) were significantly lower than those in primary tumors before C/T.
We suggest that the p53 proteins in our oral SCC specimens are mainly wild-type p53 proteins, because p53 gene mutation is rarely found in betel quids chewing and cigarette smoking-related oral cancers in Taiwan. Therefore, the production of p21 in oral SCCs was predominantly regulated by the p53-dependent pathway. However, the production of MDM2 in oral SCCs was probably regulated by the p53-independent pathway. C/T induces the necrosis, keratinization and differentiation of cancer cells, resulting in changes of the proportions of p53, p21 and MDM2 positive and negative-staining cells. These changes further cause the increase of p53 and p21 labeling indices and the decrease of MDM2 labeling index in primary tumors after C/T. The labeling index of PCNA in primary tumors before and after C/T merely reflects the proliferating activity of individual cancer cells before and after C/T.

中文摘要………………………………………………………………....1
英文摘要………………………………………………………………....2
第一章 緒論………………………………………………………………..3
第一節 研究動機…………………………………………………………..3
第二節 研究目的……………………………………………………………3
第二章 文獻回顧…………………………………………………………..5
第一節 口腔癌……………………………………………………………..5
第二節 臺灣口腔癌………………………………………………………..5
第三節 口腔癌患者的危險因子…………………………………………..7
第四節 口腔癌的治療……………………………………………………..7
第五節 p53抑癌基因及其產物…………………………………………...8
第六節 p21 WAF1/CIP1基因及其產物……………………………………10
第七節 MDM2基因及其產物………………………………………………11
第八節 增殖細胞核抗原(proliferating cell nuclear antigen, PCNA)…………….................................................13
第九節 免疫組織化學染色法……………………………………………14
第三章 材料與方法………………………………………………………16
第一節 研究個案標本選取………………………………………………16
第二節 標本固定與包埋…………………………………………………16
第三節 實驗方法…………………………………………………………16
第四節 資料處理與分析…………………………………………………20
第四章 結果………………………………………………………………21
第一節 研究個案之臨床與組織病理學發現……………………………21
第二節 組織學結果………………………………………………………22
第三節 p53蛋白之免疫組織化學染色結果…………………………….22
第四節 p21蛋白之免疫組織化學染色結果…………………………….22
第五節 MDM2蛋白之免疫組織化學染色結果………………………...23
第六節 PCNA蛋白之免疫組織化學染色結果………………………….23
第七節 p53、p21、MDM2和PCNA蛋白之消長變化情形，
任何兩者之間的相關性…………………………………………24
第八節 術前化學治療與手術治療之時間間隔與
p53、p21、MDM2和PCNA蛋白之變化量的相關性………………24
第九節 臨床病理參數和p53、p21、MDM2和PCNA蛋白之消長變化情形與
口腔鱗狀細胞癌患者預後的關係………………………………24
第十節 p53、p21、MDM2和PCNA蛋白於化學治療前、化學治療後之表現，
及其變化量與預後之相關性……………………………………25
第五章 討論………………………………………………………………27
第一節 口腔鱗狀細胞癌經化學治療後組織學表現之討論……………27
第二節 p53蛋白免疫組織化學染色結果之討論…………………….…27
第三節 p21蛋白免疫組織化學染色結果之討論……………………….28
第四節 MDM2蛋白免疫組織化學染色結果之討論…………………...28
第五節 PCNA蛋白免疫組織化學染色結果之討論…………………….29
第六節 p53、p21、MDM2和PCNA蛋白經化學治療表現變化之討論…30
第七節 臨床病理參數及p53、p21、MDM2和PCNA蛋白之表現與
口腔鱗狀細胞癌患者預後關係之討論…………………………31
第六章 結論………………………………………………………………33
參考文獻………………………………………………………………..34

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