Nm23-H1於子宮頸癌化多重步驟之表現與其高度表現於子宮頸上皮內贅瘤及早期侵入性癌之臨床意義

本篇論文研究目的為評估nm23-H1蛋白於子宮頸正常、癌前和癌組織之表現情形，以及其在子宮頸癌化過程中所扮演的角色。總共蒐集86個子宮頸病理樣本，包括30個子宮頸鱗狀上皮癌 (squamous cell carcinoma; SCC)、3個腺癌 (adenocarcinoma)、1個明亮細胞癌(clear cell carcinoma)、19個高度和13個低度子宮頸鱗狀上皮內病變(high-grade and low-grade squamous intraepithelial lesions; HSILs and LSILs) 暨20個正常子宮頸檢体。這些檢体用免疫組織化學法，並以streptavidin-biotin peroxidase方式行免疫染色。更進一步，對其中30個子宮頸鱗狀上皮癌病例，探討nm23-H1蛋白表現和癌症病人臨床病理特徵之關係。此外，並評估這些病人之累計復發危險性(cumulative recurrence hazard)。 以卡方試驗 (Chi-square test)、Fisher’s exact試驗及卡方趨勢檢定(Chi-square test for trend) 比較nm23-H1蛋白在子宮頸正常、低度和高度鱗狀上皮內病變及癌組織之表現情形。以Fisher’s exact試驗評估nm23-H1蛋白表現和癌症病人臨床病理特徵之關係。這些臨床病理特徵包括年齡 (大於等於或小於50歲)、分化層級 (分化好、中等或不好)、基質侵犯深度 (大於等於或小於基質1/2侵犯深度) 及癌症轉移情形 (淋巴、子宮旁或陰道轉移)。再將癌症病人依nm23-H1蛋白表現高低分成兩組，並畫出累計復發危險性之Kaplan-Meier曲線，且以long-rank試驗比較nm23-H1蛋白表現高和低兩組隨著時間其復發分佈 (recurrence distributions) 之差異。 結果發現，有統計差異之nm23-H1蛋白表現，出現於低度和高度子宮頸鱗狀上皮內病變檢体之間 (P = 0.016) 以及低度子宮頸鱗狀上皮內病變和子宮頸鱗狀上皮癌檢体之間 (P = 0.002)，然而nm23-H1蛋白之表現於高度子宮頸鱗狀上皮內病變和子宮頸鱗狀上皮癌檢体之間以及正常子宮頸和低度子宮頸鱗狀上皮內病變檢体之間則未有統計上的差異。更進一步發現，子宮頸病變愈厲害，nm23-H1蛋白有表現愈高的趨勢 (P < 0.05)。而於眾多臨床病理特徵當中，只有大於等於基質1/2侵犯深度和nm23-H1蛋白之高度表現呈現統計學上有意義的關連 ( P = 0.003)。甚且，nm23-H1蛋白高度表現之組別，有較高之累計復發危險性。 總而言之，nm23-H1蛋白之高度表現可以誘導細胞增殖 (cellular proliferation)，而由低度進展至高度子宮頸鱗狀上皮內病變，並演變成子宮頸鱗狀上皮癌且和癌症基質深度侵犯有關；nm23-H1蛋白並且可以作為癌症預後之標記。

To evaluate the expression of nm23-H1 protein in normal, precancerous and cancerous tissues of the uterine cervix and its role in cervical carcinogenesis, 86 cervical specimens, including 30 squamous cell carcinomas (SCC), 3 adenocarcinomas, one clear cell carcinoma; 19 high- and 13 low-grade squamous intraepithelial lesions (HSILs and LSILs) and 20 normal samples, were stained using an immunohistochemical method with streptavidin-biotin peroxidase immunostaining. Among the 30 SCC cases, the relationships between immunohistochemical expression of nm23-H1 and various clinicopathological characteristics for early-stage cervical cancer were evaluated. The cumulative recurrence hazard of these patients were also assessed. The Chi-square and Fisher’s exact tests, as well as Chi-square test for trends, were used for comparing nm23-H1 expression among normal, LSIL, HSIL and cancerous tissues. Fisher’s exact test was also used to determine the relationship between nm23-H1 immunoreactivity and the clinicopathologic variables, such as age (≥ 50 or < 50 years old), grade of differentiation (well, moderate or poorly differentiated), depth of stromal invasion ( ≥ 1/2 or < 1/2 of stromal depth), and metastatic status (lymph nodal, parametrial or vaginal variants). Subjects were further subdivided into low and high nm23-H1 expression groups, and Kaplan-Meier curves were used to plot the cumulative recurrence hazard. The log-rank test was then used to compare the recurrence distributions for different nm23-H1 expression groups over time. There were significant differences in levels of nm23-H1 expression between LSIL and HSIL (P = 0.016) and between LSIL and SCC (P = 0.002), but not between HSIL and SCC or normal and LSIL samples. Furthermore, a positive relationship was demonstrated for high nm23-H1 protein expression and degree of malignant transformation (P < 0.05). Among various clinicopathological characteristics, only deep stromal invasion ( ≥ 1/2 of stromal depth) was significantly associated with high nm23-H1 expression. Moreover, a high cumulative recurrence hazard was demonstrated for the high nm23-H1 expression group. In conclusion, high nm23-H1 expression may induce the cellular proliferation for the progression from low to high-grade intraepithelial lesions, with the subsequent emergence of invasive carcinoma, as well as deep stromal invasion and be used as a prognostic indicator.