人類表皮生長因子第二型之表現和上尿路上皮癌之關聯性研究

The Study of the Association of HER-2 Expression and Upper Tract Urothelial Carcinoma

李威明(Wei-Ming Li)

指導教授 ： 黃俊雄

高雄醫學大學/醫學院/醫學研究所/碩士(2008年)

摘要

目的 人類表皮生長因子第二型接受器是人類表皮生長因子家族的一員，它具有酪氨酸激酶活性且調控著細胞的生長與增值。當其過度表現會造成無法抑制的細胞增生和腫瘤生成。本研究的目的是要探討人類表皮生長因子第二型在上尿路上皮癌表現的程度，並分析其和疾病進展之間的關聯性。

材料與方法 我們回溯性地分析85位因上尿路上皮癌接受根除性腎臟輸尿管全切除手術的病患。研究中使用手術切除的檢體製作組織微陣列，並以病歷回顧的方式記錄病患的基本資料。使用免疫組織化學染色去分析人類表皮生長因子第二型蛋白質表現的狀態。將病人的臨床、組織病理資料和人類表皮生長因子第二型蛋白質表現的狀態進行相關預後分析及比較，並試著找出可以有效預測膀胱復發、疾病進展和疾病別存活率的重要因子。

結果 病人追蹤時間的中位數是54個月。總共有38位病人是人類表皮生長因子第二型蛋白質過度表現佔44.7%。在手術後追蹤過程中，有22位病人(25.9%)發生膀胱復發，腫瘤分級(p=0.01)是唯一有意義的預測因子；有20位病人(23.5%)術後疾病有惡化，在多變數分析後，只有腫瘤分期(相對危險性：12.67 [95%信賴區間：2.30-120.67]，p=0.005)和人類表皮生長因子第二型蛋白質表現狀態(相對危險性：2.86 [95%信賴區間：1.03-7.88], p=0.043)和無疾病進展存活率(progression-free survival)有顯著相關。在85位病人中有28位(39.2%)因為疾病死亡，死亡時間的中位數是20個月。在多變數分析後，只有腫瘤分期(相對危險性：44.65 [95%信賴區間：9.91-201.25]，p<0.001)和人類表皮生長因子第二型蛋白質表現狀態(相對危險性：4.68 [95%信賴區間：1.78-12.30]，p=0.002)是有顯著意義可預測疾病別存活率(disease-specific survival)的預後因子。

結論 上尿路上皮癌的病人在接受根除性腎臟輸尿管全切除手術後，人類表皮生長因子第二型蛋白質的過度表現意謂著：疾病較容易惡化且病患預後較差。評估這群病人的人類表皮生長因子第二型蛋白質的表現狀態不僅可以提供具有實用價值的預後資訊，同時可確認高危險群的病人，並提供臨床是否給予輔助治療的參考。未來研究應該進一步確認，針對人類表皮生長因子第二型接受體的標靶治療在上尿路上皮癌的療效。

關鍵字

上尿路上皮癌 ； 人類表皮生長因子第二型

並列摘要

Objectives Human epidermal growth factor receptor 2 (HER-2) is a member of the HER tyrosine kinase family, which regulates cell growth and proliferation. HER-2 overexpression will induce cancerous transformation and show increased aggressiveness. In the present study, we aimed to investigate the expression of HER-2 and the association with oncological outcomes of patients treated by radical nephrouretectomy for upper tract urothelial carcinoma (UTUC).

Materials and methods We retrospectively analyzed the data of 85 patients underwent radical nephrouretectomy for UTUC. Tissue microarrays were constructed from each resected specimen. The medical records of these patients were retrospectively reviewed. Immunohistochemistry staining was used to evaluate the expression of HER-2. The clinical, histopathological data and HER-2 status were analyzed to evaluate the predictive factors of bladder recurrence, disease progression and survival.

Results The median follow-up time was 54 months. Overexpression of HER-2 was noted in 38 patients (44.7%). In total, 22 patients (25.9%) developed subsequent bladder tumors. Predictive factor of bladder tumor recurrence was tumor grade (p=0.001). Disease progression developed in 20 patients (23.5%); only the tumor stage (hazard ratio 12.67 [95% CI 2.30-120.67], p=0.005) and HER-2 status (hazard ratio 2.86 [95% CI 1.03-7.88], p=0.043) were significantly associated with progression-free survival in multivariate analyses. Of the 85 patients, 28 (32.9%) died of urothelial cancer at a median period of 20 months. Only the tumor stage (hazard ratio 44.65 [95% CI 9.91-201.25], p<0.001) and HER-2 status (hazard ratio 4.68 [95% CI 1.78-12.30], p=0.002) were prognostic factors to predict disease-specific survival in multivariate analyses.

Conclusion Overexpression of HER-2 entails a progressively worse prognosis in patients with UTUC underwent radical nephrouretectomy. Assessment of HER-2 status in these patients provides prognostic information that could help to identify those at high risk for disease progression and mortality, who could benefit from early adjuvant treatment. Future studies on the efficacy of Her2-targeted therapies in UTUC are warranted.

並列關鍵字

Upper tract urothelial carcinoma ； HER-2

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