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標題: | 犬乳房腫瘤預後因子之研究 The Study of Prognostic Factors of Canine Mammary Gland Tumors |
作者: | Pei-Yi Chu 朱旆億 |
指導教授: | 劉振軒 |
關鍵字: | 比較病理,犬,乳房腫瘤,腫瘤分類系統,免疫組織化學染色,預後因子, comparative pathology,canine,mammary gland tumor,tumor classification system,immunohistochemistry,prognostic factor, |
出版年 : | 2012 |
學位: | 博士 |
摘要: | 自然發生的犬乳房腫瘤已經被證實是一個研究人類乳癌相當合適的動物模型。本研究主要在探討犬乳房腫瘤預後不良的生物標記。第二章中,主要為比較犬和人的乳房腫瘤的分類系統。三位人醫病理醫師仔細比較WHO/AFIP腫瘤分類系統在犬和人乳房腫瘤的差異。在39個犬乳房腫瘤的分類中,共有22個(56.4%)的分類可以和人乳房腫瘤相通,因此可以證明犬和人乳房腫瘤在分類上有相當高的一致性。第三章中,共有136片犬乳房腫瘤的病理切片,分成兩組,分別由3位獸醫病理醫師和3位人醫病理醫師閱片。病理醫師間的一致性程度是用統計Kappa值(κ)來評估。在三位人醫病理醫師間,呈現中等到良好程度的一致性 (κ=0.68-0.81)。而在三位獸醫病理醫師間,一致性程度則較不理想(κ= -0.06 to 0.25)。第四章中,邀請10位訓練良好且相當有經驗的獸醫病理醫師各自參與相同的15個犬乳房腫瘤切片的病理閱片診斷。結果呈現中等程度的一致性(平均κ = 0.43)。故由第三章和第四章的研究顯示,診斷不一致的情況確實是存在,因此具有高正確性和高再現性之國際間皆可接受的犬乳房腫瘤病理診斷分類及定義是相當重要的。第五章中,肌上皮細胞標記,p63和calponin,在人類乳房腫瘤中,已被廣泛使用在日常病理診斷中,用來評估乳房腫瘤是否具有侵犯性。19例原先診斷為管狀乳突癌的犬之病理切片,用免疫組織化學染色法,研究p63和calponin的表現,9例的p63和calponin並未表現,故顯示有肌上皮細胞的缺少,且其中5例產生遠端轉移或因癌症死亡。臨床症狀初次表現到病理診斷確診時間和存活時間在9例缺少肌上皮細胞的犬中,皆明顯較短 (P值分別是0.001和0.021)。根據上述研究,管狀乳突癌在犬乳房腫瘤中,也許被過度診斷。在犬乳房的管狀乳突瘤的困難診斷病例,針對p63和calponin進行免疫組織化學染色是一個相當推薦的病理診斷輔助工具。第六章中,α-Enolase (ENO1)是一個重要的醣解酵素,在很多人類癌症的生發過程中,包括乳癌,扮演一定程度的角色。本研究中,收集82例犬乳房腫瘤,利用免疫組織化學染色法,來研究ENO1在犬乳房腫瘤中的表現,並以Quick score為免疫組織化學法染色結果的定量方法。ENO1的過度表現和較短的存活時間有關(P=0.019)。因此ENO1的過度表現可以用來當成是犬乳房癌症的一項預後不良的預後指標。第七章中,Krüppel-like factors (KLFs)是生物和生理系統的一群重要調節因子,它們在癌症的細胞增生、分化和存活所扮演的角色也被廣泛的研究。在這群KLFs中,KLF4在人類乳癌中是高度表現且被證實扮演一個致癌因子的角色。本研究中,收集142例犬乳房腫瘤,利用免疫組織化學染色法,來研究KLF4在犬乳房腫瘤中的表現,並以Quick score為免疫組織化學法染色結果的定量方法。KLF4的高表現和腫瘤細胞分化程度較差、癌症期別較晚、以及單純癌和複雜癌的亞型有關。Kaplan-Meier存活分析亦顯示具有高度細胞核表現KLF4的犬,其存活時間較低度/中度表現的犬為短 (P=0.011)。因此KLF4在犬乳癌中是高度表現的話,則是較為惡性的。 Spontaneous occurring canine mammary gland tumors (MGTs) are proved to be a suitable animal model for tumor-related studies of human breast cancer. Biomarkers of poor prognosis were surveyed in the present study. In chapter II, comparisons of tumor classification systems between canine and human mammary tumors were conducted. WHO/AFIP tumor classification system for canine mammary gland tumors was thoroughly reviewed by three human pathologists blindly. Overall, 22 (56.4%) of canine tumor classification can fit into human breast tumor classification system and it showed a relatively high concordant rate between canine and human mammary tumor classification systems. In chapter III, one hundred and thirty-six selected canine MGTs with histological slides were divided into two groups and were randomly reviewed blindly by three veterinary pathologists and three human pathologists. Kappa (κ) statistics were calculated to evaluate the level of agreement. For three human pathologists involved in this study, a moderate to good level of agreement was present among their diagnosis (κ=0.68-0.81). However, three veterinary pathologists participated in this study showed only a low levels of agreement (κ= -0.06 to 0.25). In chapter IV, fifteen canine MGTs slides were coded and evaluated independently by ten well-trained and experienced veterinary pathologists. Overall, we found only moderate interobserver agreement among veterinary pathologists (mean kappa=0.43). We conclude that substantially high interobserver variations do exist among pathologists and internationally accepted pathological diagnostic definitions with high accuracy and reproducibility among pathologists are required. In chapter V, immunohistochemical stains for p63 and calponin, described as myoepithelial cell markers, are helpful in determining the invasiveness of human breast tumors. Nineteen canine cases with original diagnosis of tubulopapillary carcinoma were selected for study of p63 and calponin. Nine of the selected 19 cases revealed loss of myoepithelial cells by negative staining for p63 and calponin and five of them developed metastasis or tumor-related death. The time of initial presence of clinical symptoms to pathological diagnosis and the survival time were also statistically lesser in the 9 cases without the expression of p63 and calponin (p=0.001 and p=0.021, respectively). In conclusion, tubulopapillary carcinoma may be an over-diagnosed entity in canine MGTs. Immunohistochemical stains for p63 and calponin are recommended for difficult cases to determine the malignancy in canine mammary tubulopapillary tumors. In chapter VI, α-Enolase (ENO1) is a key glycolytic enzyme implicated in the development of many human cancers including breast cancer. Immunohistochemical staining was employed to investigate the expression of ENO1 in 82 cases of canine mammary tumor. Quantification of immunohistochemistry was carried out using Quick score. Overexpression of ENO1 correlated significantly with shorter cause-specific survival (P = 0.019). Our findings suggest that overexpression of ENO1 may be used as a prognostic marker for poor outcome in canine mammary carcinoma. In Chapter VII, Krüppel-like factors (KLFs) are critical regulators of biological and physiological systems and have been extensively studied for their roles in cell proliferation, differentiation and survival in the context of cancer. Among the KLFs, KLF4 is highly expressed in human breast cancers and plays an oncogenic role. Immunohistochemistry was employed to investigate the expression of KLF4 in 142 cases of canine MGTs. Quick score system was used for the immunohistochemical quantification of KLF4. High expression level of KLF4 expression was statistically associated with high grade, late stage, and histological subtypes of simple and complex carcinoma. The Kaplan-Meier survival analysis also indicated that dogs with high nuclear KLF4 expression had a significantly shorter cause-specific survival than those with low/moderate KLF4 expression (P = 0.011). KLF4 is highly and frequently expressed in canine mammary carcinoma and correlates with a more aggressive phenotype. |
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