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研究生:楊馥華
研究生(外文):Fu-Hua Yang
論文名稱:犬貓神經內分泌腫瘤回溯及 INSM1 在其診斷應用之研究
論文名稱(外文):Retrospective Study on Canine and Feline Neuroendocrine Neoplasms and Diagnostic Application of Insulinoma-associated Protein 1 (INSM1)
指導教授:黃威翔黃威翔引用關係
指導教授(外文):Wei-Hsiang Huang
口試委員:鄭永銘劉振軒陳雅媚
口試委員(外文):Yung-Ming JengChen-Hsuan LiuYa-Mei Chen
口試日期:2022-12-26
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:分子暨比較病理生物學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2022
畢業學年度:111
語文別:中文
論文頁數:101
中文關鍵詞:胰島素瘤相關蛋白 1(INSM1)嗜鉻細胞分泌素 A突觸素神經內分泌腫瘤免疫組織化學染色診斷病理
外文關鍵詞:Insulinoma-Associated Protein 1 (INSM1)chromogranin Asynaptophysinneuroendocrine neoplasmsimmunohistochemistryveterinary diagnostic pathology
DOI:10.6342/NTU202300266
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神經內分泌細胞除了分佈於內分泌系統以外,亦以低密度分佈於全身各處, 因此,神經內分泌腫瘤可以從全身各處發生。現有的獸醫文獻缺乏對犬貓神經內 分泌腫瘤的大型回溯性調查,再加上神經內分泌腫瘤的低發生率和複雜性,使其 單靠組織病理檢查之型態學特徵可能會與其他上皮來源的腫瘤混淆。透過免疫組 織化學染色,使用神經內分泌標誌偵測腫瘤內的神經內分泌分化,是診斷神經內 分泌腫瘤的可靠工具。目前普遍用於犬貓神經內分泌腫瘤診斷的傳統神經內分泌 標誌為 chromogranin A 和 synaptophysin,近年來人醫文獻提出第二代神經內分泌 標誌,其中胰島素瘤相關蛋白 1 (Insulinoma-Associated Protein 1, INSM1)更被世 界衛生組織(WHO)評論為同時具有高敏感性與特異性的神經內分泌標誌。本研 究的研究主旨是回溯性調查犬貓神經內分泌腫瘤病例,並將新興抗體 INSM1 應用 於犬貓神經內分泌腫瘤之診斷。透過回溯性調查收集犬貓正常組織、神經內分泌 腫瘤與增生及非神經內分泌腫瘤病例,使用抗體 INSM1 進行免疫組織化學染色。 結果發現 INSM1 在大部分犬貓正常神經內分泌組織皆有表現,除了副甲狀腺。我 們對 84例犬隻與 19例貓隻神經內分泌腫瘤與增生病例進行 INSM1、chromogranin A 和 synaptophysin 的 IHC 染色,發現 INSM1 在所有副甲狀腺腫瘤皆為陰性。扣 除副甲狀腺來源腫瘤,INSM1抗體於 91例犬貓神經內分泌腫瘤與增生病例的陽性 率高達 97.8%。除此之外,INSM1 在診斷默克細胞癌(Merkel cell carcinoma)的 敏感性比 chromogranin A 和 synaptophysin 高。相較之下,於 75 例犬貓非神經內分 泌腫瘤病例中,僅有 3 例發現 INSM1 陽性。本研究證明 INSM1 於犬貓神經內分 泌腫瘤診斷的高價值與廣泛應用,同時也是少數對犬貓神經內分泌腫瘤的大型回 溯性研究調查。
Neuroendocrine (NE) neoplasms can arise from almost any anatomical location and could be histopathologically misdiagnosed as other neoplasms of epithelial origin owing to their complexity and rarity. Insulinoma-Associated Protein 1 (INSM1), a recently demonstrated NE marker, is reported in a growing number of research studies in human medicine. As a transcriptional regulator, highly conserved INSM1 homologues in various species have been confirmed in previous studies. The study aims to introduce INSM1 as a new IHC biomarker for diagnosing canine and feline NE neoplasms. We found that anti- INSM1 antibody could detect nuclear expression in most canine and feline normal NE tissues, except parathyroid glands. We performed INSM1, chromogranin A (CGA) and synaptophysin (SYP) IHC on 84 canine and 19 feline formalin-fixed, paraffin-embedded NE hyperplastic and neoplastic lesions. Twelve parathyroid neoplasms were negative for INSM1. In the rest of specimens, INSM1 was detectable in 97.8% of 91 NE hyperplastic and neoplastic lesions. Moreover, INSM1 appears more sensitive in Merkel cell carcinoma than CGA and SYP. In contrast, INSM1 was detected in only three of 75 non- neuroendocrine neoplasms. These findings confirm that INSM1 is a useful IHC marker for diagnosing canine and feline NE neoplasms and we suggest it be considered as part of immunohistochemical panels to improve the diagnostic capability. As there is a lack of large NE neoplasm studies in veterinary literature, a retrospective study of NE neoplasms in dogs and cats is also conducted in the present research.
目 錄

口試委員會審定書 .................................................... I
謝辭 ............................................................... II
摘要 .............................................................. III
ABSTRACT ........................................................... IV
圖目錄 ........................................................... VIII
表目錄 ............................................................ XII
ABBREVIATION LIST ................................................. XIV
第一章 前言 ......................................................... 1
第二章 文獻探討 ..................................................... 2
2.1 神經內分泌系統的組成.................................................................................. 2
2.2 犬貓神經內分泌腫瘤...................................................................................... 3
2.2.1 介紹.............................................................................................................. 3
2.2.2 命名與分類.................................................................................................. 4
2.2.3 組織形態學特徵.......................................................................................... 5
2.2.4 診斷.............................................................................................................. 6
2.3 新興蛋白質胰島素瘤相關蛋白 1(INSM1) ................................................ 8
2.3.1 介紹.............................................................................................................. 8
2.3.2 INSM1 應用於人類神經內分泌腫瘤診斷 .................................................. 9
2.3.3 INSM1 於動物的表現 ................................................................................ 10
2.4 研究假說與目的............................................................................................ 12
第三章 材料與方法 .................................................. 13
3.1 實驗設計與流程............................................................................................ 13
3.2 材料來源........................................................................................................ 13
3.2.1 基本資料與病史........................................................................................... 14
3.2.2 陽性對照組篩選條件................................................................................... 14
3.2.3 非神經內分泌腫瘤篩選條件....................................................................... 14
3.3 組織病理學檢查............................................................................................ 15
3.4 免疫組織化學染色........................................................................................ 16
3.4.1 初級抗體.................................................................................................... 16
3.4.2 免疫組織化學染色流程............................................................................ 18
3.4.3 評估免疫組織化學染色結果.................................................................... 19
第四章 結果 ........................................................ 21
4.1 神經內分泌腫瘤與增生病例分析 ...................................................................... 21
4.1.1 犬................................................................................................................... 21
4.1.2 貓................................................................................................................... 30
4.2 神經內分泌腫瘤與增生之組織形態學特色 ...................................................... 34
4.2.1 犬................................................................................................................... 34
4.2.2 貓................................................................................................................... 52
4.3 免疫組織化學染色評估 ...................................................................................... 60
4.3.1 INSM1 於犬貓正常組織表現 ....................................................................... 60
4.3.2 INSM1 於犬貓神經內分泌腫瘤與增生病例表現 ....................................... 65
4.3.3 INSM1 與 CGA 和 SYP 比較 .......................................................................... 74
4.3.4 INSM1 於犬貓非神經內分泌腫瘤表現 ....................................................... 76
第五章 討論 ........................................................ 80
5.1 犬貓神經內分泌腫瘤與增生病例之分析 .......................................................... 80
5.1.1 犬................................................................................................................... 80
5.1.2 貓................................................................................................................... 83
5.1.3 犬、貓、人神經內分泌腫瘤好發位置比較............................................... 84
5.2 神經內分泌標誌於犬貓正常組織的表現與比較 .............................................. 84
5.2.1 犬貓正常副甲狀腺無法穩定表現神經內分泌標誌................................... 85
5.2.2 INSM1 與 CGA 可於犬貓正常腸胃道腸內分泌細胞表現,SYP 之表現則有待釐清.................................................................................................................... 87
5.2.3 INSM1 於非神經內分泌細胞之表現 ........................................................... 87
5.3 INSM1 於犬貓各部位神經內分泌腫瘤的表現與應用 ...................................... 89
5.3.1 INSM1 於副甲狀腺腫瘤的應用 ................................................................... 89
5.3.2 INSM1 於默克細胞癌的應用 ....................................................................... 90
5.3.3 INSM1 於胰島細胞腫瘤的應用 ................................................................... 90
5.3.4 INSM1 於甲狀腺 C 細胞腫瘤的應用........................................................... 91
5.3.5 INSM1 於嗜鉻細胞腫瘤的應用 ................................................................... 92
5.3.6 INSM1 於其他部位神經內分泌腫瘤之表現探討 ....................................... 93
5.4 研究限制 .............................................................................................................. 93
5.5 結論 ...................................................................................................................... 94
第六章 參考資料 .................................................... 97
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