2020-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/699702嗜鉻細胞瘤-副神經節瘤(PPGLs)是罕見神經內分泌腫瘤，特徵是兒茶酚胺過度分泌。若沒有被診斷治療會帶來嚴重併發症甚至死亡。反之PPGLs有機會經手術治療而治癒。因此及時診斷和適當治療至關重要。但PPGLs症狀變化多端，需仰賴可靠生化檢測來診斷，此步驟確充滿困難。傳統生化檢測靈敏度低易造成偽陰性導致無法正確偵測PPGLs。使用液相層析串聯質譜儀(HPLC-MS/MS)檢測「血漿游離腎上腺素」(Plasma free metanephrines, PFMs)可提供最高PPGLs診斷準確性，為首選檢測方法。然而此檢測在台灣並不普及。而在不適當狀態下採檢會導致PFMs上限臨界值偏高，使診斷靈敏度大幅下降，應採用完全仰臥下採樣來建立參考區間。也需重視診斷特異性以避免造成太多偽陽性而增加接受不必要手術的患者。不同實驗室的PFMs參考區間與上限臨界值有所差異，多數來自歐美研究，台灣沒有相關研究報告，本研究將收集參考人群與PPGL患者檢體以HPLC-MS/MS測定PFMs來建立台灣「PFMs」參考區間和診斷臨界值 (Aim A)。另外，多數PPGLs具良性病程，可以透過手術成功治療。大約15% PPGLs是惡性的或具侵略性的(快速生長或多次復發)，這些目前仍缺乏適當的治療選擇。目前對於PPGLs具良性病程、侵略性、或轉移性的預測因素有限且不準確，無法將真正良性 PPGLs與那些會發展為惡性或具侵略性疾病的PPGLs區別開來，尋找可靠的預測與識別標誌物是治療策略中十分艱鉅的挑戰。腫瘤大小和位置已被證實是惡性風險預測因素，而兒茶酚胺分泌類型可間接做為腫瘤定位標記，其代謝產物metanephrines更能忠實地反應腫瘤分泌型態。本研究將探討「PFMs」和PPGLs位置、大小、臨床行為的關連性，應用於預測PPGLs臨床表型、侵略性以及預後 (Aim B)。最後，PPGLs在所有人類腫瘤中具最高遺傳力，約40%為家族性疾病，30-40%有體細胞突變。PPGLs是遺傳異質性腫瘤，目前已有34個基因被報告參與PPGLs形成。建議對所有PPGLs進行遺傳診斷提供最適切的臨床治療策略。隨著相關基因列表增加加上PPGLs的表現型無法很好地預測基因型，導致遺傳診斷成為一個耗時且耗費資源的過程。本研究將探討「PFMs」和PPGLs基因突變模式的關聯性，提供標的性基因篩檢訊息 (Aim C)。Pheochromocytoma-paraganglioma (PPGLs) are rare neuroendocrine tumors characterized by excessive secretion of catecholamines. If not accurate diagnosed or left untreated, it can cause serious complications and even death. PPGLs also have the opportunity to be cured by surgery. Therefore, timely diagnosis and appropriate treatment are essential. However, the symptoms of PPGLs are "great mimickers" and the diagnosis depends on reliable biochemical tests, which step is really challenging. Traditional 24-hr urine VMA & catecholamines had inadequate sensitivity, which lead to false negative results and miss diagnose PPGLs. Plasma free metanephrines (PFMs) measured by liquid chromatography tandem mass spectrometry (HPLC-MS / MS) provides highest diagnostic accuracy and became the recommended screening and diagnostic tool. However, this test is not common applied in clinical practice in Taiwan.Unfortunately, reference intervals for PFMs are all too often inappropriately established, and use of inappropriately high upper cutoffs of PFMs leads to lower diagnostic sensitivity. Diagnostic specificity should also be enhanced to minimize false-positive results and avoid unnecessary surgery. The reference intervals and upper cutoffs are different in different laboratories, which most of them reported from Europe and America. There is no relevant research in Taiwan. This study will collect reference populations and PPGLs patients to establish the Taiwan reference intervals and appropriate upper cutoffs of "PFMs" to improve the diagnosis accuracy of PPGLs (Aim A).In addition, most PPGLs have a benign course and can be successfully treated by surgery. About 15% of PPGLs are malignant or aggressive (rapid growth or multiple relapses), which was lack of appropriate treatment options. The predictive factors to differential benign course, aggressiveness, or metastasis are limited and imprecise. Search for the reliable predictors to distinguish true benign PPGLs from those eventually develop malignant or aggressive diseases is important. Tumor size and location have been proven to be predictors of PPGLs malignant risk. Secretion pattern of catecholamines can be used as indirect tumor localization markers, and its metabolites metanephrines are more faithfully reflect tumor secretion patterns. This study will explore the relationship between "PFMs" and the position, size, and clinical behavior of PPGLs, and apply them to predict the clinical phenotype, aggressiveness, and prognosis of PPGLs (Aim B).The last, PPGLs are highest hereditary tumors in all human tumors, with about 40% of familial diseases and 30-40% of somatic mutations. PPGLs are genetically heterogeneous tumors, and currently 34 genes have been reported. Genetic test is recommended for all the PPGLs to provide appropriate treatment strategy. However, with the increasing list of the potential gene mutations, and the genotype is not always predicted well by phenotype, these makes genetic test a time- and resource-consuming process. This study will explore the correlation between "PFMs" and PPGLs gene mutation patterns, and provide further information to guide targeted gene screening protocol (Aim C).游離腎上腺素嗜鉻細胞瘤副神經節瘤診斷預後基因學Free MetanephrinesPheochromocytomas and Paragangliomas (PPGLs)DiagnosisPhenotypePrognosisGenetics