2017-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648626摘要：腎上腺偶發瘤(adrenal incidentaloma, AI)是指在沒有腎上腺臨床表徵或已知腎上腺疾病的狀況下，經由影像檢查偶然發現的腎上腺腫瘤。其盛行率平均約為2.3%，在年齡分布上，年齡小於30 歲族群不到1%、50 歲族群約3%、而70 歲以上則高達10-15%。隨著影像技術的進步與臨床實務上廣泛使用，加上人口逐步高齡化，使得AI 的盛行率逐漸上升，臨床工作上也越來越常見。對於AI 有兩個關鍵問題，第一、惡性腫瘤的可能性，第二、是否有腎上腺賀爾蒙分泌異常。這兩個關鍵問題與診斷結果會影響治療的決策。AI 的病因最常見的是無功能性良性腫瘤、其次是自發性皮質醇分泌腫瘤；subclinicalCushing’s syndrome (SCS)是AI 中最常見的賀爾蒙分泌異常，其盛行率在不同的研究有很大的差異，從1%至29%，平均約9%。SCS 是指臨床上沒有出現Cushing’s syndrome (CS)或hypercortisolism 的臨床表徵，但生化檢驗顯示有autonomous cortisol secretion 的傾向。由於cortisol 分泌是連續性的，從正常到顯著增加、經常是可變的，而且個體差異大。SCS沒有cortisol分泌過多的特異性體徵，臨床上沒有的“gold standard”來幫助診斷。而且平時用於篩選CS 的標準生化檢查並非針對這些SCS 中微小cortisol 變化而設計的，現今研究中似乎沒有單一的檢驗具有足夠的sensitivity 和specificity 可以可靠地診斷SCS 。其中1mg overnightdexamethasone suppression test (DST)目前認為最可靠、可重複、也最被廣為接受的診斷方法，但是對於1mg overnight DST cortisol 的診斷臨界值(cutoff)非常不一致，從1–5 μg/dL 都有。採用不同的診斷cutoff 可能導致一些患者被misclassification，進而影響患者的治療決策。因此，找出準確診斷subclinical Cushing’s syndrome 的方法是一個重要的問題，準確的診斷有助於給予適切的治療。針對診斷方法與cutoff，就CS 來說先有典型的臨床表徵引起醫師的高度懷疑，才進行相關生化檢驗，使得這些檢驗有很高的pretest probability of disease，降低了false-positive；反之，這些SCS 的患者幾乎沒有典型的臨床表徵，醫師的臨床懷疑度很低，造成這些生化檢查的pretest probability of disease 很低，考慮到檢查、治療、與後續追蹤的成本，以及診斷AI 與SCS對患者的情緒影響，需要較高的positive predictive value，儘管損失sensitivity，應該選擇具有更高specificity 的測試與cutoff 較為恰當。本計畫將探討在AI 患者中，診斷SCS 的最佳檢驗方法與cutoff。本計畫包括兩部份，透過cross-section analysis (specific aim A)與longitudinal cohort study (specific aim B)來進行。Specific aim A 是回溯性研究，預計收集300 例因AI 接受手術切除治療者，以病理組織immunohistochemical (IHC) stain 來定義SCS，結合術前cortisol 數據，分析與尋找診斷SCS最適當的cut-off。Specific aim B 將建立台灣AI 長期的cohort。第一年為pilot study，預計先收錄50 人，進行常規hormone 檢查，合併其他評估HPA axis 生化參數以及相關共病症的檢查。挑選有接受手術者，分別利用以病理組織IHC stain 和post-adrenalectomy hypocortisolism 所定義的SCS，來validate specific aim A 的診斷cut-off，以及將此診斷cutoff 與目前推薦不同的診斷標準比較diagnostic performance。<br> Abstract: Adrenal incidentalomas (AI) are defined as adrenal lesions discovered serendipitously on aradiological examination that has been performed for reasons others than suspected adrenal disease.Its mean prevalence is 2.3% without significant differences between females and males. Theprevalence increases with the patient’s age, being less than 1% in young subjects as compared with10-15% in subjects older than 70 years of age. There are two key points for AI, the first is the riskof malignancy, and the second is excess hormone production.The majority of AI are non-functioning benign cortical adenoma (NFAI). The lesions arecharacterized by autonomous cortisol production without specific signs and symptoms of Cushing’ssyndrome (CS), a condition termed subclinical Cushing’s syndrome (SCS). It is the most commonhormonal abnormality detected in patients with AIs. The diagnosis of SCS in patients with AIremains a challenge because in SCS the specific signs of hypercortisolism are absent, and there isno clinical gold standard to facilitate the diagnosis. Due to the standard biochemical tests used toscreen for CS were not designed to reveal the subtle changes encountered in SCS, a combination ofvarious parameters used to assess the integrity of the hypothalamus-pituitary-adrenal (HPA) axishave been employed. However, the use of a combination of different tests to assess the HPA axishas not shown to be superior to the 1mg overnight dexamethasone suppression test (DST). Allpublished guidelines agree with the use of 1mg overnight DST for the screening of hypercortisolism.However, there is disagreement on the best cutoff for cortisol after DST, since the values of 1.8μg/dL as well as 5.0 μg/dL are recommended as limits for normal cortisol suppression. In the caseof symptomatic CS, the clinician’s index of suspicion is high and there is a high pretest probabilityof disease so therefore the likelihood of a false-positive test is reduced. In contrast, in patients withSCS, symptoms are subtle so the clinician’s index of suspicion is lower and therefore a test withgreater specificity is preferable, despite the loss of sensitivity.The diagnostic flow-chart of SCS is highly challenging and clear standards are still lacking.We propose this projects to develop the best diagnostic test and cutoff to diagnose SCS in patientswith AI. There are two specific aims in this project, including a retrospective cross-section analysis(specific aim A) and a prospective longitudinal follow-up cohort study (specific aim B).In specific aim A, we will collect 300 tissue samples, which are preserved from patients withAI who received adrenalectomy, and perform immunohistochemical (IHC) stain. Then we will usethe results of IHC stain to define SCS, and search the best diagnostic test and cutoff to diagnoseSCS in combination of the pre-operative adrenal hormonal data.In specific aim B, we will setup a long-term follow-up cohort of AI in Taiwan. In the first year,we will enroll 50 subjects with AI as pilot study. All subjects will receive routine hormonalevaluation for AI, and additional parameters and tests to assess the integrity of HPA axis andco-morbidities. We will analyze subjects undergo adrenalectomy first. By using of the results ofIHC stain and post-adrenalectomy hypocortisolism to define SCS, we will validate the diagnosticperformance of the cutoff developed from specific aim A, and also compare the diagnosticperformance between the cutoff developed from specific aim A and previously used by studies.腎上腺偶發瘤(adrenal incidentaloma, AI)是指在沒有腎上腺臨床表徵或已知腎上腺疾病的 狀況下，經由影像檢查偶然發現的腎上腺腫瘤。其盛行率平均約為2.3%，在年齡分布上，年 齡小於30 歲族群不到1%、50 歲族群約3%、而70 歲以上則高達10-15%。隨著影像技術的 進步與臨床實務上廣泛使用，加上人口逐步高齡化，使得AI 的盛行率逐漸上升，臨床工作上 也越來越常見。對於AI 有兩個關鍵問題，第一、惡性腫瘤的可能性，第二、是否有腎上腺賀 爾蒙分泌異常。這兩個關鍵問題與診斷結果會影響治療的決策。 AI 的病因最常見的是無功能性良性腫瘤、其次是自發性皮質醇分泌腫瘤；subclinical Cushing’s syndrome (SCS)是AI 中最常見的賀爾蒙分泌異常，其盛行率在不同的研究有很大的 差異，從1%至29%，平均約9%。SCS 是指臨床上沒有出現Cushing’s syndrome (CS)或 hypercortisolism 的臨床表徵，但生化檢驗顯示有autonomous cortisol secretion 的傾向。由於 cortisol 分泌是連續性的，從正常到顯著增加、經常是可變的，而且個體差異大。SCS沒有cortisol 分泌過多的特異性體徵，臨床上沒有的“gold standard”來幫助診斷。而且平時用於篩選CS 的 標準生化檢查並非針對這些SCS 中微小cortisol 變化而設計的，現今研究中似乎沒有單一的 檢驗具有足夠的sensitivity 和specificity 可以可靠地診斷SCS 。其中1mg overnight dexamethasone suppression test (DST)目前認為最可靠、可重複、也最被廣為接受的診斷方法， 但是對於1mg overnight DST cortisol 的診斷臨界值(cutoff)非常不一致，從1–5 μg/dL 都有。採 用不同的診斷cutoff 可能導致一些患者被misclassification，進而影響患者的治療決策。因此， 找出準確診斷subclinical Cushing’s syndrome 的方法是一個重要的問題，準確的診斷有助於給 予適切的治療。 針對診斷方法與cutoff，就CS 來說先有典型的臨床表徵引起醫師的高度懷疑，才進行相 關生化檢驗，使得這些檢驗有很高的pretest probability of disease，降低了false-positive；反之， 這些SCS 的患者幾乎沒有典型的臨床表徵，醫師的臨床懷疑度很低，造成這些生化檢查的 pretest probability of disease 很低，考慮到檢查、治療、與後續追蹤的成本，以及診斷AI 與SCS 對患者的情緒影響，需要較高的positive predictive value，儘管損失sensitivity，應該選擇具有 更高specificity 的測試與cutoff 較為恰當。 本計畫將探討在AI 患者中，診斷SCS 的最佳檢驗方法與cutoff。本計畫包括兩部份，透 過cross-section analysis (specific aim A)與longitudinal cohort study (specific aim B)來進行。 Specific aim A 是回溯性研究，預計收集300 例因AI 接受手術切除治療者，以病理組織 immunohistochemical (IHC) stain 來定義SCS，結合術前cortisol 數據，分析與尋找診斷SCS 最適當的cut-off。 Specific aim B 將建立台灣AI 長期的cohort。第一年為pilot study，預計先收錄50 人，進 行常規hormone 檢查，合併其他評估HPA axis 生化參數以及相關共病症的檢查。挑選有接受 手術者，分別利用以病理組織IHC stain 和post-adrenalectomy hypocortisolism 所定義的SCS， 來validate specific aim A 的診斷cut-off，以及將此診斷cutoff 與目前推薦不同的診斷標準比較diagnostic performance。Adrenal incidentalomas (AI) are defined as adrenal lesions discovered serendipitously on a radiological examination that has been performed for reasons others than suspected adrenal disease. Its mean prevalence is 2.3% without significant differences between females and males. The prevalence increases with the patient’s age, being less than 1% in young subjects as compared with 10-15% in subjects older than 70 years of age. There are two key points for AI, the first is the risk of malignancy, and the second is excess hormone production. The majority of AI are non-functioning benign cortical adenoma (NFAI). The lesions are characterized by autonomous cortisol production without specific signs and symptoms of Cushing’s syndrome (CS), a condition termed subclinical Cushing’s syndrome (SCS). It is the most common hormonal abnormality detected in patients with AIs. The diagnosis of SCS in patients with AI remains a challenge because in SCS the specific signs of hypercortisolism are absent, and there is no clinical gold standard to facilitate the diagnosis. Due to the standard biochemical tests used to screen for CS were not designed to reveal the subtle changes encountered in SCS, a combination of various parameters used to assess the integrity of the hypothalamus-pituitary-adrenal (HPA) axis have been employed. However, the use of a combination of different tests to assess the HPA axis has not shown to be superior to the 1mg overnight dexamethasone suppression test (DST). All published guidelines agree with the use of 1mg overnight DST for the screening of hypercortisolism. However, there is disagreement on the best cutoff for cortisol after DST, since the values of 1.8 μg/dL as well as 5.0 μg/dL are recommended as limits for normal cortisol suppression. In the case of symptomatic CS, the clinician’s index of suspicion is high and there is a high pretest probability of disease so therefore the likelihood of a false-positive test is reduced. In contrast, in patients with SCS, symptoms are subtle so the clinician’s index of suspicion is lower and therefore a test with greater specificity is preferable, despite the loss of sensitivity. The diagnostic flow-chart of SCS is highly challenging and clear standards are still lacking. We propose this projects to develop the best diagnostic test and cutoff to diagnose SCS in patients with AI. There are two specific aims in this project, including a retrospective cross-section analysis (specific aim A) and a prospective longitudinal follow-up cohort study (specific aim B). In specific aim A, we will collect 300 tissue samples, which are preserved from patients with AI who received adrenalectomy, and perform immunohistochemical (IHC) stain. Then we will use the results of IHC stain to define SCS, and search the best diagnostic test and cutoff to diagnose SCS in combination of the pre-operative adrenal hormonal data. In specific aim B, we will setup a long-term follow-up cohort of AI in Taiwan. In the first year, we will enroll 50 subjects with AI as pilot study. All subjects will receive routine hormonal evaluation for AI, and additional parameters and tests to assess the integrity of HPA axis and co-morbidities. We will analyze subjects undergo adrenalectomy first. By using of the results of IHC stain and post-adrenalectomy hypocortisolism to define SCS, we will validate the diagnostic performance of the cutoff developed from specific aim A, and also compare the diagnostic performance between the cutoff developed from specific aim A and previously used by studies.