Abstract：
OBJECTIVE: Endonasal endoscopic transsphenoidal surgery (TSS) and resection of pituitary adenomas are considered the gold standard treatment for Cushing disease (CD). Even with various recent advances in management, disease persistence and recurrence are common in these patients. The remission rate in the global population after surgery has been reported to vary widely from 64% to 93%. This study aims to determine the various clinical, biochemical, radiological, and histological factors that correlate with persistence and recurrence in patients with CD. This study also aims to understand the clinicopathological significance of EGFR-MAPK, NF-κB, and SHH pathway activation and to study the protein expression of activation markers of these pathways (i.e., c-Fos, c-Jun, GLI-1, pMEK, NR4A1, and p44) in functioning corticotroph pituitary adenomas.
METHODS: From January 2009 to September 2022, the clinical data of 167 patients who underwent surgical treatment (n = 174 surgeries) for CD with a median follow-up of 8.1 years (range, 1-13.29 years) were ambispectively analyzed. The preoperative clinical, biochemical, and radiological features, operative findings, postoperative clinical and biochemical data, and histopathological and molecular profiles were retrieved from the electronic medical records. The patients were followed up to assess their remission status.
RESULTS: Among the 174 surgeries performed, 140 were primary surgeries, 22 were revision surgeries, 24 surgeries were for pediatric patients, and 12 surgeries were for patients with Nelson syndrome. In the primary surgery cohort, 74.3% were female, and the average age was 28.73 ± 10.15 years. Of the primary surgery cohort, 75% of the patients experienced remission compared with 47.4% after revision surgery. The remission rate for the pediatric patients was 55.5%. The postoperative day 1 plasma cortisol (P < 0.001; area under the curve, 0.8894; range, 0.8087-0.9701) and adrenocorticotropic hormone (P < 0.001; area under the curve, 0.9; range, 0.7386-1) levels were seen to be strong independent predictors of remission in the primary surgery cohort. The remission rate after endoscopic TSS was greater than that after microscopic TSS in patients undergoing primary surgery (81.08% vs. 57.14%; P = 0.008). The presence of adenoma on histopathological examination (HPE) was also a strong predictor of disease remission (P = 0.020). On stratifying by surgical approach and HPE, microscopically operated patients without histopathological evidence of adenoma had significantly higher odds of nonremission (odds ratio, 38.1; 95% confidence interval, 4.2-348.3) compared with endoscopically operated patients with adenoma found on HPE. A lower immunoreactivity score for NR4A1 was found to correlate with higher remission rates (P = 0.074). However, none of the molecular markers studied (i.e., c-Fos, c-Jun, GLI-1, pMEK, and p44) showed a significant correlation with the preoperative cortisol values.
CONCLUSIONS: The remission rate after primary surgery is higher than that after revision surgery and is lower for pediatric patients than for adults. The postoperative day 1 plasma cortisol and adrenocorticotropic hormone levels are strong independent predictors of remission in the primary surgery cohort. An endoscopic approach with histopathological evidence of adenoma is associated with a higher remission rate; thus, endoscopy should be the approach of choice for these patients with the goal of identification of an adenoma on HPE.
METHODS: From January 2009 to September 2022, the clinical data of 167 patients who underwent surgical treatment (n = 174 surgeries) for CD with a median follow-up of 8.1 years (range, 1-13.29 years) were ambispectively analyzed. The preoperative clinical, biochemical, and radiological features, operative findings, postoperative clinical and biochemical data, and histopathological and molecular profiles were retrieved from the electronic medical records. The patients were followed up to assess their remission status.
RESULTS: Among the 174 surgeries performed, 140 were primary surgeries, 22 were revision surgeries, 24 surgeries were for pediatric patients, and 12 surgeries were for patients with Nelson syndrome. In the primary surgery cohort, 74.3% were female, and the average age was 28.73 ± 10.15 years. Of the primary surgery cohort, 75% of the patients experienced remission compared with 47.4% after revision surgery. The remission rate for the pediatric patients was 55.5%. The postoperative day 1 plasma cortisol (P < 0.001; area under the curve, 0.8894; range, 0.8087-0.9701) and adrenocorticotropic hormone (P < 0.001; area under the curve, 0.9; range, 0.7386-1) levels were seen to be strong independent predictors of remission in the primary surgery cohort. The remission rate after endoscopic TSS was greater than that after microscopic TSS in patients undergoing primary surgery (81.08% vs. 57.14%; P = 0.008). The presence of adenoma on histopathological examination (HPE) was also a strong predictor of disease remission (P = 0.020). On stratifying by surgical approach and HPE, microscopically operated patients without histopathological evidence of adenoma had significantly higher odds of nonremission (odds ratio, 38.1; 95% confidence interval, 4.2-348.3) compared with endoscopically operated patients with adenoma found on HPE. A lower immunoreactivity score for NR4A1 was found to correlate with higher remission rates (P = 0.074). However, none of the molecular markers studied (i.e., c-Fos, c-Jun, GLI-1, pMEK, and p44) showed a significant correlation with the preoperative cortisol values.
CONCLUSIONS: The remission rate after primary surgery is higher than that after revision surgery and is lower for pediatric patients than for adults. The postoperative day 1 plasma cortisol and adrenocorticotropic hormone levels are strong independent predictors of remission in the primary surgery cohort. An endoscopic approach with histopathological evidence of adenoma is associated with a higher remission rate; thus, endoscopy should be the approach of choice for these patients with the goal of identification of an adenoma on HPE.
摘要：
目的：经鼻内镜经蝶入路手术（TSS）和垂体腺瘤切除术被认为是治疗库欣病（CD）的金标准。即使最近在管理方面取得了各种进步，在这些患者中，疾病持续和复发很常见。据报道，全球人群手术后的缓解率在64％至93％之间差异很大。本研究旨在确定各种临床，生物化学，与CD患者的持久性和复发相关的放射学和组织学因素。本研究还旨在了解EGFR-MAPK的临床病理意义,NF-kB和SHH途径的激活，并研究这些途径的激活标记物的蛋白质表达水平。c-Fos,c-Jun,GLI-1,pMEK,NR4A1和p44在功能性促肾上腺皮质激素垂体腺瘤中的作用。
方法：2009年1月至2022年9月，对167例因库欣病接受手术治疗（n=174例手术）的患者的临床资料进行了综合分析，中位随访时间为8.1年（1-13.29年）。术前临床,生物化学，放射学特征，手术发现，术后临床和生化数据，组织病理学和分子概况，是从电子记录中检索的。对患者进行随访以评估缓解状态。
结果：在执行的174例手术中，140个是初级手术，22是修正手术，24例儿科患者手术，12例Nelson综合征患者手术。在初级手术队列中，74.3%为女性,平均年龄28.73岁(SD10.15)。75％的患者在初次手术后缓解，而翻修手术为47.4％。儿科患者的缓解率为55.5%。术后第1天血浆皮质醇（p<0.001；AUC0.8894[0.8087-0.9701]）和ACTH（p<0.001；AUC0.9[0.7386-1]）水平被视为主要手术队列缓解的强独立预测因子。内镜下TSS术后缓解率高于显微镜下TSS，在接受初次手术的患者中（81.08%vs57.14%；p=0.008）。组织病理学检查（HPE）中腺瘤的存在也是疾病缓解的强预测因子（p=0.020）。在根据手术方法和HPE进行分类时，与接受HPE的内镜手术的腺瘤患者相比,无腺瘤组织病理学证据的显微镜手术患者未缓解的几率显著较高(OR38.195%CI4.2-348.3).发现NR4A1的较低免疫反应性评分（IRS）与较高的缓解率相关（p=0.074）。然而,没有一个分子标记研究。c-Fos,c-Jun,GLI-1，pMEK和p44与术前皮质醇值显着相关。
结论：初次手术后的缓解率高于翻修手术后的缓解率，与成年人相比，儿科患者的比例较低。术后第1天血浆皮质醇和ACTH水平是主要手术队列缓解的强独立预测因子。具有腺瘤组织病理学证据的内窥镜检查方法与较高的缓解率相关，因此内窥镜检查应成为这些患者的首选方法，目的是在组织病理学分析中鉴定腺瘤。
方法：2009年1月至2022年9月，对167例因库欣病接受手术治疗（n=174例手术）的患者的临床资料进行了综合分析，中位随访时间为8.1年（1-13.29年）。术前临床,生物化学，放射学特征，手术发现，术后临床和生化数据，组织病理学和分子概况，是从电子记录中检索的。对患者进行随访以评估缓解状态。
结果：在执行的174例手术中，140个是初级手术，22是修正手术，24例儿科患者手术，12例Nelson综合征患者手术。在初级手术队列中，74.3%为女性,平均年龄28.73岁(SD10.15)。75％的患者在初次手术后缓解，而翻修手术为47.4％。儿科患者的缓解率为55.5%。术后第1天血浆皮质醇（p<0.001；AUC0.8894[0.8087-0.9701]）和ACTH（p<0.001；AUC0.9[0.7386-1]）水平被视为主要手术队列缓解的强独立预测因子。内镜下TSS术后缓解率高于显微镜下TSS，在接受初次手术的患者中（81.08%vs57.14%；p=0.008）。组织病理学检查（HPE）中腺瘤的存在也是疾病缓解的强预测因子（p=0.020）。在根据手术方法和HPE进行分类时，与接受HPE的内镜手术的腺瘤患者相比,无腺瘤组织病理学证据的显微镜手术患者未缓解的几率显著较高(OR38.195%CI4.2-348.3).发现NR4A1的较低免疫反应性评分（IRS）与较高的缓解率相关（p=0.074）。然而,没有一个分子标记研究。c-Fos,c-Jun,GLI-1，pMEK和p44与术前皮质醇值显着相关。
结论：初次手术后的缓解率高于翻修手术后的缓解率，与成年人相比，儿科患者的比例较低。术后第1天血浆皮质醇和ACTH水平是主要手术队列缓解的强独立预测因子。具有腺瘤组织病理学证据的内窥镜检查方法与较高的缓解率相关，因此内窥镜检查应成为这些患者的首选方法，目的是在组织病理学分析中鉴定腺瘤。
