Abstract

Abstract Despite recent advances in management, disease persistence and recurrences are common in patients with ACTH secreting pituitary adenomas-Cushing’s disease (CD). The study aims to determine clinical, biochemical, radiological, histological factors that correlate with persistence and recurrence in patients with CD, and also aims to understand the clinico-pathological significance of EGFR-MAPK, NF-kB, SHH pathway activation. Clinical data of 167 patients who underwent surgical treatment (n = 174 surgeries) for CD was ambispectively analysed with median follow-up of 8.1years(1-13.29 years). Among the 174 surgeries performed, 140 were primary, 22 were redo, 24 were for paediatric patients and 12 surgeries were performed in Nelson syndrome. In the primary surgery cohort, 74.3% were females and the average age was 28.73years(SD = 10.15). 75% of patients experienced remission after primary surgery compared to 47.4% in redo surgery. The remission rate in paediatric patients was 55.5%. Post-operative day-1 plasma cortisol (p < 0.001;AUC = 0.8894[0.8087-0.9701]) and ACTH (p < 0.001;AUC 0.9[0.7386-1]) levels were seen to be strong independent predictors of remission in primary surgery cohort. Remission rates after endoscopic trans-sphenoidal surgery- TSS were more than those after microscopic TSS, in patients undergoing primary surgery (81.08%vs57.14%;p = 0.008). Presence of adenoma on histopathological examination(HPE) was also strong predictor of disease remission (p = 0.020). On categorising based on surgical approach and HPE, microscopically operated patients without histopathological evidence of adenoma had significantly higher odds of non-remission (OR 38.1;95%CI-4.2-348.3) compared to endoscopically operated patients with adenoma on HPE. Lower immune reactivity score (IRS) of NR4A1 was found to correlate with higher remission rates (p = 0.074). However, none of the molecular markers studied - NR4A1, c-Fos, c-Jun, GLI1, pMEK, p44 showed a significant correlation with the preoperative cortisol values. Post-operative day-1 serum cortisol and ACTH are reliable predictors of remission. Additionally, endoscopic approach and histopathological evidence of adenoma are associated with higher remission rate, with both features together raising the odds significantly.

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