Nelson syndrome (NS), or corticotroph tumor progression after bilateral adrenalectomy (CTP-BADX/NS), is a serious complication in patients with Cushing disease (CD) following BADX. Surgical tumor removal is the recommended treatment, though adjuvant therapies may be necessary. To evaluate clinical, radiological, and hormonal features of CD patients after BADX, identify risk factors for CTP-BADX/NS and assessed treatment outcome and cardio-metabolic complications. Retrospective study of 30 patients (male/female: 9/21; median age at CD diagnosis: 33 years, IQR 27-42) who underwent BADX and had a minimum follow-up of 18 months. Data were collected at diagnosis and during follow-up (6, 24 months and last visit). Over a median follow-up of 135 months, 9/30 patients (30%) developed NS, median 60 months after BADX. NS patients had earlier CD diagnosis and higher ACTH levels two years post-BADX [458 ng/L (IQR 245-723) vs. 146 ng/L (61-247), p = 0.020]. They also took lower fludrocortisone [0.05 mg/day vs. 0.1 mg/day, p = 0.001] and tended to use less hydrocortisone [20 mg/day [20-25] vs. 30 [25-30], p = 0.06]. Pre-BADX stereotactic radiosurgery (SRS) was more frequent in non-NS patients (52% vs. 22%, p = 0.11). Hypertension was more common in NS patients (78% vs 43%), but diabetes less so (33% vs 48%). In the CTP-BADX group, 6/9 required pituitary surgery and/or radiotherapy; medical therapy was used in 5 patients with varied results. CTP-BADX/NS occurred in 30% of cases in our cohort. Higher ACTH post-BADX and younger age at CD onset may predict NS. No hormonal or radiological markers reliably predicted tumor progression. SRS before BADX and higher hydrocortisone doses might offer protection. Tumor control often needed a multimodal approach, with limited success from medical therapy alone.

Nelson's syndrome (NS) is an uncommon but serious complication after bilateral adrenalectomy (BA) in patients with Cushing's disease (CD). Stereotactic radiosurgery (SRS) has increasingly been used as a treatment option for NS patients; however, its effectiveness and safety remain uncertain. This meta-analysis aims to assess the role of SRS in NS. A systematic review and meta-analysis were conducted following PRISMA guidelines. PubMed, Embase, Scopus, and Web of Science were searched through June 11, 2025, for studies reporting outcomes of SRS in NS. Pooled estimates were calculated for local control (LC), endocrine remission (ER), new pituitary dysfunction (NPD), salvage treatment (ST), and adverse radiation effects (ARE). Seven studies with 122 patients were included. Pooled LC was 95% (95% CI: 89-99%), ER was 21% (95% CI: 13-30%), NPD was 20% (95% CI: 11-31%), ST was 4% (95% CI: 0-9%), and ARE was 0% (95% CI: 0-11%). Meta-regression analysis revealed that larger lesion volume, longer interval from prior resection, and higher pre-SRS ACTH levels were significantly associated with an increased risk of ARE. SRS provides high local control rates and a low safety risk for NS patients, although endocrine remission remains limited. These results support SRS as a viable choice in multidisciplinary management, although further prospective studies are needed.

Pituitary carcinoma is a condition defined by metastasis of a pituitary tumor to a distant location, and it is a very rare type of adenohypophyseal tumor. We present a case of a 29-year-old female who was followed up in our Endocrinology Department. Past medical history included the diagnosis of Cushing disease and transsphenoidal tumor resection at 12 years of age, followed by transcranial resection two years later because of persistently elevated adrenocorticotropic hormone (ACTH). Despite the surgical management, the patient persisted with increased ACTH and hypercortisolism, and, thus, bilateral adrenalectomy was performed a year later. Two years after the procedure, the patient presented with a newly diagnosed pituitary macroadenoma, and the diagnosis of Nelson syndrome was made. Linear accelerator radiotherapy was given, which reduced the size of the tumor. Later, several imaging studies showed multiple lesions on the falx cerebri, posterior clinoid process, retroclival region, cerebellopontine angle, pterygopalatine fossa, infratentorial region, and posterior ethmoidal cells. Biopsy and immunohistochemistry of the falx cerebri lesions described ACTH-producing pituitary adenocarcinoma. Treatment was given with intramuscular octreotide, dabrafenib, and trametinib. Despite persistently elevated ACTH levels, the patient has since remained clinically stable, without new development or worsening of symptoms. There are three unique aspects of our case. First, we reported an unusual presentation of this disease, since the patient in our case was a female with an early age of onset. Second, this is the first reported case demonstrating pituitary carcinoma in the falx cerebri. Third, the prognosis of pituitary carcinoma is usually very poor, and mortality is extremely high; however, the patient in our case has been followed up for seven years since the diagnosis of the metastatic lesions and has remained clinically stable.

Since the first description of Nelson syndrome 60 years ago, the way to consider corticotroph pituitary neuroendocrine tumors (PitNETs) after bilateral adrenalectomy has evolved. Today, it is globally acknowledged that only a subset of corticotroph PitNETs is aggressive.After adrenalectomy, corticotroph tumor progression (CTP) occurs in about 30 to 40% of patients during a median follow-up of 10 years. When CTP occurs, various CTP speeds (CTPS) can be observed. Using simple metrics in patients with CTP, CTPS was reported to vary from a few millimeters to up to 40 mm per year. Rapid CTPS/ Nelson's syndrome was associated with more severe Cushing's disease, higher adrenocorticotropic hormone (ACTH) in the year following adrenalectomy, and higher Ki67 on pituitary pathology. Complications such as apoplexy, cavernous syndrome, and visual defects were associated with higher CTPS. During follow-up, early morning ACTH, absolute variations properly reflected CTPS. Finally, CTPS was not higher after than before adrenalectomy, suggesting that cortisol deprivation after adrenalectomy does not impact CTPS in a majority of patients.Taken together, rapid CTPS/ Nelson's syndrome probably reflects the intrinsic aggressiveness of some corticotroph PitNETs. The precise molecular mechanisms related to corticotroph PitNET aggressiveness remain to be deciphered. Regular MRIs combined with intermediate morning ACTH measurements probably provide a reliable way to detect early and manage fast-growing tumors and, therefore, limit the complications.

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. 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. 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. 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.