Corticotroph tumor progression after bilateral adrenalectomy: data from ERCUSYN.

Corticotroph tumor progression after bilateral adrenalectomy/Nelson's syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing's disease (CD) included in the European Registry on Cushing's Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2-9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5-6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P < 0.05). Twenty-seven CTP-BADX/NS patients underwent surgery, 48% radiotherapy and 27% received medical therapy. The median time since diagnosis of CTP-BADX/NS to the last follow-up visit was 2 years (IQR, 1-5). Control of tumor progression was not achieved in 16 of 33 (48%) patients, of whom 8 (50%) died after a mean of 4 years. Maximum adenoma size at diagnosis of CD was associated with further tumor growth in CTP-BADX/NS despite treatment (P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.

Pituitary adenomas.

Pituitary adenomas produce a complex collection of disorders. Some are incidental findings. Some distort local anatomical structures which can lead to disorders of vision or hormone production. Some produce excesses of hormones which can be either life threatening or clinically distressing. The management requires the expertise of a variety of experts who plan together. No single treatment is universally successful in controlling these conditions. Medical, biochemical, surgical and radiosurgical management can all have parts to play. Coordinate co-operation between specialists will provide patients with the best available treatment.

Prevalence of Nelson's syndrome after bilateral adrenalectomy in patients with cushing's disease: a systematic review and meta-analysis.

PURPOSE: Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson's syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. DATA SOURCES: Systematic literature search in four databases. STUDY SELECTION: Observational studies reporting the prevalence of NS after BA in adult patients with CD. DATA EXTRACTION: Data extraction and risk of bias assessment were performed by three independent investigators. DATA SYNTHESIS: Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22-31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27-50%). The prevalence of treatment for NS was 21% (95% CI 18-26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5-1.6)] or pituitary surgery [0.6 (95% CI 0.4-1.0)]. CONCLUSIONS: Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

Updates in the outcomes of radiation therapy for Cushing's disease.

External radiation therapy (RT) directed to the pituitary gland is generally recommended in patients with Cushing's disease (CD) as adjuvant to transsphenoidal surgery, among other second-line therapies offered to patients with residual or recurrent hypercortisolism (i.e., medical treatment, repeat surgery or bilateral adrenalectomy). RT is effective for the control of tumor growth, even in invasive tumors and in Nelson's syndrome. Progress in radiation stereotactic techniques lead to improved tumor targeting and radiation delivery, thus sparing the adjacent brain structures. Stereotactic RT is associated with a 55-65% rate of cortisol normalization after several months to a few years and potentially with a lower risk of long-term complications, compared with conventional RT. Cortisol-lowering medical therapy is recommended while awaiting the radiation effects. Hypopituitarism is the most frequent side-effect, damage to optic or cranial nerves or second brain tumors are rarely reported. This review presents the updates in the efficacy and safety of the stereotactic radiation techniques in CD patients. Practical points which should be considered by the clinician before recommending RT are also presented.

Stereotactic radiosurgery before bilateral adrenalectomy is associated with lowered risk of Nelson's syndrome in refractory Cushing's disease patients.

BACKGROUND: Nelson's syndrome is a rare but challenging sequelae of Cushing's disease (CD) after bilateral adrenalectomy (BLA). We sought to determine if stereotactic radiosurgery (SRS) of residual pituitary adenoma performed before BLA can decrease the risk of Nelson's syndrome. METHODS: Consecutive patients with CD who underwent BLA after non-curative resection of ACTH secreting pituitary adenoma and had at least one follow-up visit after BLA were studied. Nelson's syndrome was diagnosed based on the combination of rising ACTH levels, increasing volume of the pituitary adenoma and/or hyperpigmentation. RESULTS: Fifty patients underwent BLA for refractory CD, and 43 patients (7 men and 36 women) had at least one follow-up visit after BAL. Median endocrine, imaging, and clinical follow-up were 66 months, 69 months, and 80 months, respectively. Nine patients (22%) were diagnosed with the Nelson's syndrome at median time after BLA at 24 months (range: 0.6-119.4 months). SRS before BLA was associated with reduced risk of the Nelson's syndrome (HR = 0.126; 95%CI [0.022-0.714], p=0.019), while elevated ACTH level within 6 months after BLA was associated with increased risk for the Nelson's syndrome (HR = 9.053; 95%CI [2.076-39.472], p=0.003). CONCLUSIONS: SRS before BLA can reduce the risk for the Nelson's syndrome in refractory CD patients requiring BLA and should be considered before proceeding to BLA. Elevated ACTH concentration within 6 months after BLA is associated with greater risk of the Nelsons' syndrome. When no prior SRS is administered, those with a high ACTH level shortly after BLA may benefit from early SRS.

Gamma knife radiosurgery in patients with Nelson's syndrome.

PURPOSE: Nelson's syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with Cushing's disease. The best therapeutic strategy in NS has not been well defined. Gamma knife radiosurgery (GKRS) is very effective to stop the growth of the pituitary adenoma, which is the main goal of the treatment of patients with NS. We report the largest series of patients with NS treated by GKRS at a single center. METHODS: The study was an observational, retrospective analysis of 28 consecutive patients with NS treated by GKRS in our department between 1995 and 2019. All patients had a growing ACTH-secreting pituitary adenoma. The main outcome of the study was to assess by the Kaplan-Meier method the risk of tumor progression after GKRS. RESULTS: The median follow-up after GKRS treatment was 98 months (IQR 61-155 months, range 7-250 months). Two patients (7.1%) had a recurrence of disease during follow-up. The 10-year progression-free survival was 91.7% (95% CI 80.5-100%). No patient had deterioration of visual function or oculomotor function after GKRS. New onset of hypogonadism and hypothyroidism occurred in 18.8% and 14.3% of the patients at risk. CONCLUSION: Our study confirms that GKRS may stop the tumor growth in the majority of patients with NS, even though very aggressive adenomas may ultimately escape this treatment. Safety of GKRS was good in our experience, but due attention must be paid to planning the distribution of radiation to critical structures, especially in patients previously treated by radiation.

ACTH increment post total bilateral adrenalectomy for Cushing's disease: a consistent biosignature for predicting Nelson's syndrome.

PURPOSE: Nelson's syndrome (NS) is regarded as an aggressive complication of total bilateral adrenalectomy (TBA) for Cushing's disease (CD). This challenge may be addressed by using clinical criteria to guide frequency of neuroimaging to enable timely management of NS and also avoid unnecessary frequent imaging. METHODS: All patients (n = 43) with CD subjected to TBA over 35 years at a tertiary care centre were included. NS was defined as a newly appearing or expanding (> 2 mm) pituitary adenoma with or without ACTH levels exceeding 500 pg/ml. Pre-and post-TBA parameters like clinical symptomatology, cortisol, ACTH and radiology were analysed for the prediction of NS. RESULTS: NS developed in 39.5% (n = 17) patients with a median follow-up of 7 years. Half of them had new appearance, while rest had an expansion of pre-existing pituitary tumour. Majority (90%) had ACTH above 500 pg/ml. On Cox proportional hazards analysis, frequent discriminatory features of protein catabolism (≥ 4) (HR 1.15, CI 0.18, 7.06), proximal myopathy (HR 8.82, CI 1.12, 69.58) and annual ACTH increment of 113 pg/ml (HR 12.56, CI 1.88, 88.76) predicted NS. First post-operative year ACTH indices predicting NS included ACTH rise of 116 pg/ml and absolute ACTH of 142 pg/ml (sensitivity, specificity exceeding 90%). Annual ACTH increment exceeding 113 pg/ml, ≥ 4 discriminatory features and uncontrolled hypertension had the best overall prediction. CONCLUSION: Patients who developed NS had higher rebound rise of ACTH following TBA and a more severe disease phenotype at baseline. Consistent ACTH increment can be used as a marker for predicting the development of NS.

Cushing's syndrome - Disease monitoring: Recurrence, surveillance with biomarkers or imaging studies.

Pituitary surgery is the first-line treatment for patients with Cushing's disease. For patients who are not considered candidates for pituitary surgery, pituitary radiation and bilateral adrenalectomy are further treatment alternatives. Not all patients are cured with pituitary surgery, and a substantial number of patients develop recurrence, sometimes many years after an apparently successful treatment. The same applies to patients treated with radiotherapy. Far from all patients are cured, and in many cases the disease recurs. Bilateral adrenalectomy, although always curative, causes chronic adrenal insufficiency and the remaining pituitary tumour can continue to grow and cause symptoms due to pressure on adjacent tissues, a phenomenon called Nelson's syndrome. In this paper the rate of recurrence of hypercortisolism, as well as the rate of development of Nelson's syndrome, following treatment of patients with Cushing's syndrome, will be reviewed. The aim of the paper is also to summarize clinical and biochemical factors that are associated with recurrence of hypercortisolism and how the patients should be monitored following treatment.

Pituitary Adenoma Deposit in the Nasolabial Region Following Sublabial Transsphenoidal Surgery in the Setting of Nelson Syndrome.

Pituitary adenomas are a group of tumors arising from the anterior pituitary gland, and with the exception of prolactin-secreting adenomas, transsphenoidal resection is the cornerstone of treatment. Although most adenomas are located within the pituitary fossa, ectopic adenomas have been reported, primarily occurring along the route of embryologic development. In this article, we present the case of an ectopic pituitary adenoma in the nasolabial fold that likely resulted from seeding during transsphenoidal resection via sublabial approach.

Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson's tumor.

OBJECTIVE: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing's disease (CD). Corticotroph tumor progression, the so-called Nelson's syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson's tumors has not been studied in detail so far. DESIGN AND METHODS: Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. RESULTS: Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson's tumor. CONCLUSION: Somatic mutations in USP8 are common in Nelson's tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson's tumor.

Outcomes in pituitary surgery in Nelson's syndrome--therapeutic pitfalls.

INTRODUCTION: Nelson's syndrome (NS) is a rare clinical syndrome caused by an enlarging, aggressive corticotroph pituitary adenoma that can occur following bilateral adrenalectomy performed in the treatment of refractory Cushing's disease (CD). Such tumours respond poorly to currently available therapeutic options, which include surgery, radiotherapy, pharmacotherapy, and chemotherapy. They are a challenging problem in neurosurgical practice. The aim of this work was to evaluate the early and long-term results of microsurgery in a single surgeon's series of patients with NS. MATERIAL AND METHODS: During the period from January 2000 to December 2005, 10 patients with NS underwent surgery. The authors analysed surgical outcomes in the NS group of seven women and three men with the mean age of 47.99 years (range 39-66, SD ± 8.47 years). NS was diagnosed based on clinical signs and symptoms, especially hyperpigmentation of the skin, elevated serum ACTH levels, and pituitary tumour growth. Parasellar extension of the adenomas was assessed in both groups according to Knosp's and Hardy-Wilson classifications. Pituitary function and radiographs were evaluated in the early postoperative period, 30 days after the operation, and during follow-up. Histological examination was based on the WHO (2004) criteria. RESULTS: According to the criteria for Nelson's syndrome remission, five patients (50%) were cured. No perioperative mortality was reported. Three patients developed pituitary insufficiency and two patients developed diabetes insipidus. There was one case of postoperative cerebrospinal fluid leakage. One patient was diagnosed with pituitary carcinoma. CONCLUSIONS: Transsphenoidal microsurgical removal of pituitary adenomas is a safe and effective treatment of Nelson' syndrome.

Gamma knife radiosurgery for Cushing's disease and Nelson's syndrome.

PURPOSE: This paper presents our 18 years of experience in treating ACTH secreting adenomas (Cushing's disease and Nelson's syndrome) using the Leksell gamma knife (LGK) irradiation. METHODS: Twenty-six patients with Cushing's disease were followed-up after LGK irradiation for 48-216 months (median 78 months). Seventeen patients had undergone previous surgery, in nine patients LGK irradiation was the primary therapy. Furthermore, 14 patients with Nelson's syndrome were followed-up for 30-204 months (median 144 months). RESULTS: LGK treatment resulted in hormonal normalization in 80.7 % of patients with Cushing's disease. Time to normalization was 6-54 months (median 30 months). The volume of the adenoma decreased in 92.3% (in 30.7% disappeared completely). There was no recurrence of the disease. In all 14 patients with Nelson's syndrome ACTH levels decreased (in two patients fully normalized) their ACTH levels. When checked up 5-10 years after irradiation regrowth of the adenoma was only detected in one patient (9.1%), in 27.3% adenoma volume remained unchanged, in 45.4% adenoma volume decreased and in 18.2% adenoma completely disappeared. Hypopituitarism did not develop in any patient where the critical dose to the pituitary and distal infundibulum was respected. CONCLUSION: LGK radiation represents an effective and well-tolerated option for the treatment of patients with Cushing's disease after unsuccessful surgery and may be valuable even as a primary treatment in patients who are not suitable for, or refuse, surgery. In the case of Nelson's syndrome it is possible to impede tumorous growth and control the size of the adenoma in almost all patients.

Nelson's syndrome: single centre experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy.

Nelson's syndrome is a unique clinical phenomenon of growth of a pituitary adenoma following bilateral adrenalectomies for the control of Cushing's disease. Primary management is surgical, with limited effective medical therapies available. We report our own institution's series of this pathology managed with radiation: prior to 1990, 12 patients were managed with conventional radiotherapy, and between 1990 and 2007, five patients underwent stereotactic radiosurgery (SRS) and two patients fractionated stereotactic radiotherapy (FSRT), both using the linear accelerator (LINAC). Tumour control was equivocal, with two of the five SRS patients having a reduction in tumour volume, one patient remaining unchanged, and two patients having an increase in volume. In the FSRT group, one patient had a decrease in tumour volume whilst the other had an increase in volume. Treatment related morbidity was low. Nelson's syndrome is a challenging clinical scenario, with a highly variable response to radiation in our series.

Cerebrovascular complications and utilization of endovascular techniques following transsphenoidal resection of pituitary adenomas: a study of the Nationwide Inpatient Sample 2001-2010.

PURPOSE: Cerebrovascular complications following transsphenoidal resection of pituitary tumors are rare and often evaluated and treated with endovascular techniques. We determined the utilization rate and outcomes of endovascular procedures in transsphenoidal pituitary resection patients using an administrative database. METHODS: Using the Nationwide Inpatient Sample 2001-2010, patients receiving transsphenoidal resection of benign pituitary tumors were identified. The rate of cerebrovascular complications and utilization of endovascular repair procedures and cerebral angiography were compared between high (≥ 75 procedures/year) and low volume (<75 procedures/year) centers. Chi squared tests were used to compare categorical variables. RESULTS: 70,878 were patients included in this study. ICH/SAH occurred in 0.9 % of patients (652/70,878) and stroke occurred in 0.5 % of patients (327/70,878). Patients treated at high volume centers had significantly lower rates of stroke (0.5 % vs. 1.0 %, P = 0.04), and ICH/SAH (0.5 vs. 1.0 %, P = 0.05) when compared to patients treated at low-volume centers. Overall, 531 patients (0.7 %) received post-operative angiography and 83 patients (0.1 %) received endovascular repair procedures. High volume center patients underwent angiography in 0.4 % of cases compared to 0.9 % for low volume center patients (P = 0.02). There was no significant difference in endovascular repair procedure rates at high and low volume centers (0.1 vs. 0.2 %, P = 0.37). CONCLUSIONS: Cerebrovascular surgical complications requiring cerebral angiography and endovascular repair are rare among transsphenoidal pituitary resection patients. These occur with higher frequency at low volume centers and are associated with high mortality rates.

Effect of stereotactic radiosurgery before bilateral adrenalectomy for Cushing's disease on the incidence of Nelson's syndrome.

OBJECT: Nelson's syndrome (NS) is a significant and frequent risk for patients with Cushing's disease (CD) who undergo bilateral adrenalectomy. A recent study has shown tumor progression in 47% of patients at risk for NS. The authors sought to define the rate of NS in patients who were treated with Gamma Knife stereotactic radiosurgery (GK SRS) prior to bilateral adrenalectomy. METHODS: Consecutive patients with CD who were treated with GK SRS after pituitary surgery but before bilateral adrenalectomy were included. Serial MRI sequences were analyzed to evaluate for pituitary tumor growth. Clinical evaluations were performed to screen for NS. Follow-up for adrenocorticotropic hormone levels and hormone studies of other pituitary axes was performed. RESULTS: Twenty consecutive patients were followed with neuroimaging and clinically for a median of 5.4 years (range 0.6-12 years). One patient (5%) developed pituitary tumor growth consistent with NS 9 months after adrenalectomy. By Kaplan-Meier analysis, progression-free survival was 94.7% at 1, 3, and 7 years. No predisposing factors were identified for the tumor progression. Two patients developed new pituitary dysfunction and no patient developed cranial neuropathy or visual deficit after GK SRS. CONCLUSIONS: These findings suggest that GK SRS not only serves a role as second-line therapy for CD, but that it also provides prophylaxis for NS when used before bilateral adrenalectomy.

A 52-year-old male with visual changes.

A 52 year-old male with a history of Cushing's Disease at age 18 and bilateral adrenalectomy at age 23 presented with visual changes. An MRI scan showed a pituitary macroadenoma (Nelson's syndrome). Other than the development of diabetes mellitus at age 32, his disease was stable until presentation. Serum studies show markedly elevated ACTH levels, but he had no hyperpigmentation. The tumor was removed by endoscopic surgery. Microscopic examination showed a pituitary adenoma with strong immunostaining for ACTH. In addition, the tumor cells showed Crooke's hyaline change and stained strongly for cytokeratin (Crooke's Cell Adenoma). Normal pituitary was not present. Crooke's cell adenomas are extremely rare and have not been previously reported in Nelson's Syndrome.

Nelson's syndrome.

Nelson's syndrome is a potentially life-threatening condition that does not infrequently develop following total bilateral adrenalectomy (TBA) for the treatment of Cushing's disease. In this review article, we discuss some controversial aspects of Nelson's syndrome including diagnosis, predictive factors, aetiology, pathology and management based on data from the existing literature and the experience of our own tertiary centre. Definitive diagnostic criteria for Nelson's syndrome are lacking. We argue in favour of a new set of criteria. We propose that Nelson's syndrome should be diagnosed in any patient with prior TBA for the treatment of Cushing's disease and with at least one of the following criteria: i) an expanding pituitary mass lesion compared with pre-TBA images; ii) an elevated 0800 h plasma level of ACTH (>500 ng/l) in addition to progressive elevations of ACTH (a rise of >30%) on at least three consecutive occasions. Regarding predictive factors for the development of Nelson's syndrome post TBA, current evidence favours the presence of residual pituitary tumour on magnetic resonance imaging (MRI) post transsphenoidal surgery (TSS); an aggressive subtype of corticotrophinoma (based on MRI growth rapidity and histology of TSS samples); lack of prophylactic neoadjuvant pituitary radiotherapy at the time of TBA and a rapid rise of ACTH levels in year 1 post TBA. Finally, more studies are needed to assess the efficacy of therapeutic strategies in Nelson's syndrome, including the alkylating agent, temozolomide, which holds promise as a novel and effective therapeutic agent in the treatment of associated aggressive corticotroph tumours. It is timely to review these controversies and to suggest guidelines for future audit.