Management of Nelson's Syndrome.

Nelson's syndrome is a potentially severe condition that may develop in patients with Cushing's disease treated with bilateral adrenalectomy. Its management can be challenging. Pituitary surgery followed or not by radiotherapy offers the most optimal tumour control, whilst pituitary irradiation alone needs to be considered in cases requiring intervention and are poor surgical candidates. Observation is an option for patients with small lesions, not causing mass effects to vital adjacent structures but close follow-up is required for a timely detection of corticotroph tumour progression and for further treatment if required. To date, no medical therapy has been consistently proven to be effective in Nelson's syndrome. Pharmacotherapy, however, should be considered when other management approaches have failed. A subset of patients with Nelson's syndrome may develop further tumour growth after primary treatment, and, in some cases, a truly aggressive tumour behaviour can be demonstrated. In the absence of evidence-based guidance, the management of these cases is individualized and tailored to previously offered treatments. Temozolomide has been used in patients with aggressive Nelson's with no consistent results. Development of tumour-targeted therapeutic agents are an unmet need for the management of aggressive cases of Nelson's syndrome.

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.

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. RESULTS: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.

Nelson's Syndrome: An Update.

Nelson's syndrome (NS) is a condition which may develop in patients with Cushing's disease after bilateral adrenalectomy. Although there is no formal consensus on what defines NS, corticotroph tumor growth and/or gradually increasing ACTH levels are important diagnostic elements. Pathogenesis is unclear and well-established predictive factors are lacking; high ACTH during the first year after bilateral adrenalectomy is the most consistently reported predictive parameter. Management is individualized and includes surgery, with or without radiotherapy, radiotherapy alone, and observation; medical treatments have shown inconsistent results. A subset of tumors demonstrates aggressive behavior with challenging management, malignant transformation and poor prognosis.

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.

Long-term outcome after bilateral adrenalectomy in Cushing's disease with focus on Nelson's syndrome

ABSTRACT Objective We analyzed the clinical, biochemical, and imaging findings of adrenalectomized patients with Cushing's disease (CD) in order to compare the characteristics of those who developed Nelson's syndrome (NS) versus those who did not develop this complication (NNS), aiming to identify possible predictive factors for its occurrence. Subjects and methods We performed a retrospective review of the clinical records of a group of patients with CD who underwent TBA between 1974 and 2011. Results Out of 179 patients with CD, 13 (7.3%) underwent TBA. NS occurred in 6 of them (46%) after a mean of 24 months from the total bilateral adrenalectomy (TBA). Age at diagnosis, duration of Cushing's syndrome (CS) until TBA, and steroid replacement doses were similar in both groups. Initial urinary cortisol levels (24-hour urinary free cortisol [UFC]) were significantly higher in the NS group than in the NNS group (p = 0.009). Four patients in the NS group and three of those in the NNS group received radiotherapy before TBA (p = 0.26). Three patients in the NS group presented residual tumors before TBA, compared with none in the NNS group (p = 0.04). At 1 year after TBA, the median ACTH level was 476 ng/L (240-1500 ng/L) in the NS group and 81 ng/L (48-330 ng/L) in the NNS group (p = 0.0007). Conclusion In conclusion, a residual tumor before TBA, higher 24-hour UFC at diagnosis, and increasing ACTH levels within 1 year after TBA emerged as predictive factors of development of NS.

Long-term outcome after bilateral adrenalectomy in Cushing's disease with focus on Nelson's syndrome.

OBJECTIVE: We analyzed the clinical, biochemical, and imaging findings of adrenalectomized patients with Cushing's disease (CD) in order to compare the characteristics of those who developed Nelson's syndrome (NS) versus those who did not develop this complication (NNS), aiming to identify possible predictive factors for its occurrence. SUBJECTS AND METHODS: We performed a retrospective review of the clinical records of a group of patients with CD who underwent TBA between 1974 and 2011. RESULTS: Out of 179 patients with CD, 13 (7.3%) underwent TBA. NS occurred in 6 of them (46%) after a mean of 24 months from the total bilateral adrenalectomy (TBA). Age at diagnosis, duration of Cushing's syndrome (CS) until TBA, and steroid replacement doses were similar in both groups. Initial urinary cortisol levels (24-hour urinary free cortisol [UFC]) were significantly higher in the NS group than in the NNS group (p = 0.009). Four patients in the NS group and three of those in the NNS group received radiotherapy before TBA (p = 0.26). Three patients in the NS group presented residual tumors before TBA, compared with none in the NNS group (p = 0.04). At 1 year after TBA, the median ACTH level was 476 ng/L (240-1500 ng/L) in the NS group and 81 ng/L (48-330 ng/L) in the NNS group (p = 0.0007). CONCLUSION: In conclusion, a residual tumor before TBA, higher 24-hour UFC at diagnosis, and increasing ACTH levels within 1 year after TBA emerged as predictive factors of development of NS.

Radiotherapy as a tool for the treatment of Cushing's disease.

Treatment of Cushing's disease (CD) is one of the most challenging tasks in endocrinology. The first-line treatment, transsphenoidal pituitary surgery, is associated with a high failure rate and a high prevalence of recurrence. Re-operation is associated with an even higher rate of a failure and recurrence. There are three main second-line treatments for CD - pituitary radiation therapy (RT), bilateral adrenalectomy and chronic cortisol-lowering medical treatment. All these treatments have their limitations. While bilateral adrenalectomy provides permanent cure of the hypercortisolism in all patients, the unavoidable chronic adrenal insufficiency and the risk of development of Nelson syndrome are of concern. Chronic cortisol-lowering medical treatment is not efficient in all patients and side effects are often a limiting factor. RT is efficient for approximately two-thirds of all patients with CD. However, the high prevalence of pituitary insufficiency is of concern as well as potential optic nerve damage, development of cerebrovascular disease and secondary brain tumours. Thus, when it comes to decide appropriate treatment for patients with CD, who have either failed to achieve remission with pituitary surgery, or patients with recurrence, the pros and cons of all second-line treatment options must be considered.

Bilateral adrenalectomy in Cushing's disease: Altered long-term quality of life compared to other treatment options.

OBJECTIVE: Bilateral adrenalectomy (BADX) has become an important treatment of Cushing's disease (CD), especially when other treatment options have failed. The aim of this study was to evaluate the long-term quality of life (QoL) of patients having undergone BADX for CD, in comparison to other therapeutic options. METHODS: Thirty-four patients with CD were identified in two French centers: 17 underwent BADX and the remaining 17 one or more of the following treatments: surgery, medical therapy or radiotherapy. Three questionnaires were filled in by each patient in order to evaluate their QoL: Short Form-36 Health Survey (SF-36), Cushing QoL questionnaire and Beck depression inventory (BDI). RESULTS: The mean age of patients was 49.3±15.2 years. Average time lapse between diagnosis and BADX was 6.1 years. Results from each questionnaire adjusted to age showed a lower QoL among patients who underwent BADX. These were significant in most aspects of the SF-36 questionnaire (bodily pain P<0.01, general health P<0.01, vitality P≤0.05, social functioning P≤0.05), as well as in the Cushing QoL questionnaire (P<0.05) and BDI (P≤0.05). Adrenal insufficiency appeared to be the major predictor of poor QoL whatever their initial treatment. CONCLUSIONS: Despite their clinical remission, patients who undergo BADX appear to be at a greater risk of suffering an impaired QoL due to more prolonged period of time with imperfectly controlled hypercortisolism combined with definitive adrenal insufficiency.

A Long-Term Study of the Treatment of Nelson's Syndrome With Gamma Knife Radiosurgery.

BACKGROUND: Nelson's syndrome may be a devastating complication for patients with Cushing's disease who underwent a bilateral adrenalectomy. Previous studies have demonstrated that stereotactic radiosurgery (SRS) can be used to treat patients with Nelson's syndrome. OBJECTIVE: To report a retrospective study of patients with Nelson's syndrome treated with Gamma Knife radiosurgery to evaluate the effect of SRS on endocrine remission and tumor control. METHODS: Twenty-seven patients with Nelson's syndrome treated with Gamma Knife radiosurgery after bilateral adrenalectomy were included in this study. After radiosurgery, patients were followed with serial adrenocorticotropic hormone (ACTH) levels and MRI sequences to assess for endocrine remission and tumor control. Cox proportional hazards regression analysis was used to evaluate the relationship between the time to remission and potential prognostic factors. RESULTS: In 21 patients with elevated ACTH prior to SRS and endocrine follow-up data, 14 (67%) had decreased or stable ACTH levels, and 7 achieved a normal ACTH level at a median of 115 mo (range 7-272) post-SRS. Tumor volume was stable or reduced after SRS in 92.5% of patients (25/27) with radiological follow-up. Time to remission was not significantly associated with the ACTH prior to SRS (P = .252) or with the margin dose (P = .3). However, a shorter duration between the patient's immediate prior transsphenoidal resection and SRS was significantly associated with a shorter time to remission (P = .045). CONCLUSION: This retrospective analysis suggests that SRS is an effective means of achieving endocrine remission and tumor control in patients with Nelson's syndrome.

Characterizing and predicting the Nelson-Salassa syndrome.

OBJECTIVE Nelson-Salassa syndrome (NSS) is a rare consequence of bilateral adrenalectomy (ADX) for refractory hypercortisolism due to Cushing disease (CD). Although classically defined by rapid growth of a large, invasive, adrenocorticotropin hormone (ACTH)-secreting pituitary tumor after bilateral ADX that causes cutaneous hyperpigmentation, visual disturbance, and high levels of ACTH, clinical experience suggests more variability. METHODS The authors conducted a retrospective chart review of all patients 18 years and older with a history of bilateral ADX for CD, adequate pituitary MRI, and at least 2 years of clinical follow-up. Statistical tests included Student's t-test, chi-square test, Fisher's exact test, multivariate analysis, and derived receiver operating characteristic curves. RESULTS Between 1956 and 2015, 302 patients underwent bilateral ADX for the treatment of hypercortisolism caused by CD; 88 had requisite imaging and follow-up (mean 16 years). Forty-seven patients (53%) had radiographic progression of pituitary disease and were diagnosed with NSS. Compared with patients who did not experience progression, those who developed NSS were significantly younger at the time of CD diagnosis (33 vs 44 years, p = 0.007) and at the time of bilateral ADX (35 vs 49 years, p = 0.007), had larger tumors at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03), and were more likely to have undergone external-beam radiation therapy (EBRT, 43% vs 12%, p = 0.005). Among NSS patients, the mean tumor growth was 7 mm/yr (SE 6 mm/yr); the median tumor growth was 3 mm/yr. Prevalence of pathognomonic symptoms was low; the classic triad occurred in 9%, while hyperpigmentation without visual field deficit was observed in 23%, and 68% remained asymptomatic despite radiographic disease progression. NSS required treatment in 14 patients (30%). CONCLUSIONS NSS is a prevalent sequela of CD after bilateral ADX and affects more than 50% of patients. However, although radiological evidence of NSS is common, it is most often clinically indolent, with only a small minority of patients developing the more aggressive disease phenotype characterized by clinically meaningful symptoms and indications for treatment. Young age at the time of CD diagnosis or treatment with bilateral ADX, large tumor size at CD diagnosis, and EBRT are associated with progression to NSS and may be markers of aggressiveness.

Re-examining Nelson's syndrome.

PURPOSE OF REVIEW: Nelson's syndrome is a rare complication that can occur during the course of management of Cushing's disease. This article summarizes the recent literature on the diagnosis, monitoring and treatment of this potentially life-threatening outcome. RECENT FINDINGS: Nelson's syndrome, with rising adrenocorticotropin hormone levels and corticotroph tumor progression on diagnostic imaging, can develop following treatment of refractory Cushing's disease with total bilateral adrenalectomy with/without radiotherapy. However, data showing that radiotherapy prevents Nelson's syndrome is inconsistent. In addition to the treatment of Nelson's syndrome with neurosurgery with/without adjuvant radiotherapy, selective somatostatin analogs and dopamine agonists, as well as other novel agents, have been used with increasing frequency in treating cases of Nelson's syndrome with limited benefit. The risk-benefit profile of each of these therapies is still not completely understood. SUMMARY: Consensus guidelines on the evaluation and management of Nelson's syndrome are lacking. This article highlights areas in the surveillance of Cushing's disease patients, and diagnostic criteria and treatment regimens for Nelson's syndrome that require further research and review by experts in the field.

Nelson syndrome: definition and management.

Nelson syndrome is an important complication of treatment with total bilateral adrenalectomy (TBA) for patients with refractory Cushing's disease. Although early cases of Nelson syndrome often presented with the clinical features of large sellar masses, the modern face of Nelson syndrome has changed primarily due to earlier detection (with highly resolved magnetic resonance imaging (MRI) and sensitive ACTH assays) and greater awareness of the condition, resulting in reduced morbidity and mortality. Although lack of administration of neoadjuvant pituitary radiotherapy post-TBA surgery may predict future development of Nelson syndrome, other predictive factors remain controversial. Therefore, Nelson syndrome should be screened for closely and long-term in all patients with a history of Cushing's disease and TBA. The diagnosis of Nelson syndrome remains controversial, and the pathogenesis of this condition is incompletely understood. Current hypotheses include the "released negative feedback" mechansism (residual pituitary corticotropinoma cells are "released" from the negative feedback effects of cortisol following TBA), and the "aggressive corticotropinoma" mechanism (Nelson syndrome is most likely to develop in those patients with refractory treatments - including TBA - for an underlying aggressive corticotropinoma). Effective management of Nelson syndrome with pituitary surgery and radiotherapy is often a challenge. Other therapies (such as Gamma Knife surgery and temozolomide) play an important role and merit further research into their efficacy and placement in the management pathway of Nelson syndrome.

Nasally located ectopic ACTH-secreting pituitary adenoma (EAPA) causing Nelson's syndrome: diagnostic challenges.

PURPOSE: We report the first case of an Ectopic adrenocorticotrophin (ACTH)-secreting pituitary adenoma (EAPA) located within the posterior nasal septum associated with Nelson's syndrome, which eluded diagnosis for over a decade. In this report, we explore the reasons for such diagnostic difficulty and suggest ways in which an earlier diagnosis may be made. METHODS AND RESULTS: A 19 years old Lebanese man presented in 2000, with overt Cushing's syndrome confirmed with markedly elevated urine free cortisols and failed dexamethasone suppression tests. An unsuppressed ACTH and a possible 5 mm adenoma on MRI (Magnetic Resonance Imaging) pituitary suggested Cushing's disease. The patient underwent trans-sphenoidal surgery (TSS), but histology revealed normal pituitary tissue and Cushing's syndrome persisted. A repeat MRI pituitary showed no anomaly, and extensive investigations failed to locate an ectopic lesion. Subsequently a bilateral adrenalectomy was performed. Over the ensuing years, the patient developed Nelson's syndrome with hyperpigmentation and markedly elevated ACTH levels. Repeated high dose dexamethasone suppression tests, corticotrophin releasing hormone (CRH) tests, and CRH stimulated inferior petrosal sinus samplings (IPSS) suggested a pituitary origin of the ACTH. Two further TSS were unsuccessful. The pituitary was irradiated. Subsequent review of his previous MRIs revealed an enlarging mass within the posterior nasal septum, which was excised in 2011. The histology confirmed the diagnosis of an EAPA within the nasal septum. CONCLUSION: Ectopic ACTH-secreting pituitary adenomas can occur not only along the developmental route of Rathke's pouch, but other aberrant locations giving a clinical and biochemical picture identical to Cushing's disease or Nelson's syndrome. Clinicians should suspect an EAPA, when a central ACTH source seems to be apparent with no obvious pituitary adenoma. A detailed MRI involving possible EAPA sites aids in locating these unusual lesions.

Low immunohistochemical expression of MGMT in ACTH secreting pituitary tumors of patients with Nelson syndrome.

MGMT expression in tumors has been correlated with response to treatment with temozolomide therapy. Few medical therapies are available for Nelson syndrome, and the efficacy of such therapeutics remains limited. The aim of the present study was to assess immunohistochemical expression of MGMT in ACTH-secreting pituitary adenomas of patients with Nelson syndrome. Our material consisted of eight specimens from ACTH-secreting pituitary adenomas of patients with Nelson syndrome. Immunohistochemical staining for MGMT was performed using the streptavidin-biotin-peroxidase complex method. MGMT immunoreactivity was assessed microscopically and recorded as an estimated percentage of nuclear MGMT immunostaining (0 = none, 1=<10%, 2=<25%, 3=<50%, 4=>50%). Five of the eight specimens (65%) exhibited no MGMT immunoreactivity, with two out of eight cases (25%) showing slight MGMT staining (<10%) and one out of eight cases (12%) demonstrating moderate MGMT positivity (<25%). Patient male/female ratio was 3:5, with average patient age being 62.4 (range 57­66). Our findings suggest that temozolomide therapy may be of potential use in patients with Nelson syndrome, as these tumors express absent/low levels of MGMT. Absent or low MGMT staining in brain and other neoplasms has been shown to correlate with successful treatment with temozolomide, and recent reports of aggressive pituitary adenomas suggest similar outcomes.

Síndrome de Nelson: una causa infrecuente de hiperpigmentación cutánea generalizada / Nelson syndrome: a rare cause of generalized hyperpigmentation of the skin

El síndrome de Nelson (SN) supone una causa infrecuente de hiperpigmentación mucocutánea generalizada, cuyas manifestaciones clínicas se derivan de la secreción excesiva de corticotropina por un adenoma hipofisario secundario a la realización de una suprarrenalectomía bilateral terapéutica. Debido a que esta intervención quirúrgica ha caído en desuso en la actualidad, su presentación es hoy sumamente rara y poco reconocible. Presentamos un caso muy grave de hiperpigmentación generalizada por SN en una paciente de 37 años (AU)

Nelson syndrome is a rare cause of generalized mucocutaneous hyperpigmentation. Its clinical manifestations are due to excessive secretion of adrenocorticotropic hormone from a pituitary adenoma, which develops after bilateral therapeutic adrenal ectomy. As this operation has fallen into disuse, Nelson syndrome is now extremely rare and difficult to recognize. We present a very severe case of generalized hyperpigmentation due to Nelson syndrome in a 37-year-old woman (AU)

[Nelson syndrome: a rare cause of generalized hyperpigmentation of the skin]. / Síndrome de Nelson: una causa infrecuente de hiperpigmentación cutánea generalizada.

Nelson syndrome is a rare cause of generalized mucocutaneous hyperpigmentation. Its clinical manifestations are due to excessive secretion of adrenocorticotropic hormone from a pituitary adenoma, which develops after bilateral therapeutic adrenalectomy. As this operation has fallen into disuse, Nelson syndrome is now extremely rare and difficult to recognize. We present a very severe case of generalized hyperpigmentation due to Nelson syndrome in a 37-year-old woman.

[Effects of adrenalectomy on the treatment of Cushing disease].

OBJECTIVE: To discuss the effects of adrenalectomy (ADX) on the treatment of Cushing's disease(CD). METHODS: Clinical data of 15 cases of CD between January 1980 and December 2005 were analyzed to evaluate operative indications, complications and the changes of hypercortisolism and hormone levels pre- and post- adrenalectomy. RESULTS: All the patients involved underwent transsphenoidal pituitary surgery previously. Repeated transsphenoidal surgery was performed in 4 cases. Pituitary radiotherapy was done in 4 cases. The average time from original transsphenoidal operation to ADX was 25.7 months. Pre- and post- adrenalectomy serum cortisol median level were 1156.4 nmol/L and 99.4 nmol/L, the 24 h urinary-free cortisol median level were 315.0 and 5.4 microg, respectively. Hormone replacement therapy was needed in all cases. Average follow-up period was 47 months (9-120 months). Nelson syndrome (NS) appeared in 5 cases (33.3%), while 10 cases showed no NS. CONCLUSIONS: ADX is an effective and symptomatic treatment to relieve hypercortisolism caused by CD but with the risk of NS. Longtime hormone replacement therapy and follow up are needed after ADX.