Figure 3 - uploaded by Niki Karavitaki
Content may be subject to copyright.
Nelson's syndrome: coronal and axial T 1 W unenhanced MRI (a and b) showing tumour involving the right cavernous sinus, and chiasmatic cistern with axial CT (c) showing a hyperdense (probably haemorrhagic) component of the tumour. An intracranial metastasis developed over the next 12 months as shown on axial views of T 1 W MRI scans performed after gadolinium administration (d) at the time of (a-c) and 1 year later (e).
Source publication
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 o...
Citations
... RT is also used for the prevention or treatment of Nelson's syndrome potentially occurred 30~50% following bilateral adrenalectomy for uncontrolled CD [290]. In several studies, conventional prophylactic RT achieved pituitary tumor control in 75%-100% of the patients with Nelson's syndrome at a median time of 8 years [291]. ...
In patients with Cushing’s disease (CD), prompt diagnosis and treatment are essential for favorable long-term outcomes, although this remains a challenging task. The differential diagnosis of CD is still difficult in some patients, even with an organized stepwise diagnostic approach. Moreover, despite the use of high-resolution magnetic resonance imaging (MRI) combined with advanced fine sequences, some tumors remain invisible. Surgery, using various surgical approaches for safe maximum tumor removal, still remains the first-line treatment for most patients with CD. Persistent or recurrent CD after unsuccessful surgery requires further treatment, including repeat surgery, medical therapy, radiotherapy, or sometimes, bilateral adrenalectomy. These treatments have their own advantages and disadvantages. However, the most important thing is that this complex disease should be managed by a multidisciplinary team with collaborating experts. In addition, a personalized and individual-based approach is paramount to achieve high success rates while minimizing the occurrence of adverse events and improving the patients’ quality of life. Finally, the recent new insights into the pathophysiology of CD at the molecular level are highly anticipated to lead to the introduction of more accurate diagnostic tests and efficacious therapies for this devastating disease in the near future.
... NS was documented months or years in up to 15% of children with CD after BA [20,24]. NS appears to be more frequent in children than in adults (an incidence of 8-43% in adults [101] and 25-75% in children [102][103][104] and often requires pituitary surgery or RT [105]. Children after BA seem to have higher risk of NS in comparison to adults-for this reason they should be carefully monitored-they require annual monitoring with MRI and assessment of plasma ACTH values [102][103][104]. ...
Cushing’s disease (CD) is a rare endocrine condition caused by a corticotroph pituitary tumor that produces adrenocorticotropic hormone. The current state of knowledge of CD treatment is presented in this article including factors that can be helpful in predicting remission and/or recurrence of the disease. The primary goals in CD treatment are quick diagnosis and effective, prompt treatment as the persistent disease is associated with increased morbidity and mortality. Cooperation of a team consisting of experienced pediatrician/adult endocrinologist, neuroradiologist, transsphenoidal neurosurgeon and (if necessary) radiotherapist contribute to the best treatment effects.
... In NSS, adrenalectomy removes cortisolmediated negative feedback on the adenoma remnant, which may rapidly progress and yield a large adrenocorticotropic hormone (ACTH)-secreting macroadenoma and, in the classic description, precipitating visual field deficits from chiasmatic compression, and skin hyperpigmentation from the marked increase in circulating alpha-melanocyte-stimulating hormone-a metabolic byproduct of ACTH synthesis. Interestingly, although radiographic evidence of NSS has been reported in up to 50% of post-adrenalectomy CD patients, the pathognomonic triad is rarely observed in practice [1][2][3][4][5]. Risk factors for NSS include young age, larger pituitary adenoma at time of adrenalectomy, and a history of external beam radiotherapy (EBRT). ...
Nelson-Salassa Syndrome (NSS) is a rare sequela of bilateral adrenalectomy as a treatment for persistent hypercortisolism in refractory Cushing disease (CD). Radiographic NSS has been observed in half of CD patients after adrenalectomy, yet often follows a mild course and rarely requires treatment. We present the case of a 44-year-old male with a history of CD who underwent primary treatments including transsphenoidal resection, radiotherapy, and bilateral adrenalectomy. He subsequently presented with acute vision loss and progressive somnolence. MRI revealed marked enlargement of an invasive sellar and suprasellar lesion exerting significant mass effect on the chiasm, and multiple new enhancing bony lesions. The patient was taken for emergent transsphenoidal resection and calvarial biopsy; visual function was restored postoperatively, and pathologic analysis confirmed pituitary carcinoma. While NSS typically follows an indolent course, pituitary carcinoma is a highly morbid metastatic disease, and has been theorized to occur at a higher frequency in the NSS population. We review all published cases of NSS to pituitary carcinoma progression, which further underscores the highly aggressive nature and considerable mortality of this patient cohort. Although mild, asymptomatic NSS is more commonly observed, symptomatic patients or those with rapid growth after adrenalectomy, should be targeted for routine close clinical follow-up and serial radiographic surveillance.
... Therefore, patients with persistent or recurrent CD might benefit from a second pituitary operation (which leads to remission in 50-70% of the cases), radiation therapy (RT) on the pituitary gland, or total bilateral adrenalectomy (TBA) (1,3). TBA offers an 85-100% success rate in controlling hypercortisolemia, and is particularly useful in patients with severe comorbidities associated with this condition (2,4,5). However, one of the limitations of TBA is the Outcome after adrenalectomy in CD Arch Endocrinol Metab. ...
... Most patients developed NS during the first years after TBA, as described by several authors (5,11,15). Gil-Cárdenas and cols. (15) reported the occurrence of NS after a mean of 15 months (range 2-33 months) after surgery, while in a series by Kelly and cols. ...
... Concerning the definition of NS, although more than 100 cases have been documented in reports and short series, definitive diagnostic criteria for NS have not been established yet (17). The diagnosis of NS is controversial, but the existing criteria focus on an enlarging pituitary tumor after TBA (the appearance of a new adenoma or progression of the remnant corticotroph) and increasing ACTH levels (5,17). Addressing the former issue, Assié and cols. ...
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.
... Transsphenoidal pituitary surgery is the first line of treatment for Cushing's disease; though recurrence has been observed in about 20% of patients (3). In 1958, Don Nelson et al were the first to report a corticotroph macroadenoma in a 33 year old lady who had underwent total bilateral adrenalectomy (TBA)for refractory Cushing's syndrome (4). TBA may be proposed in any patient with a non-localized pituitary source of ACTH or failure of pituitary surgery and those refractory to medical therapy. ...
... The usual presentation involves progressive hyperpigmentation of the skin and mucous membranes with ACTH levels >500pg/ml despite adequate corticosteroid supplementation. Visual field defects and cranial nerve palsies were additional presenting features due to the mass effects of the tumor invading adjacent structures as was seen in the present case, but are uncommon in recent years (4,5). Dopamine agonist like Cabergoline have been documented to induce remission and tumour reduction in some patients with NS (4).Selective somatostatin analogues (SSAs) like Octreotide may decrease plasma ACTH levels and reduce tumour volume in some patients with Nelson's syndrome (5). ...
Nelson’s syndrome is an infrequent pituitary mass with an incidence of 8–43% in adults and 25–66% in children that develops following total bilateral adrenalectomy (TBA) for the treatment of Cushing’s disease. It is one of the most challenging of all endocrine conditions. The frequent aggressiveness of the underlying ACTH-secreting pituitary adenoma (corticotrophinoma) necessitates regular biochemical and radiological screening. Current evidence favours a lack of prophylactic neoadjuvant pituitary radiotherapy at the time of TBA and a rapid rise of ACTH levels in the year post TBA as factors that may predict the occurrence of Nelson’s syndrome. Though, computerized tomography (CT)/magnetic resonance imaging (MRI) have led to the early diagnosis and improvement in management. Nelson’s related tumours are sometimes detected late, through clinical manifestations of invasion and compression of the surrounding structures. With this perspective in mind, we describe a 22 year old gentleman 10 years after TBA who presented with right sided hemiparesis due to a corticotroph adenoma.
... Frequent clinical manifestations are cutaneous hyperpigmentation due to an excess of proopiomelanocortin derivatives, as well as headache, visual defects and cranial nerve palsy due to tumor enlargement and compression. However, not all symptoms are presented in each NS case (5,6) and thus there is a lack of consensus both on the definition and the diagnostic criteria of NS (5,7,8,9). Of note, it has also been suggested to replace NS by the term corticotroph tumor progression since incident tumor growth can be identified in up to 50% of the patients after modern MRI imaging years before hyperpigmentation develops (7). ...
... In detail, half of the female patients presented tumors with USP8 mutations, a frequency that resembles that observed for CD (14,15,16,17). These similarities as well as the consistency in the USP8 mutational status between paired CD/NS samples strongly support the hypothesis of NS tumors as a progression or a recurrence of the initial CD tumor (2,8). However, the same prevalence of USP8 mutations between CD and NS tumors makes it unlikely that these mutations trigger the progression from Cushing's to 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.
... Frequent clinical manifestations are cutaneous hyperpigmentation due to an excess of proopiomelanocortin derivatives, as well as headache, visual defects and cranial nerve palsy due to tumor enlargement and compression. However, not all symptoms are presented in each NS case (5,6) and thus there is a lack of consensus both on the definition and the diagnostic criteria of NS (5,7,8,9). Of note, it has also been suggested to replace NS by the term corticotroph tumor progression since incident tumor growth can be identified in up to 50% of the patients after modern MRI imaging years before hyperpigmentation develops (7). ...
... In detail, half of the female patients presented tumors with USP8 mutations, a frequency that resembles that observed for CD (14,15,16,17). These similarities as well as the consistency in the USP8 mutational status between paired CD/NS samples strongly support the hypothesis of NS tumors as a progression or a recurrence of the initial CD tumor (2,8). However, the same prevalence of USP8 mutations between CD and NS tumors makes it unlikely that these mutations trigger the progression from Cushing's to Nelson's tumor. ...
... Recurrence of CD was defined as the presence of biochemical features of CD i.e. increased midnight sleeping cortisol, lack of suppression of cortisol during LDDST and increased 24 h urinary free cortisol values, which recurred after definitive therapy that resulted in clinical remission. Nelson syndrome was defined as enlarging pituitary corticotropinoma with elevated and rising ACTH levels following bilateral adrenalectomy [24]. ...
... In our series, mean follow-up was more than 10 years. We report a small but important prevalence of recurrence, demonstrating that life-long follow-up is required, and this is consistent with data from long-term follow-up in adult patients with CD (24). ...
Purpose:
Pediatric Cushing's disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients.
Methods:
Retrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7-17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9-27.2).
Results:
Fifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson's syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients.
Conclusions:
The long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.
... The usual presentation involves progressive hyperpigmentation of the skin and mucous membranes with very high ACTH levels (>500pg/ml) despite adequate corticosteroid supplementation. Visual field defects and cranial nerve palsies that could occur due to the mass effects of the tumor invading adjacent structures as was seen in the present case are uncommon in modern clinical practice (4,5). ...
Nelson’s syndrome is a pituitary mass that develops following total bilateral adrenalectomy (TBA) for the treatment of Cushing’s disease. It is one of the most challenging of all endocrine conditions. The frequent aggressiveness of the underlying ACTH-secreting pituitary adenoma (corticotrophinoma) necessitates regular biochemical and radiological screening. Failure to administer prophylactic neoadjuvant pituitary radiotherapy at the time of TBA and a rapid rise of ACTH levels during the first year following TBA are the main factors that may predict the occurrence of Nelson’s syndrome. Though, computerized tomography (CT) and magnetic resonance imaging (MRI) have led to the early diagnosis and improvement in management, these tumours are sometimes detected late, through clinical manifestations of invasion and compression of the surrounding structures. With this perspective in mind, we describe a 22-year-old gentleman who presented 10 years after TBA with right sided hemiparesis caused by a corticotroph adenoma.
... The usual presentation involves progressive hyperpigmentation of the skin and mucous membranes with very high ACTH levels (>500pg/ml) despite adequate corticosteroid supplementation. Visual field defects and cranial nerve palsies that could occur due to the mass effects of the tumor invading adjacent structures as was seen in the present case are uncommon in modern clinical practice (4,5). ...
