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-secreting Crooke cell carcinoma of the pituitary.

PURPOSE: While pituitary adenomas are common, pituitary carcinomas are rare. It is unclear whether pituitary carcinomas arise de novo or evolve from adenomas. METHODS: We studied the clinical characteristics and tissue samples from eight pituitary surgeries and the autopsy from a patient with pituitary carcinoma. A 16-year-old female patient was diagnosed with an aggressive Crooke cell macroadenoma. Following transsphenoidal surgery, clinical signs of Cushing disease quickly reappeared. During the 14-year course of the illness, eight pituitary surgeries, three courses of extracranial irradiation and two (90) Yttrium-DOTATOC treatments were undertaken. A bilateral adrenalectomy was performed. The patient died of metastatic disease and uncontrolled hypercortisolism due to an adrenal remnant. A systematic morphologic study (histologic staining, electron microscopy) of all available surgical and autopsy specimens was undertaken. RESULTS: Brisk mitotic activity, high Ki-67 and p53 immunolabelling were present in the pituitary samples from the onset. High proportion of tumour cells showed irregular nuclei and large nucleoli, and gradual increase in MGMT staining was observed. The tumour remained of Crooke cell type throughout the course. Autopsy disclosed a postirradiation sarcoma in the pituitary area. CONCLUSIONS: The question whether pituitary carcinomas arise de novo or transform from an adenoma cannot be answered at present with certainty.

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 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.

Easy endotracheal intubation of a patient suffering from both Cushing's and Nelson's syndromes predicted by the upper lip bite test despite a Mallampati Class 4 airway.

A 31-yr-old woman with concurrent Cushing's and Nelson's syndromes was scheduled for transsphenoidal hypophysectomy. The patient had generalized edema, morbid obesity, and a history of sleep apnea. Her Mallampati assessment was Class 4, suggesting very difficult intubation, but the upper lip bite test predicted easy intubation. After rapid sequence induction, there was a Class 1 view on laryngoscopy, and intubation was accomplished easily.

Pituitary corticotroph hyperplasia preceding adenoma in a patient with Nelson's syndrome.

We report the case of a 42-year-old woman with Cushing's disease and Nelson's syndrome. When she was 17 years old, transsphenoidal surgery was performed. A detailed morphologic study demonstrated nodular hyperplasia of corticotroph cells but no adenoma. Following a long-lasting remission (14 years), Cushing's disease recurred. After an unsuccessful second transsphenoidal surgery, Cushing's disease persisted and both adrenals were removed (at the age of 34). Subsequently the patient developed Nelson's syndrome. The pituitary tumor proved to be a corticotroph adenoma; it was removed by the transsphenoidal approach (at the age of 42). Although in most patients Cushing's disease is due to an ACTH-secreting pituitary corticotroph adenoma which precedes the manifestation of Nelson's syndrome, our case indicates not only that corticotroph hyperplasia may cause Cushing's disease but that it may exist before the development of Nelson's syndrome after the removal of both adrenals. Our study supports the view that protracted stimulation of corticotrophs resulting from the elimination of the negative inhibitory feedback effect by corticosteroids plays a role in adenoma initiation.

Adrenocorticotropin and lipotropin secretion by dispersed cell cultures of a human corticotropic adenoma: effect of hypothalamic extract, arginine vasopressin, hydrocortisone, and serotonin.

Basal and modulated secretion of ACTH and lipotropin (LPH) by cultures of trypsin-dispersed cells of a biopsy of a human corticotropic adenoma have been examined. ACTH secretion was detectable throughout the period of culture (13 days) but declined steadily from an initial production rate of 238 +/- 124 ng/3 X 10(5) cells/12 h. The time course of secretion showed a slower phase over the first 4 h, with increases up to 12 h. An extract of rat stalk median eminence caused a significant (P less than 0.005) dose-dependent increase in both ACTH and LPH secretion during 30 min. The patterns of response for ACTH and LPH were very similar; both exhibited a decline in the basal release of peptide subsequent to the period of stimulation. The addition of hydrocortisone (0.2 micrograms/ml) did not suppress basal ACTH secretion during 30 min but significantly (P less than 0.05) inhibited stimulation produced by rat stalk median eminence extract. Arginine vasopressin (dose range, 1-9 ng/ml) significantly (P less than 0.025) stimulated both ACTH and LPH secretion during 30 min. The patterns of response were again very similar. Serotonin (dose range, 0.01-10 micrograms/ml) did not affect ACTH secretion during incubations of 30 min to 4 h. The results obtained with the cell cultures of a human corticotropic cell adenoma concur with in vivo findings of incomplete autonomy of secretion, parallel secretion of ACTH and LPH in response to provocative stimuli, and suppression by corticosteroids. The technique has potential for exploring the cellular mechanisms controlling secretion by human corticotropic adenomas as well as the nature of the hormones produced.

The evaluation of sodium valproate in the treatment of Nelson's syndrome.

It has previously been reported that sodium valproate (Epilim) lowers plasma ACTH levels in Nelson's syndrome. This report describes further experience with its use. Ten patients with Nelson's syndrome were treated with sodium valproate (600-1200 mg/day) for 5-32 weeks. Plasma ACTH was measured by cytochemical methods and RIA. Initial treatment for 5-12 weeks significantly (P less than 0.005) lowered plasma ACTH from a pretreatment mean of 2460 +/- 1870 ng/liter to 480 +/- 330 ng/liter, and the ACTH circadian rhythm was restored in two patients. On discontinuing treatment, plasma ACTH levels remained suppressed for 3 weeks and rose to pretreatment values in 5-12 weeks. Two patients' plasma ACTH levels failed to show a second response to treatment, while a third patient had a favorable second response to treatment over 32 weeks. In six patients, skin pigmentation lightened with treatment, and in one patient, a reduction in size of a pituitary microadenoma, demonstrated radiographically, occurred with treatment. gamma-Aminobutyric acid and sodium valproate were shown to be ineffective in inhibiting ACTH secretion from cultured pituitary tumor cells from a patient with Nelson's syndrome. The results show that sodium valproate is effective in some cases of Nelson's syndrome. We suggest that it reduces the hypersecretion of ACTH by enhancing gamma-aminobutyric acid function in the hypothalamus, thereby inhibiting the release of corticotropin-releasing factor.

Early diagnosis of Nelson's syndrome.

Nelson's syndrome is a specific form of Cushing's disease treated by bilateral adrenalectomy, presenting with a deep hyperpigmentation caused by a pituitary adenoma (corticotropinoma). These ACTH-secreting tumors are frequently aggressive, so early diagnosis is of prime importance. We have studied 33 patients with Nelson's syndrome, 28 women and 5 men, aged 14-56 yr at the time of adrenalectomy and 16-58 yr at the time of Nelson's syndrome diagnosis (observed for 5-32 yr). Methods of examination included simultaneous adrenocorticotropic hormone (ACTH) and cortisol measurements during routine hydrocortisone replacement therapy, computed tomography (CT), pituitary magnetic resonance imaging (MRI), and visual field examination. The results obtained in a group of six patients diagnosed in the last 3 yr were compared with those obtained in a group of 27 patients examined before 1992. High plasma ACTH levels accompanied by normal serum cortisol concentration were characteristic for a late stage of the disease. Absolute temporal scotomas were an early finding. MRI, especially with the gadolinium enhancement, was superior to CT in demonstrating pituitary microadenomas in Nelson's syndrome. Thus, MRI diagnosis allowed for an early neurosurgical treatment of the patients with Nelson's tumors.

Massive hyperplasia of testicular adrenal rests in a patient with Nelson's syndrome.

The case of a 23-year-old man with Nelson's syndrome is presented. He had undergone bilateral adrenalectomy at age 15 years for Cushing's syndrome. Postoperatively, his cushingoid features resolved; however, 13 months later, he became hyperpigmented and showed radiographic evidence of sellar enlargement and midline expansion of the sellar floor. In 1972, he received radiation therapy to the pituitary gland. He underwent transsphenoidal hypophysectomy in 1974 and 1975 for recurrent pituitary adenoma, and recurrent Cushing's syndrome developed concomitantly with bilateral firm testicular masses in 1978. External scanning with NP-59 localized steroid production to the testes, and bilateral orchiectomy was performed. Immunohistochemical studies of the pituitary tumor confirmed the presence of adrenocorticotropic hormone, and morphologic and ultrastructural examinations of the testes supported the adrenal nature of the testicular tumors.

Nelson's syndrome: one disease or two?

We present a case of Nelson's syndrome in which the clinical, radiographic, and surgical findings are indicative of a discrete microadenoma rather than of diffuse pituitary hyperplasia. Ultrastructural analysis reveals this to be the first example of a sparsely granulated lesion in Nelson's syndrome and only the second such adrenocorticotropic hormone-secreting tumor reported. Unfortunately, there do not seem to be any firm ultrastructural features that differentiate between hyperplasia and discrete adenoma. Separation of the two entities may be important in delineating the pathogenesis and treatment of Nelson's syndrome; these are discussed.

Coexisting corticotroph and lactotroph adenomas: case report with reference to the relationship of corticotropin and prolactin excess.

A 57-year-old obese woman with hypertension, diabetes mellitus, osteoporosis, and a 40-year history of secondary amenorrhea was diagnosed with corticotropin-dependent Cushing's syndrome. Dynamic endocrine testing and radiological evaluation did not reveal definitively the source of the excess corticotropin. Bilateral adrenalectomy was performed with resolution of the signs and symptoms of hypercortisolism. Four years later, the patient was noted to have rising serum corticotropin levels and an enlarging pituitary mass; hyperprolactinemia also was documented. A diagnosis of Nelson-Salassa syndrome was made, and she underwent a transsphenoidal adenomectomy. A histological examination of the specimen revealed two distinct, albeit contiguous, adenomas: a corticotroph adenoma and a lactotroph adenoma. Postoperatively, the serum prolactin and corticotropin levels decreased significantly. Although the stalk section effect resulting from compression by a pituitary adenoma can raise serum prolactin levels, a concurrent lactotroph adenoma should be considered in patients with nonfunctional or functional pituitary adenomas of other types associated with significantly elevated prolactin levels. The mechanisms underlying simultaneous adrenocorticotropic hormone and prolactin excess are discussed.

Pituitary pathology in Cushing's disease.

Pituitaries of 137 cases with Cushing's disease were microscopically and immunohistologically studied. Many alterations and parameters (sex, age, anamnesis, cortisol plasma levels, tumor size, invasiveness, localization, differentiation of adenomas, immunohistological hormone content, capillarity, recurrences, peritumorous ACTH cell hyperplasia, and Crooke's cells) were analyzed and compared. Whereas most parameters were not correlated, we found some important statistically significant correlations: Undifferentiated adenomas are more frequently invasive than differentiated ones. Invasive adenomas recur more frequently than non-invasive adenomas. Extremely laterally localized adenomas are more often invasive. Larger adenomas are more frequently invasive than micro-adenomas. ACTH cell hyperplasia are more often demonstrable in specimens from total hypophysectomies (confined to our earlier series) than from partial hypophysectomies and adenomectomies. Recurrences of adenomas are more frequent in pituitaries with periadenomous ACTH cell hyperplasia. Very rarely ACTH cell hyperplasia are the only source of ACTH hyperfunction. The more Crooke's cells are demonstrable, the longer the post-operative replacement dose of Cortisol is required. Adenomas in Cushing's disease and adenomas in Nelson's syndrome differ significantly in the following points: Adenomas in Nelson's syndrome are larger and contain more plurinuclear cells. In the ultrastructure, adenomas in Cushing's disease show more cytofilaments. Paraadenomous Crooke's cells are lacking in Nelson's syndrome.

Human corticotroph cell adenomas.

Sixty-one pituitary corticotroph adenomas from 47 patients with Cushing's disease, 10 with Nelson's syndrome, and four eucorticoid patients were studied by light microscopy, immunoperoxidase, and electron microscopy. Seventy nine percent of all tumors and 70% of Nelson's cases were microadenomas, sometimes minute. A contiguity between the posterior lobe and the adenoma was seen in ten cases. Spontaneous infarction of the tumor with remission of Cushing's syndrome occurred in one case. Light microscopy revealed that the adenoma cells were basophilic and contained PAS-positive granules also staining with Herlant tetrachrome and lead-hematoxylin. The granules stained positively with antiserum to adrenocorticotrophic hormone (ACTH), beta-lipotropic hormones (beta-LPH) and beta-endorphin. The most characteristic ultrastructural finding was the presence of perinuclear bundles of microfilaments found in all our cases. Oncocytic changes were seen in three tumors. Four silent corticotroph adenomas, two of them originally microadenomas that had enlarged to enclosed adenomas while being treated with bromocriptine for hyperprolactinemia and one a large diffuse invasive tumor, did not differ in their microscopic, immunocytological, or ultrastructural features.

[Pituitary gland imaging in Cushing's disease]. / L'imagerie dans la maladie de Cushing.

Specific MR techniques are required for optimal detection of adenocorticotropic hormone secreting adenomas responsible for Cushing's disease. Adequate MR sequences, high resolution coronal T1 and T2 - weighted images, dynamic MR imaging, post-gadolinium delayed images, dose of gadolinium adjusted for each sequence can routinely demonstrate pituitary adenomas less than 3 mm in Cushing's disease.

[Immunoelectron microscopical study on human pituitary corticotrophic adenomas].

5 cases of pituitary adenomas associated with Cushing's disease or Nelson's syndrome were studied with electron microscopy and immunoelectron microscopy by using protein A--gold complex. Diversified ultrastructure was displayed in these tumors, among which 4 revealed presence of ACTH positive secretory granules. These granules were round or polyhedric in shape, varied in number, size and electronic density. Bundles of microfilaments could be seen in the tumor cells frequently, which were of the highest diagnostic value. There was no significant difference found in ultrastructure and immunocytochemical reaction of adenomas in Cushing's disease and Nelson's syndrome.

[Case of Nelson syndrome]. / Sluchai sindroma Nel'sona.

A clinical description of Nelson syndrome developing in a woman of 44 is presented. Histologically the tumour of the hypophysis was an adenoma of mixed structure, electron microscopically it was found to consist of corticotropocytes in various stages of the secretory cycle. Adenoma of the hypophysis was diagnosed 4 years after bilateral adrenalectomy.

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.

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.