scholarly journals Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Carlotta Pozza ◽  
Chiara Graziadio ◽  
Elisa Giannetta ◽  
Andrea Lenzi ◽  
Andrea M. Isidori
Keyword(s):  
Cushing’S Syndrome ◽  
Somatostatin Receptor ◽  
Cushing's Syndrome ◽  
Chemotherapeutic Agents ◽  
Peroxisome Proliferator ◽  
Significant Activity ◽  
Ectopic Acth ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ectopic Acth Secretion ◽  
Free Cortisol

Cushing’s syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing’s disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptorγ“PPAR-γ” ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.

scholarly journals Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion

2012 ◽  
Vol 166 (3) ◽  
pp. 531-536 ◽  
Author(s):  
S T Sharma ◽  
L K Nieman
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Term Treatment ◽  
Sustained Remission ◽  
Ectopic Acth ◽  
Ectopic Acth Secretion ◽  
Free Cortisol ◽  
Long Term Treatment ◽  
History Of

Spontaneous remission is rare in ectopic ACTH syndrome (EAS). We describe four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3–10 years in these patients was followed by a prolonged period of remission (15–60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h urinary free cortisol (UFC), and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity and case 3 has been in remission for ∼5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.

scholarly journals Mifepristone Effects on Tumor Somatostatin Receptor Expression in Two Patients with Cushing's Syndrome due to Ectopic Adrenocorticotropin Secretion

2012 ◽  
Vol 97 (2) ◽  
pp. 455-462 ◽  
Author(s):  
C. de Bruin ◽  
L. J. Hofland ◽  
L. K. Nieman ◽  
P. M. van Koetsveld ◽  
A. M. Waaijers ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Quantitative Pcr ◽  
Cushing’S Syndrome ◽  
Somatostatin Receptor ◽  
Cushing's Syndrome ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Ectopic Acth ◽  
Ectopic Acth Secretion

Context: Two patients presented with Cushing's syndrome due to ectopic ACTH secretion. Initial localization studies included computed tomography, magnetic resonance imaging, and octreoscans (111In-pentreotide scintigraphy), which were negative in both patients. They were treated with the glucocorticoid receptor antagonist mifepristone, with improvement in their clinical symptoms. Follow-up octreoscans after, respectively, 6 and 12 months showed the unequivocal presence of a bronchial carcinoid in both patients. Objective: The objective of the study was to correlate in vivo and in vitro findings in patients with ectopic ACTH-producing syndrome. Methods: We determined the expression of somatostatin and dopamine receptors by immunohistochemistry (patients 1 and 2), quantitative PCR, and in vitro culturing of tumor cells (patient 1 only). In Vitro Results: Both tumors were strongly positive for somatostatin receptor type 2 (sst2) on immunohistochemistry, whereas one of the tumors (patient 1) was also dopamine receptor subtype 2 (D2) positive on both immunohistochemistry and quantitative PCR. Octreotide (a sst2 preferring analog) and cabergoline (D2 agonist) both decreased the ACTH levels in the cultured tumor cells of patient 1. Conclusion: We describe two patients with ACTH-producing bronchial carcinoids, in whom a direct down-regulatory effect of glucocorticoid levels on tumoral sst2 receptor expression is suggested by a remarkable change in octreoscan status after successful mifepristone therapy. Further studies will have to demonstrate whether glucocorticoid lowering or antagonizing therapy may be used to improve the diagnostic accuracy of somatostatin receptor scintigraphy in patients with ectopic ACTH production of unknown primary origin.

scholarly journals Vandetanib induces a marked anti-tumor effect and amelioration of ectopic Cushing’s syndrome in a medullary thyroid carcinoma patient

2016 ◽  
Vol 2016 ◽  
Author(s):  
Hashem Bseiso ◽  
Naama Lev-Cohain ◽  
David J Gross ◽  
Simona Grozinsky-Glasberg
Keyword(s):  
Cushing’S Syndrome ◽  
Tumor Size ◽  
Cushing's Syndrome ◽  
Whole Body ◽  
List Type ◽  
Ectopic Acth ◽  
Ectopic Acth Secretion ◽  
Ectopic Cushing’S Syndrome ◽  
Free Cortisol

Summary A 55-year-old woman diagnosed with sporadic MTC underwent total thyroidectomy 20 years ago. After the first surgery, elevated calcitonin levels in parallel with local disease persistence were noted and therefore she underwent repeated neck dissections. During follow-up, multiple foci of metastatic disease were noted in the neck and mediastinal lymph nodes, lungs and bones; however, the disease had an indolent course for a number of years, in parallel with a calcitonin doubling time of more than two years and without significant symptoms. During a routine follow-up visit 2 years ago, findings suggestive of Cushing’s syndrome were observed on physical examination. The biochemical evaluation demonstrated markedly elevated serum calcitonin level, in parallel with lack of cortisol suppression after an overnight 1 mg dexamethasone suppression test, lack of cortisol and ACTH suppression after high-dose IV dexamethasone 8 mg, elevated plasma ACTH up to 79 pg/mL (normal <46 pg/mL) and elevated 24-h urinary free cortisol up to 501 µg/24 h (normal 9–90 µg/24 h). After a negative pituitary MRI, she underwent IPSS, which was compatible with EAS. Whole-body CT demonstrated progressive disease at most of the tumor sites. Treatment with vandetanib at a dosage of 200 mg/day was commenced. The patient showed a significant, rapid and consistent clinical improvement already after two months of treatment, in parallel with biochemical improvement, whereas a decrease in tumor size was demonstrated on follow-up CT. Learning points: Ectopic Cushing’s syndrome due to ectopic ACTH secretion (EAS) by MTC is an uncommon and a poor prognostic event, being associated with significant morbidity and mortality. We demonstrate that vandetanib is effective in controlling the signs and symptoms related to the EAS in patients with advanced progressive MTC. We demonstrate that vandetanib is effective in decreasing tumor size and in inducing tumor control.

scholarly journals The Value of Ga68-DOTATATE PET/CT in Diagnosis and Management of Suspected Pituitary Tumors

2021 ◽  
Author(s):  
Fuad Novruzov ◽  
Aziz Aliyev ◽  
Ming Young S Wan ◽  
Rizwan Syed ◽  
Elnur Mehdi ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Somatostatin Receptor ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Receptor Subtype ◽  
Somatostatin Analogue ◽  
Ectopic Acth ◽  
Ectopic Acth Secretion ◽  
Pet Ct

Abstract Backroud Gallium 68-tetraazacyclododecane-tetraacetic acid-octreotate (Ga-68‑DOTATATE) is a selective somatostatin analogue ligand, which shows increased affinity for somatostatin receptor subtype (SSTR) 2 and has been used routinely for imaging neuroendocrine tumors with PET/CT. We investigated the utility of ­­Ga-68‑DOTATATE positron emission tomography/computed tomography (PET/CT) in patients with suspected pituitary pathology. We reviewed imaging for twenty consecutive patients (8 men, 12 women, mean age of 48.2, range: 14-78) with suspected pituitary pathology who were referred for Ga-68-DOTATATE PET-CT. Results Nine patients presented with recurrent Cushing's syndrome following surgical resection of pituitary adenomas due to recurrent Cushing's disease (seven patients) and ectopic ACTH secreting tumor (2 patients). All seven patients with recurrent Cushing's disease showed positive pituitary Ga-68-DOTATATE uptake while both cases of ectopic hormonal secretion had absent pituitary uptake. In 1 of these 2 patients Ga-68-DOTATATE was able to localize the source of ectopic ACTH tumor. Six patients presented de novo with Cushing's due to ectopic ACTH secretion; Ga-68‑DOTATATE PET/CT was able to localize ectopic tumors in six of eight patients (3 lungs, 2 pancreases, 1 mid-gut) There was high uptake Ga-68-DOTATATE in 3 cases of recurrent central hyperthyroidism (SUVmax 6.6-14.3) and 2 cases of prolactinoma (SUVmax 5.5 and 11.3).Conclusion Absent Ga-68-DOTATATE activity in the pituitary fossa is useful in excluding pituitary disease in recurrent Cushing’s. Recurrent pituitary thyrotropinomas and prolactinomas showed moderate to high pituitary activity. In addition, in Cushing’s syndrome Ga-68-DOTATATE is useful for detection of ectopic sources of ACTH production, especially where anatomic imaging is negative.

scholarly journals The value of [68Ga]Ga-DOTA-TATE PET/CT in diagnosis and management of suspected pituitary tumors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Fuad Novruzov ◽  
Aziz Aliyev ◽  
Ming Young S. Wan ◽  
Rizwan Syed ◽  
Elnur Mehdi ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Somatostatin Receptor ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Receptor Subtype ◽  
Somatostatin Analogue ◽  
Ectopic Acth ◽  
Ectopic Acth Secretion ◽  
Pet Ct

Abstract Background Gallium 68-tetraazacyclododecane-tetraacetic acid-octreotate ([68Ga]Ga-DOTA-TATE) is a selective somatostatin analogue ligand, which shows increased affinity for somatostatin receptor subtype (SSTR) 2 and has been used routinely for imaging neuroendocrine tumors with PET/CT. We investigated the utility of [68Ga]Ga-DOTA-TATE positron emission tomography/computed tomography (PET/CT) in patients with suspected pituitary pathology. We reviewed imaging for twenty consecutive patients (8 men, 12 women, mean age of 48.2, range 14–78) with suspected pituitary pathology who were referred for [68Ga]Ga-DOTA-TATE PET/CT. Results Nine patients presented with recurrent Cushing’s syndrome following surgical resection of pituitary adenomas due to recurrent Cushing’s disease (seven patients) and ectopic ACTH secreting tumor (2 patients). All seven patients with recurrent Cushing’s disease showed positive pituitary [68Ga]Ga-DOTA-TATE uptake while both cases of ectopic hormonal secretion had absented pituitary uptake. In 1 of these 2 patients, [68Ga]Ga-DOTA-TATE was able to localize the source of ectopic ACTH tumor. Six patients presented de novo with Cushing’s due to ectopic ACTH secretion; [68Ga]Ga-DOTA-TATE PET/CT was able to localize ectopic tumors in six of eight patients (3 lungs, 2 pancreases, 1 mid-gut) There was high uptake [68Ga]Ga-DOTA-TATE in 3 cases of recurrent central hyperthyroidism (SUVmax 6.6–14.3) and 2 cases of prolactinoma (SUVmax 5.5 and 11.3). Conclusion Absent [68Ga]Ga-DOTA-TATE activity in the pituitary fossa is useful in excluding pituitary disease in recurrent Cushing’s. Recurrent pituitary thyrotropinomas and prolactinomas showed moderate to high pituitary activity. In addition, in Cushing’s syndrome, [68Ga]Ga-DOTA-TATE is useful for detection of ectopic sources of ACTH production, especially where anatomic imaging is negative.

scholarly journals Clinical Characteristics and Treatment Outcomes in Endogenous Cushing’s Syndrome: A 15-Year Experience from Thailand

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Wasita Warachit Parksook ◽  
Nitchakarn Laichuthai ◽  
Sarat Sunthornyothin
Keyword(s):  
Treatment Outcomes ◽  
Cushing’S Syndrome ◽  
Clinical Characteristics ◽  
Remission Rate ◽  
Urinary Free Cortisol ◽  
Cushing's Syndrome ◽  
Ectopic Acth Syndrome ◽  
Normal Body Mass Index ◽  
Ectopic Acth ◽  
Free Cortisol

The most common subtype of endogenous Cushing’s syndrome (CS) is Cushing’s disease (CD), with higher proportions of adrenal CS reported from Asia, compared to other continents. However, little was known about CS in this territory. This study was to investigate the distribution, clinical characteristics, and treatment outcomes of CS in a single tertiary hospital in Thailand. We performed a retrospective evaluation of 82 patients with endogenous CS during 2001–2015. The most common subtype was CD, followed by adrenal CS and ectopic ACTH syndrome (EAS), respectively. Weight gain was the most common presentation. Normal body mass index (BMI), Asian cutoff, was observed in 33% of patients. Specific features of CS (plethora, muscle weakness, bruising, and/or wide purplish striae) were documented in less than half of patients. The median age, adrenocorticotropic hormone (ACTH), and urinary free cortisol (UFC) concentrations were significantly different among 3 subtypes of CS and were highest among patients with EAS. An initial remission rate after transsphenoidal surgeries in CD was 62%, with higher rates in pituitary microadenomas compared to macroadenomas. All patients with unilateral adrenal disease achieved CS remission after adrenal surgeries. Patients with EAS achieved CS remission mostly from bilateral adrenalectomy. The highest mortality rate was observed in the EAS group. These findings were consistent with previous studies in Asia, with more proportions ACTH-independent CS.

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