Ectopic ACTH syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing’s disease

Abstract Context: The diagnosis, differential diagnosis, and treatment of Cushing’s syndrome are challenging problems in clinical endocrinology. We focus on critical questions addressing screening for Cushing’s syndrome, differentiation of Cushing’s subtypes, and treatment options. Evidence Acquisition: Ovid’s MEDLINE (1996 through April 2006) was used to search the general literature. We also relied on previously published reviews and a recent monograph and cite a mix of primary articles and recent reviews. Evidence Synthesis: Although this article represents our opinion, it draws heavily on a recent consensus statement from experts in the field and a recent monograph on Cushing’s syndrome. Conclusions: We concluded that: 1) measurement of late-night or bedtime salivary cortisol is a useful approach to screen for Cushing’s syndrome; 2) measurement of suppressed plasma ACTH by immunometric assay is useful to differentiate ACTH-dependent and -independent Cushing’s syndrome; 3) inferior petrosal sinus sampling for ACTH should be performed in patients with ACTH-dependent hypercortisolism in whom a pituitary magnetic resonance imaging is normal or equivocal (in the absence of a pituitary ACTH gradient, prolactin levels should be measured to confirm the integrity of venous sampling); 4) computed tomography of the chest and abdomen and somatostatin receptor scintigraphy should be performed in patients with the occult ectopic ACTH syndrome; and 5) patients with Cushing’s disease should be referred to a neurosurgeon with extensive experience operating on corticotroph microadenomas. Bilateral laparoscopic adrenalectomy should be considered in patients with Cushing’s disease who fail therapies directed at the pituitary.

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Cavernous Sinus Sampling Is Highly Accurate in Distinguishing Cushing’s Disease from the Ectopic Adrenocorticotropin Syndrome and in Predicting Intrapituitary Tumor Location1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.5.5654 ◽

1999 ◽

Vol 84 (5) ◽

pp. 1602-1610 ◽

Cited By ~ 1

Author(s):

Kathryn E. Graham ◽

Mary H. Samuels ◽

Gary M. Nesbit ◽

David M. Cook ◽

Oisin R. O’Neill ◽

...

Keyword(s):

Cavernous Sinus ◽

Cushing’S Disease ◽

Tumor Location ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Plasma Acth ◽

Catheter Position ◽

Venous Flow ◽

Ectopic Acth ◽

Before And After

Inferior petrosal sinus sampling (IPSS) is used to distinguish pituitary Cushing’s disease from occult cases of the ectopic ACTH syndrome, but is limited in that it requires the use of ovine CRH (oCRH) and is not highly accurate at predicting the intrapituitary location of tumors. This study was designed to determine whether cavernous sinus sampling (CSS) is as safe and accurate as IPSS, whether CSS can eliminate the need for oCRH stimulation, and whether CSS can accurately predict the intrapituitary location of tumors. Ninety-three consecutive patients with ACTH-dependent Cushing’s syndrome were prospectively studied with bilateral, simultaneous CSS before and after oCRH stimulation. Prediction of a pituitary or ectopic ACTH source was based on cavernous/peripheral plasma ACTH ratios. Intrapituitary tumor location was predicted based on lateralization (side to side) ACTH ratios. These predictions were compared to surgical outcome in the 70 patients who had surgically proven pituitary (n= 65) or ectopic (n = 5) disease. CSS distinguished pituitary Cushing’s disease from the ectopic ACTH syndrome in 93% of patients with proven tumors before oCRH administration and in 100% of patients with proven tumors after oCRH. It was as safe and efficacious as published IPSS results. CSS accurately predicted the intrapituitary lateralization of the tumor in 83% of all patients and 89% of those patients with good catheter position and symmetric venous flow. CSS is as safe and accurate as IPSS for distinguishing patients with pituitary Cushing’s disease from those with the ectopic ACTH syndrome. In addition, CSS appears to be superior to IPSS for predicting intrapituitary tumor lateralization.

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Circulating Plasma microRNA to Differentiate Cushing's Disease From Ectopic ACTH Syndrome

Frontiers in Endocrinology ◽

10.3389/fendo.2020.00331 ◽

2020 ◽

Vol 11 ◽

Author(s):

Zhanna Belaya ◽

Patimat Khandaeva ◽

Larisa Nonn ◽

Alexey Nikitin ◽

Alexander Solodovnikov ◽

...

Keyword(s):

Cushing’S Disease ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Ectopic Acth ◽

Plasma Microrna

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Intraoperative Adrenocorticotropin Levels During Transsphenoidal Surgery for Cushing’s Disease Do Not Predict Cure

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.6.4005 ◽

1997 ◽

Vol 82 (6) ◽

pp. 1776-1779

Author(s):

Kathryn E. Graham ◽

Mary H. Samuels ◽

Hershel Raff ◽

Stanley L. Barnwell ◽

David M. Cook

Keyword(s):

Cushing’S Disease ◽

Pituitary Tumor ◽

Transsphenoidal Surgery ◽

Tumor Resection ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Plasma Acth ◽

Tumor Removal ◽

Ectopic Acth ◽

Percentage Decrease

Abstract Recently, intraoperative rapid immunochemiluminometric assay (ICMA) ACTH measurements have been used to evaluate the completeness of resection of ectopic ACTH-secreting tumors. This study evaluates whether this method can be applied to patients undergoing transsphenoidal surgery (TSS) for Cushing’s disease to predict complete pituitary tumor resection. Eighteen patients with Cushing’s disease undergoing TSS had plasma ACTH concentrations measured by a standard ICMA every 10 min for 1 h immediately after pituitary tumor removal. Patients were evaluated postoperatively for cure by standard criteria. ACTH levels were evaluated for percentage decrease from baseline at each time point. Patients who were cured (n = 11) had statistically greater decreases in ACTH levels (mean decrease 54%) than patients who were not (n = 7; 26% mean decrease, P < 0.04). By Receiver-Operator Characteristic (ROC) analysis, a reduction of at least 40% best predicted which patients were cured and which were not cured. This level of reduction was observed in 82% of cured patients, and a reduction of less than 40% was observed in 71% of those not cured. The analysis misclassified 4 of the 18 patients, resulting in a diagnostic accuracy of 78%. Although the mean maximal decrease in ACTH concentrations after tumor removal was significantly different between cured and not cured patients with Cushing’s disease, it was less dramatic than results in the previous ectopic ACTH study. This may relate to incomplete suppression and/or surgical manipulation of normal pituitary corticotrophs in patients with pituitary disease. In summary, in contrast to the ectopic ACTH syndrome, decline of plasma ACTH during TSS does not accurately predict complete tumor resection.

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Androgen Secretion in Ectopic ACTH Syndrome and in Cushing’s Disease: Modifications Before and After Surgery

Hormone and Metabolic Research ◽

10.1055/s-2001-17906 ◽

2001 ◽

Vol 33 (10) ◽

pp. 596-601 ◽

Cited By ~ 5

Author(s):

L. Barbetta ◽

C. Dall’Asta ◽

T. Re ◽

P. Colombo ◽

P. Travaglini ◽

...

Keyword(s):

Cushing’S Disease ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Ectopic Acth ◽

Before And After ◽

Androgen Secretion

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Usefulness of inferior petrosal sinus venous endocrine markers in Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.1988.68.2.0205 ◽

1988 ◽

Vol 68 (2) ◽

pp. 205-210 ◽

Cited By ~ 30

Author(s):

John Zovickian ◽

Edward H. Oldfield ◽

John L. Doppman ◽

Gordon B. Cutler ◽

D. Lynn Loriaux

Keyword(s):

Cushing’S Disease ◽

Venous Blood ◽

Pituitary Hormones ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Inferior Petrosal Sinus ◽

Ectopic Acth ◽

Content Type ◽

Acth Secreting ◽

Fine Print

✓ Bilateral and simultaneous sampling of the inferior petrosal sinuses in patients with Cushing's disease has been used to establish the presence and laterality of adrenocorticotropic hormone (ACTH)-producing microad-enomas prior to transsphenoidal surgery. Successful preoperative lateralization depends upon equivalent dilution of pituitary venous blood on the two sides since samples which are diluted by unequal amounts of non-pituitary blood may lead to erroneous results. To assure valid sampling results, the use of other pituitary hormones, measured simultaneously, has been proposed to correct the ACTH concentrations from the inferior petrosal sinuses against unequal dilution by non-pituitary venous blood. This proposal presumes that ACTH-secreting microadenomas will not cause unequal delivery of the other pituitary hormones into the two inferior petrosal sinuses. The inferior petrosal sinus concentrations of prolactin (PRL), thyrotropin (TSH), and the alpha subunit of human chorionic gonadotropin (α-HCG) were evaluated as indicators of pituitary venous blood dilution in 11 patients with Cushing's disease. Four patients with ectopic ACTH syndrome served as controls. Blood was withdrawn simultaneously from catheters in both inferior petrosal sinuses and from a peripheral vein for measurement of ACTH, PRL, TSH, and α-HCG. The ACTH concentrations were then corrected for dilution by non-pituitary blood by dividing the ACTH concentration from each side by the ratio of the inferior petrosal sinus to peripheral blood concentrations of PRL, TSH, and α-HCG for that side. At surgery, all 11 patients had ACTH-secreting microadenomas on the side predicted by the uncorrected ACTH concentrations. However, in three patients the corrected ACTH values would have led to erroneous results. Among the 18 sets of corrected inferior petrosal sinus measurements in these three patients, the corrected ACTH values failed to show an inferior petrosal sinus gradient in six and localized the tumor to the side opposite the adenoma in four. Incorrect lateralization was obtained with each of the hormones (PRL, TSH, and α-HCG) used for correction. Furthermore, the ipsilateral (side of tumor)-to-contralateral inferior petrosal sinus gradient of ACTH in patients with Cushing's disease was generally paralleled by a significant inferior petrosal sinus gradient of PRL, TSH, and α-HCG to the side of the tumor, whereas patients with the ectopic ACTH syndrome tended not to exhibit lateralizing (side-to-side) gradients. These findings indicate that the simultaneous measurement of inferior petrosal sinus concentrations of PRL or TSH or of the glycoprotein hormone α subunit does not improve preoperative localization of ACTH-secreting microadenomas and may lead to incorrect lateralization of the tumor. The results also suggest that ACTH-secreting microadenomas cause enhanced delivery of PRL, TSH, and α subunit into the inferior petrosal sinus ipsilateral to the tumor which, in turn, may reflect paracrine stimulation of hormone secretion in the anterior pituitary gland surrounding ACTH-secreting microadenomas.

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Comparative value of plasma ACTH and beta-endorphin measurement with three different commercial kits for the etiological diagnosis of ACTH-dependent Cushing's syndrome

Acta Endocrinologica ◽

10.1530/acta.0.1260308 ◽

1992 ◽

Vol 126 (4) ◽

pp. 308-314 ◽

Cited By ~ 11

Author(s):

A Tabarin ◽

JB Corcuff ◽

M Rashedi ◽

A Navarranne ◽

D Ducassou ◽

...

Keyword(s):

Cushing’S Disease ◽

Cushing's Disease ◽

Molar Ratio ◽

Ectopic Acth Syndrome ◽

Discriminative Power ◽

Plasma Acth ◽

Ectopic Acth ◽

Etiological Diagnosis ◽

Commercial Kits ◽

Better Than

Recent reports suggest that, contrary to radioimmunoassays (RIA), immunoradiometric assays (IRMA) artifactually decrease plasma ACTH levels in patients with the ectopic ACTH syndrome. Discrepancies between RIA and IRMA results may provide a means of discriminating this entity from Cushing's disease. We have compared the results of these two techniques, together with those of a β-endorphin assay, in 1 7 patients with Cushing's disease, 9 with the ectopic ACTH syndrome and 30 controls. ACTH-RIA and ACTH-IRMA levels in patients with Cushing's disease were similar (17.5±2.5 vs 15.1±2.8 pmol/l) and were correlated (rs=0.59, p<0.01). ACTH-RIA levels in patients with the ectopic ACTH syndrome were higher than ACTH-IRMA levels (27.3±2.9 vs 14.5±2.5, p<0.01) and these did not correlate. The ACTH-RIA and ACTH-RIA/ACTH-IRMA ratio levels in patients with the ectopic ACTH syndrome were higher than those of patients with Cushing's disease (p<0.01), but they overlapped with these in 27 and 31% of cases respectively. Plasma β-endorphin level was higher in patients with the ectopic ACTH syndrome than in patients with Cushing's disease (81.9±19.4 vs 26.4±5.6 pmol/l, p <0.01) and was correlated with ACTH only in patients with Cushing's disease. The overlap in β-endorphin and β-endorphin/ACTH-IRMA molar ratio levels between the two groups were 19 and 27% respectively. Although no parameter could be used to make clearcut distinction between Cushing's disease and the ectopic ACTH syndrome, the discriminative power of β-endorphin level was clearly better than that of the comparison between ACTH-RIA and ACTH-IRMA levels.

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Phosphorylated forms of adrenocorticotropin and corticotropin-like intermediary lobe peptide in human tumors

Acta Endocrinologica ◽

10.1530/eje.0.1310341 ◽

1994 ◽

Vol 131 (4) ◽

pp. 341-346 ◽

Cited By ~ 6

Author(s):

Jean Francis Massias ◽

Sandrine Hardouin ◽

Didier Vieau ◽

Frédéric Lenne ◽

Xavier Bertagna

Keyword(s):

Cushing’S Disease ◽

Pituitary Tumors ◽

Human Tumors ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Ectopic Acth ◽

Port Royal ◽

Phosphatase Treatment ◽

Highperformance Liquid Chromatography ◽

Set Up

Massias JF, Hardouin S, Vieau D, Lenne F, Bertagna X. Phosphorylated forms of adrenocorticotropin and corticotropin-like intermediary lobe peptide in human tumors. Eur J Endocrinol 1994;131:341–6. ISSN 0804–4643 Many peptides contribute to the heterogeneity of immunoreactive adrenocorticotropin (ACTH) in man. The use of a radioimmunoassay (RIA) specifically directed against the C-terminal end of ACTH allowed us to study precisely the following four peptides: ACTH itself, corticotropin-like intermediary lobe peptide (CLIP) or ACTH(18–39) and their phosphorylated forms on Ser31. We have set up a highperformance liquid chromatography system that separates these four molecules in a single run, to establish their relative distributions in tumors responsible for Cushing's disease or for the ectopic ACTH syndrome, and to evaluate the possible interference of phospho-Ser on various RIA or immunoradiometric assay (IRMA) recognition systems for ACTH. In this system, alkaline phosphatase treatment shifted the retention time of the phosphorylated peptides to that of their non-phosphorylated counterparts. In three tumors responsible for the ectopic ACTH syndrome, CLIP peptides were predominant in two and phosphorylated molecules represented between 22% and 50% of immunoreactive materials. In five pituitary tumors responsible for Cushing's disease, ACTH peptides were predominant and the phosphorylated molecules varied between 35% and 75% in four of them. In the same tumor the ratios of phosphorylated to non-phosphorylated CLIP or ACTH were identical. The presence of phospho-Ser31 did not affect the recognition ability of two mid-ACTH and two C-terminal ACTH RIAs, nor of the ACTH IRMA (Allegro, Nichols). Xavier Bertagna, CJF 92-08 Endocrinologie, Faculté Cochin-Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France

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Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2734 ◽

2008 ◽

Vol 93 (7) ◽

pp. 2454-2462 ◽

Cited By ~ 540

Author(s):

B. M. K. Biller ◽

A. B. Grossman ◽

P. M. Stewart ◽

S. Melmed ◽

X. Bertagna ◽

...

Keyword(s):

Medical Therapy ◽

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Consensus Statement ◽

Tumor Resection ◽

Cushing's Syndrome ◽

Scientific Data ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Ectopic Acth

Abstract Objective: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing’s syndrome, because there is no recent consensus on the management of this rare disorder. Participants: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing’s syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing’s disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing’s disease, and 5) management of ectopic ACTH syndrome, Nelson’s syndrome, and special patient populations. Evidence: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. Consensus Process: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. Conclusions: ACTH-dependent Cushing’s syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing’s syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing’s disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing’s syndrome, early diagnosis and prompt therapy are warranted.

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