A Re-Examination of the oCRH Stimulation Test for the Diagnosis of Ectopic ACTH Secretion

Abstract Background: Previous studies of the oCRH test for the differential diagnosis of ACTH-dependent Cushing’s syndrome gave imprecise point estimates of specificity because of small numbers (n<20) of patients with ectopic ACTH secretion (EAS). We examined a large EAS population to re-assess the test’s performance and whether benign tumors were associated with a positive response (i.e. Cushing’s disease (CD). Methods: We evaluated 103 EAS patients, including 58 females, with median age of 38 years (range 10 - 83); 99 had surgically-proven tumors and four had biochemical testing consistent with EAS. ACTH and cortisol were measured 5 and 0 minutes before and 15, 30 and 45 minutes after administration of oCRH, 1 ug/kg up to 100 ug, iv. Previous criteria were used to determine EAS responses: mean ACTH increase of <34% at 15 and 30 min or mean cortisol increase of <20% at 30 and 45 min. Mean responses and UFC (expressed as fold increase above upper limit of normal, ULN) were compared with t-tests; a p-value of < 0.05 was considered significant. Results: Tumor types included NET (pulmonary n=67; with 4 spindle type and 5 tumorlets, thymic n=9, pancreas n=7, appendix n=1, prostate n=1), SCLC (N=3), pheochromocytoma/paraganglioma (n=3/1), metastatic without known primary (n=3), teratoma with corticotroph elements (n=1) and occult (n=4). 23 patients had “CD” responses that were significantly higher than those of non-responders: 11 with ACTH (mean+SD: 83.7 + 49.8% vs 1.2 + 18.8%, p=00025), 15 with cortisol (mean+SD: 34.7 + 8.9% vs -1.7 + 14.2%, p< 0.00001). Three patients responded to both ACTH and cortisol. Among the ACTH (only) responders, 6 had cortisol increases of < 10% (range 0-2-8.5%); a similar discordant response was seen among cortisol (only) responders, of whom 7 had ACTH increases of <20% (range -18 - 13.4%). 70% of responders, including 3 with both ACTH and cortisol responses, had pulmonary NET (n=13), spindle cell NET (n=2) or tumorlets (n=4). Other responders had thymic NET (n=3), appendiceal NET n=1, teratoma (n=1) or were occult (n=2). The patient with corticotroph elements in a teratoma had an ACTH response only. UFC fold-increases above ULN were similar in responders and non-responders (20.20 + 26.9 xULN vs 31.4 + 38.4 xULN, p =0.21). Four of 10 patients with UFC cyclicity responded to CRH. Conclusions: Among patients with EAS the rate of false positive responses to CRH was similar to that of initial reports, 11–15%, and was associated with hormonal cyclicity and presence of a thymic carcinoid. The marked discordance of ACTH and cortisol responses may result from reduced sensitivity to ACTH, less biologically active ACTH, or autonomous cortisol release.

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The 24-h cortisol secretory pattern in Cushing's syndrome

Acta Endocrinologica ◽

10.1530/acta.0.1120230 ◽

1986 ◽

Vol 112 (2) ◽

pp. 230-237 ◽

Cited By ~ 9

Author(s):

J. Tourniaire ◽

D. Chalendar ◽

B. Rebattu ◽

M. Fevre-Montange ◽

L. Bajard ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Plasma Cortisol ◽

Adrenal Adenoma ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Cortisol Release

Abstract. The 24-h plasma cortisol profile was obtained at 20-min intervals in 18 patients with Cushing's syndrome (10 with Cushing's disease, 5 with adrenal adenoma, 2 with ectopic ACTH secretion and 1 of questionable aetiology). The mean cortisol level was maximum in the case of ectopic ACTH secretion. The coefficient of variation of cortisol levels was subnormal in all except 2 subjects. Periodogram calculations, providing a best-fit curve (B F C) for each profile, showed that the existence of a significant baseline variation is a frequent feature. In certain cases, it is compatible with the persistance of a true circadian rhythm (2 patients with Cushing's disease; 1 patient with adrenal adenoma). The alteration of plasma cortisol pulsatility is much more pronounced in patients with adrenal adenoma than in patients with Cushing's disease. This is consistent with the hypothesis of a predominantly tonic secretion blunting the episodic hormone release. In 9 patients with Cushing's disease, the plasma cortisol pattern was suggestive of a combination of episodic cortisol release under CRF control and of continuous cortisol secretion due to constant stimulation from an autonomous ACTH source. Two cases were possibly of hypothalamic origin, as suggested by the presence of enhanced cortisol pulsatility and of a normal circadian amplitude. The analysis of the 24-h profile of plasma cortisol in Cushing's syndrome contributes to our understanding of the physiopathological mechanisms underlying this disorder and may help the diagnosis of its aetiology.

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Cushing syndrome due to ectopic ACTH secretion

10.32388/furzp1 ◽

2020 ◽

Author(s):

Keyword(s):

Cushing Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion

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The value of corticotropin-releasing hormone (CRH) test for differential diagnosis of Cushing’s syndrome

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0702031p ◽

2007 ◽

Vol 135 (1-2) ◽

pp. 31-37 ◽

Cited By ~ 1

Author(s):

Zorana Penezic ◽

Milos Zarkovic ◽

Svetlana Vujovic ◽

Miomira Ivovic ◽

Biljana Beleslin ◽

...

Keyword(s):

Differential Diagnosis ◽

Roc Curve ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Test Sensitivity ◽

Basal Cortisol ◽

Area Under Roc Curve ◽

Curve Method ◽

Acth Secreting

Introduction: Diagnosis and differential diagnosis of Cushing?s syndrome (CS) remain considerable challenge in endocrinology. For more than 20 years, CRH has been widely used as differential diagnostic test. Following the CRH administration, the majority of patients with ACTH secreting pituitary adenoma show a significant rise of plasma cortisol and ACTH, whereas those with ectopic ACTH secretion characteristically do not. Objective The aim of our study was to assess the value of CRF test for differential diagnosis of CS using the ROC (receiver operating characteristic) curve method. Method A total of 30 patients with CS verified by pathological examination and postoperative testing were evaluated. CRH test was performed within diagnostic procedures. ACTH secreting pituitary adenoma was found in 18, ectopic ACTH secretion in 3 and cortisol secreting adrenal adenoma in 9 of all patients with CS. Cortisol and ACTH were determined -15, 0, 15, 30, 45, 60, 90 and 120 min. after i.v. administration of 100?g of ovine CRH. Cortisol and ACTH were determined by commercial RIA. Statistical data processing was done by ROC curve analysis. Due to small number, the patients with ectopic ACTH secretion were excluded from test evaluation by ROC curve method. Results In evaluated subgroups, basal cortisol was (1147.3?464.3 vs. 1589.8?296.3 vs. 839.2?405.6 nmol/L); maximal stimulated cortisol (1680.3?735.5 vs. 1749.0?386.6 vs. 906.1?335.0 nmol/L); and maximal increase as a percent of basal cortisol (49.1?36.9 vs. 9.0?7.6 vs. 16.7?37.3 %). Consequently, basal ACTH was (100.9 ?85.0 vs. 138.0?123.7 vs. 4.8?4.3 pg/mL) and maximal stimulated ACTH (203.8 ?160.1 vs. 288.0?189.5 vs. 7.4?9.2 pg/mL). For cortisol, determination area under ROC curve was 0.815?0.083 (CI 95% 0.652-0.978). For cortisol increase cut-off level of 20%, test sensitivity was 83%, with specificity of 78%. For ACTH, determination area under ROC curve was 0.637?0.142 (CI 95% 0.359-0.916). For ACTH increase cut-off level of 30%, test sensitivity was 70%, with specificity of 57%. Conclusion Determination of cortisol and ACTH levels in CRH test remains reliable tool in differential diagnosis of Cushing?s syndrome.

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Cushing's Syndrome Due to Ectopic ACTH Secretion by Bilateral Pheochromocytomas in Multiple Endocrine Neoplasia Type 2A

New England Journal of Medicine ◽

10.1056/nejm198812153192419 ◽

1988 ◽

Vol 319 (24) ◽

pp. 1610-1611 ◽

Cited By ~ 14

Keyword(s):

Cushing’S Syndrome ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Cushing's Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

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Diagnostic Accuracy of Chromogranin A and Calcitonin Precursors Measurements for the Discrimination of Ectopic ACTH Secretion from Cushing’s Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0604 ◽

2009 ◽

Vol 94 (8) ◽

pp. 2962-2965 ◽

Cited By ~ 8

Author(s):

Marina S. Zemskova ◽

Eric S. Nylen ◽

Nicholas J. Patronas ◽

Edward H. Oldfield ◽

Kenneth L. Becker ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Cushing’S Disease ◽

Chromogranin A ◽

Cushing's Disease ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion

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The Desmopressin and Combined CRH-Desmopressin Tests in the Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome: Constraints Imposed by the Expression of V2 Vasopressin Receptors in Tumors with Ectopic ACTH Secretion

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.4.8358 ◽

2002 ◽

Vol 87 (4) ◽

pp. 1646-1653

Author(s):

S. Tsagarakis ◽

C. Tsigos ◽

V. Vasiliou ◽

P. Tsiotra ◽

J. Kaskarelis ◽

...

Keyword(s):

Differential Diagnosis ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Vasopressin Receptors ◽

V2 Vasopressin Receptors

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SUN-938 Rare Case of Ectopic Cushing Syndrome Caused by ACTH Secreting Thymic Neuroendocrine Tumor in a Patient with Multiple Endocrine Neoplasia Type 1

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1068 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Yamuna Gorantla ◽

Jorge Soria Moncada ◽

Juan Sarmiento ◽

Ambika Amblee ◽

Malini Ganesh

Keyword(s):

Neuroendocrine Tumor ◽

Poor Prognosis ◽

Rare Case ◽

Cushing Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Multiple Tumors ◽

Men 1 ◽

Acth Secreting

Abstract Introduction Cushing syndrome (CS) represents an uncommon manifestation of MEN1 and can be caused by both ACTH dependent or independent etiologies. Among them, ectopic ACTH secretion from a Thymic neuroendocrine tumor (TNET) in MEN1 is rare, with very few cases reported so far in literature. We report a case of Ectopic Cushing syndrome (ECS) in a MEN1 patient (pt) with multiple tumors, secondary to ACTH-secreting TNET. Case description: A 44 year old male presented to our institution for nausea, vomiting, dizziness. He had initial workup which revealed multiple tumors (papillary thyroid cancer, thymic mass, parathyroid adenomas, bilateral adrenal nodules, macroprolactinoma, peripancreatic nodules). Given concern for MEN 1, genetic testing was performed which was confirmative. Hormonal workup at this time for adrenal nodules was negative including low dose dexamethasone suppression test(DST). The immobile thymic mass was found to be poorly differentiated NET on biopsy with Ki-67 >50% with vascular invasion and adhesions to lung/chest wall on VATS, not amenable to surgery. The pt declined chemotherapy and radiotherapy due to poor social support. Six months later, he presented with complaints of shortness of breath, proximal muscle weakness, anasarca. Evaluation revealed AM cortisol >60 ug/dL(range 6.7-22), high-dose DST Cortisol >60 ug/dL, 24hr urine free cortisol: 8511mcg (range 4-50) and ACTH level: 278pg/mL(range 6-50) confirming ACTH-dependent CS. Special stains from the previous TNET biopsy demonstrated positive staining for ACTH confirming ectopic ACTH secretion. Ketoconazole and chemotherapy with Etoposide and Carboplatin was started, however he clinically deteriorated and expired a few weeks after diagnosed of ECS. Discussion: TNET in MEN 1 is rare, with a prevalence of 3-8%. TNET are unusual neoplasms that account for 2% to 7% of all mediastinal tumors. TNET in MEN1 rarely secrete functional hormones with very few reported Ectopic ACTH secretion. MEN1 associated ECS from TNET is an aggressive disease with local invasion of adjacent mediastinal structures or metastasis being common, resulting in poor prognosis as demonstrated in few case reports including our case. Radical surgery of involved adjacent structures and adjuvant local RT can provide local disease control. Conclusion: Our pt is a rare case of ECS from TNET in MEN1 with poor prognosis. A special feature of this case is that the patient had initial negative evaluation for hypercortisolemia, however 6 months later he presented with signs and symptoms of severe hypercortisolism, with evaluation confirming transformation into ACTH producing TNET. This conversion is very rarely found in literature and adds to the unique presentation of the case.

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