Clinical Spectrum of Adrenal Cushing’s Syndrome and the Caution for Interpretation of Adrenocorticotrophic Hormone: A Single-Center Experience

Abstract

To describe the differences in presentation, biochemistry, and radiological evaluation of various etiologies of adrenal Cushing’s syndrome (CS) from a single center. To emphasize caution for interpretation of plasma adrenocorticotropic hormone (ACTH), as a spuriously unsuppressed ACTH level by immunometric assay may lead to therapeutic misadventures in adrenal CS. Design: Retrospective, single-center, observational study. Methods:  Fifty-eight adrenal CS patients [Adrenocortical carcinoma (ACC), n=30; Adenoma (ACA), n=15; Primary pigmented nodular adrenocortical disease (PPNAD), n=10; ACTH independent macronodular adrenal hyperplasia (AIMAH), n=3) evaluated at a tertiary care center in western India between January 2006 to March 2020 were included. Data on demography, clinical evaluation, biochemistry, imaging, management, histopathology, and outcome were recorded in a standard format and analyzed. Results:  Cortisol secreting ACC presented at 38(1–50) years with abdominal mass in 26/30 (86.7%) and 16/30 (53.3%) had metastases at presentation. ACA with autonomous cortisol excess presented at 25(4.9–40) years with discriminating features of CS in 14/15 (93.3%), sex steroid production in 2/15, unenhanced HU <10 in only one, and relative washout >40% in 8/11 (72.7%). One ACA and eight ACC patients had plasma ACTH (by Siemens Immulite assay) > 20 pg/ml, despite hypercortisolemic state. Conclusions:  Cortisol-secreting ACC and ACA most often present with mass effects and florid CS, respectively. Baseline HU has low sensitivity to differentiate cortisol-secreting ACA from ACC. Plasma ACTH measured by Seimens Immulite is often unsuppressed, especially in ACC patients, which can be addressed by measuring ACTH by more accurate assays.

Key words

adrenal Cushing’s syndrome - adrenocorticotrophic hormone - Cushing's syndrome - adrenocortical carcinoma

• References

• 1 Lodish M, Stratakis CA. A genetic and molecular update on adrenocortical causes of Cushing syndrome. Nat Rev Endocrinol 2016; 12: 255-262
• 2 Stratakis CA. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin-independent Cushing syndrome). Endocr Dev 2008; 13: 117-132
• 3 Else T, Kim AC, Sabolch A. et al. Adrenocortical carcinoma. Endocr Rev 2014; 35: 282-326
• 4 Albiger NM, Ceccato F, Zilio M. et al. An analysis of different therapeutic options in patients with Cushing’s syndrome due to bilateral macronodular adrenal hyperplasia: a single-centre experience. Clin Endocrinol (Oxf) 2015; 82: 808-815
• 5 Sharma ST. AACE Adrenal Scientific Committee. An individualized approach to the evaluation of Cushing syndrome. Endocr Pract 2017; 23: 726-737
• 6 Lacroix A, Feelders RA, Stratakis CA. et al. Cushing’s syndrome. Lancet 2015; 386: 913-927
• 7 Jarial KD, Walia R, Kumar S. et al. Adrenocortical carcinoma masquerading as Cushing’s disease. BMJ Case Rep 2017; bcr2016217519
• 8 Donegan DM, Algeciras-Schimnich A, Hamidi O. et al. Corticotropin hormone assay interference: A case series. Clin Biochem 2019; 63: 143-147
• 9 Greene LW, Geer EB, Page-Wilson G. et al. Assay-specific spurious ACTH results lead to misdiagnosis, unnecessary testing, and surgical misadventure – a case series. J Endocr Soc 2019; 3: 763-772
• 10 Valassi E, Franz H, Brue T. et al. Diagnostic tests for Cushing’s syndrome differ from published guidelines: data from ERCUSYN. Eur J Endocrinol 2017; 176: 613-624
• 11 Nieman LK, Biller BMK, Findling JW. et al. The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
• 12 Goroshi M, Jadhav SS, Sarathi V. et al. Radiological differentiation of phaeochromocytoma from other malignant adrenal masses: importance of wash-in characteristics on multiphase CECT. Endocr Connect 2019; 8: 898-905
• 13 Elmlinger MW, Kühnel W, Ranke MB. Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults. Clin Chem Lab Med 2002; 40: 1151-1160
• 14 Nakamoto J. Endocrine testing. In: Endocrinology: Adult and Pediatric. Philadelphia: Elsevier Saunders; 2016
• 15 Memon SS, Thakkar K, Patil V. et al. Primary pigmented nodular adrenocortical disease (PPNAD): single centre experience. J Pediatr Endocrinol Metab 2019; 32: 391-397
• 16 Ammini AC, Tandon N, Gupta N. et al. Etiology and clinical profile of patients with Cushing’s syndrome: a single center experience. Indian J Endocrinol Metab 2014; 18: 99-105
• 17 Tella SH, Kommalapati A, Yaturu S. et al. Predictors of survival in adrenocortical carcinoma: an analysis from the national cancer database. J Clin Endocrinol Metab 2018; 103: 3566-3573
• 18 Ayala-Ramirez M, Jasim S, Feng L. et al. Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol 2013; 169: 891-899
• 19 Danilowicz K, Albiger N, Vanegas M. et al. Androgen-secreting adrenal adenomas. Obstet Gynecol 2002; 100: 1099-1102
• 20 Chentli F, Bekkaye I, Azzoug S. Feminizing adrenocortical tumors: literature review. Indian J Endocrinol Metab 2015; 19: 332-339
• 21 Di Dalmazi G, Berr CM, Fassnacht M. et al. Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing’s syndrome: a systematic review of the literature. J Clin Endocrinol Metab 2014; 99: 2637-2645
• 22 Boland GW, Lee MJ, Gazelle GS. et al. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roentgenol 1998; 171: 201-204
• 23 Humbert A-L, Lecoanet G, Moog S. et al. The computed tomography adrenal wash-out analysis properly classifies cortisol secreting adrenocortical adenomas. Endocrine 2018; 59: 529-537
• 24 Chambre C, McMurray E, Baudry C. et al. The 10 Hounsfield units unenhanced computed tomography attenuation threshold does not apply to cortisol secreting adrenocortical adenomas. Eur J Endocrinol 2015; 173: 325-332
• 25 Jia A-H, Du H-Q, Fan M-H. et al. Clinical and pathological analysis of 116 cases of adult adrenal cortical adenoma and literature review. Onco Targets Ther 2015; 8: 1251-1257
• 26 Petersenn S, Richter P-A, Broemel T. et al. Computed tomography criteria for discrimination of adrenal adenomas and adrenocortical carcinomas: analysis of the German ACC registry. Eur J Endocrinol 2015; 172: 415-422
• 27 Sangwaiya MJ, Boland GWL, Cronin CG. et al. Incidental adrenal lesions: accuracy of characterization with contrast-enhanced washout multidetector CT-10-minute delayed imaging protocol revisited in a large patient cohort. Radiology 2010; 256: 504-510
• 28 He X, Caoili EM, Avram AM. et al. 18F-FDG-PET/CT Evaluation of indeterminate adrenal masses in noncancer patients. J Clin Endocrinol Metab 2021; 106: 1448-1459
• 29 Bolstad N, Warren DJ, Nustad K. Heterophilic antibody interference in immunometric assays. Best Pract Res Clin Endocrinol Metab 2013; 27: 647-661
• 30 Yener S, Demir L, Demirpence M. et al. Interference in ACTH immunoassay negatively impacts the management of subclinical hypercortisolism. Endocrine 2017; 56: 308-316
• 31 Grasko J, Willliams R, Beilin J. et al. A diagnostic conundrum: heterophilic antibody interference in an adrenocorticotropic hormone immunoassay not detectable using a proprietary heterophile blocking reagent. Ann Clin Biochem 2013; 50: 433-437
• 32 Morton A, Dover T. Heterophile antibody to adrenocorticotropin hormone interfering with the investigation of Cushing’s syndrome. Indian J Clin Biochem 2019; 34: 234-236
• 33 Invitti C, Pecori Giraldi F, de Martin M. et al. Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. Study group of the Italian society of endocrinology on the pathophysiology of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1999; 84: 440-448
• 34 Pecori Giraldi F, Saccani A, Cavagnini F. et al. Assessment of ACTH assay variability: a multicenter study. Eur J Endocrinol 2011; 164: 505-512
• 35 Shi J, Dhaliwal P, Zi Zheng Y. et al. An intact ACTH LC-MS/MS assay as an arbiter of clinically discordant immunoassay results. Clin Chem 2019; 65: 1397-1404
• 36 Taylor DR, Ghataore L, Couchman L. et al. A 13-tseroid serum panel based on LC-MS/MS: use in detection of adrenocortical carcinoma. Clin Chem 2017; 63: 1836-1846
• 37 Ismail AA, Burr WA, Taylor NF. et al. Elevated plasma adrenocorticotropin (ACTH) with adrenal hyperplasia: a new factor in ACTH regulation?. J Clin Endocrinol Metab 1991; 73: 752-757
• 38 Louiset E, Duparc C, Young J. et al. Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. N Engl J Med 2013; 369: 2115-2125
• 39 Lwin TM, Galal N, Gera S. et al. Adrenal Cushing syndrome with detectable ACTH from an unexpected source. BMJ Case Rep 2016; 2016: bcr2016216965