Download PDF
Horm Metab Res 2021; 53(03): 161-168
DOI: 10.1055/a-1253-2854
Endocrine Care

High Prevalence of Adrenal Remnant Tissue in Patients Undergoing Bilateral Adrenalectomy for Cushing’s Disease

Julian B. Wilson
1   Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
,
Mohan Zopey
1   Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
,
Jaimie Augustine
1   Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
,
Randolph Schaffer
2   Department of Surgery, Scripps Green Hospital, La Jolla, CA, USA
,
Manfred Chiang
3   Brookfield Surgical Associates, Brookfield, WI, USA
,
Theodore C. Friedman
1   Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
› Author Affiliations Funding Information TF received funding by the Accelerating Excellence in Translational Science (AXIS) grant #U54MD007598, National Institute on Minority Health and Health Disparities grant #S21MD000103, Diversity- Promoting Institution Drug Abuse Research Program (DIDARP) grant (R24DA017298) and California Tobacco-Related Disease Research Program (TRDRP) Grant 251P003 and 28CP-0040.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Bilateral adrenalectomy (BLA) is a treatment option for patients with Cushing’s Disease (CD) if transsphenoidal pituitary surgery fails or is not a therapeutic option. For most patients, BLA eliminates endogenous glucocorticoid and mineralocorticoid production, but for a small number of patients, endogenous secretion of adrenal hormones from adrenal tissue continues or recurs, leading to signs and symptoms of hypercortisolism. If adrenal tissue is confined to the adrenal bed, it is considered adrenal remnant tissue, while if it is outside the adrenal bed, it is considered adrenal rest tissue. We retrospectively evaluated morning serum cortisol, nighttime serum cortisol, nighttime salivary cortisol, and 24-h urine free cortisol on at least three occasions in 10 patients suspected of having endogenous cortisol production. Imaging of adrenal remnant tissue was also reviewed. Ten of 51 patients who underwent BLA during this time period had adrenal remnant/rest tissue marked by detectable endogenous glucocorticoid production; 9 of the 10 patients had signs and symptoms of hypercortisolism. Localization and treatment proved difficult. We conclude that the incidence of adrenal remnant/rest tissue in those undergoing BLA following unsuccessful pituitary surgery was 12% although there may have been a selection bias affecting this prevalence. The first indication of remnant tissue occurrence is a reduction in glucocorticoid replacement with symptoms of hypercortisolism. If this occurs, endogenous cortisol production should be tested for by cortisol measurements using a highly specific cortisol assay while the patient is taking dexamethasone or no glucocorticoid replacement. Endocrinologists need to monitor the development of both adrenal remnant tissue and Nelson’s syndrome following BLA.

Key words

Cushing's syndrome - remnant tissue - rest tissue - hypercortisolism - episodic - adrenalectomy


Publication History

Received: 13 August 2020

Accepted after revision: 27 August 2020

Article published online:
22 October 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Friedman TC. The adrenal gland. In: Benjamin IB, Griggs RC, Wing EJ, Fitz JG, Eds. Andreoli and Carpenter’s Cecil Essentials of Medicine 9th ed.. Philadelphia: Saunders Elsevier; 2015: 642-651
    Google Scholar
  • 2 Newell-Price J, Bertagna X, Grossman AB. et al. Cushing’s syndrome. Lancet 2006; 367: 1605-1617
    CrossrefPubMedGoogle Scholar
  • 3 Stewart PM, Newell-Price JDC. The Adrenal Cortex. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, Eds. Williams Textbook of Endocrinology. 13th edition. Philadelphia, PA: Elsevier; 2016: 489-555
    Google Scholar
  • 4 Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: Epidemiology and developments in disease management. Clin Epidemiol 2015; 7: 281-293
    PubMedGoogle Scholar
  • 5 Nieman LK, Biller BM, Findling JW. et al. The diagnosis of Cushing’s syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
    CrossrefPubMedGoogle Scholar
  • 6 Petersenn S, Beckers A, Ferone D. et al. Therapy of endocrine disease: Outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: Systematic review assessing criteria used to define remission and recurrence. Eur J Endocrinol 2015; 172: R227-R239
    CrossrefPubMedGoogle Scholar
  • 7 Rizk A, Honegger J, Milian M. et al. Treatment Options in Cushing’s Disease. Clin Med Insights Oncol 2012; 6: 75-84
    CrossrefPubMedGoogle Scholar
  • 8 Ritzel K, Beuschlein F, Mickisch A. et al. Clinical review: Outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 2013; 98: 3939-3948
    CrossrefPubMedGoogle Scholar
  • 9 Reincke M, Ritzel K, Osswald A. et al. A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur J Endocrinol 2015; 173: M23-M32
    CrossrefPubMedGoogle Scholar
  • 10 Chaffee WR, Moses AM, Lloyd CW. et al. Cushing’s syndrome with accessory adrenocortical tissue. JAMA 1963; 186: 799-801
    CrossrefPubMedGoogle Scholar
  • 11 Kemink L, Hermus A, Pieters G. et al. Residual adrenocortical function after bilateral adrenalectomy for pituitary-dependent Cushing’s syndrome. J Clin Endocrinol Metab 1992; 75: 1211-1214
    PubMedGoogle Scholar
  • 12 Strauch GO, Vinnick L. Persistent Cushing’s syndrome apparently cured by ectopic adrenalectomy. JAMA 1972; 221: 183-184
    CrossrefPubMedGoogle Scholar
  • 13 Siegal AM, Kreisberg RA, Hershman JM. et al. Recurrent Cushing’s disease following total adrenalectomy. Arch Intern Med 1972; 129: 642-647
    CrossrefPubMedGoogle Scholar
  • 14 Leibowitz J, Pertsemlidis D, Gabrilove J. Recurrent Cushing’s syndrome due to recurrent adrenocortical tumor—fragmentation or tumor in ectopic adrenal tissue?. J Clin Endocrinol Metab 1998; 83: 3786-3789
    PubMedGoogle Scholar
  • 15 Ayala AR, Basaria S, Udelsman R. et al. Corticotropin-independent Cushing’s syndrome caused by an ectopic adrenal adenoma. J Clin Endocrinol Metab 2000; 85: 2903-2906
    PubMedGoogle Scholar
  • 16 Schechter DC. Aberrant adrenal tissue. Ann Surg 1968; 167: 421-426
    CrossrefPubMedGoogle Scholar
  • 17 Ben-Mordechay D, Ben-Shlush A, Raviv-Zilka L. et al. Sonographic detection of accessory adrenal tissue in neonates. J Ultrasound Med 2016; 35: 959-963
    CrossrefPubMedGoogle Scholar
  • 18 Kempná P, Flück CE. Adrenal gland development and defects. Best Pract Res Clin Endocrinol Metab 2008; 22: 77-93
    CrossrefPubMedGoogle Scholar
  • 19 Nickerson PA, Brownie AC, Skelton F. An electron microscopic study of the regenerating adrenal gland during the development of adrenal regeneration hypertension. Am J Pathol 1969; 57: 335
    PubMedGoogle Scholar
  • 20 Kahri A. Histochemical and electron microscopic studies on the cells of the rat adrenal cortex in tissue culture. Acta Endocrinol 1966; 52: S8-S96
    CrossrefPubMedGoogle Scholar
  • 21 Wiesel J. Ueber Compensations-Hypertrophie der accessorischen Nebennieren bei der Ratte. Centr Physiol 1898; XII: 780
    PubMedGoogle Scholar
  • 22 Karakascheff KI. Weitere Beitrage zur pathologischen Anatomie der Nebennieren. Beitr Pathol 1906; 39: 373
    PubMedGoogle Scholar
  • 23 Chalmers R, Mashiter K, Joplin G. Residual adrenocortical function after bilateral “total” adrenalectomy for Cushing’s disease. Lancet 1981; 318: 1196-1199
    CrossrefPubMedGoogle Scholar
  • 24 Blichert-Toft M, Nielsen MD, Lockwood K. et al. Urinary excretion of corticosterone metabolites in demonstrating the adrenocortical remnant. Brit J Surg 1974; 61: 955-959
    CrossrefPubMedGoogle Scholar
  • 25 Gotlieb N, Albaz E, Shaashua L. et al. Regeneration of functional adrenal tissue following bilateral adrenalectomy. Endocrinology 2017; 159: 248-259
    CrossrefPubMedGoogle Scholar
  • 26 Speiser PW, Arlt W, Auchus RJ. et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2018; 103: 4043-4088
    CrossrefPubMedGoogle Scholar
  • 27 Morris LF, Harris RS, Milton DR. et al. Impact and timing of bilateral adrenalectomy for refractory adrenocorticotropic hormone-dependent Cushing’s syndrome. Surgery 2013; 154: 1174-1183 discussion 1183–1174
    CrossrefPubMedGoogle Scholar
  • 28 Friedman T. An update on the overnight dexamethasone suppression test for the diagnosis of Cushing’s syndrome: Limitations in patients with mild and/or episodic hypercortisolism. Exp Clin Endocrinol Diabetes 2006; 114: 356-360
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Friedman T, Ghods D, Shahinian H. et al. High prevalence of normal tests assessing hypercortisolism in subjects with mild and episodic Cushing’s syndrome suggests that the paradigm for diagnosis and exclusion of Cushing’s syndrome requires multiple testing. Horm Metab Res 2010; 42: 874-881
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Mojtahedzadeh M, Shaesteh N, Haykani M. et al. Low-dose and standard overnight and low dose-two day dexamethasone suppression tests in patients with mild and/or episodic hypercortisolism. Horm Metab Res 2018; 50: 453-461
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Berber E, Tellioglu G, Harvey A. et al. Comparison of laparoscopic transabdominal lateral versus posterior retroperitoneal adrenalectomy. Surgery 2009; 146: 621-625 discussion 625–626
    CrossrefPubMedGoogle Scholar
  • 32 Lee CR, Walz MK, Park S. et al. A comparative study of the transperitoneal and posterior retroperitoneal approaches for laparoscopic adrenalectomy for adrenal tumors. Ann Surg Oncol 2012; 19: 2629-2634
    CrossrefPubMedGoogle Scholar
  • 33 Esoterix Laboratory Sciences I. Cortisol by HPLC with Mass Spectrometry. 2006, Test # 803990
  • 34 Augustine J, Schaffer R, Friedman TC. Successful treatment of adrenal remnant tissue using alcohol ablation in a patient with episodic cushing disease. Endocrine Soc (Abstract) 2011; 93: P2-P650
    PubMedGoogle Scholar
  • 35 Friedman TC, Ghods DE, Shahinian HK. et al. High prevalence of normal tests assessing hypercortisolism in subjects with mild and episodic Cushing’s syndrome suggests that the paradigm for diagnosis and exclusion of Cushing’s syndrome requires multiple testing. Horm Metab Res 2010; 42: 874-881
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Sandouk Z, Johnston P, Bunch D. et al. Variability of late-night salivary cortisol in Cushing disease: A prospective study. J Clin Endocrinol Metab 2018; 103: 983-990
    CrossrefPubMedGoogle Scholar
  • 37 Petersenn S, Newell-Price J, Findling JW. et al. High variability in baseline urinary free cortisol values in patients with Cushing’s disease. Clin Endocrinol (Oxf) 2014; 80: 261-269
    CrossrefPubMedGoogle Scholar
  • 38 Findling JW, Doppman JL. Biochemical and radiologic diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am 1994; 23: 511-537
    CrossrefPubMedGoogle Scholar
  • 39 Lindsay JR, Nieman LK. Differential diagnosis and imaging in Cushing’s syndrome. Endocrinol Metab Clin North Am 2005; 34: 403-421 x
    CrossrefPubMedGoogle Scholar
  • 40 Haioun C, Itti E, Rahmouni A. et al. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: An early prognostic tool for predicting patient outcome. Blood 2005; 106: 1376-1381
    CrossrefPubMedGoogle Scholar
  • 41 Wang W, Macapinlac H, Larson SM. et al. [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography localizes residual thyroid cancer in patients with negative diagnostic (131)I whole body scans and elevated serum thyroglobulin levels. J Clin Endocrinol Metab 1999; 84: 2291-2302
    CrossrefPubMedGoogle Scholar
  • 42 Bell J, Brooker G, Harding BW. ACTH activation of glycolysis in the rat adrenal gland. Biochem Biophys Res Commun 1970; 41: 938-943
    CrossrefPubMedGoogle Scholar
  • 43 Crocker MK, Barak S, Millo CM. et al. Use of PET/CT with cosyntropin stimulation to identify and localize adrenal rest tissue following adrenalectomy in a woman with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2012; 97: E2084-E2089
    CrossrefPubMedGoogle Scholar
  • 44 Lila AR, Malhotra G, Sarathi V. et al. Localization of remnant and ectopic adrenal tissues with cosyntropin-stimulated 18F-FDG-PET/CT in a patient with Nelson syndrome with persistent hypercortisolism. J Clin Endocrinol Metab 2010; 95: 5172-5173
    CrossrefPubMedGoogle Scholar
  • 45 Miles JM, Wahner HW, Carpenter PC. et al. Adrenal scintiscanning with NP-59, a new radioiodinated cholesterol agent. Mayo Clin Proc 1979; 54: 321-327
    PubMedGoogle Scholar
  • 46 Kazerooni EA, Sisson JC, Shapiro B. et al. Diagnostic accuracy and pitfalls of [iodine-131]6-beta-iodomethyl-19-norcholesterol (NP-59) imaging. J Nucl Med 1990; 31: 526-534
    PubMedGoogle Scholar
  • 47 Mendichovszky IA. Powlson et al. Targeted Molecular Imaging in Adrenal Disease-An Emerging Role for Metomidate PET-CT. Diagnostics (Basel) 2016; 6: 42
    CrossrefPubMedGoogle Scholar
  • 48 Wannachalee T, Turcu AF, Bancos I. et al. The clinical impact of [(68) Ga]-DOTATATE PET/CT for the diagnosis and management of ectopic adrenocorticotropic hormone - secreting tumours. Clin Endocrinol (Oxf) 2019; 91: 288-294
    CrossrefPubMedGoogle Scholar
  • 49 Redvanly RD, Chezmar JL, Strauss RM. et al. Malignant hepatic tumors: Safety of high-dose percutaneous ethanol ablation therapy. Radiology 1993; 188: 283-285
    CrossrefPubMedGoogle Scholar
  • 50 Shiina S, Tagawa K, Unuma T. et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study. Cancer 1991; 68: 1524-1530
    CrossrefPubMedGoogle Scholar
  • 51 Curley SA, Izzo F, Delrio P. et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: Results in 123 patients. Ann Surg 1999; 230: 1-8
    CrossrefPubMedGoogle Scholar
  • 52 Demolin JM, Eick OJ, Münch K. et al. Soft thrombus formation in radiofrequency catheter ablation. Pacing Clin Electrophysiol 2002; 25: 1219-1222
    CrossrefPubMedGoogle Scholar
  • 53 Martirossian A, Jacob R, Riley K et al. A novel approach to ectopic adrenal tissue in Nelson’s Syndrome Endocrine Soc 101: MON-416 (Abstract) 2019
  • 54 Castinetti F, Guignat L, Giraud P. et al. Ketoconazole in Cushing’s disease: Is it worth a try?. J Clin Endocrinol Metab 2014; 99: 1623-1630
    CrossrefPubMedGoogle Scholar
  • 55 Cook DM, Loriaux DL. Cushing’s: Medical approach. Curr Ther Endocrinol Metab 1997; 6: 59-62
    PubMedGoogle Scholar
  • 56 Loose DS, Kan PB, Hirst MA. et al. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 1983; 71: 1495-1499
    CrossrefPubMedGoogle Scholar
  • 57 Duret C, Daujat-Chavanieu M, Pascussi JM. et al. Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Mol Pharmacol 2006; 70: 329-339
    CrossrefPubMedGoogle Scholar
  • 58 Loose DS, Stover EP, Feldman D. Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells. J Clin Invest 1983; 72: 404-408
    CrossrefPubMedGoogle Scholar
  • 59 McCance DR, Hadden DR, Kennedy L. et al. Clinical experience with ketoconazole as a therapy for patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 1987; 27: 593-599
    CrossrefPubMedGoogle Scholar
  • 60 Kannan CR. The Adrenal Gland. New York: Plenum Medical Book Co. 1988
    CrossrefGoogle Scholar
  • 61 Allolio B, Hahner S, Weismann D. et al. Management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 2004; 60: 273-287
    CrossrefPubMedGoogle Scholar
  • 62 Baudry C, Coste J, Bou Khalil R. et al. Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol 2012; 167: 473-481
    CrossrefPubMedGoogle Scholar
  • 63 ] Cushing’s Syndrome Redux. Endocrine News: Puzzler Page Sept 2011