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Diagnosis and treatment of adrenocorticotrophic hormone independent macronodular adrenocortical hyperplasia: 23 cases of experience in a single center LI Jiang, YANG Chang-hai Department of Urology, Tianjin Medical University General Hospital, Tianjin 300052, China Corresponding author: YANG Chang-hai, Department of Urology, Tianjin Medical University General Hospital, No 154, Anshan Street, Heping district, Tianjin 300052, China Tel: 86- 22-60362443 Fax: 86- 22-60362444 E-mail: [email protected] Abstract AIM: We aim to report our experience in treatment of adrenocorticotrophic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH) in a single medical center. Methods: A total of 23 AIMAH cases were retrospectively reviewed according to patient’s clinic features. All cases have physical signs and biochemical evidence of Cushing’s syndrome. High and low dose dexamethas failed to suppress cortisone secretion on suppression tests and ACTH levels were low in all cases. Bilateral massively enlarged adrenal glands were screened on CT scan in 23 cases and all were bilateral adrenal macronodular hyperplasia by pathological examination. Results: There were 8 cases have normal blood pressure after 2~8 years of bilateral adrenalectomy. Fifteen cases underwent single side adrenalectomy and their blood pressures were remarkable decrease in 3 years after operation, 12 cases of them (12/15) had medicine treatment; Three cases of them (3/15) underwent the contralateral adrenalectomy, then have normal blood pressure. There was no Nelson’s syndrome in all cases. Conclusions: AIMAH had unique endocrinological, radiological and pathological features, presenting as an independent etiological factor of Cushing’s syndrome. Diagnosis of AIMAH mostly derived from pathological examination. Long term remission can be achieved by unilateral adrenalectomy. Contralateral adrenalectomy should be performed in case of recurrence when followed with periodical examination of symptom and serum concentration of cortisol. Key words: Adrenocortical Macronodular Hyperplasia; Cushing's syndrome Introduction Adrenocorticotrophic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production with subclinical or overt Cushing’s syndrome (CS). (1, 2) AIMAH represents less than 1% of cases of endogenous CS; however, as 10% of incidentally found adrenal lesions are bilateral, AIMAH with subclinical cortisol secretion is being increasingly recognized. (3) Patients with AIMAH are identified either following an incidental radiological finding or the investigation of an adrenal over-secretion syndrome. (4, 5) The most common clinical presentation is subclinical, followed by clinical Cushing’s syndrome (CS). So far the most common cause (in 95% of patients) of AIMAH is adrenocortical adenoma or carcinoma. Most of the remaining patients have primary pigmented nodular adrenal disease, a syndrome that is characterized by multiple small bilateral pigmented adrenocortical nodules and is often associated with the Carney complex.(6) The diagnosis and management of patients with ACTH-independent Cushing’s syndrome and bilateral adrenal masses are problematic, (7, 8) particularly for the bilateral adrenal adenomas. In this report, we present 23 cases of AIMAH; these patients were admitted from July 1994 to 2010 in our hospital diagnosed by pathology. Patients and methods There 23 patients (14 males and 9 females, mean age 49 years) were admitted to our hospital from July 1994 to 2010. All patients presented with several symptoms characteristic of Cushing’s syndrome, and hypertension were discovered incidentally during the examination. The duration of their disease ranged from 1 to 5 years. Diabetes occurred in 10 cases (10/23), Central obesity occurred in 8 cases. Sanguine appearance occurred in 6 cases. Fourteen patients have purple stripes. The levels of plasma cortisol, ACTH, and urinary free cortisol (UFC) were measured in all patients, the patients were treated by high-dose and low-dose dexamethasone suppression test (HDDST and LDDST), the results of HDDST and LDDST were negative. There were 4 patients received plasma cortisol rhythm determination, and the other 19 cases only examined at 8:00. Measurement results showed that plasma cortisol levels elevated in 20 patients and UFC increased and ACTH levels lowered in all 23 patients (Table 1). Imaging examination MRI examination showed pituitary was normal in 17 patients; however, pituitary MRI examination didn’t been performed in another 6 patients. On CT scan, bilateral adrenal nodules of soft tissue density, measuring up to 5 cm, distort the normal adrenal glands appear diffusely enlarged but lack. CT scan results in these patients showed that the adrenal lesion with macronodularity were significantly enlarged (Figure 1), and the largest diameter of adrenal nodular was 6 cm. Operative procedures Bilateral adrenallectomy was performed in 8 patients and unilateral adrenalectomy was performed in another 15 cases. The operative procedure has been described by Shinbo et al.(9) Briefly, under general anesthesia, patient underwent right adrenalectomy were placed in a left lateral position. A 10/12-mm trocars at the mid-clavicular line below the costal margin and at the median line 5 cm above the umbilicus and 5-mm trocars were placed at approximately three finger-widths below the xyphoid process and at the anterior axillary line 5 cm below the costal margin. Laparosonic coagulating shears with suction and irrigation device with cautery and L-hook tip were used when necessary. The two trocars at median line remained on the abdominal wall while skin wounds at the other trocar sites were closed. Left laparoscopic adrenalectomy was performed as follows: patient was repositioned to the right half lateral position and two 5-mm trocars were placed at the left below the costal margin and at the midclavicular line below the costal margin. The left adrenal gland was isolated similarly to right side and enclosed in an endoscopic pouch. Skin wounds were closed. Results Operation and discharge After operation, all resected samples were confirmed positive by histopathological examination (Figure 2), the nodules composed of bright cells. The normal cortical structure disappeared. We summarized the general clinical and biochemical conditions of these patients in Table 2. The lumbar open operations were performed in 9 patients; retroperitoneal laparoscopic operations were performed in 7 patients; Single abdominal open operations were performed in 3 patients; multiple lumbar open operations were performed in 2 patients and the Laparoscopic operations were performed in 2 patients. Only1 patient occurred in infection after operation, and soon got control after treatment. The resected adrenal nodular mass of all patients was diffused grayish yellow or golden yellow (Figure 3). The largest nodular was 6 × 4 × 4 cm with 40g of weight and no clear coat. The surface of resected slide was golden brown with diameter of 0.6~1.7cm. Patients with unilateral resection were not treated with hormone drug therapy at discharge, while bilateral resection patients received dose of 5 or 10 mg of prednisone treatment. Postoperative follow-up After surgery, hypertension of these patients alleviated significantly. The 8 patients received bilateral adrenallectomy were followed up for 2 to 8 years, treated by glucocorticoid replacement, and they had normal blood pressure and breath. Their obesity and sanguine appearance alleviated. Decreased blood pressure after surgery was observed in others 15 patients. However, only three years later, 12 cases of 15 patients had hypertension about 150~170/90~100mmHg and maintained at 130~150/70~85mmHg after taking oral antihypertensive drugs. The other 3 patients (Case 11, 12, 23) had no response on oral antihypertensive drugs and their blood pressure reached to 170~180/90~110 mm Hg. Plasma cortisol, UFC, ACTH and CT examination were performed, and their contralateral adrenal increased up to 35 ml, 32ml and 38ml respectively. Their blood pressure returned to normal after their contralateral adrenal being removed and underwent hormone replacement therapy. No Nelson syndrome occurred after therapy. Discussion Cushing's syndrome is due to excess cortisol secretion and is associated to increased mortality and severe morbidity that are not fully reversible despite biochemical control. CS is 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. (10) The diagnosis of Cushing’s syndrome is based on the clinical features of hypercortisolism, absence of serum cortisol diurnalrhythm, elevated midnight sleeping cortisol levels, and incomplete cortisol suppression test.(11) Cushing’s syndrome due to AIMAH was first reported in an isolated case.(12) AIMAH is characterized by bilateral macronodular hyperplasia of the adrenal glands and is one of the causes of Cushing’s syndrome.(13) Clinical manifestations include hypertension, weight gain, impaired glucose tolerance or diabetes mellitus, osteoporosis, and bruisability. Hypogonadism and gynecomastia have been reported occurred in males and hirsutism occurred in females.(14) The precise etiology of AIMAH is unknown, recent studies have demonstrated that the aberrant adrenal expression and aberrant function of one to several peptide hormone receptors, such as receptors for glucose-dependent insulinotropic hormone (GIP), vasopressin, luteinzing hormone/human chorionic gonadotropin (LH/hCG), beta adrenergic agonists, and serotonin, can lead to adrenal cell proliferation and abnormal regulation of steroidogenesis in AIMAH.(15, 16) Cross sectional imaging is commonly used to identify adrenaldisease in patients have Cushing’s syndrome. CT scan and MR imaging are used to document the lesion size and shape; presence or absence of calcification, hemorrhage, and necrosis; On MRI, T1-weighted images are hypointense relative to the liver and isointense relative to muscle. T2-weighted images tend to be hyperintense relative to the liver.(17, 18) In contrast, the nodules of patients with chronic ACTH stimulation appear isointense relative to the liver on T2-weighted MR images. (19) On histology, a remarkable increase in the number of small clear cells, which are mostly derived from the upper fascicularzone. The amount of cortisol produced by each cell is slight, so that significant enlargement of the adrenal gland is necessary before excessive cortisol production causes Cushing’s syndrome.(20) The definitive treatment of CS consists in surgical resection of the tumor secreting ACTH. When the source of the excessive secretion is the pituitary gland, the standard approach is to perform an endoscopic endonasal trans-sphenoidal exploration, with excision of the tumor, if found. This surgical procedure is demanding and should only be performed in centers with extensive experience, to minimize operative risks, reduce the possibility of remission, and maintain other pituitary functions. Bilateral adrenalectomy by overt or laparoscopic approach is the most useful treatment in patients with AIMAH and hormonal hypersecretion.(21, 22) However, in patients with moderately increased hormonal production, unilateral adrenalectomy is proposed as a safe and effective alternative; it is expected that, as the cell mass increases in the contralateral adrenal, a second adrenalectomy may be necessary.(23, 24) In this report, we presented 23 cases of that were diagnosed with AIMAH. High and low dose dexamethas failed to suppress cortisone secretion on suppression tests and ACTH levels were low in all cases. Bilateral massively enlarged adrenal glands could be seen on CT scan, and all were bilateral adrenal macronodular hyperplasia confirmed by pathological examination. Consistent with previous case report content, our result showed AIMAH had unique endocrinological, radiological and pathological features. Diagnosis of AIMAH mostly derived from pathological examination. Long term remission can be achieved by unilateral adrenalectomy. Contralateral adrenalectomy should be performed in case of recurrence when followed with periodical examination of symptom and serum concentration of cortisol. Conflict of interest The authors declare there is no conflict of interest. Reference 1. Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing's disease. Best Pract Res Clin Endocrinol Metab. 2009;23:607-23. 2. Goni Iriarte MJ. [Cushing's syndrome: special issues]. Endocrinol Nutr. 2009;56:251-61. 3. Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009;23:245-59. 4. Bourdeau I, D'Amour P, Hamet P, Boutin JM, Lacroix A. Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome. J Clin Endocrinol Metab. 2001;86:5534-40. 5. Yamada Y, Sakaguchi K, Inoue T, Kubo M, Fushimi H, Sekii K, et al. Preclinical Cushing's syndrome due to adrenocorticotropin-independent bilateral adrenocortical macronodular hyperplasia with concurrent excess of gluco- and mineralocorticoids. Intern Med. 1997;36:628-32. 6. Stratakis CA, Carney JA, Lin JP, Papanicolaou DA, Karl M, Kastner DL, et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest. 1996;97:699-705. 7. Karapanou O, Vlassopoulou B, Tzanela M, Stratigou T, Tsatlidis V, Tsirona S. Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: is medical treatment always an option? Endocr Pract. 2013;19:e77-82. 8. Yoshida M, Umeda H, Iwama S, Nakayama S, Miyata M, Ogawa K, et al. Assessment of long-term efficacy and safety of metyrapone monotherapy in a patient with ACTH-independent macronodular adrenal hyperplasia. Endocrine. 2012;41:160-1. 9. Shinbo H, Suzuki K, Sato T, Kageyama S, Ushiyama T, Fujita K. Simultaneous bilateral laparoscopic adrenalectomy in ACTH-independent macronodular adrenal hyperplasia. Int J Urol. 2001;8:315-8. 10. Pozza C, Graziadio C, Giannetta E, Lenzi A, Isidori AM. Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics. J Oncol. 2012;2012:685213. 11. Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev. 1998;19:647-72. 12. Kirschner MA, Powell RD, Jr., Lipsett MB. Cushing's Syndrome: Nodular Cortical Hyperplasia of Adrenal Glands with Clinical and Pathological Features Suggesting Adrenocortical Tumor. J Clin Endocrinol Metab. 1964;24:947-55. 13. Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. Endocr Rev. 2001;22:75-110. 14. Doppman JL, Chrousos GP, Papanicolaou DA, Stratakis CA, Alexander HR, Nieman LK. Adrenocorticotropin-independent macronodular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism. Radiology. 2000;216:797-802. 15. Mircescu H, Jilwan J, N'Diaye N, Bourdeau I, Tremblay J, Hamet P, et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome? J Clin Endocrinol Metab. 2000;85:3531-6. 16. Bertagna X, Groussin L, Luton JP, Bertherat J. Aberrant receptor-mediated Cushing's syndrome. Horm Res. 2003;59 Suppl 1:99-103. 17. Doppman JL, Nieman LK, Travis WD, Miller DL, Cutler GB, Jr., Chrousos GP, et al. CT and MR imaging of massive macronodular adrenocortical disease: a rare cause of autonomous primary adrenal hypercortisolism. J Comput Assist Tomogr. 1991;15:773-9. 18. Rockall AG, Babar SA, Sohaib SA, Isidori AM, Diaz-Cano S, Monson JP, et al. CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome. Radiographics. 2004;24:435-52. 19. Verma A, Mohan S, Gupta A. ACTH-independent macronodular adrenal hyperplasia: imaging findings of a rare condition : A case report. Abdom Imaging. 2008;33:225-9. 20. Sasano H, Suzuki T, Nagura H. ACTH-independent macronodular adrenocortical hyperplasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes. Mod Pathol. 1994;7:215-9. 21. Swain JM, Grant CS, Schlinkert RT, Thompson GB, vanHeerden JA, Lloyd RV, et al. Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation. Arch Surg. 1998;133:541-5; discussion 5-6. 22. Stratakis CA, Kirschner LS. Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res. 1998;30:456-63. 23. Boronat M, Lucas T, Barcelo B, Alameda C, Hotait H, Estrada J. Cushing's syndrome due to autonomous macronodular adrenal hyperplasia: long-term follow-up after unilateral adrenalectomy. Postgrad Med J. 1996;72:614-6. 24. Imohl M, Koditz R, Stachon A, Muller KM, Nicolas V, Pfeilschifter J, et al. [Catecholamine-dependent hereditary Cushing's syndrome - follow-up after unilateral adrenalectomy]. Med Klin (Munich). 2002;97:747-53. Figure legend Figure 1 CT result of one patient, whose bilateral adrenal demonstrated irregular nodular masses after enhancement. Figure 2 Histopathological analysis of the resected adrenal specimen. Figure 3 Macroscopic appearance of the adrenal glands of a patient.