July 2008.indd Cushing’s Disease Pituitary Surgery versus Adrenalectomy Omayma El-Shafie,1 Fatma B Abid,1 Nayal Al-Kindy,1 Dilip Sankhla,2 Nicholas J Woodhouse3 SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL JULY 2008, VOLUME 8, ISSUE 2, P. 211-214 SULTAN QABOOS UNIVERSITY© SUBMITTED - 31ST OCTOBER 2007 ACCEPTED - 31ST MARCH 2008 C A S E R E P O R T كوشينغ مرض الكظرية الغدة استئصال مقابل النخامية الغدة جراحة وودهاوز نيكوالس شنكال، ديليب الكندي، نايل عبد، بن اميمة الشفيع، فاطمة املرض سبب كان عمان. ــلطنة س في قابوس ــلطان الس جامعة ــفى الطب الباطني مبستش ــم قس ــينغ من ملرض كوش حالتني امللخص: هذا وصف األول املريض ــافه. اكتش من ــي املغناطيس الرنني صور ــتطع تس النخامية لم بالغدة حجم الورم لصغر ونظرا بالغدة النخامية. جدا ورم صغير وجود الدم ارتفاع ضغط العظام، في أدى إلى هشاشة وكسور مما مبكرا يكتشف ولم سنوات لعدة هذا املرض من يعاني وكان عاما ((14 العمر من يبلغ إزالة بواسطة عالجها 40 عاما ومت العمر من فتبلغ الثانية املريضة أما املنظار. بواسطة الكظرية الغدة استئصال بواسطة عالجه مت قامته. وقصر لعالج املثلى والطريقة كلتا العمليتني ــاوئ ومس لفوائد كامل وصف املقال هذا في متاما. املريضني ــفاء ش مت األنف. فتحة خالل من النخامية الغدة األمراض. النوع من هذا عمان. حالة، تقرير الكظر، استئصال الداخلي، التنظير النخامية، الغدة اجلراحة، الكلمات: مرض كوشينغ، مفتاح Department of 1Medicine, 2Radiology & Molecular Imaging, Sultan Qaboos University Hospital, Muscat, Oman; 3Department of Medicine, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman *To whom correspondence should be addressed. Email: omayma0@hotmail.com CUSHING’S DISEASE IS AN UNCOMMON AND complex disorder.1 Only six cases have been seen at Sultan Qaboos University Hospital, (Oman) since 1986 (personal observation by Nicholas J Woodhouse). Cushing’s disease is caused by exces- sive adrenocorticotropic hormone (ACTH) produc- tion by a pituitary tumour2 and must be distinguished from Cushing’s syndrome, due to ectopic ACTH over- production by endocrine tumours of the lung, pan- creas and other rarer sites.3 In this article, we describe two patients with Cushing’s disease whose pituitary magnetic resonance imaging (MRI) scans were nega- tive. Additional studies were then required to docu- ment the presence of a pituitary lesion and exclude an ectopic ACTH source. Our adult female patient was cured by transphenoidal surgery (TSS) and the young boy with growth retardation by bilateral endoscopic adrenalectomy. The reasons for these different thera- peutic approaches are discussed below. C A S E 1 A 40-year-old English woman was referred for fur- ther investigation of recent onset hypertension. On examination, central obesity was observed. She also had ulcerated mosquito bites on both shins that had not healed for four months. Cushing’s syndrome was suspected clinically and ACTH dependant disease confirmed by finding raised cortisol and ACTH levels. Cortisol levels were suppressed by more than 50% by high dose dexamethasone which suggested pituitary ABSTRACT We describe two patients of the Department of Medicine at Sultan Qaboos University Hospital, Muscat, Oman, with Cushing’s disease. Their magnetic resonance imaging scans of the pituitary were negative. One patient was treated by transsphenoidal surgery and the other by bilateral endoscopic adrenalectomy. Both procedures were successful and the patients cured. The advantages and disadvantages of these two approaches are discussed. Key words: Cushing’s disease; Surgery, pituitary; Endoscopy; Adrenalectomy; Case report; Oman. O M AY M A E L -S H A F I E , FAT M A B A B I D , N AYA L A L - K I N D Y, D I L I P K U M A R A N D N I C H O L A S J WO O D H O U S E 212 disease. As there was no evidence of a pituitary or ec- topic tumour on the MRI or computed tomography (CT) scans, her disorder was initially controlled us- ing oral ketaconazole and metyrapone. She was then referred to the endocrine unit at the Hammersmith Hospital in London where she underwent selective inferior petrosal sinus sampling with ACTH measure- ment following the intravenous administration of cor- tisol releasing hormone. This confirmed the presence of a left-sided pituitary lesion, and subsequently the left side of the pituitary gland was blindly removed by TSS sugery. Histology revealed a basophilic tumour positive for ACTH on immunofluroscence. She re- mains well four years later, only taking replacement thyroxine. C A S E 2 A 14-year-old boy was referred with a five-year his- tory of growth retardation, hypertension, obesity, delayed sexual development (testosterone 1.8 (n = 6- 27nmol/l)) and severe low back pain. Earlier studies had shown ACTH levels repeatedly within the ‘nor- mal’ (4.2, 4.0, 3.5 [n=2.2-10.0pmol/l]) range at a time when his cortisol levels were elevated (923, 918, 812 [n = 240-620nmol/L]). Upon examination, he was clini- cally short with a height of 128 cm, and cushingoid features. His BP was 140/80 on lisinopril. An X-ray of the lumbar spine revealed severe loss of bone min- eral density and multiple wedge compression fractures [Figure 1]. The bone densitometry was very low at 0.542 g/cm2. Cortisol levels were suppressed by 95% after high dose dexamethasone suppression [Table 1] indicative of pituitary ACTH production, but as in Case 1, there was no evidence of a pituitary tumour on his initial MRI scan. Ectopic ACTH production was deemed unlikely in the absence of any obvious source on the CT or MRI scans of the lungs or abdo- men; furthermore, the administration of octreotide (100 mcg 8 hourly subcutaneously for 3 days), failed to lower his cortisol levels. The patient then under- went bilateral laparoscopic adrenalectomy rather than pituitary surgery, as there were concerns that his subsequent growth and sexual development might be adversely affected. The histology revealed bilateral ad- renal hyperplasia. Within twenty-six months of taking replacement hydrocortisone and fludrocortisone his Table 1: Cortisol levels both patients after dexa- methasone given 2 mg 6 hourly for 48 hours Cortisol nmol/l Cortisol nmol/l Before dexametasone After dexametasone Patient 1 861 344 Patient 2 812 40 Figure 1: Patient 2. X-Ray of the lumbar spine showing severe loss of bone mineral density with multiple wedge compression fractures in the lower dorsal and upper lumbar vertebral body (D12 & 4) C U S H I N G ’ S D I S E A S E 213 height had increased from 123 to 140 cm and testo- sterone from 1.8 to 10.1 nmol/l. Unfortunately, there was only minimal improvement of his bone mineral density 0.554 g/cm2, but his total skeletal calcium must have increased considerably having grown 17cm. We expect his bone mineral density to increase when his growth spurt is completed. Twenty six months later, however, he had become more pigmented, the ACTH level having increased from 4 to 22.6pmol/L and he developed an obvious microadenoma in the anterior lobe of the pituitary [Figure 2]. He was then referred for TSS abroad. D I S C U S S I O N Both of these patients had Cushing’s disease but their pituitary tumours were not visible on MRI at presen- tation. This is reportedly the case in up to 40 % of newly diagnosed patients.3 In these circumstances, therapeutic decision-making becomes more difficult as invasive measures are required to document the pituitary origin of the excess circulatory ACTH lev- els before referral for surgery. The first patient under- went canulation with sampling of the petrosal sinus veins, and later removal of the left half of her pituitary gland. The disease was cured, but five years later she still requires thyroxine replacement therapy. Varying degrees of postoperative hypopituitarism are seen in 30-40 % of all cases particularly those whose surgery is carried out blindly as in this case.4 Recently the Eu- ropean Cushing’s disease survey group reviewed 668 patients: major non-hormonal complications of trans- septosphenoidal occurred in 14.5% of the patients; hypogonadism in 14-53%; hypothyroidism in 14-40%, and severe growth hormone deficiency in 13%.5 We concluded that the second patient also had pituitary dependant disease evidenced by his response to high dose dexamethasone6 and an absence of any obvi- ous ectopic ACTH source on CT or MRI scanning of the lungs and abdomen. Furthermore, there was no response to octreotide; cortisol levels are usually unchanged in Cushing’s disease whereas a fall is ob- served in patients with ectopic ACTH production as such tumours express somatostatin receptors.7 In the 14 year-old boy whose complaints were short stature and back ache, we were faced with two options: ei- ther to refer him abroad for petrosal sinus sampling and pituitary surgery, or to remove his adrenals. The former procedure would involve the risk of develop- ing growth or sex hormone deficiencies5 whereas adrenalectomy by laparoscopy is safe and immedi- ately curative.8 Moreover, the patient’s sphenoid si- nus had failed to pneumatise making a transsphenoi- dal approach more difficult. We therefore proceeded with laparoscopic bilateral adrenalectomy. Nelson’s syndrome, characterized by accelerated growth of the pituitary tumour in the face of postoperatively reduced cortisol levels, occurs in between 8 and 38%9, 10 of patients with Cushing’s disease after adrena- lectomy, usually 7 to 24 years after surgery.11, 12 After 26 months, he became more pigmented, his ACTH level increased and an MRI scan showed an 8 mm anterior lobe tumour [Figure 2]. The rapid growth of our patient’s tumour is unusual and might have been related to the dramatic response to dexamethasone evidenced by a 95% reduction of his cortisol level dur- ing testing. This observation prompted us to specu- late that patients with Cushing’s disease who have the most dexamethasone sensitive pituitary tumours are more likely to develop Nelson’s syndrome following adrenalectomy than those whose tumours are more resistant. However, in two other reports, the degree of susceptibility to the dexamethasone suppression test did not provide evidence for prediction of Nelson’s syndrome.9-12 Age itself appears to be important; Nel- son’s syndrome being more common in young patients Figure 2: (Patient 2) Magnetic resonance imag- ing of the pituitary (T1W sagittal image, 2007) shows an 8 mm hypointense lesion in anterior lobe (microadenoma) after adrenalectomy. and rare after the age of 40.9 The patient has now been referred for TSS abroad. R E F E R E N C E S 1. Brown RL, Weiss RE. An approach to the evaluation and treatment of Cushing’s disease. Expert Rev Anticancer Ther 2006; 6:S37-S46. 2. Labeur M, Theodoropoulou M, Sievers C, Paez-Pereda M, Castillo V, Arzt E, et al. New aspects in diagnosis and treatment of Cushing’s disease. Front Horm Res 2006; 35:169-178. 3. Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med 1990; 112:434-444. 4. de Herder WW, Uitterlinden P, Pieterman H, Tanghe HL, Kwekkeboom DJ, Pols HA, et al. Pituitary locali- zation in patients with Cushing’s disease by magnetic resonance imaging. Is there a place for petrosal sinus sampling? Clin Endocrinol 1994; 40:87-92. 5. Bochicchio D, Losa M, Buchfelder M. Factors influenc- ing the immediate and late outcome of Cushing’s dis- ease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s Disease Survey Group. J Clin Endocrinol Metab 1995; 80:3114-3120. 6. Damian G, Morris, Grossman B. Cushing’s syndrome. Endotext.com, Chapter 7, 6 Dec 2002. From www.En- dotext.com. Accessed October 2007. 7. Woodhouse NSY, Dagogo-Jack S, Ahmed M, Judzewitsh R. Acute and long term effects of octreotide in patients with ACTH dependant Cushing’s syndrome. Am J Med 1993; 95:305-308. 8. McCance E, Russell CF, Kennedy TL, Hadden DR, Kennedy L, Atkinson AB. Bilateral adrenalectomy: low mortality and morbidity in Cushing’s disease. Clin En- docrinol 1993; 39:315-321. 9. Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg P. Patient’s age is a simple predictive factor for the devel- opment of Nelson’s syndrome after total adrenalectomy for Cushing’s disease. J Clin Endocrinol Metab 1994; 79:887-889. 10. Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, et al. Corticotroph progression after adrenalecto- my in Cushing’s disease: A reappraisal of Nelson’s syn- drome. J Clin Endocrinol Metab 2007; 92:172-179. 11. Assié G, Bahurel H, Bertherat J, Kujas M, Legmann P, Bertagna X. The Nelson syndrome revisited. Pituitary. 2004; 7:209-215. 12. Nagesser SK, van Seters AP, Kievit J, Hermans J, Krans HM, van de Velde CJ. Long-term results of total adrena- lectomy for Cushing’s disease. World J Surg 2000; 24:108-113. O M AY M A E L -S H A F I E , FAT M A B A B I D , N AYA L A L - K I N D Y, D I L I P K U M A R A N D N I C H O L A S J WO O D H O U S E 214