1. Dr Tsang Yi Po Department of Surgery Pamela Youde Nethersole Eastern Hospital Joint Hospital Surgical Grand Round 2013 Management of Adrenal Incidentaloma

2. Introduction

3. Mass lesion in adrenal gland >1cm Discovered incidentally during radiologic exams for other medical condition Prevalence ~4-6% in general population Prevalence increases with age –20-29 years old: 0.2% –>70 years old: 7% Bovio et al. J Endocrinol Invest 2006 Young. N Engl J Med 2007 Boland et al. Radiology 2008

4. Introduction Hypersecreting ? Malignant?

5. Introduction Causes Differential diagnosesPrevalence (%)Size (cm) Non-functioning adenoma70-801-4 Hypersecreting tumours Cortisol secreting Aldosterone secreting Phaeochromocytoma ~20 10-20 1-3 5-10 Variable Other adrenal tumours Myelolipoma Cysts 5-10 <5 Variable Primary adrenal carcinomas<5Usually >4 Metastasis from other malignancy 1-5Variable, usually <3 Infection / granulomas<1Variable Young. N Engl J Med 2007 Anagnostis et al. Hormones 2009 Ridho et al. Acta Med Indones 2009 Terzolo et al. Eur J Endocrinol 2011

6. Introduction Hormonal evaluation Imaging

7. Hormonal evaluation Subclinical Cushing’s syndrome Phaeochromocytoma Conn’s syndrome

8. Subclinical Cushing’s syndrome (SCS) For all patients with incidentaloma Features –Most frequent endocrine dysfunction in patients with adrenal incidentalomas –Lack typical signs / symptoms but may have metabolic disturbances Difficult demonstration of SCS in clinical practice –Spectrum and heterogenicity of clinical presentation – may be overlooked –Flexible approach with biochemical test and clinical judgement Anagnostis et al. Hormones 2009 Terzolo et al. Eur J Endocrinol 2011 Chiodini. J Clin Endocrinol Metab 2011

9. SCS Blood (screening) –Overnight dexamethasone suppression test (ONDST) – 1mg oral dexamethasone nocte Threshold: 50nmol/l or 1.8µg/dl Values –<50nmol/l or <1.8µg/dl – clearly exclude Cushing’s –>138nmol/l or >5µg/dl – likely Cushing’s –50-138nmol/l or 1.8-5µg/dl – indeterminate (DDx: alcoholism, stress, obesity, depression etc.) Sensitivity: 91% Urine (screening) –24-hr urinary free cortisol (UFC) Normal: <250nmol/24hr Young. N Engl J Med 2007 Anagnostis et al. Hormones 2009 Terzolo et al. Eur J Endocrinol 2011

10. SCS Confirmatory test –Low dose dexamethasone suppression test (LDDST) – 0.5mg oral dexamethasone Q6H for 48hrs For indeterminate results after ONDST Check serum cortisol / 24hr UFC Normal if serum cortisol 50% fall in serum and/or urine cortisol Sensitivity 98%, specificity 80-98% Young. N Engl J Med 2007 Anagnostis et al. Hormones 2009 Terzolo et al. Eur J Endocrinol 2011

11. Phaeochromocytoma For all patients with incidentaloma Urine (screening) –24hr urine fractionated metanephrines and catecholamines –Sensitivity / specificity: 90-98% Blood (screening) –Plasma free metanephrines if urine test normal and high suspicion –Sensitivity: 96-100%, specificity 85-89% Normal screening tests exclude diagnosis Sawka et al. J Clin Endocrinol Metab 2003 Young. N Engl J Med 2007 Terzolo et al. Eur J Endocrinol 2011

12. Conn’s syndrome For all hypertensive and/or hypokalaemia patients with incidentaloma Blood (screening) –Ambulatory morning plasma aldosterone (PA) + plasma renin activity (PRA)  aldosterone / renin ratio (ARR) ≥20 confirm diagnosis (PA ng/dl; PRA ng/ml/hr) Confirmatory test –Aldosterone suppression test Saline infusion test 24hr urinary aldosterone excretion test with high salt diet –Adrenal venous sampling Young. N Engl J Med 2007 Terzolo et al. Eur J Endocrinol 2011

13. Imaging Ultrasound Computed tomography Magnetic resonance imaging Positron emission tomography Scintigraphy Image guided fine needle aspiration

14. Ultrasound Advantage –Good reliability for mass size and growth –Non-invasive –No radiation Drawbacks –Operator dependent –Difficult visualisation especially if obesity / overlying gas –Cannot differentiate between benign and malignant masses Sensitivity: 65% for 3cm Larger role in follow-up Fontana et al. Urology 1999 Friedrich-Rust et al. Am J Roentgenol 2008 Terzolo et al. Eur J Endocrinol 2011

15. Computed tomography (CT) Cornerstone of imaging studies Features of malignancy –Calcifications –Heterogenicity / tumour necrosis –Irregular border –Invasion / displacement of adjacent structures –Size Anagnostis et al. Hormones 2009 Nieman. J Clin Endocrinol Metab 2010 Terzolo et al. Eur J Endocrinol 2011 Palmeiro et al. SEDIA 2012

16. CT – Plain Hounsfield unit (HU) –Up to 70% of adenoma – abundant fat –Benign lesion <10HU Sensitivity 96-100% Specificity 50-100% –Indeterminate lesions >10HU Need further characterisations 30% adenoma with >10HU –Lipid-poor  Another parameter Boland et al. Am J Roentgenol 1998 Hamrahian et al. J Clin Endocrinol 2005 McDermott et al. Best Pract Res Clin Endocrinol Metab 2012 Palmeiro et al. SEDIA 2012

17. CT – Contrast Delayed washout –Washout at 10-15min –>50% washout: typical in adenoma –<50% washout (i.e. more contrast retention): malignancy / phaeo- chromocytoma –Sensitivity 98%, specificity 100% –Cost-effective Caoili et al. Am J Roentgenol 2000 Pena et al. Radiology 2000 Terzolo et al. Eur J Endocrinol 2011 Palmeiro et al. SEDIA 2012

18. Magnetic resonance imaging (MRI) Characteristics TypeT1T2 Non-functioning adenoma Hypo-/Iso-intense  liverIso-intense  liver Hypersecreting tumours Cortisol secreting Aldosterone secreting Phaeochromocytoma Hypo-/Iso-intense  liver Hyper-/Iso-intense  liver Hyper-intense Primary adrenal carcinomas Hyper-intense Metastasis Iso-intense  liver Myelolipoma Hypo-intense Cysts Heinz-Peer G et al. Am J Roentgenol 1999 Anagnostis et al. Hormones 2009 Terzolo et al. Eur J Endocrinol 2011

19. MRI – Chemical shift imaging Detect lipid content in adrenal tissue Differentiate adenoma (lipid-rich) from non-adenoma Lipid-rich adenoma: loss of signal intensity in out-of-phase image –Compare with spleen (to avoid confounding of liver steatosis) –Sensitivity: 84-100%; specificity: 92-100% Comparable to CT in sensitivity / specificity –No additional benefit to CT Outwater et al. Am J Roentgenol 1995 Israel et al. Am J Roentgenol 2004 Haider et al. Radiology 2004 Aron et al. Best Pract Res Clin Endocrinol Metab 2012

20. Positron emission tomography (PET) 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18F-FDG) –Increase glucose uptake by malignant lesions Highly accurate for differentiation between benign and malignant lesions –Sensitivity 93-100%, specificity 80-100% Necrotic / haemorrhagic lesions  poor FDG uptake  false negative –Further improves sensitivity / specificity if +CT –Further improves yield of CT scan Metser et al. J Nucl Med 2006 Caoili et al. Acad Radiol 2007 Boland et al. Am J Roentgenol 2009 Groussin et al. J Clin Endocrinol Metab 2009

21. PET Maximum standardised uptake value (SUVmax) < 1.60  highly predictive of benign lesions Indicated if inconclusive CT findings Drawbacks –Not reliable for lesions < 1cm –Cannot differentiate among malignant lesions Metser et al. J Nucl Med 2006 Caoili et al. Acad Radiol 2007 Boland et al. Am J Roentgenol 2009 Groussin et al. J Clin Endocrinol Metab 2009 Boland. Am J Roentgenol 2011

22. Scintigraphy [I-131]-6-beta-iodomethyl-norcholesterol (NP-59) / [Se-75]- selenomethyl-19-norcholesterol scan –Morphological and functional imaging of cortex –Bind to specific low-density lipoproteins  stored in adrenocortical lipid droplets –Normal uptake: 5days after tracer injection Hypersecretion of cortisol / aldosterone / sex hormone: uptake before 5days Malignancies (primary / secondary): cold masses as most not secreting –Sensitivity: 71-100%, specificity: 50-100% Gross et al. J Nucl Med 1994 Ilias et al. Endocr Relat Cancer 2007 Anagnostis et al. Hormones 2009

23. Scintigraphy [I-123]-metaiodo-benzylguanidine (MIBG) scan –Morphological and functional imaging of medulla –Noradrenaline analogue taken up by phaeochromocytoma cells –Sensitivity: 91-97%, specificity: 87-98% Octreotide scan –Lower sensitivity than MIBG scan Jacobson et al. J Clin Endocrinol Metab 2010

24. Fine needle aspiration (FNA) Not recommended Cannot differentiate adenoma from carcinoma Associates with complications: 2.8-14% –Pneumothorax –Bleeding Haemothorax Adrenal haematoma Haematuria –Hypertensive crisis due to bleeding in phaeochromocytoma –Needle track seeding of tumour cells Young. N Engl J Med 2007 Anagnostis et al. Hormones 2009 Terzolo et al. Eur J Endocrinol 2011

25. Summary – Imaging Imaging modalities Sensitivity (%) Specificity (%) Features USG 65 ( 3cm) Operator dependent Cannot differentiate nature of lesion Plain CT – HU96-10050-100Malignancy: Higher HU Contrast CT – Washout 98100 Malignancy: Less washout, heterogenous, invasion, size MRI – Chemical shift imaging 84-10092-100 Malignancy: Persistent signal intensity PET93-10080-100Malignancy: More FDG uptake Scintigraphy NP-59 MIBG 71-100 91-97 50-100 87-98 Malignancy: Cold lesions Functioning: More tracer uptake Image guided FNA81-9699-100 Cannot differentiate adenoma from carcinoma Complications

26. Risks of adrenal incidentaloma Hypersecreting ? Malignant?

27. Malignant potential Size: Chance of malignancy 6cm NIH Consens State Sci Statements 2002 Bulow B et al. Eur J Endocrinol 2006 2%6%25%

28. Hormonal oversecretion Autonomous hormonal oversecretion <1% –Most common: cortisol secretion  SCS –Very rare: catecholamine (phaeochromocytoma) / aldosterone (Conn’s syndrome) Barzon et al. Eur J Endocrinol 2003 Terzolo et al. Eur J Endocrinol 2011

29. Management Surgery Follow-up

30. Follow-up and indication for surgery Malignant potential –No consensus / specific recommendations on serial imaging protocol –Recommend CT scan at 6, 12, 24months –To closely monitor tumour behaviour through imaging Suspicious of malignancy on imaging Size >4cm (risk of malignancy starts to increase significantly when size >4cm) Size ≥1cm / year on imaging NIH Consens State Sci Statements 2002 Grumbach et al. Ann Intern Med 2003 Young. N Engl J Med 2007 Zeiger et al. Endocr Prac 2009 Terzolo et al. Eur J Endocrinol 2011

31. Follow-up and indication for surgery Hormonal hypersecretion –Recommend hormonal evaluation annually for 4years –Hormonal profile normal at diagnosis can become autonomous during subsequent 4years –Risks of hyperfunction plateau after 4years NIH Consens State Sci Statements 2002 Grumbach et al. Ann Intern Med 2003 Young. N Engl J Med 2007 Zeiger et al. Endocr Prac 2009 Terzolo et al. Eur J Endocrinol 2011

32. Adrenalectomy Laparoscopic adrenalectomy –Gold standard since 1992 –Advantages vs open surgery Less blood loss Lower morbidity Shorter hospital stay Faster functional recovery Gagner et al. N Engl J Med 1992 Lai G et al. Surg Oncol 2003 Grumbach et al. Ann Intern Med 2003 Terzolo et al. Eur J Endocrinol 2011

33. Adrenalectomy Karanikola et al. Tohoku J Exp Med 2010 Nigri et al. Surgery 2013 Lee et al. Ann Surg Oncol 2013 No consistent superiority between different laparoscopic approaches (anterior or lateral transperitoneal; posterior retroperitoneal) –Bulky / malignant – transperitoneal Metastasis / vascular pedicle especially for large tumour –Unilateral benign tumour – mostly posterior retroperitoneal Direct access to adrenal without handling of intraperitoneal organs Avoidance of previous intraabdominal adhesions –Bilateral – transperitoneal Can assess both lesions at the same time without the need to reposition the patient

34. Adrenalectomy Contraindications for minimal invasive surgery –Local tumour invasion of surrounding tissue or metastatic disease –Size >12cm Ramacciato et al. Surg Endosc 2008 Zografos et al. JSLS 2009 Karanikola et al. Tohoku J Exp med 2010 Carter et al. Endocr Pract 2012

35. Young. N Engl J Med 2007

36. End