1. Adrenal incidentalomas Antonia Brooke

2. To cover………. Epidemiology Chances of progression Imaging Assessment of functionality – Which tests – What is subclinical Cushings, what does it matter, how to treat Implications for our service

3. Definition Adrenal mass >1cm discovered incidentally when investigating for something else No clinical syndrome associated or presence of metastatic disease

4. Background and Incidence Prevalence around 4% (on CT) – Increasingly common with age – 1% at 40, 7% at 70 History of malignant disease then metastasis in 50% of cases (frequently bilateral) – 2.5% adenomas are mets Bilateral disease differential: – CAH – Hyperplasia – bilateral phaeos – infiltrative diseases (mets) – rare causes

5. Hormonal secretion Hormonally active in up to 12% – Phaeochromocytomas 5% – Cushing’s syndrome / Sub-clinical Cushing’s 5% or possibly more – Primary hyperaldosteronism / Conn’s syndrome 1% – Androgen secreting / virilising tumour <1%) Remaining incidentalomas were ganglioneuromas, myelolipomas, or benign cysts

6. Follow up - 16 studies over 2-7yrs Cawood et al EJE 2009 %Mean (%)95% CI that↑ size14.78-21 unchanged6846-90 that ↓ size7-2.4-16.4 Became malignant0.20-0.4 Became functional0.90.5-2.2 Develop Cushings0.3 Dvp subclinical Cushings0.3 Dvp phaeo0.2 Dvp Conns0

7. Imaging CT better at eliminating malignancy (dedicated CT looking at Hounsfield units (HU) and washout characteristics) – <10HU = benign (sens 71%, spec 100%) MRI may characterise phaeos better FDG-PET good for phaeos and cancer FNA – consider if cancer history and >10HU on CT after exclusion of phaeo

8. Imaging - size >4cm 90% sensitivity carcinomas 24% specificity (ie only 24% cancer) >6cm 25% chance of it being carcinoma <2cm + hypodense then unlikely to grow If change in size >1cm over 6 months consider resection Guidelines suggest: – NIH: 2 CTs 6M apart – Young et al + UptoDate: 0,6,12,24m – BES: Repeat image – increase in size of 0.8cm over 6-12M consider surgery

9. Risk of CT Abdo CT = 10mSv (adrenal less but about same if delayed washout) = 3.3yrs background radiation Lifetime absolute risk of cancer as consequence is 0.048% 1 cancer related death for every 5000 scans in those >30yrs

10. Practical suggestion Most have not had dedicated CT (ie bottom of CT chest or CT colon) If <4cm do dedicated adrenal CT 6 months after presentation – No need to rescan if no change in size (or <0.8cm) If >4cm do dedicated adrenal CT when referred to get characteristics and consider repeat or MRI in a further 6 months if looks benign <2cm and no change then discharge 2- 4cm monitor clinically for longer?

11. Function

12. Biochemistry – initial screen 2x 24hr metanephrines or single plasma metanephrine Overnight dexamethasone suppression Renin-aldosterone (if hypertensive or hypokalaemic)

13. Phaeo: Metanephrines Urine sensitivity and specificity of 91 – 98%) 4x normal = diagnostic Cost around £21 each False positives: – Drugs (eg amitriptyline, phenoxybenzamine) ?doxazosin ? Mirtazepine – Sleep apnoea Plasma If one or more are positive, measure plasma metanephrines (sensitivity around 80% - higher if inherited, good specificity) – Cost approx £51 – Disadv – need to be supine for 20mins – Certain foods leading to high readings: nuts, fruits, potatoes, tomatoes, beans

14. Other tests MIBG scan preoperatively if +ve Consider Clonidine suppression test (0.3mg orally) plasma MN at base + after 3 hrs if doubt about diagnosis

15. Drugs If suspicion high start alpha blocakade prior to biochemical confirmation: – Doxazosin 1mg titrated up (even if normotensive) – Phenoxybenzaime 10mg bd up to 20mg qds (more complete blockade) if extremely high metanephrines or initial BP >160/90. SE: postural hypotension, nasal stuffiness and erectile problems Calcium channel blockers if unable to tolerate alpha or beta blockade Blocked > 3 weeks prior to surgery

16. Diagnosis of Phaeo Consider genetic screening for VHL / RET/ succinate dehydrogenase (SDH) (+ve in 25%) especially in the young or extra adrenal disease. SDHB – strong association with malignancy 24% have germline mutation even if ‘sporadic’ Familial syndromes less likely to be malignant (unless SDH) Follow up > 5 years (long term risk of recurrence 10- 15%) If large preop tumour consider baseline scan 6M postop

17. Conns – RAA ratio Measure if hypertensive or hypokalaemic exclude aldosterone antagonists for 6 weeks (and ideally ACE and Ang II but effect prob minimal) b blockers suppress renin – However normal test on treatment is reassuring Ideally control BP on Ca channel blockers, Doxazosin and hydralazine Ensure diet is not salt restricted or load with slow na for 3 days (120mmol/day = 3 tabs QDS)

18. RAA cont Positive = Aldosterone to renin ratio >20 – treat with spironolactone or epleronone Venous sampling – If young ( 1cm with normal contralateral adrenal then reasonable to not venous sampling – Only do if patient would consider adrenalectomy (right adrenal vein cannulation is difficult) – Corrected aldosterone/cortisol ratios of > 4 to 1 = likely unilateral Untreated aldosterone excess can lead to – myocardial fibrosis – left ventricular hypertrophy – increased mortality from congestive heart failure – more ischemic events, and increased vascular and clotting abnormalities

19. Cortisol

20. What is subclinical Cushings ACTH independent cortisol secretion not fully restrained by pituitary feedback Found in up to 20% of adenomas To make diagnosis: – Have to have adrenal adenoma – Not cushingoid – Have ACTH independent autonomous secretion

21. Subclinical Cushings Syndrome For assymptomatic patients Overnight dexamethasone suppression test (1mg) – enzyme inducers (eg anti epileptics) or uncontrolled diabetes – Pt can eat and drink normally. – Tablet at 11pm then 9am cortisol 95% spec 70-80% >140nmol/l sens 70%spec >95%

22. Evidence for harm from cortisol low grade secretion ‘incidentalomas’ Metabolic complications: – hypertension – obesity – diabetes mellitus – osteoporosis

23. What’s the evidence Lots of retrospective cross sectional studies showing associated risks No prospective studies showing link to mortality Not likely to progress to clinical Cushings

24. Tests to detect ACTH independent autonomous secretion Most surgical studies look for 2 abnormal tests but: UFC usually normal Midnight salivary cortisol usually normal Altered response to overnight dex ACTH usually low (ACTH <5pg/ml ) Low DHEAS would support diagnosis (but often normal and declines with age)

25. But….. Virtually impossible to recognise false positives on dex testing What should be the cut off…. – NIH 138nmol/l – Endo Soc guidelines suggest 50nmol/l for OVERT Cushings – Why not grey area where consideration to clinical phenotype is considered (metabolic syndrome and osteoporosis)?

26. Practical solution Overnight dex >138nmol/l – 2 nd test of cortisol hypersecretion (eg UFC, ACTH) – Look for metabolic risk – consider adrenalectomy if both positive and young or treat metabolic risk factors (patient choice?!) 50 – 138nmol/l – look at metabolic risk factors (HbA1c, DEXA, lipid profile, BP) and consider treatment at lower threshold than Framlingham <50nmol/l – reassure and never repeat

27. How to treat? Treat cortisol excess – Nocturnal metyrapone – Surgical: adrenalectomy Treat metabolic complications – Vit D / bisphos – Metformin – Antihypertensives GP: No follow up studies beyond 7 yrs so maybe role for GP to monitor metabolic risk factors or be aware of it?

28. Evidence that adrenalectomy works Treating metabolic complications and treating with late night metyrapone – evidence free Treating surgically – limited evidence

29. Main surgical studies Erbil: case controlled 28 pts – 11SCS lead to ↓ BP post adrenalectomy↓ Tsuiki 20pts SCS (followed 15-69M) – 10 adrenalectomy: 8/10 improved – 10 conservative: 5/10 worsened Toniati: prospective 45pts SCS (mean FU 8Y) – 23 adrenalectomy: 2/3 N or improved BP and DM – 22 conservative: some worsening

30. More surgical studies Sereg: retrospective uncontrolled followed 9 yrs – 47/125 NON functioning had adrenalectomy – 78 treated conservatively – No benefit Chiodini 108pts followed 18-48M – SCS recommend surgery + some pts without had – Surgery – reduced BP

31. Issues to discuss Where are they all? Can we do a nurse protocol? What are the most appropriate tests? How long should they be followed for and how? What constitutes a positive test and how should they be treated?

32. Adrenal imaging

60. Adrenocortical cancers Incidence 0.5 to 2 per million Bimodal: childhood and 4 th to 5 th decade 1.5 F : 1 M 60% are secretory – High DHEAS suggestive (suppressed in adenomas) – Check estradiol in males (more likely malignant) – Allows tumour markers and predict post op course

61. Can be seen in syndromes: CAH, MEN, familial polyposis Sporadic mutations in tumor suppressor gene (TP53) seen in 1/3 adrenocortical ca Prognosis: <15% at 5 years if locally advanced disease: – Stage 1: 60% – Stage 2: 58% – Stage 3: 24% – Stage 4: 0%

62. Imaging >6cm high suspicion of malignancy 3-6cm repeat imaging in 3-6M Delayed washout on contrast is suggestive most are often inhomogeneous, irregular margins Look for invasion of IVC Always do CAP and consider bone scan and pet if in doubt Don’t ever biopsy (tumour spill)

63. Surgery Open adrenalectomy (ESMO clinical practice guidelines suggests >10 adrenalectomies a year, Dutch studies show improved survival if part of cancer network) Laparoscopic can be considered if <8cm and not obviously invasive Margin free resection only way to long term survival (hence take kidney, IVC, liver as necessary)

64. Consider resection of primary (even if metastatic) as improved survival and endocrinology Even seemingly complete resection initially: 50% chance of recurrence Surgery for recurrent disease good idea if prolonged disease free interval, particularly if chance of ‘complete’ resection

65. HIstology Histology: Challenging as no marker to suggest malignancy Weiss score (>3): mitotis, atypical mitoses, necrosis, venous invasion, capsular invasion, sinusal invasion, nuclear atypia, diffuse architecture and clear cell. Score >3 = suggests malignancy Ki67: measure of proliferative activitiy useful Disease stage and margins most useful predictor

66. Radiotherapy Consider to tumour bed if incomplete resection

67. Post op treatment - Mitotane Evidence: case control study: 47 pts on Mitotane (italy) compared to 130 italian / german pts not offered – improved survival Who? – Potential residual disease – Ki67>10% Therapeutic mitotane considerably better outcome than non therapeutic How long – minimum 2 years

68. Side effects Endocrine All patients should receive concomitant glucocorticoids (as adrenolytic) and higher dose (increased metabolic clearance). Mitotane increases CBG so measuring cortisol unreliable May need thyroxine and testosterone

69. Gastrointestinal – Nausea and vomiting – Diarrhoea Neurological – Tremor

70. Chemotherapy – FIRM-ACT NEJM 2012 FIRM-ACT trial (median survival 12-15M) Etoposide, Doxorubicin, Cisplatin (and Mitotane) – response rate 23% Streptozotocin (Mitotane) – RR 9% No chemotherapy No increase in survival but, but better response rates and progression free survival