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Adrenal Incidentalomas

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Adrenal Incidentalomas

  1. 1. Adrenal incidentalomas Antonia Brooke
  2. 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. 3. Definition • Adrenal mass >1cm discovered incidentally when investigating for something else • No clinical syndrome associated or presence of metastatic disease
  4. 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. 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. 6. Follow up - 16 studies over 2-7yrs % Mean (%) 95% CI that↑ size 14.7 8-21 unchanged 68 46-90 that ↓ size 7 -2.4-16.4 Became malignant 0.2 0-0.4 Became functional 0.9 0.5-2.2 Develop Cushings 0.3 Dvp subclinical Cushings 0.3 Dvp phaeo 0.2 Dvp Conns 0 Cawood et al EJE 2009
  7. 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. 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. 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. 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. 11. Function
  12. 12. Biochemistry – initial screen • 2x 24hr metanephrines or single plasma metanephrine • Overnight dexamethasone suppression • Renin-aldosterone (if hypertensive or hypokalaemic)
  13. 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. 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. 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. 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 1015%) • If large preop tumour consider baseline scan 6M postop
  17. 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. 18. RAA cont • Positive = Aldosterone to renin ratio >20 – treat with spironolactone or epleronone • Venous sampling – If young (<40yrs), lesion >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. 19. Cortisol
  20. 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. 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 <50nmol/l >140nmol/l sens>95% spec 70-80% sens 70% spec >95%
  22. 22. Evidence for harm from cortisol low grade secretion ‘incidentalomas’ • Metabolic complications: – hypertension – obesity – diabetes mellitus – osteoporosis
  23. 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. 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. 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. 26. Practical solution • Overnight dex >138nmol/l – 2nd 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. 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. 28. Evidence that adrenalectomy works • Treating metabolic complications and treating with late night metyrapone – evidence free • Treating surgically – limited evidence
  29. 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. 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. 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. 32. Adrenal imaging
  33. 33. Adrenocortical cancers • • • • Incidence 0.5 to 2 per million Bimodal: childhood and 4th to 5th 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
  34. 34. • 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%
  35. 35. 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)
  36. 36. 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)
  37. 37. • 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
  38. 38. 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
  39. 39. Radiotherapy • Consider to tumour bed if incomplete resection
  40. 40. 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
  41. 41. 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
  42. 42. • Gastrointestinal – Nausea and vomiting – Diarrhoea • Neurological – Tremor
  43. 43. 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

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