This document discusses adrenal incidentalomas, which are adrenal masses greater than 1cm discovered incidentally on imaging. It covers the epidemiology, risks of progression, imaging techniques, and assessment of hormonal functionality. For hormonally inactive incidentalomas, the risks of malignancy and developing hormonal hypersecretion are low. Dedicated adrenal imaging can help characterize lesions and determine need for follow up. Biochemical testing assesses for hormonal hypersecretion from conditions like pheochromocytoma, Cushing's syndrome, and primary hyperaldosteronism. Subclinical Cushing's syndrome is defined and testing approaches are outlined. Surgical resection may be considered for larger lesions or biochemically active

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
%
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. 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 1015%)
• 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 (<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. 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
<50nmol/l
>140nmol/l
sens>95% spec 70-80%
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
– 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. 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
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•
•
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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

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
•
•
•
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>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