Adrenal Incidentaloma
DEFINITION

Adrenal lesion 1cm or more discovered on a radiological exam performed for an indication other than adrenal disease.
- ie excludes patients undergoing cancer staging.

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EPIDEMIOLOGY

Large increase at present due to increasing CT usage.
- between 1-5% of CTs may have an incidental adrenal abnormality

Increases with age.
- <1% in pts <30, and >7% in pts >70
--> Greater concern for malignant potential with larger lesions in younger patients


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AETIOLOGY

Vast majority are benign non-functional adenomas.
- except referral bias to surgeons means we see the more significant ones.

Adenoma
- non-functioning adenoma ~80%
Functioning adenoma
- cortisol producing adenoma / (subclinical) Cushings ~5%
- aldosteronoma / Conn's syndrome ~1%
Phaeochromocytoma ~5%
Adenocortical carcinoma ~5%
Metastatic disease ~2.5%

Less frequent causes include: adrenal cyst, haemorrhage, lymphoma, sarcoma, neuroganglioma.
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BIOLOGICAL BEHAVIOUR

Important are:
1. Is the lesion biochemically active?
2. Is the lesion benign or malignant?
Paramount to work with radiologists and endocrinologists to achieve good workup.

Adrenal Physiology
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Adrenal Hormone Overproduction
Phaeochromocytoma
Aldosteronoma
- remember not all pts are hypokalaemic, so screen all hypertensives
Cortisol-producing adenoma
Androgen excess


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MANIFESTATIONS

Biochemical Manifestations
As per cause, including:
- hypertension that is difficult to control despite multiple meds
- cortisol excess e.g. unexplained weight gain, hyperglycaemia, hypertension, osteopenia, fatigue (moon facies, buffalo hump, striae more typical in full Cushing's disease)


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INVESTIGATIONS

Evaluation of Hormonal Function
Keep it as simple as possible and focus on highest yield investigations

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Principles

1. For Phaeo, most sensitive markers are serum metanephrines and normetanephrines
- ie breakdown products of adrenaline and noradrenaline; measuring these directly is pointless due to wild fluctuations
- if 2x normal or higher, pt has a phaeo
- if normal, virtually no possibility of a false negative test.
- if in-between (common)... exclude drug effect e.g. beta blockers and ACE inhibitors and discontinue and retest
- if still in doubt, proceed to 24h urine collections of catecholamines, metanephrines and vanillylmandelic acid (an end-stage metabolite.

2. For cortisol-secreting adenoma, need dexamethasone suppression test; this is >95% sensitive.
- note pt (by def'n of being an incidentaloma) won't have full blown Cushing's.
- 1mg of dexamethasone before bedtime
- then morning fasting blood sampling: morning cortisol should suppress to <5 ug/dL.
- if not, do confirmatory testing for elevated 24-hr urinary free cortisol.
- if confirmed, then do serum ACTH (adrenocorticotropic hormone) to confirm excess cortisol is from adrenal and not pituitary or ectopic source.

3. For aldosterone; only significant testing yield if hypertensive or hypokalemic.
- typically these lesions are small (1-2cm) and benign in appearance.
- measure both serum aldosterone and plasma renin activity, and then calculate aldosterone to renin ratio
- if >20 then reflects autonomous aldosterone secretion and positive for primary hyperaldosteronism.
- then do confirmatory 24h urine collect for aldosterone.

Complicating matters is that 1/3 of hyperaldosteronism is caused by bilateral hyperplasia.
- so contralateral slight enlargement may be significant.
- then adrenal venous vein sampling may be required, but this is complex as requires simultaneous IV ACTH while collecting aliquots from both veins for aldosterone and cortisol.

What if pt has bilateral incidentaloma?
That is rare.
If tests show fx, e.g. for phaeo, must gather as much info about each lesion prior to surgery
- e.g. further imaging with MRI if reqd; try show that one is likely a benign cortical adrenal adenoma and go for the other.
If suggest bilateral macronodular adrenal hyperplasia, and subclinical Cushing's, unilateral adrenalectomy may suffice.

Imaging Studies
General picture gained by size, contour, complexity, presence of calcification and necrosis, and Hounsfield unit density.

1. Lesion Size
- <4cm: <2% will be ACC; vs 20% of lesions >6cm.
Review previous imaging for size changes
- if no change over 2y, risk of malignancy is extremely low... if was not present within 5y window, then risk extremely high

2. Features
Heterogeneous, irregular lesions with necrosis are suspicious
- particularly so if invasive.
Benign lesions typically small, homogenous, and well defined.

3. Hounsfield Units
Vary by lipid concentration.
Lipid rich: typically <18
- If unenhanced HU <10, then 98% likely to be benign
- And if not biochemically active, can follow in
Phaeo and malignancies have few lipids and measure higher.
- but lipid-poor adenomas account for ~20% or more, so be aware that high HU not necessarily all bad

4. Adrenal Protocol CT
Useful when dealing with a small, relatively benign-appearing incidentaloma with higher HU density
Three phases with thin 3mm cuts
- with and without IV contrast; immediate vs 15m delayed imaging to take advantage of differences in uptake and washout.
If washout ratio 40% or more then more likely benign
- if washout <40%, suspicious for malignancy
This is highly accurate regardless of HU density and sensitivity / specificity each >90% with experienced radiologists.

5. Role of MRI?
Well accepted and useful diagnostic tool.
Images without radiation, useful in contrast allergy, excellent resolution for tissue characterization and superior to CT for local invasion.
- less spatial resolution
Both T1 and T2 weighted images used.
Primary and metastatic malignancies are denser than benign so brighter (higher fluid content).
- also true of phaeo, but 30% will have low intensity.
- adenomas usually have low intensity on T2 imaging.
Fat suppression used so that T2 images are not degraded; important also for fatty content of lesions (myelolipoma).
Contrast helps determine patterns
- washout curves are similar to those observed on CT; delayed washout for malignancies.
More advanced techniques are known such as chemical shift imaging.

6. Pathognomonic Features
MIBG imaging for phaeo
- a neuroendocrine scan (iodine-123-meta-iodobenzylguanidine); nuclear imaging; high uptake in phaeo unless poorly differentiated.
Myelolipoma shows macroscopic fat
Cysts can be clearly diagnosed if no solid component
Haemorrhage into a lesion may be observed (most should be excised.

Adrenal Biopsy?
Rarely helpful or indicated.
Should not be performed; produces haemorrhage, obliterates planes and makes surgical dissection difficult.
No role in workup, unless suspecting metastatic disease in pts with lymphoma, melanoma, or extra-adrenal cancer.

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MANAGEMENT

Indications for Excision : Non-functional Incidentaloma

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Principles
All functioning lesions should be removed.
In general, lesions >4cm should be removed.
But safe features as above may allow nonoperative approach in older or high-risk patients.

Adrenalectomy
Lap now standard approach.
- less blood loss, fewer wound complications, reduced postoperative pain and complications shorter stay
- complexity increases with size, but excision of lesions <10cm is pretty routine.

Technical aspects
Performed transabdominally in lateral decubitus position or retroperitoneally with pt prone.
- latter useful if past surgery but access more limited especially when tumours are large.
- trans-abdo more widely used, now low complications rates.
Patient on beanbag, axillary role, bed flexed to open operating space.
- 12 mm scope port two fingers below costal margin, midclavicular line
- 2x 5mm ports 6cm apart lateral to camera port, further 5mm port medial on right for liver retraction.
On left side:
- mobilize splenic attachments to fundus
- spleen falls medially, pulling tail of pancreas and allowing better adrenal exposure.
- avoid similar-looking pancreatic tissue
- avoid entering plane lateral to kidney; mobilizing it will obscure the adrenal.
On right side:
- be cognizant of IVC
It is not essential to find and ligate the adrenal vein first, even in phaeo
- safer to do a top-down approach, peeling out of retroperitoneum until attached by vein.
- be aware of tail of adrenal cortical tissue travelling down the vein in proximity to its jx with renal vein on left and IVC on right.  Do not leave tissue.

Lap for malignant lesions?
More controversial but now commonly done.
Open remains gold standard for ACC for oncologically clear margins; don't violate capsule or spill tumour.
- also facilitates control of the IVC, aorta, renal vessels; max exposure for en-bloc resections.

Patient Preparation

Depends on if tumour is functional.

Phaeo?
1. Alpha-blockade with phenoxybenzamine 10mg daily, titrated to 10mg tds over 3weeks.
- then lap adrenalectomy
- side effects are orthostatic hypotension, fatigue and sinus congestion.
- beta-blockade not recommended unless tachycardic.
2. Adequately hydrate to make up for volume depletion
3. Experienced anaesthetist essential; even the best prepared patients can experience extreme intraoperative hemodynamic instability

Cortisol Excess?
Adrenally insufficient so require periop stress steroid doses.
- addisonian state for up to a year, so endocrine boss required.

Aldosterone?
No specific recommendations.
Usually hypokalaemia resolves spontaneously; many still require some anti-hypertensive meds.

Follow Up
Estimated 5yr risk of adrenal incidentaloma enlargement or hyperfunction estimated at 20%
So annual screening for phaeo and cortisol for 3 years.
If <4cm, and safe features, annual CT for 2-3 years until no change.
If suspect at all, then 3, 6, and 12 month CTs.
Growth expected to be >2cm per year. 
Lesions >1cm should be removed.


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REFERENCES
Cameron 10th