Aaron G. Boonjindasup, MD, MPH
Raju Thomas, MD, MHA, FACS
BASICS
DESCRIPTION
• Adrenal adenoma is a benign cortical neoplasm that may or may not have endocrine activity (functioning)
• Up to 80% are nonfunctioning and benign; the other 20% need further evaluation
– Generally <4 cm and discovered incidentally
EPIDEMIOLOGY
Incidence
∼1% if <30 yr old and 7% if >70 yr old
Prevalence
• Found in 1.8–8.7% of autopsies
• Incidental adrenal masses found on 0.5–5% of abdominal CTs (82% nonfunctional, 5% Cushing, 5% pheochromocytoma, 1% Conn)
– Usually between 20 and 60 yr old
RISK FACTORS
Slightly more common in females
Genetics
More common in multiple endocrine neoplasia (MEN) type I, Beckwith–Wiedemann syndrome, and the Carney complex
PATHOPHYSIOLOGY
• Primary hyperaldosteronism (Conn syndrome)
– Excess production of aldosterone (Zona Glomerulosa): Hypokalemia, Alkalosis, HTN
• Cushing syndrome
– Excess production of cortisol (Zona Fasciculata): Suppresses ACTH from pituitary
ASSOCIATED CONDITIONS
• Hypertension
• Glucose intolerance
• MEN1 syndrome
• Subclinical Cushing syndrome (SCS) (obesity, hypertension, type 2 diabetes, hypercholesterolemia)
DIAGNOSIS
HISTORY
• Determine history of hypertension, obesity, and glucose intolerance
– Suggestive of Cushing syndrome or adrenocortical carcinoma
• Hypertension and history of hypokalemia
– Aldosterone-producing adenoma
• History of malignancy
• Patient medications (“polypharmacy” for hypertension)
• Family history
PHYSICAL EXAM
• Blood pressure and heart rate
• Look for stigmata of Cushing syndrome
– Hirsutism, oligomenorrhea, easy bruising, excessive acne, muscle weakness, truncal obesity, buffalo hump, purple striae
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Extent of endocrine evaluation in patients with adrenal adenoma is controversial. Basic screening evaluation consists of:
– Basic metabolic panel (BMP)
If elevated K+ and patient also hypertensive may be aldosterone-secreting lesion
– Plasma metanephrines: Most sensitive test for pheochromocytoma
– 24-hr urine cortisol
– Low-dose dexamethasone suppression test to R/O SCS if suspected clinically
• Complete endocrine evaluation should be performed if findings on examination and history suggest excess of specific hormone or if positive findings found on screening examination
• Primary hyperaldosteronism (Conn syndrome)
– Basic metabolic profile
Hypokalemia, alkalosis, HTN
– Aldosterone: Renin ratio
Values that define a positive screen subject to lab variability but >30 suggested by NIH as cutoff for positive aldosterone to renin ratio and indicates need for confirmatory testing
– Confirmatory testing for hyperaldosteronism
3-day oral sodium-loading test—high sodium diet for 3 days followed by 24-hr urine measurements of aldosterone, sodium, and creatinine
+ test = 24-hr aldosterone > 12 mg/d
Captopril suppression test may be used for patients with cardiac and renal disease which prohibit sodium loading
• Cushing syndrome
– 24-hr urine cortisol >100 mg
– If equivocal, perform low-dose dexamethasone suppression test
1 mg dexamethasone at 11 PM
Plasma cortisol between 8 AM and 9 AM
Normal: Cortisol <5 ng/mL
Cushing syndrome: Inability to suppress cortisol production
– Rule out ACTH-dependent cause (ectopic or pituitary hypersecretion of ACTH)
– Measure late-afternoon ACTH
– >15 pg/mL – ACTH dependent
– <15 pg/mL – ACTH independent (adrenal)
– Adrenal venous sampling may be indicated if bilateral adrenal lesions present to establish lateralization of aldosterone secretion in surgical candidates
ALERT
Subclinical Cushing syndrome (SCS can occur where abnormalities of the hypothalamic–pituitary–adrenal axis exists in the absence of overt signs and symptoms of Cushing syndrome.
• May occur in 5–24% of patients with incidentally discovered adrenal tumors.
• May not be clinically evident following standard screening for cortisol hypersecretion.
• 1 mg overnight dexamethasone suppression test most sensitive for SCS.
• Should be performed in ALL patients with adrenal mass and metabolic syndrome.
• SCS is an indication for adrenalectomy.
• Patients are at risk for postoperative adrenal insufficiency (AI).
• Pheochromocytoma:
– If screening: Stop tricyclic antidepressants, phenoxybenzamine before testing
– Screening tests
– Plasma-free metanephrines
Stop acetaminophen 5 days prior
Draw sample in supine position
– 24-hr fractionated urinary metanephrines
Verify normal renal function before testing
• See pheochromocytoma section for details.
Imaging
• Adrenal adenoma: Small, well defined, homogeneous
• Size criteria important
– ≤5 cm usually benign
– ≥6 cm – 25% malignant
• May see atrophy of contralateral adrenal
• CT (triphasic adrenal scan)
– CT Adenoma characteristics: Sharp margin, smooth and homogeneous, lipid rich, <10 HU density on noncontrasted images, density reduces by 60% on initial contrast density at scan delayed 15 min
– <10 HU on noncontrast CT
71% sensitive, 98% specific for adenoma
– >60% washout at 15 min
100% sensitive/100%specific for adenoma
– Adrenal myelolipoma – low HU, but never below 20 HU
• MRI
– Both carcinoma and pheochromocytomas are hyperintense on T2 images (ie, they “light up” as they go from T1 to T2)
– Signal from cortical adenomas drops out in opposed phase
Loss of signal between in- and out-of-phase images (microscopic fat-sensitive sequence) suggest adenoma
MRI T2 intensity <0.8 compared to liver
80% sensitive/80% specific for adenoma
Diagnostic Procedures/Surgery
• Adrenal biopsy or fine needle aspiration may be performed in select cases
– Reserved for differentiation of metastatic disease and benign lesion
– May not be able to differentiate between benign from malignant adrenocortical tumor
• Rule out pheochromocytoma with plasma metanephrine screening before performing biopsy on an adrenal mass
Pathologic Findings
• Aldosterone-producing adenoma
– Spironolactone bodies – eosinophilic laminated cytoplasmic inclusions
Found after treatment with spironolactone
– Cortisol-producing adenoma
– Vacuolated neoplastic cells
– Intracytoplasmic lipid
• Bilateral adrenal adenomas
– Fungal, TB, histoplasmosis
DIFFERENTIAL DIAGNOSIS
• Adrenal cortical carcinoma (up to 80% functional)
• Adrenal hemorrhage
– Bilateral lesions
• Adrenal hyperplasia (pituitary hypersecretion of ACTH)
• Adrenal myelolipoma
• Lymphoma
• Metastatic lesion
– Melanoma, lung, breast, kidney
• Neuroblastoma
• Nonfunctioning adenoma
• Pheochromocytoma
• TB, or other infectious cause
TREATMENT
GENERAL MEASURES
• Based on functional status and size of lesion
• Correct hypertension and electrolyte abnormalities.
MEDICATION
First Line
• For hormonally active adenomas in patients who refuse surgery or have contraindications to surgery
• Conn syndrome
– Spironolactone, eplerenone
Aldosterone receptor antagonists in the distal convoluted tubule (DCT).
– 2nd line – Amiloride, triamterene
Inhibitors of DCT aldosterone sensitive sodium channels
• Cushing syndrome
– Aminoglutethimide
Blocks the 1st step in cortisol synthesis (cholesterol to pregnenolone)
– Metapyrone
Blocks the final step in cortisol synthesis (11-deoxycortisol to cortisol)
– Ketoconazole
Inhibits 1st step and to a lesser extent the last step in cortisol synthesis
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Surgical indications
– Hormonally active masses
– Any masses ≥5 cm (25% of masses >6 cm are assumed to be adrenal cortical carcinomas)
– Masses with suspicious imaging characteristics of carcinoma
Homogeneous, irregular borders, HU >20
• Laparoscopic and robotic approaches described, but may have limitations with larger lesions
• Retroperitoneal approach possible for both open and laparoscopic surgery; may reduce ileus
• Perioperative stress dose steroids indicated during unilateral adrenalectomy for cortisol-producing adenomas and may be indicated for patients with SCS
• Preoperatively: 50 mg hydrocortisone IV q8h postop day 1
• Steroid supplementation will be needed after adrenalectomy for cortisol-producing tumors until suppressed HPA recovers (median of 15 mo)
– Postoperatively (POD 2): Hydrocortisone 20 mg PO qAM, 10 mg qPM
– Hydrocortisone slowly tapered over 3 mo to 10 mg daily
– AM cortisol should be measured and repeated until >10 ng/dL
– Confirm recovery of HPA with cosyntropin test
• Monitor for electrolyte disturbances with BMP and postoperative AI in patients with hormonally active tumors and/or SCS
• Acute AI (addisonian state)
ALERT
This is a life-threating condition often preceded by hypotension unresponsive to fluid resuscitation.
• May occur in the postoperative state in the setting of cortisol-secreting lesion with downregulated contralateral adrenal function, and in patients with previous contralateral adrenal resection or due to concurrent illness or infection.
• Other nonspecific symptoms may include abdominal pain, salt craving, nausea, vomiting, fatigue, and fever.
• Electrolyte abnormalities such as hypernatremia or hyperkalemia and other laboratory anomalies such as anemia, lymphocytosis, or eosinophilia may also be found.
• Prolonged use of etomidate may increase risk of postoperative adrenal insufficiency.
• May begin steroid replacement if high clinical index of suspicion.
• Diagnosis Obtain AM serum cortisol and ACTH level:
– Normal >10 ng/dL, low–normal (3.4–10 ng/dL), AI <3.4 ng/dL
– Confirmatory testing with evaluation of response to ACTH stimulation (cosyntropin test)
Measure serum cortisol at baseline
Give cosyntropin 0.25 mg IV × 1
Measure serum cortisol 60 min after dose
Adequate response: Cortisol >18 μg/dL
• If acute AI is highly suspected, don’t wait for result before treating:
– Give 2–3 L D5 NS quickly and 4 mg dexamethasone IV
– Use dexamethasone because IV cortisol will interfere with the diagnosis later during hospitalization
• Maintenance therapy:
– Hydrocortisone 30 mg/d
– Fluorohydrocortisone 0.05–0.1 μg/d
ONGOING CARE
PROGNOSIS
• Untreated Cushing syndrome can be fatal due to cardiovascular, thromboembolic, or hypertensive complications or infection
• Surgical removal of hormonally active adenomas is usually curative
COMPLICATIONS
• Hypertension
• Diabetes mellitus
• Atherosclerosis
• Poor wound healing
• Nephrolithiasis
– 15% of patients with Cushing syndrome – due to hypercalciuria
• Adrenal insufficiency (Addison disease)
FOLLOW-UP
Patient Monitoring
• Nonfunctioning benign adrenal mass can be followed with physical and radiologic examinations
– 5–20% show enlargement >1 cm
– No guideline on growth velocity on surgical treatment
REFERENCES
1. Kapoor A, Morris T, Rebello R. Guidelines for the management of the incidentally discovered adrenal mass. Can Urol Assoc J. 2011;5(4):241–247.
2. Gill IS. The case for laparoscopic adrenalectomy. J Urol. 2001;166:429–436.
3. Bittner JG, Brunt LM. Evaluation and management of adrenal incidentaloma. J Surg Onc. 2012;106:557–564.
4. Mandevillle J, Moinzadeh A. Adrenal incidentalomas: AUA Update Series. 2010;29:33–39.
See Also (Topic, Algorithm, Media)
• Adrenal Adenoma Image 
• Adrenal Cortical Carcinoma
• Adrenal Cysts and Pseudocysts
• Adrenal Hemorrhage
• Adrenal Incidentaloma
• Adrenal Mass
• Adrenal Mass, Algorithm 
• Adrenal Mass Image
• Adrenal Metastasis
• Adrenal Myelolipoma
• Adrenal Myelolipoma (Adrenal Myolipoma)
CODES
ICD9
• 227.0 Benign neoplasm of adrenal gland
• 255.0 Cushing’s syndrome
• 255.12 Conn’s syndrome
ICD10
• D35.00 Benign neoplasm of unspecified adrenal gland
• E24.0 Pituitary-dependent Cushing’s disease
• E26.01 Conn’s syndrome
CLINICAL/SURGICAL PEARLS
• Adrenal lesions should be surgically treated if ≥5 cm or if functional/active.
• No guideline on normal growth velocity for adrenal lesions.
• Melanoma, lung, breast, colon, and renal cell cancers have metastatic predilection to adrenal gland.