Kyle A. Richards, MD
BASICS
DESCRIPTION
• An adrenal mass is generally considered to be an adrenal lesion >1 cm
• Often found after abdominal imaging and often termed “adrenal incidentaloma”
• Rarely presents with acute or chronic symptoms
EPIDEMIOLOGY
Incidence
• Incidental adrenal mass (1,2)[A]
– Peak incidence at age 50–70
– 50–60% right side, 30–40% left side, 10–15% bilateral
• Female:Male 1.2–1.5:1
• Nonsecretory adenoma 75%
• Cortisol-producing 8%
• Pheochromocytoma 5%
• Adrenocortical carcinoma 5% (3)[A]
– Bimodal age distribution: Age <5 and 40–50
– 1–2 per million persons per year
– 2–6% bilateral
– Slightly higher incidence on left side
• Metastases 2%
• Aldosteronoma 1%
Prevalence
• 4% in patients undergoing CT scan
• 6% in autopsy series
• Increases with age (2)[A]
– 0.2% age 20–29; 7% age ≥70
RISK FACTORS
• Sex (1)[A]
– Malignant adrenal mass: Male > female (2:1)
– Benign adrenal mass: Female > male (1.7:1)
• Aging
• Prior history of cancer especially melanoma, lung, breast, or kidney
– 50% of these adrenal masses are metastases
Genetics
• Rare genetic syndromes may predispose to adrenal masses (1,4)[B]
– Beckwith–Wiedemann
Overexpression of insulin-like growth factor II gene
Adrenocortical carcinoma
– Li–Fraumeni
Mutations in p53 tumor suppressor gene
10–20% have adrenocortical carcinoma
– Multiple endocrine neoplasia 1
40% have adrenal masses
Adenoma and adrenocortical carcinoma
– Multiple endocrine neoplasia 2
RET-2 proto-oncogene abnormalities associated with pheochromocytoma
40–50% have adrenal masses
– Carney complex
30% have adrenal hypercortisolism
– McCune–Albright syndromes
Associated with adrenal hypercortisolism
– Von Hippel–Lindau disease
10–20% have pheochromocytoma
– Neurofibromatosis type 1
Up to 5% have pheochromocytoma
PATHOPHYSIOLOGY
• Adrenal glands consist of an outer cortex and inner medulla and are part of endocrine system
• Aberrant secretion of hormones = symptoms
• Adrenal cortex
– Zona glomerulosa
Produces mineralocorticoid aldosterone
Regulates sodium and fluid homeostasis
Promotes exchange of potassium for sodium in distal tubule of nephron
Excess aldosterone = Conn’s syndrome
– Zona fasciculata
Produces glucocorticoid cortisol
Regulates cellular and glucose metabolism, immune processes, and other regulatory functions
Excess cortisol = Cushing’s syndrome
– Zona reticularis
Produces adrenal androgens
Excess androgens = virilization
• Adrenal medulla
– Produces catecholamines
– Excess catecholamines = pheochromocytoma
• Addison’s disease = adrenal insufficiency
– Usually not caused by adrenal masses
ASSOCIATED CONDITIONS
• See “Genetics”
• Hypertension (paroxysmal or sustained)
• Osteoporosis/osteopenia (cortisol excess)
• Diabetes mellitus (cortisol excess)
• Hypokalemia (aldosterone excess)
• Hyperlipidemia (cortisol excess)
• Pheochromocytomas
– Multiple endocrine neoplasia IIa or IIb
– Neurofibromatosis type 1
– Von Hippel–Lindau syndrome
– Tuberous sclerosis
– Sturge–Weber syndrome
– Carney triad
• Adrenocortical carcinoma
– Multiple endocrine neoplasia 1
– Li–Fraumeni syndrome
– Carney complex
– Beckwith–Wiedemann
GENERAL PREVENTION
None
DIAGNOSIS
HISTORY
• Focus on symptoms suggestive of adrenal hyperfunction or malignant disease
– Cushing’s syndrome
Weight gain
Easy bruising
Poor wound healing
Proximal muscle weakness
Emotional and cognitive changes
Opportunistic and fungal infections
Altered reproductive function
– Pheochromocytoma
Episodic symptoms
Forceful heartbeat, pallor, tremor, headache, and diaphoresis
Spontaneous or precipitated by postural change, anxiety, meds, and Valsalva
– Primary hyperaldosteronism
Nocturia/polyuria (due to hypokalemia)
Muscle cramps and palpitations
– Adrenocortical carcinoma
Abdominal/back pain
Cushing’s syndrome (see above)
Altered reproductive or sexual function
Hyperaldosteronism (see above)
– Sex steroid-secreting tumor
Altered reproductive or sexual function
– Metastatic cancer
History of extra-adrenal cancer
• Medical history
– Malignancy or syndromes
• Medications such as exogenous steroids
• Family history: See “Genetics”
PHYSICAL EXAM
• Blood pressure and heart rate
• Focus on signs suggestive of adrenal hyperfunction or malignant disease
– Cushing’s syndrome
Hypertension
Central adiposity
Facial rounding and plethora
Supraclavicular and upper back fat pads
Thin skin, purple striae, and acne
Hirsutism
– Pheochromocytoma
Hypertension, orthostasis, tachycardia
Fever, pallor, tremor
Retinopathy
– Primary hyperaldosteronism
Edema, paresthesias, weakness, tremors
– Adrenocortical carcinoma
Abdominal mass
Cushing’s syndrome signs (see above)
Gynecomastia
– Sex steroid-secreting tumor
Gynecomastia or testicular atrophy
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Assess all for biochemical function (2)[A]
• Cushing’s syndrome
– Hyperkalemic, hyperglycemic
– 24-hr urinary free cortisol (5)[A]
<80 μg/24 h excludes diagnosis
– Cortisol suppression testing
1 mg dexamethasone at 11 PM and measure serum cortisol at 8 AM next day
Serum cortisol > 5 μg/dL is diagnostic
97% specificity
• Pheochromocytoma
– Plasma metanephrines
96–100% sensitivity, 85–89% specificity
– 24-hr urine fractionated metanephrines
91–98% sensitivity and specificity
• Primary hyperaldosteronism
– Hypokalemia, mild hypernatremia, alkalosis
– 40% normokalemic
– Aldosterone-to-renin ratio (morning)
Patients must stop spironolactone, eplerenone, or amiloride
Cutoff for + result is lab dependent
– Confirmatory testing
Saline infusion test
24-hr urinary aldosterone excretion test while patient maintains high sodium diet
• Adrenocortical carcinoma (3)[A]
– Most commonly cortisol secreting
– Serum dehydroepiandrosterone (DHEA)
• Sex steroid-secreting tumor
– Serum testosterone and 17β-estradiol in women with virilization or men with feminization
Imaging
• CT scan (2)[A]
– Benign adrenal adenoma
Usually <3 cm and homogeneous
Density <10 HU with >50% washout of contrast at 10 min
– Adrenocortical carcinoma or adrenal mets
Usually >4 cm, heterogeneous, calcifications, necrosis
Density >25 HU and <50% washout of contrast at 10 min
• MRI
– Benign adrenal adenoma
Rapid contrast washout and high lipid content; isointense with liver on T2
– Adrenocortical carcinoma or adrenal mets
Hyperintense with liver on T2 imaging
– Pheochromocytoma
“Light bulb” sign: see very high signal intensity on T2-weighted imaging
• Metaiodobenzylguanidine (MIBG) scan
– Useful for extra-adrenal pheochromocytoma
Diagnostic Procedures/Surgery
• Primary hyperaldosteronism
– Adrenal vein sampling for lateralization of aldosterone production, if unclear by imaging
• Biopsy
– Rule out pheochromocytoma prior to biopsy
– Helpful if concern for metastases or infection
Pathologic Findings
See “Differential Diagnosis”
DIFFERENTIAL DIAGNOSIS
• Adrenal cortical tumors (4)[A]
– Adenoma
– Carcinoma
– Nodular hyperplasia
• Adrenal medullary tumors
– Pheochromocytoma
– Ganglioneuroma/neuroblastoma
• Other adrenal tumors
– Myelolipoma, lipoma, hemangioma
– Metastases
– Hamartoma, teratoma
• Infectious or inflammatory
– Abscess or fungal infection
– Amyloidosis, sarcoidosis
– Cytomegalovirus
– Cysts (pseudocysts, parasitic, epithelial- and endothelial-lined cysts)
• Congenital adrenal hyperplasia
• Hemorrhage
• Pseudoadrenal masses
– Splenic, pancreatic, renal lesions
– Vascular lesions or technical artifacts
TREATMENT
GENERAL MEASURES
• Observation, resection, or medical therapy
• Depends on size of lesion, functionality, malignant potential, and overall health of patient
MEDICATION
First Line
• Cushing’s syndrome (5)[C]
– Aminoglutethimide, metyrapone, ketoconazole
• Pheochromocytoma
– Phenoxybenzamine, propranolol
• Primary hyperaldosteronism: Spironolactone
• Adrenocortical carcinoma: Mitotane
Second Line
• Adrenocortical carcinoma
– Cisplatin, etoposide, 5-flurouracil, doxorubicin, vincristine
SURGERY/OTHER PROCEDURES
• Should remove all functional adrenal masses
• Open surgery if large or locally advanced; evaluate for vein thrombus or adjacent organ invasion
• Minimally invasive surgery is now accepted
• Remove masses >5 cm; high malignancy risk
• Consider partial adrenalectomy for solitary adrenals, bilateral disease, familial syndromes
ADDITIONAL TREATMENT
Radiation Therapy
Only for palliation of bone metastases from adrenal cortical carcinoma
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Adrenalectomy cures hypertension in 33–72% of patients with primary hyperaldosteronism (5)[B]
• 10–15% recurrence rate after resection of pheochromocytoma
• Adrenocortical carcinoma has poor prognosis
– Mean survival 18 mo (4)[B]
– 5-yr survival 15–47%
COMPLICATIONS
• Adrenal insufficiency post adrenalectomy
• Unrecognized malignancy/pheochromocytoma
FOLLOW-UP
Patient Monitoring
• Conservative management principles (2)[B]
– Repeat imaging at 6, 12, and 24 mo
– Repeat hormonal testing annually for 4 yr
– If growth ≥1 cm or autonomous hormonal secretion, consider surgery
Patient Resources
• www.pheochromocytoma.org
• www.cancer.gov/cancertopics/types/adrenocortical
REFERENCES
1. Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol. 2003;149:273–285.
2. Young WF. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601–610.
3. Ng L, Libertino JM. Adrenocortical carcinoma: Diagnosis, evaluation, and treatment. J Urol. 2003;169:5–11.
4. Aron D, Terzolo M, Cawood TJ. Adrenal incidentalomas. Best Pract Res Clin Endocrinol Metab. 2012;26:69–82.
5. Mandeville J, Moinzadeh A. Adrenal incidentaloma. AUA Update Series. 2010;29:34–39.
ADDITIONAL READING
Taffel M, Haji-Momenian S, Nikolaidis P, et al. Adrenal imaging: A comprehensive review. Radiol Clin N Am. 2012;50:219–243.
See Also (Topic, Algorithm, Media)
• Addison Disease
• Adrenal Adenoma and Cortical Carcinoma
• Adrenal Angiomyelolipoma
• Adrenal Calcifications
• Adrenal Cysts and Pseudocysts
• Adrenal Hemorrhage
• Adrenal Incidentaloma
• Adrenal Mass Algorithm 
• Adrenal Mass Image 
• Adrenal Metastasis
• Adrenal Myelolipoma
• Adrenal Oncocytoma
• Cushing’s Disease and Syndrome
• Pheochromocytoma
CODES
ICD9
• 194.0 Malignant neoplasm of adrenal gland
• 227.0 Benign neoplasm of adrenal gland
• 255.9 Unspecified disorder of adrenal glands
ICD10
• C74.90 Malignant neoplasm of unsp part of unspecified adrenal gland
• D35.00 Benign neoplasm of unspecified adrenal gland
• E27.9 Disorder of adrenal gland, unspecified
CLINICAL/SURGICAL PEARLS
• Assess all for biochemical function.
• Remove all adrenal masses >5 cm.
• Do not biopsy pheochromocytoma.