Adrenal Incidentaloma - Approach to the Patient

Overview and Recommendations

Background

● Adrenal incidentalomas are adrenal masses > 1 cm in diameter incidentally discovered during
abdominal imaging for reasons other than suspected adrenal disease.

● Etiology of adrenal incidentalomas is variable, including benign and malignant lesions derived from the
adrenal cortex or medulla or of extra-adrenal origin.

● Tumors arising from the adrenal cortex may include:

⚬ adrenocortical adenoma
⚬ cortisol-producing adenoma
⚬ aldosterone-producing adenoma
⚬ adrenocortical carcinoma
⚬ adrenal lymphoma
⚬ adrenal metastases
⚬ bilateral adrenocortical tumors

● Tumors of the adrenal medulla may include pheochromocytoma and paraganglioma.

Evaluation

● Assess every patient with adrenal incidentalomas for signs and symptoms of adrenal hormone excess
(Strong recommendation).

● Obtain a history and physical to look for signs of a functional tumor, such as hypertension or recent
weight changes. Suggestive signs and symptoms may include:
⚬ hypercortisolism - central obesity, easy bruising, striae, severe hypertension, or virilization
⚬ aldosteronism - muscle cramps, weakness, or hypertension
⚬ pheochromocytoma - headaches, weight loss, sweating, or palpitations
⚬ metastatic cancer - weight loss or history of cancer or smoking

● In patients with adrenal lesions < 1 cm, further diagnostic workup is not indicated unless there are signs
or symptoms of adrenal hormone excess.

● In patients with adrenal incidentalomas with short axis > 1 cm, additional imaging studies are indicated
if initial characteristics do not mark it as clearly benign to determine if it is benign or malignant.

● Computed tomography (CT) is generally used as first line of investigation.

⚬ Perform a noncontrast (unenhanced) computed tomography (CT) to determine if the mass is

homogenous and lipid-rich and therefore benign (Strong recommendation).
⚬ If noncontrast CT is consistent with benign adrenal mass (Hounsfield units [HU] ≤ 10, homogenous,
and < 4 cm), consider not performing any additional imaging (Weak recommendation).
⚬ If unenhanced density cutoff > 10 HU and is not consistent with a benign adrenal mass, consider
performing a contrast-enhanced CT.

● Consider performing magnetic resonance imaging (MRI) with contrast shift imaging rather than a CT in
children, adolescents, adults < 40 years of age, and pregnant patients in order to avoid radiation
exposure in these populations (Weak recommendation).

● Biochemical evaluation includes performing 1 mg overnight dexamethasone suppression test to

exclude cortisol excess in all patients with an adrenal incidentaloma (Strong recommendation).
● Perform additional biochemical evaluation based on clinical presentation.

⚬ If pheochromocytoma is suspected, test plasma metanephrines and/or 24-hour urinary fractionated

metanephrines, especially before biopsy or resection of an adrenal tumor (Strong recommendation).
⚬ In patients with concomitant hypertension or unexplained hypokalemia, test for primary
aldosteronism by assessing aldosterone/renin ratio (Strong recommendation).
⚬ In patients with suspected adrenal cortical carcinoma (such as irregular shape or size > 4 cm),
consider measuring sex steroids and steroid precursors (Weak recommendation). If patient is
hypertensive, consider evaluating for aldosteronism.

● Evaluation of suspected metastases

⚬ Suspect metastatic lesion in a patient with a history of cancer and an adrenal mass that is not
consistent with incidentaloma (Weak recommendation).
⚬ To evaluate for metastases in patients with history of malignancy, perform further testing, such as

– CT
– FDG-PET and FDG PET/CT
– MRI with chemical shift
– biopsy

⚬ Fine needle aspiration (FNA) biopsy can be used to confirm diagnosis of metastatic disease (Weak
recommendation) but should not be performed if adrenocortical carcinoma is suspected and only
after pheochromocytoma has been ruled out.

Management

● All patients with adrenal incidentaloma may benefit from management by a multidisciplinary team with
expertise in adrenal tumors.

● Surgical management:

⚬ Surgery is not recommended for patients with asymptomatic, nonfunctioning unilateral adrenal
masses with obvious benign features on imaging studies (Strong recommendation).
⚬ Rule out pheochromocytoma biochemically prior to resection of any adrenal mass.
⚬ Adrenalectomy is recommended in patients with unilateral tumors with clinically significant
hormone excess (Strong recommendation).
⚬ For subclinical Cushing syndrome, surgical resection should be limited to patients with worsening
hypertension, abnormal glucose tolerance, dyslipidemia, and/or osteoporosis surgical resection.
⚬ For primary aldosteronism with unilateral source of aldosterone excess, laparoscopic total
adrenalectomy is treatment of choice due to excellent outcomes and low morbidity risk relative to
open approaches.
⚬ Perform surgical resection for all pheochromocytomas and give alpha-adrenergic blocking agent
preoperatively to reduce risk of intraoperative hemodynamic instability.

● Management of suspected malignancy:

⚬ Resect any adrenal mass with concerning radiographic characteristics and most lesions ≥ 4 cm due
to increased risk of adrenal cancer.
⚬ Consider performing laparoscopic adrenalectomy in patients with unilateral masses ≤ 6 cm and
suspicion of malignancy, but without evidence of local invasion (Weak recommendation).
⚬ Perform open adrenalectomy if adrenal cortical carcinoma is suspected.
⚬ Open adrenalectomy is recommended for unilateral adrenal masses with suspicion of malignancy
and signs of local invasion (Strong recommendation)

● Follow-up monitoring:

⚬ Perform hormonal evaluation annually for 5 years for all adrenal tumors.
 ⚬ If no surgical resection performed, reevaluate radiographically in 3-6 months, then annually for 1-2
years. Further imaging for follow-up may not be required if adrenal lesions < 4 cm in diameter with
benign characteristics (Weak recommendation).
⚬ In patients with a history of extra-adrenal malignancy, follow-up imaging recommended to assess
potential growth of lesion at the same time interval as imaging of the primary malignancy, or
consider fluorodeoxyglucose-positron emission tomography/computed tomography, surgical
resection, or biopsy (Strong recommendation).

Related Topics
● Adrenal Cortical Adenoma

● Adrenocortical Carcinoma

● Cushing Syndrome - Diagnostic Approach

● Cushing Disease

● Pheochromocytoma and Paraganglioma

● Primary Aldosteronism

General Information
Definitions

● adrenal incidentalomas are adrenal masses > 1 cm in diameter incidentally discovered during

abdominal imaging for reasons other than suspected adrenal disease 1 , 2 , 3 , 4

Also Called

● incidental adrenal mass

● incidental adrenal tumor

Types

● tumors of the adrenal cortex

⚬ nonfunctioning adrenocortical adenoma 1 , 2 , 4

⚬ functioning adenomas

– cortisol-producing adenoma 1 , 2 , 4

– aldosterone-producing adenoma 1 , 2 , 4

– some adenomas can secrete more than one hormone (Conn-shing syndrome) (J Hypertens 2017
Dec;35(12):2548 PDF )
⚬ adrenocortical carcinoma 2 , 4

⚬ adrenal lymphoma 2

⚬ adrenal metastases 1 , 4

⚬ bilateral adrenocortical tumors 2

● tumors of the adrenal medulla 1 , 2

⚬ pheochromocytoma
⚬ paraganglioma

● other adrenal masses

 ⚬ myelolipomas 1 , 2

⚬ adrenal cyst 1 , 2

⚬ adrenal hemorrhage 1

Incidence/Prevalence

● prevalence of adrenal incidentaloma is reported to vary by diagnostic approach and patient age 1 , 2

⚬ 1.1%-8.7% in autopsy studies

⚬ 0.6%-5% in computed tomography studies
⚬ 2% in people age < 70 years
⚬ 7% in people age > 70 years
⚬ reported to be more common in women in imaging studies but not autopsy studies

Differential Diagnosis
Causes
General Considerations

● etiology of adrenal incidentalomas is variable, including benign and malignant lesions derived from the

adrenal cortex or medulla or of extra-adrenal origin 1 , 2

● reported prevalence of causes in patients with incidentalomas in studies of patients with adrenal

masses 1
⚬ adenoma in 80% (range 33%-96%)

– nonfunctioning adenoma in 75% (range 71%-84%)

– autonomous cortisol-secreting adenoma in 12% (range 1%-29%)
– aldosterone-secreting adenoma in 2.5% (range 1.6%-3.3%)

⚬ adrenocortical carcinoma in 8% (range 1.2%-11%)

⚬ pheochromocytoma in 7% (range 1.5%-14%)
⚬ metastases from other primary malignancies in 5% (range 0%-18%)

Tumors of the Adrenal Cortex

Adrenal Cortical Adenoma

● adrenal cortical adenomas are benign neoplasms of the adrenal cortex that may or may not be

functional (secrete hormones) 3

● most adrenal cortical adenomas are nonsecreting and asymptomatic, and thus are discovered

incidentally during routine imaging performed for unrelated reasons 3

● types of adrenal cortical adenomas include 3

⚬ nonfunctioning adenomas
⚬ functioning adenomas that release

– cortisol, resulting in hypercortisolism, with subclinical or overt Cushing syndrome

– aldosterone, resulting in primary hyperaldosteronism
– estrogens or androgens, resulting in feminization, virilization, or hirsutism (rare)

● may be associated with familial syndromes such as

⚬ multiple endocrine neoplasia type 1 (MEN1) (Endocr Connect 2019 Mar 1;8(3):230 )
⚬ familial adenomatous polyposis (FAP) (Dis Colon Rectum 2018 Jun;61(6):679 )
Adrenocortical Carcinoma

● adrenocortical carcinoma is a rare and aggressive malignancy of the adrenal cortex

⚬ diagnosed incidentally in 20%-30% of patients

⚬ presents with clinical features of hormone excess in 40%-60% of patients
⚬ diagnosed following nonspecific symptoms due to local tumor growth in about 33% of patients

● occurs more frequently in women than in men and has a bimodal age distribution with peaks in
childhood and the fourth to fifth decades of life

● adrenocortical carcinoma types based on hormonal status

⚬ nonfunctional adrenocortical carcinoma (reported in about 40-60% of cases)

⚬ functional adrenocortical carcinoma that produces cortisol (most common), androgens, estrogen, or
aldosterone (rare and usually more aggressive)

● patients most commonly present with clinical features of hypercortisolism and/or hyperandrogenism or
with advanced disease

● see Adrenocortical Carcinoma for details

Bilateral Adrenocortical Tumors

● adrenal incidentalomas are typically unilateral but reported to potentially occur bilaterally in 10%-15 of

cases 2

● common causes include 2

⚬ metastasis
⚬ primary bilateral macronodular adrenal hyperplasia, which presents on imaging with multiple
characteristic bilateral macronodules
⚬ bilateral cortical adenomas

● other causes include 2

⚬ bilateral pheochromocytomas
⚬ congenital adrenal hyperplasia, which presents with nodule of < 1 cm if micronodular or ≥ 1 cm in
macronodular
⚬ Cushing disease
⚬ ectopic adrenocorticotropic hormone secretion with secondary bilateral adrenal hyperplasia

Tumors of the Adrenal Medulla

● pheochromocytomas are rare neuroendocrine tumors that arise from sympathetic and
parasympathetic paraganglia, which are neural crest-derived cells that are present within the adrenal
medulla and in tissues along the paravertebral axis (GeneReviews 2018 Oct 4 )

● pheochromocytomas usually secrete catecholamines within the adrenal medulla (Adv Exp Med Biol
2017;956:239 )

● most pheochromocytomas are not malignant, with metastases reported in 5%-20% of cases and most
commonly occurring in the bones, lungs, liver, and lymph nodes (Endocr Rev 2017 Dec 1;38(6):489
full-text )

● pheochromocytoma may be associated with familial syndromes caused by mutations in 3

⚬ RET gene (multiple endocrine neoplasia type 2)

⚬ VHL gene (von Hippel-Lindau disease)
⚬ succinate dehydrogenase genes
Metastasis

● incidentalomas in patients with known malignancies are often metastases 1 , 2

⚬ adrenal glands are reported to be a common site of metastases

⚬ sources of metastases may include

– carcinomas, typically in the lung, gastrointestinal system, kidney, or breast

– lymphomas
– melanomas

⚬ most adrenal incidentalomas in patients with extra-adrenal cancer are reported to be metastases
⚬ when bilateral, adrenal metastases may rarely result in adrenal insufficiency

STUDY
● SUMMARY
lung and kidneys may be most common sites of primary tumors in adults with adrenal metastases

COHORT STUDY: Cancer 2006 Apr 1;106(7):1624

Details

⚬ based on retrospective cohort study

⚬ 4,399 adults with metastatic cancer from 11 primary tumor sites and 15 metastatic sites were
included
⚬ adrenal metastasis in 202 adults (4.6%)

– lung in 104 adults (51%)

– kidney in 57 adults (28%)
– gastrointestinal system in 25 adults (12%)
– breast in 8 adults (4%)
– liver in 5 adults (2%)
– pancreas in 2 adults (1%)

⚬ Reference - Cancer 2006 Apr 1;106(7):1624

Mimics

● adrenal tuberculosis

⚬ characterized by

– bilateral adrenal enlargement in active infection

– atrophy and calcification in remote infection

⚬ adrenal enlargement is reported to improve with antibiotic treatment

⚬ adrenal insufficiency may not improve with antibiotic treatment
⚬ Reference - Int J Endocrinol 2014;2014:876037 full-text

● adrenal myelolipoma

⚬ myelolipomas are rare, benign neoplasms that typically occur in the adrenal gland and are
comprised of mature adipose tissue and scattered groupings of hematopoietic elements (Int J Surg
Case Rep 2014;5(8):494 full-text )
⚬ typically small and asymptomatic but may present with flank pain, abdominal discomfort, necrosis,
rupture, hemorrhage, or hemorrhagic shock (Int J Surg Case Rep 2014;5(8):494 full-text )
⚬ affect men and women equally and most commonly occur in the fifth to seventh decades of life (Int J
Surg Case Rep 2014;5(8):494 full-text )
⚬ magnetic resonance imaging (MRI) techniques such as frequency-selective fat suppression may be
useful for diagnosing adrenal myelolipomas (Int J Surg Case Rep 2014;5(8):494 full-text )
● adrenal cyst

⚬ adrenal cysts are rare, typically unilateral lesions discovered incidentally with imaging, surgery, or
autopsy
⚬ reported to be endothelial or lymphangiomatous in about 45% of cases and are typically 0.1-1.5 cm
in diameter
⚬ often diagnosed in fourth or fifth decade of life
⚬ may rarely be hormonally active
⚬ usually asymptomatic, but may present with acute abdominal pain and may mimic acute abdomen if
bleeding occurs
⚬ Reference - J Minim Access Surg 2012 Oct;8(4):145 full-text

● acute hematoma or hemorrhage

⚬ acute hemorrhage is relatively rare and typically caused by

– trauma
– stress
– infection and sepsis
– adrenal tumors
– anticoagulation
– surgery
– hemorrhagic disorders
– antiphospholipid syndrome
– pregnancy

⚬ adrenal tumors most commonly associated with hemorrhage include

– pheochromocytomas
– adrenocortical cancers
– metastatic lesions from other organs

⚬ symptoms (due to acute hemorrhage and possible concurrent adrenal insufficiency if bilateral
adrenals are compromised) may include
– nausea
– abdominal pain
– fever
– hypotension
– vomiting
– weakness
– dizziness
– tachycardia
– anorexia
– fatigue
– back pain

⚬ may result in death

⚬ computed tomography (CT) and MRI may be useful for detecting adrenal hemorrhage but may not
be able to determine if hemorrhage is associated with tumors
⚬ may be difficult to diagnosis without surgery
⚬ Reference - Int J Surg Case Rep 2016;28:15 full-text

● ganglioneuroma

⚬ ganglioneuromas are rare, benign tumors that originate in the neural crest
⚬ reported in up to 6% of adrenal incidentalomas
⚬ may occur between the neck and the pelvis along the paravertebral sympathetic ganglia
 ⚬ typically hormonally silent but may have secretory activity
⚬ more commonly occurs in younger people (< 40 years)
⚬ usually asymptomatic even if large
⚬ definitive diagnosis can only be made based on histopathology
⚬ Reference - J Minim Access Surg 2019 Jul;15(3):259 full-text

● adrenal schwannoma (also called nerve sheath tumor)

⚬ schwannomas originate from neural crest cells of neuroectodermal tissue and typically occur in the
cranial and peripheral nerves, but may be adrenal in extremely rare cases
⚬ typically asymptomatic due to the absence of endocrine function, but may present with compression
symptoms and abdominal discomfort due to hemorrhage or necrosis as the tumor grows
⚬ usually found incidentally during physical exams
⚬ ultrasound, CT, and MRI may be used to aid in diagnosis
⚬ pre-operative diagnosis is based on imaging features of hypoechoic calcifications and mild
enhancement
⚬ diagnosis is confirmed with histopathology, with typical features including
– in gross specimens

● varying lesion size

● round or nodular contour and integrated capsule
● pink or brownish-gray and slightly transparent cross-sections
● solid and tough texture
● spiral structure
● in some cases, focal, jelly-like necrosis may be visible

– with hematoxylin-eosin staining

● spindle cells observable with microscope

● may be complicated with hemorrhage, cystic, or hyaline degeneration

⚬ Reference - Endocr Pract 2015 Apr 2;21(4):323 EBSCOhost Full Text

History and Physical

Clinical Presentation

● adrenal incidentalomas are often asymptomatic, though patients with large tumors may experience

compressive symptoms and hormonally active tumors may have specific clinical features 2

● large tumors may result in local mass effect with symptoms such as abdominal or flank pain 2

● hormonally active tumors can be asymptomatic initially or may have signs and symptoms related to the
specific secreted hormone
⚬ hypercortisolism can be asymptomatic, or signs and symptoms may include 2 , 4

– muscle weakness
– easy bruising/bleeding
– poor wound healing
– decreased libido
– psychiatric disturbances
– insomnia
– flushing
– insulin resistance
– type 2 diabetes mellitus
obesity
 –– metabolic syndrome

– osteoporosis (in men, premenopausal women, and postmenopausal women)

– cardiovascular effects, such as

● palpitations
● left ventricular hypertrophy
● hypertension
● coronary heart disease
● stroke
● myocardial infarction

⚬ primary aldosteronism may present with 2 , 4

– muscle cramping
– muscle weakness
– fatigue
– headache
– polydipsia
– polyuria
– hypertension
– hypokalemia (majority of patients with primary hyperaldosteronism are not hypokalemic)
– diabetes mellitus
– metabolic syndrome
– renal disease
– decreased bone mineral density
– osteoporosis (in men, premenopausal women, and postmenopausal women)

⚬ androgen-secreting tumors (which are more likely to be malignant) may present with symptoms of

virilization, including 2
– excessive facial hair growth
– skin changes such as acne
– deepening of the voice
– clitoromegaly
– male pattern baldness

● pheochromocytoma can be asymptomatic, or present with classical paroxysmal symptoms in about

50% of patients, including 2 , 4

⚬ headache
⚬ sweating
⚬ tachycardia
⚬ anxiety
⚬ sense of impending doom
⚬ signs include hypertension, tachycardia, hypotension (if predominantly epinephrine secreting),
insulin-resistance
⚬ chest pain
⚬ flushing/hot flashes
⚬ pallor

● adrenocortical carcinomas reportedly present with compressive symptoms (such as abdominal or flank

pain) due to the tumor mass in about 30% of patients and are functional tumors in 40%-60% of cases 2
⚬ around 45% present with symptoms of Cushing syndrome
 ⚬ about 10% are androgen secreting and patients may present with hirsutism and virilization without
features of glucocorticoid excess
⚬ < 10% are aldosterone secreting
⚬ about 25% cosecrete cortisol and androgens and may present with symptoms of both
hypercortisolism and hyperandrogenism

● bilateral metastatic adrenal tumors may present with signs and symptoms of adrenal insufficiency 2

⚬ fatigue
⚬ anorexia
⚬ vomiting
⚬ postural hypotension
⚬ hyponatremia
⚬ hypokalemia

● estrogen-secreting tumors (very rare) may present with 2

⚬ irregular uterine bleeding and breast tenderness in women

⚬ decreased libido, testicular atrophy, and gynecomastia in men

History

● goal of history is evaluate for evidence of hormonal secretion for a functional tumor and to evaluate for

signs and symptoms concerning for malignancy such as rapid pace of virilization 3

● history suggestive of Cushing syndrome or hypercortisolism 3

⚬ depression
⚬ weight gain
⚬ menstrual irregularities
⚬ development of central obesity
⚬ new or worsening glucose intolerance or diabetes
⚬ thinning of the skin, easy bruising, violaceous striae
⚬ fracture with minimal trauma or worsening osteoporosis
⚬ severe or worsening hypertension
⚬ virilization
⚬ proximal muscle weakness
⚬ fatigue
⚬ hypertension
⚬ metabolic syndrome

● history suggestive of pheochromocytoma 2 , 3

⚬ sudden or severe headaches, reported in ≤ 90% of symptomatic patients

⚬ sweating, reported in 60%-70%
⚬ hypertension

– blood pressure reported to be normal in 5%-15% of patients

– hypotension reported in patients with tumors secreting only epinephrine

⚬ weight loss
⚬ anxiety attacks
⚬ palpitations
⚬ cardiac arrhythmias
⚬ tremors
⚬ weakness
 ⚬ constipation
⚬ visual blurring
⚬ hyperglycemia
⚬ polyuria
⚬ polydipsia

● history suggestive of aldosteronism 3

⚬ hypokalemia
⚬ muscle cramps
⚬ weakness
⚬ hypertension
⚬ diastolic heart failure

● history suggestive of metastatic cancer 3

⚬ history of or current treatment for cancer

⚬ recent weight loss
⚬ history of smoking

Physical

● measure blood pressure, pulse, and weight 3

● look for 3

⚬ central obesity
⚬ supraclavicular fat accumulation
⚬ dorsocervical fat pad
⚬ facial plethora
⚬ thinned skin
⚬ ecchymoses
⚬ purple and wide (> 1 cm) striae
⚬ proximal muscle weakness or wasting
⚬ acne
⚬ hirsutism or other signs of virilization
⚬ lymphadenopathy or other signs of malignancy

Diagnostic Approach
Making the Diagnosis

● adrenal incidentalomas are adrenal masses > 1 cm in diameter that are not clinically apparent and are

found with imaging for indications other than suspected adrenal disease 1 , 2 , 3 , 4

● further diagnostic workup is not indicated for adrenal lesions < 1 cm unless there are signs or

symptoms of adrenal hormone excess 1 , 2

● assess every patient with adrenal incidentaloma for signs and symptoms of adrenal hormone excess

(ESE/ENSAT Strong recommendation) 1

● suspect metastatic lesion in a patient with a history of cancer and an adrenal mass that is not consistent

with incidentaloma (AACE/AAES Grade C, BEL 3) 3

Testing Overview
● computed tomography (CT) is generally used as first line of investigation

⚬ perform a noncontrast (unenhanced) computed tomography (CT) to determine if the mass is

homogenous and lipid-rich and therefore benign (ESE/ENSAT Strong recommendation, Very low
quality of evidence)
⚬ if noncontrast CT is consistent with benign adrenal mass (Hounsfield units [HU] ≤ 10, homogenous,
and < 4 cm), no further imaging may be required (ESE/ENSAT Weak recommendation, Very low
quality of evidence)
⚬ if unenhanced density cutoff is > 10 HU and is not consistent with a benign adrenal mass, consider
performing a contrast-enhanced CT

● in children, adolescents, adults < 40 years old, and during pregnancy, consider performing magnetic
resonance imaging (MRI) with contrast shift imaging rather than CT in order to avoid radiation exposure
in these populations (ESE/ENSAT Weak recommendation)

● biochemical evaluation includes performing 1 mg overnight dexamethasone suppression test to

exclude cortisol excess in all patients with an adrenal incidentaloma (ESE/ENSAT Strong
recommendation, Low quality evidence)

● perform additional biochemical evaluation based on clinical presentation

⚬ if pheochromocytoma is suspected, test plasma metanephrines and/or 24-hour urinary fractionated

metanephrines, especially before biopsy or resection of an adrenal tumor (AACE/AAES Grade A, BEL
1)
⚬ in patients with concomitant hypertension or unexplained hypokalemia, test for primary
aldosteronism by assessing aldosterone/renin ratio (ESE/ENSAT Strong recommendation)
⚬ in patients with suspected adrenal cortical carcinoma (such as irregular shape or size > 4 cm)

– consider measuring sex steroids and steroid precursors (ESE/ENSAT Weak recommendation)
– consider evaluating for aldosteronism if patient is hypertensive

● evaluation of suspected metastases

⚬ suspect metastatic lesion in a patient with a history of cancer and an adrenal mass that is not

consistent with incidentaloma (AACE/AAES Grade C, BEL 3) 3

⚬ to evaluate for metastases in patients with history of malignancy, perform further testing, such as 2

– CT
– FDG-PET and FDG PET/CT
– MRI with chemical shift
– biopsy

⚬ fine needle aspiration (FNA) biopsy can be used to confirm diagnosis of metastatic disease
(AACE/AAES Grade D, BEL 4) but should not be performed if adrenocortical carcinoma is suspected
and only after pheochromocytoma has been ruled out (AACE/AAES Grade C, BEL 3)

Imaging Studies

General Considerations

● incidentaloma may be detected via ultrasound, computed tomography (CT), or magnetic resonance

imaging (MRI) 2

● for patients who do not have surgical resection for adrenal incidentaloma, depending on imaging

characteristics, consider radiographic evaluation at 3-6 months and annually for 1-2 years for stability 3

● imaging for detection of malignancy

 ⚬ additional imaging studies are indicated for patients with adrenal incidentalomas with a short axis >
1 cm if initial characteristics do not mark it as clearly benign to determine if it is benign or
malignant 5
⚬ if adrenal mass is indeterminate on initial imaging, evaluate with adrenal CT protocol 5

⚬ CT, MRI, and F-2-deoxy-d-glucose positron emission tomography (FDG-PET) can be used to

differentiate between malignant and benign adrenal nodules 1 , 2

⚬ larger size of incidentaloma is reported to be associated with increased risk of malignancy 1 , 2

⚬ rates of malignancy by tumor size in case series of 76 adults (median age 55 years, 71.1% women)
with adrenalectomy for nonfunctional adrenal incidentaloma
– 0% in tumors with diameter < 4 cm
– 2.9% in tumors with diameter 4-6 cm
– 13.6% in tumors with diameter > 6 cm
– Reference - Cureus 2020 Jan 6;12(1):e6574 full-text

● diagnostic imaging features of benign adrenal masses include 5

⚬ presence of macroscopic (bulk) fat

⚬ CT attenuation ≤10 Hounsfield units (HU)
⚬ loss of signal intensity on MRI between in-phase and opposed-phase T1- weighted gradient-echo
images
⚬ lack of enhancement (change of <10 HU between pre- and postcontrast imaging) is consistent with
benign etiology like cyst or hemorrhage
⚬ if mass meets these criteria, further imaging is generally not required

● imaging studies cannot distinguish between functioning and non-functioning tumors (Endocr Pract
2009 Jul;15(5):450 )

Computed Tomography (CT)

General Considerations

● CT allows assessment of tissue density, as measured in Hounsfield units (HU) 1 , 2

● first-line of investigation is commonly noncontrast (unenhanced) CT followed by contrast-enhanced CT

with dedicated adrenal washout protocol for patients with lipid-poor adenomas (> 10 HU) 2

● a dedicated adrenal CT protocol should include 5

⚬ unenhanced thin-section images through the upper abdomen with axial and coronal reformatted
images allowing for initial attenuation measurement of the mass
⚬ when no diagnostic benign imaging characteristics (HU <10) are seen

– perform a contrast-enhanced series 60-90 seconds after administration of intravenous contrast

– perform 15-minute delayed-phase imaging for evaluation of washout characteristics to calculate
absolute washout

Noncontrast (Unenhanced) Computed Tomography (CT)

● American College of Radiology Appropriateness Criteria for evaluating adrenal mass with noncontrast

CT in patients with adrenal incidentaloma 5

⚬ noncontrast CT imaging is not recommended for patients with adrenal masses < 1 cm and no history
of malignancy
⚬ noncontrast CT imaging is usually appropriate in patients with adrenal masses > 1 cm and < 4 cm
with or without a history of malignancy
 ⚬ noncontrast CT imaging is not recommended in patients with adrenal masses > 4 cm with or without
a history of malignancy as after biochemical evaluation, surgical resection is recommended

● European Society of Endocrinology (ESE)/European Network for the Study of Adrenal Tumors (ENSAT)

recommendations for CT use in patients with adrenal incidentaloma 1

⚬ noncontrast CT imaging is recommended for all adrenal incidentalomas to determine if the mass is
homogenous and lipid-rich and therefore benign (ESE/ENSAT Strong recommendation, Very low
quality of evidence)
⚬ if noncontrast CT is consistent with benign adrenal mass (Hounsfield units [HU] ≤ 10, homogenous,
and < 4 cm), no further imaging may be required (ESE/ENSAT Weak recommendation, Very low
quality of evidence)
⚬ in patients with a history of extra-adrenal malignancy with adrenal lesions characterized as benign
by noncontrast CT, no further specific adrenal imaging follow-up is required (ESE/ENSAT Strong
recommendation)
⚬ if noncontrast CT results are indeterminate and results of hormonal testing do not show significant
hormone excess, consider immediate additional imaging, interval imaging in 6-12 months
(noncontrast CT or magnetic resonance imaging [MRI]), or surgery without delay (ESE/ENSAT Strong
recommendation)

● for diagnosis of benign adenoma

⚬ HU ≤ 10 indicates a benign, lipid-rich adenoma 1 , 2

⚬ about 30% of benign adrenal adenomas are lipid-poor, have attenuation values of > 10 HU, and
cannot be distinguished from pheochromocytomas or malignant lesions; they thus require further
workup 2

● for diagnosis of pheochromocytomas 2 , 5

⚬ mean unenhanced CT attenuation of pheochromocytomas is reported to be 30-35 HU with greater

vascularity
⚬ only 0.5% of pheochromocytomas have unenhanced CT attenuation ≤ 10 HU

STUDY
● SUMMARY
unenhanced CT with > 36.2 Hounsfield units (HU) might help distinguish adrenal metastasis from
nonmetastatic adrenal mass in adults with extra-adrenal cancer with solitary adrenal mass
DynaMed Level 2

DIAGNOSTIC COHORT STUDY: J Surg Oncol 2018 Dec;118(8):1271

Details

⚬ based on retrospective diagnostic cohort study without independent validation

⚬ 68 adults (mean age 59 years) with extra-adrenal cancer with solitary adrenal mass had preoperative
computed tomography imaging and adrenalectomy plus histology (reference standard)
⚬ exclusion criteria included suspected metastasis of other organs detected on image studies and
positive result on functional studies
⚬ pathologically-confirmed adrenal metastasis in 32%
⚬ for detection of adrenal metastasis, precontrast HU with cutoff of 36.2 had

– sensitivity 91.3%
– specificity 81.8%

⚬ factors associated with adrenal metastasis

– male sex (adjusted odds ratio [OR] 9.78, 95% CI 1.46-65.46)

 – metachronous adrenal mass (up to 60 months of follow-up) (adjusted OR 11.09, 95% CI 1.94-
63.49)
– higher mean precontrast HU (adjusted OR 1.11, 95% CI 1.04-1.17)

⚬ no significant differences between groups in age, body mass index, smoking status, or history of
hypertension or diabetes mellitus
⚬ no significant association found between mass diameter, mass location, smoking, hypertension, or
diabetes mellitus and likelihood of adrenal metastasis
⚬ Reference - J Surg Oncol 2018 Dec;118(8):1271

STUDY
● SUMMARY
unenhanced attenuation values reported to vary with cortisol-secreting adrenocortical adenomas
and may often be > 10 HU

CASE SERIES: Eur J Endocrinol 2015 Sep;173(3):325

Details

⚬ based on case series

⚬ 72 patients (mean age 50 years, 81.9% female) who had surgery for adrenocortical adenoma were
evaluated, including 34 adenomas that were cortisol-secreting
⚬ among 34 adenomas that were cortisol-secreting

– unenhanced attenuation value < 10 HU in 7 adenomas (21%)

– unenhanced attenuation value > 10 HU in 27 adenomas consistent with lipid-poor adenoma
(79%), with ~60% confirmed benign in washout analysis after contrast administration
⚬ Reference - Eur J Endocrinol 2015 Sep;173(3):325

Contrast-enhanced Computed Tomography (CT)

● American College of Radiology Appropriateness Criteria for evaluating adrenal mass with contrast-

enhanced CT in patients with adrenal incidentaloma 5

⚬ CT with and without intravenous (IV) contrast

– is usually not appropriate for masses < 1 cm, with no diagnostic benign imaging features and no
history of malignancy
– is usually appropriate for masses between 1 cm and 4 cm, with no diagnostic benign imaging
features and no history of malignancy
– is usually appropriate (other imaging considerations include MRI with and without contrast or a
18F-2-deoxy-d-glucose positron emission tomography (FDG PET); consideration of moving forward

to adrenal biopsy after ruling out pheochromocytoma is also an option) for masses < 4 cm, with a
history of malignancy, but no diagnostic benign imaging features
– is usually not appropriate for masses ≥ 4 cm, with no diagnostic benign imaging features and
without history of malignancy
● patients without a history of malignancy should be considered for surgical resection
● patients with a history of malignancy should be considered for adrenal gland biopsy or FDG
PET/CT skull base-mid-thigh to confirm metastatic disease
⚬ CT with IV contrast alone (without unenhanced and washout protocol) is usually not appropriate for
diagnosis of adrenal incidentaloma

● for lesions with unenhanced CT attenuation values >10, contrast-enhanced CT may be considered a

second-line imaging modality (or can be done concurrent as part of a dedicated adrenal protocol) 1 , 2
⚬ absolute washout values of > 60% and relative washout values of > 40% suggest benign adenoma
 ⚬ pheochromocytomas typically show slow contrast washout but may mimic benign, lipid-poor
adenomas by showing rapid washout
⚬ follow-up imaging may be considered for suspicious lesions with indeterminate HU to ensure no
additional growth

A Image 1 of 2

dr
Adrenal adenoma
e
n Appearance of a typical, oval, hypodense, 1.5 cm right adrenal cortical adenoma (arrow).
al
Used with permission from the American College of Physicians.
a
d
e
n
o
m
a

A Image 2 of 2

dr
Adrenal incidentaloma
e
n CT scan of the abdomen showing a typical incidentally discovered left adrenal mass (thick white
al arrow) in an asymptomatic man. The normal right adrenal gland is shown as an inverted Y shape
in (thin white arrow). The mass is lipid-rich and has a low attenuation factor (< 10 HU). Abbreviations:
ci CT, computed tomography; HU, Hounsfield units.
d
Used with permission from the American College of Physicians.
e
nt
al
o
m
Magnetic Resonance Imaging (MRI) and Magnetic Resonance Chemical Shift Imaging (MR-CSI)
a
● if adrenal imaging is required in children, adolescents, adults < 40 years of age, and during pregnancy,
consider MRI rather than computed tomography (CT) in order to avoid radiation exposure in these
populations (ESE/ENSAT Weak recommendation) 1

● MRI has some advantages over CT, including 1

⚬ lack of radiation exposure

⚬ lack of iodine-based contrast media
⚬ superior tissue contrast resolution

● American College of Radiology Appropriateness Criteria for evaluating adrenal mass with MRI in

patients with adrenal incidentaloma 5

⚬ MRI abdomen without and with IV contrast

– is usually not appropriate for patients with adrenal masses < 1 cm, no benign diagnostic imaging
features, and no history of malignancy (as no further imaging is recommended)
– is usually appropriate in patients with adrenal masses between 2 cm and 4 cm, with no benign
imaging features, and without a history of malignancy
 – may be appropriate in patients with adrenal masses between 1 cm and 2 cm, with no benign
imaging features, without a history of malignancy
– is usually appropriate (other imaging studies io consider including 18F-2-deoxy-d-glucose positron
emission tomography (FDG PET), CT with and without contrast; biopsy after ruling out
pheochromocytoma is also an option) in patients with adrenal masses between < 4 cm, with no
benign imaging features, and with a history of malignancy
– is not recommended in patients with adrenal masses > 4 cm, with no benign imaging features,
and with or without a history of malignancy (as surgical resection should be considered)
● patients without a history of malignancy should be considered for surgical resection
● patients with a history of malignancy should be considered for adrenal gland biopsy or FDG
PET/CT skull base-mid-thigh to confirm metastatic disease
⚬ MRI abdomen without IV contrast

– is usually not appropriate for patients with adrenal masses < 1 cm or > 4 cm, with no benign
diagnostic imaging features, and with or without a history of malignancy
– is usually appropriate in patients with adrenal masses between 1 cm and 4 cm, with no benign
imaging features, and without a history of malignancy
– may be appropriate in patients with a history of malignancy, masses < 4 cm, with no diagnostic
benign imaging features.

● MRI-CSI (a MRI technique) can be used to distinguish between lipid-rich and lipid-poor tissue and can
identify lipid-rich adenomas, but cannot distinguish lipid-poor adenomas from malignant lesions or
pheochromocytomas 1

● loss of signal intensity on out-of-phase imaging suggests lipid-rich adrenal adenoma 1 , 2

● if MR-CSI is indeterminate, dynamic post contrast imaging without or with the addition of T2-weighted

imaging may aid in the diagnosis of adenoma 5

● reported to have inferior diagnostic value for excluding malignancy compared to CT and should only be
first choice for imaging when CT is less desirable, such as in populations vulnerable to radiation
exposure 1

STUDY
● SUMMARY
chemical shift imaging may have high sensitivity and specificity for distinguishing benign adrenal
adenoma from other adrenal lesions DynaMed Level 2

SYSTEMATIC REVIEW: Eur Radiol 2019 Feb;29(2):806

Details

⚬ based on systematic review limited by clinical heterogeneity

⚬ systematic review of 18 studies with 1,138 patients with 1,280 adrenal masses (859 adenomas, 421
non-adenomas) who had chemical shift imaging (CSI)
⚬ methods of CSI evaluation and magnetic field strengths varied across studies
⚬ reference standard was imaging follow-up, histopathology or another imaging modality, and
histopathology in 16 studies or histopathology alone in 2 studies
⚬ pooled performance of CSI for distinguishing adrenal adenomas from other adrenal masses

– sensitivity 94% (95% CI 88%-97%) in analysis of 18 studies, with results limited by significant
heterogeneity
– specificity 95% (95% CI 89%-97%) in analysis of 18 studies, with results limited by significant
heterogeneity
 ⚬ pooled performance of adrenal signal intensity index (SII) for diagnosing adrenal adenoma

– sensitivity 94% (95% CI 90%-97%)

– specificity 93% (95% CI 87%-97%)

⚬ pooled performance of adrenal-to-spleen ratio (ASR) for diagnosis of adrenal adenoma

– sensitivity 93% (95% CI 83%-97%)

– specificity 98% (95% CI 87%-100%

⚬ pooled performance of visual CSI evaluation for adrenal adenoma

– sensitivity 83% (95% CI 66%-93%)

– specificity 93% (95% CI 87%-96%)

⚬ Reference - Eur Radiol 2019 Feb;29(2):806

18F-2-deoxy-d-glucose Positron Emission Tomography (FDG-PET)

● FDG-PET is a non-invasive imaging test that can be used to differentiate benign from malignant

lesions 1 , 2
⚬ FDG-PET (commonly combined with computed tomography [CT]) can detect metabolic changes such
as increased glucose uptake that can indicate malignancy
⚬ FDG-PET/CT is recommended in patients with history of extra-adrenal malignancy as part of
investigations for underlying metastasis (ESE/ENSAT Strong recommendation)
⚬ FDG-PET-CT may be considered to exclude extra-adrenal metastatic disease in patients with
suspected adrenal metastasis being considered for adrenalectomy
⚬ absence of FDG uptake or adrenal-liver ratio < 1 suggests a benign adrenal mass
⚬ some benign adrenal lesions, such as benign pheochromocytomas and functional adenomas, can be
FDG positive
⚬ in patients with history of extra-adrenal malignancy, follow-up imaging assessing lesion growth is
recommended, or FDG-PET/CT, surgical resection, or biopsy can be considered (ESE/ENSAT Strong
recommendation)

● American College of Radiology Appropriateness Criteria for evaluating adrenal mass with FDG-PET CT in

patients with adrenal incidentaloma 5

⚬ noncontrast CT imaging is usually not appropriate for patients with adrenal masses but no history of
malignancy
⚬ noncontrast CT imaging is usually appropriate in patients with adrenal masses and a history of
malignancy

STUDY
● SUMMARY
fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) may
have high sensitivity and specificity for diagnosis of malignant adrenal lesions DynaMed Level 2

SYSTEMATIC REVIEW: Br J Radiol 2018 Jun;91(1086):20170520 | Full Text

Details

⚬ based on systematic review of diagnostic cohort studies limited by heterogeneity

⚬ systematic review of 29 diagnostic cohort studies evaluating 18F-FDG PET (4 studies) or PET/CT (25
studies) for differentiating benign from malignant adrenal disease in 2,421 patients with 2,795
adrenal lesions
⚬ reference standards included

– histopathology
 – measurement of Hounsfield unit from non-enhanced CT
– CT imaging follow-up
– clinical information follow-up

⚬ pooled diagnostic performance of 18F-FDG PET or PET/CT for differentiating benign from malignant
adrenal lesions
– sensitivity 91% (95% CI 88%-94%) in analysis of 29 studies with 2,421 patients, results limited by
significant heterogeneity
– specificity 91% (95% CI 87%-93%) in analysis of 29 studies with 2,421 patients, results limited by
significant heterogeneity
– positive predictive value 87.4% in analysis of 29 studies with 2,421 patients
– negative predictive value 90.1% in analysis of 29 studies with 2,421 patients
– positive likelihood ratio 9.9 (95% CI 7.1-13.7) in analysis of 29 studies with 2,421 patients
– negative likelihood ratio 0.09 (95% CI 0.07-0.13) in analysis of 29 studies with 2,421 patients
⚬ Reference - Br J Radiol 2018 Jun;91(1086):20170520 full-text

STUDY
● SUMMARY
fluorodeoxyglucose positron emission tomography (18F-FDG PET) may differentiate benign from
malignant adrenal disease DynaMed Level 2

SYSTEMATIC REVIEW: Radiology 2011 Apr;259(1):117

Details

⚬ based on systematic review limited by heterogeneity

⚬ systematic review of 21 diagnostic cohort studies evaluating 18F-FDG PET for differentiating benign
from malignant adrenal disease with 1,391 lesions from 1,217 patients
⚬ only 1 study met all methodologic quality criteria assessed
⚬ results limited by high degrees of heterogeneity of diagnostic test performance
⚬ reference standards included

– histopathology
– interval computed tomography (CT) follow-up
– lipid-sensitive and/or washout CT
– lipid-sensitive magnetic resonance imaging (MRI)

⚬ 567 lesions (40.8%) were malignant

⚬ diagnostic performance of FDG PET for differentiating benign from malignant adrenal disease

– pooled sensitivity 97% (95% CI 93%-98%, range 76%-100%)

– pooled specificity 91% (95% CI 87%-94%, range 73%-100%)
– positive likelihood ratio 11.1 (95% CI 7.5-16.3)
– negative likelihood ratio 0.04 (95% CI 0.02-0.08)

⚬ Reference - Radiology 2011 Apr;259(1):117 , commentary can be found in Radiology 2011

Aug;260(2):610

Biochemical Evaluation Recommendations

American Association of Clinical Endocrinologists (AACE) and American Association of Endocrine

Surgeons (AAES) Recommendations

● consider performing hormonal evaluation for all adrenal tumors at diagnosis and annually for 5 years

for subclinical Cushings if the initial evaluation was negative (AACE/AAES Grade C, BEL 3) 3
● recommendations for biochemical testing for hypercortisolism 3

⚬ consider screening all patients for cortisol excess (AACE/AAES Grade C, BEL 3)

– best strategy not established

– simplest screening test is 1 mg overnight dexamethasone suppression test
– if clinical suspicion is high, such as in patients with hypertension, obesity, diabetes mellitus, or
osteoporosis, all three of the tests can be used
● late-night salivary cortisol
● overnight dexamethasone suppression
● 24-hour urine free cortisol (UFC) excretion

⚬ diagnostic criteria for subclinical Cushings syndrome (SCS) include (AACE/AAES Grade D, BEL 4)

– adrenal adenoma
– serum cortisol level > 5 mcg/dL after 1-mg dexamethasone suppression test
– absence of typical physical symptoms of hypercortisolism
– low or suppressed adrenocorticotropic hormone (ACTH) or low dehydroepiandrosterone sulfate
levels
⚬ second abnormal hypothalamic-pituitary-adrenal (HPA) axis function test may also be required to
diagnose SCS (AACE/AAES Grade B, BEL 2)

● recommendations for biochemical testing for pheochromocytoma 3

⚬ if pheochromocytoma suspected, measure either or both of (AACE/AAES Grade A, BEL 1)

– plasma fractionated metanephrines and normetanephrines

– 24-hour total urinary metanephrines and fractionated catecholamines

⚬ rule out pheochromocytoma biochemically prior to biopsy (AACE/AAES Grade C, BEL 3)

⚬ offer genetic counseling and testing for patients with pheochromocytoma (AACE/AAES Grade C, BEL
3)
– especially important for patients of reproductive age or patients with an extra-adrenal
pheochromocytoma
– about 25% of patients with pheochromocytoma will have associated familial syndromes caused
by mutations in
● RET gene (multiple endocrine neoplasia type 2)
● VHL gene (von Hippel-Lindau disease)
● succinate dehydrogenase genes

● recommendations for biochemical testing for aldosteronism 3

⚬ nonfunctioning adenomas may co-occur with primary adrenal hyperplasia or with aldosterone-
producing adenomas
⚬ consider bilateral adrenal venous sampling (AVS) for

– older patients (> 40 years)

– patients with bilateral morphologically abnormal glands
– patients with a unilateral microadenoma

⚬ recommended testing to distinguish aldosterone-producing adenoma from primary idiopathic

hyperplasia (AACE/AAES Grade C, BEL 3)
– CT scan in all patients
– AVS in most patients > 40 years old, excluding patients who are not surgical candidates, because
they are
● are too infirm for surgical management
● have limited life expectancy
 ● are comfortable with medical therapy with mineralocorticoid blockers

● recommendations for biochemical testing for adrenocortical carcinoma 3

⚬ perform biochemical evaluation in all patients suspected of having adrenocortical carcinoma to

identify hormone excess that may act a tumor marker and to determine need for perioperative
steroid replacement due to hypercortisolism (AACE/AAES Grade D, BEL 4)
⚬ testing should include evaluation for hypercortisolism and (if patient is hypertensive) aldosteronism

● evaluate for adrenal insufficiency if bilateral adrenal metastatic lesions are identified (AACE/AAES Grade

D, BEL 4) 3

European Society of Endocrinology/European Network for the Study of Adrenal Tumors

(ESE/ENSAT) Recommendations

● careful assessment including clinical examination for signs and symptoms of adrenal hormone excess is

recommended for all patients with adrenal incidentaloma (ESE/ENSAT Strong recommendation) 1

● in patients with initially negative hormonal testing, repeat hormonal workup is not recommended
unless new clinical signs or worsening comorbidities (such as hypertension and type 2 diabetes)
concerning for hormone secretion (ESE/ENSAT Weak recommendation, Low quality evidence) 1

● recommendations for biochemical testing for hypercortisolism 1

⚬ all patients with adrenal incidentaloma should have 1 mg overnight dexamethasone suppression

test to exclude cortisol excess (ESE/ENSAT Strong recommendation, Low quality evidence) 1
⚬ interpretation of dexamethasone test results

– consider interpretation of dexamethasone test as continuous rather than categorical variable

(ESE/ENSAT Weak recommendation, Very low quality evidence)
– post-dexamethasone serum cortisol level ≤ 1.8 mcg/dL (≤ 50 nmol/L) excludes autonomous
cortisol secretion (Cushing's syndrome) (ESE/ENSAT Strong recommendation, Low quality
evidence)
– consider post-dexamethasone serum cortisol levels of 1.9-5 mcg/dL (51-138 nmol/L) as evidence
of possible autonomous cortisol secretion, and levels of > 5 mcg/dL (> 138 nmol/L) as evidence of
autonomous cortisol secretion (ESE/ENSAT Weak recommendation)
⚬ patients with autonomous cortisol secretion (subclinical Cushing's syndrome) should not be
considered high-risk for developing overt Cushing syndrome (ESE/ENSAT Strong recommendation,
Low quality evidence)
⚬ patients with possible autonomous cortisol secretion or autonomous cortisol secretion should be
screened for hypertension and type 2 diabetes mellitus (ESE/ENSAT Strong recommendation, Very
low quality evidence)
⚬ for patients with autonomous cortisol secretion, consider screening for asymptomatic vertebral
fractures (ESE/ENSAT Weak recommendation, Very low quality evidence)
⚬ in considering whether to pursue adrenal surgery for patients with cortisol excess due to benign
adenoma, consider an individualized approach taking into account age, degree of cortisol excess,
general health, comorbidities, and patient preference (ESE/ENSAT Weak recommendation, Very low
quality evidence)
⚬ in all patients being considered for adrenal surgery, adrenocorticotropic hormone-independency of
cortisol excess should be excluded (ESE/ENSAT Weak recommendation, Very low quality evidence)

● to test for pheochromocytoma, measure plasma-free metanephrines or urinary fractionated

metanephrines (ESE/ENSAT Strong recommendation) 1

● to test for primary aldosteronism, use aldosterone/renin ratio in patients with concomitant

hypertension or unexplained hypokalemia (ESE/ENSAT Strong recommendation) 1

● recommendations for biochemical testing for adrenocortical carcinoma 1

⚬ consider measuring sex hormones and steroid precursors in patients with suspected adrenocortical
carcinoma (ESE/ENSAT Weak recommendation)
⚬ testing may include

– androstenedione
– testosterone
– dehydroepiandrosterone sulfate
– 17 beta-estradiol in men and postmenopausal women

● recommendations for biochemical testing for bilateral adrenal lesions 1

⚬ assess each adrenal lesion at initial detection according to same imaging protocol as for unilateral
adrenal masses to establish if either or both masses are malignant (ESE/ENSAT Strong
recommendation)
⚬ all patients with bilateral adrenal incidentalomas should have (ESE/ENSAT Strong recommendation)

– same clinical and hormonal assessment as patients with unilateral adrenal incidentaloma
– assessment of comorbidities that may be related to autonomous cortisol secretion
– measurement of serum 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia
– testing for adrenal insufficiency if clinically suspected or imaging indicates bilateral hemorrhages
or infiltrative disease

● recommendations for biochemical testing for adrenal malignancy in patients with extra-adrenal

malignancy with indeterminate mass (ESE/ENSAT Strong recommendation) 1

⚬ measure plasma or urinary metanephrines. to exclude pheochromocytoma even if mass is likely
metastasis, prior to considering biopsy
⚬ consider additional hormonal work-up based on individualized approach

● in patients with large bilateral adrenal metastases, assess residual adrenal function (ESE/ENSAT Strong

recommendation) 1

Biopsy and Pathology

● biopsy is not recommended for diagnosis of adrenal masses 1

⚬ unless there is history of extra-adrenal malignancy (ESE/ENSAT Strong recommendation)

⚬ when the adrenal mass is likely to be adrenal carcinoma

● only consider biopsy of adrenal mass if (ESE/ENSAT Weak recommendation) 1

⚬ lesion is indeterminate and patient has history of extra-adrenal malignancy

⚬ lesion is hormonally inactive
⚬ pheochromocytoma has been excluded
⚬ lesion is not conclusively benign by imaging
⚬ management may be altered depending on histology

● American College of Radiology Appropriateness Criteria for performing an adrenal biopsy for diagnosis

in adrenal incidentaloma 5
⚬ adrenal biopsy may be appropriate for patients with adrenal masses < 4 cm, with no diagnostic
benign imaging features, and with a history of malignancy
 ⚬ adrenal biopsy is usually appropriate for patients with adrenal masses > 4 cm, with no diagnostic
benign imaging features, and with a history of malignancy
⚬ adrenal biopsy is usually not appropriate in patients with adrenal masses without history of
malignancy

● fine needle aspiration (FNA) biopsy can be used to confirm diagnosis of metastatic disease, and may

rarely be required for staging and planning of oncologic treatments (AACE/AAES Grade D, BEL 4) 3
⚬ biopsy should not be done unless pheochromocytoma has been ruled out due to risk of hemorrhage
and hypertensive crisis (AACE/AAES Grade C, BEL 3)
⚬ complications of image-guided FNA biopsy may include

– abdominal pain
– hematuria
– adrenal hematoma or abscess
– pancreatitis
– pneumothorax
– tumor recurrence along needle track

⚬ computed tomography-guided FNA biopsy may be performed to differentiate adrenal from non-
adrenal tissues if metastasis or infection is suspected on imaging, but cannot distinguish adrenal
carcinoma from benign adenoma
⚬ if metastatic disease is unlikely, an open adrenalectomy for a suspected adrenal carcinoma should

be pursued for diagnosis and treatment, rather than biopsy (AACE/AAES Grade D, BEL 4) 3

STUDY
● SUMMARY
biopsy of adrenal tumors may have high specificity and moderate sensitivity for diagnosing
malignant and metastatic lesions, but may have low sensitivity for ruling out adrenocortical
carcinoma DynaMed Level 2

SYSTEMATIC REVIEW: Eur J Endocrinol 2016 Aug;175(2):R65

Details

⚬ based on systematic review with methodological limitations

⚬ systematic review of 32 observational studies evaluating the performance of adrenal biopsy for
diagnosis of adrenal malignancy in 2,174 patients (mean age 60 years, 60.6% men) having 2,190
adrenal mass biopsy procedures
⚬ all studies included in metaanalysis had ≥ 1 limitation including

– inappropriate patient selection or exclusion

– suboptimal reference standard
– inadequate follow-up

⚬ reference standard was any of

– histology following adrenalectomy or autopsy

– imaging follow-up after 3-12 months
– clinical follow-up for ≥ 2 years

⚬ malignancy in 828 lesions (51%) of 1,621 lesions for which pathology was available
⚬ pooled complication rate 2.5% (95% CI 1.5%–3.4%) in analysis of 25 studies with 1,339 biopsies
⚬ pooled non-diagnostic rate 8.7% (95%CI 6.2%–11.2%) in analysis of 30 studies with 2,013 adrenal
biopsies, results limited by significant heterogeneity
⚬ pooled diagnostic performance of adrenal biopsy

– for overall malignancy

 ● sensitivity 87% (95% CI 78%-93%) in analysis of 7 studies with 217 patients
● specificity 100% (95% CI 76%-100%) in analysis of 7 studies with 217 patients

– for adrenocortical carcinoma

● sensitivity 70% (95% CI 42%-88%) in analysis of 4 studies with 107 patients

● specificity 98% (95% CI 86%-100%) in analysis of 4 studies with 107 patients

– for metastasis of an extra-adrenal primary tumor

● sensitivity 87% (95% CI 74%-94%) in analysis of 5 studies with 131 patients

● specificity 96% (95% CI 89%-98%) in analysis of 5 studies with 131 patients

⚬ Reference - Eur J Endocrinol 2016 Aug;175(2):R65

Management
Management Overview

● all patients with adrenal incidentaloma may benefit from management by a multidisciplinary team with

expertise in adrenal tumors 1 , 2

⚬ team should consist of an endocrinologist, radiologist, pathologist, and a surgeon
⚬ team should have access to anesthetists and an endocrine pathologist with experience in adrenal
tumors
⚬ patients are most likely to benefit if they meet one of the following criteria

– imaging shows evidence of malignancy

– there is evidence of hormonal excess
– there is evidence of significant tumor growth during follow-up imaging
– adrenal surgery is considered

● surgical management

⚬ surgery is not recommended for patients with asymptomatic, nonfunctioning unilateral adrenal
masses with obvious benign features on imaging studies (ESE/ENSAT Strong recommendation, Very
low quality evidence)
⚬ rule out pheochromocytoma biochemically prior to resection or biopsy of any adrenal mass
(AACE/AAES Grade C, BEL 3)
⚬ adrenalectomy is recommended in patients with unilateral tumors with clinically significant hormone
excess (ESE/ENSAT Strong recommendation)
⚬ for subclinical Cushing syndrome, surgical resection should be limited to patients with worsening
hypertension, abnormal glucose tolerance, dyslipidemia, and/or osteoporosis surgical resection
(AACE/AAES Grade D, BEL 4)
⚬ for primary aldosteronism with unilateral source of aldosterone excess, laparoscopic total
adrenalectomy is treatment of choice due to excellent outcomes and low morbidity risk relative to
open approaches (AACE/AAES Grade C, BEL 3)
⚬ perform surgical resection for all pheochromocytomas and give alpha-adrenergic blocking agent
preoperatively to reduce risk of intraoperative hemodynamic instability (AACE/AAES Grade C, BEL 3)

● management of suspected malignancy

⚬ resect any adrenal mass with concerning radiographic characteristics and most lesions ≥ 4 cm due to
increased risk of adrenal cancer (AACE/AAES Grade C, BEL 3)
⚬ consider performing laparoscopic adrenalectomy in patients with unilateral masses ≤ 6 cm and
suspicion of malignancy, but without evidence of local invasion (ESE/ENSAT Weak recommendation,
Very low quality evidence)
⚬ perform open adrenalectomy if adrenal cortical carcinoma is suspected (AACE/AAES Grade C, BEL 3)
 ⚬ open adrenalectomy is recommended for unilateral adrenal masses with suspicion of malignancy
and signs of local invasion (ESE/ENSAT Strong recommendation)

● follow-up monitoring

⚬ hormonal evaluation should be performed annually for 5 years for all adrenal tumors (AACE/AAES
Grade C, BEL 3)
⚬ if no surgical resection performed

– reevaluate radiographically in 3-6 months, then annually for 1-2 years (AACE/AAES Grade C, BEL 3)
– further imaging for follow-up may not be required if adrenal lesions < 4 cm in diameter with
benign characteristics (ESE/ENSAT Weak recommendation, Very low quality evidence
⚬ in patients with a history of extra-adrenal malignancy, follow-up imaging recommended to assess
potential growth of lesion at the same time interval as imaging of the primary malignancy, or
consider fluorodeoxyglucose-positron emission tomography/computed tomography, surgical
resection, or biopsy (ESE/ENSAT Strong recommendation)

Adrenal Cortical Adenoma

● surgical recommendations for adrenal cortical adenoma 1

⚬ adrenalectomy is recommended in patients with unilateral tumors with clinically significant hormone
excess (ESE/ENSAT Strong recommendation)
⚬ consider confirming adrenocorticotropic hormone-independency of cortisol excess in all patients
considered for surgery (ESE/ENSAT Weak recommendation)
⚬ surgery is not recommended for patients with asymptomatic, nonfunctioning unilateral adrenal
masses with obvious benign features on imaging studies (ESE/ENSAT Strong recommendation, Very
low quality evidence)
⚬ perioperative glucocorticoid treatment at major surgical stress doses is recommended in patients
having surgery, who do not suppress to < 5 mcg/dL (< 50 nmol/L) after 1 mg dexamethasone
overnight (ESE/ENSAT Strong recommendation)

● after adrenalectomy for a cortisol-producing adenoma, patients should be treated with exogenous
glucocorticoids until hypothalamic-pituitary-adrenal (HPA) axis has recovered, which may take 6-18
months (AACE/AAES Grade C, BEL 3) 3

● for patients with adrenal cortical adenoma with autonomous cortisol secretion (subclinical Cushing
syndrome)
⚬ until further evidence is available regarding long-term benefits of adrenalectomy, surgical resection

should be limited to patients with any of (AACE/AAES Grade D, BEL 4) 3

– worsening of hypertension
– abnormal glucose tolerance
– dyslipidemia
– osteoporosis

⚬ consider individualized approach to adrenal surgery for patients with autonomous cortisol secretion
due to benign adrenal adenoma, taking into account (ESE/ENSAT Weak recommendation, Very low
quality evidence) 1
– age
– degree of cortisol excess
– general health
– comorbidities
– patient preference
 ⚬ of patients who have surgery 1

– about 10-48% are reported to have improvement of glucose levels

– improvement in hypertension and dyslipidemia have been reported in some patients

⚬ offer perioperative glucocorticoid therapy and postoperative assessment of HPA axis recovery

(AACE/AAES Grade C, BEL 3) 3

⚬ consider screening for asymptomatic vertebral fractures and treating conditions as appropriate

(ESE/ENSAT Weak recommendation, Very low quality evidence) 1

Autonomous Cortisol Secretion

● for cortisol-producing adenoma with signs or symptoms of hypercortisolism (Cushing syndrome)

⚬ surgical resection of adrenal tumor is primary treatment of choice (BMJ 2013 Mar 27;346:f945 )
⚬ after adrenalectomy, treat with exogenous glucocorticoids until hypothalamic-pituitary-adrenal

(HPA) axis has recovered (typically 6-18 months) (AACE/AAES Grade C, BEL 3) 3

● for cortisol-producing adenoma without signs and symptoms of hypercortisolism (subclinical Cushing

syndrome) 2 , 3
⚬ adrenalectomy reserved for patients with worsening hypertension, abnormal glucose tolerance,
osteoporosis, or dyslipidemia (AACE/AAES Grade D, BEL 4)
⚬ provide perioperative glucocorticoid therapy and postoperative evaluation of HPA axis (AACE/AAES
Grade C, BEL 3)

Aldosteronism

● for primary aldosteronism with unilateral source of aldosterone excess, laparoscopic adrenalectomy is
treatment of choice due to excellent outcomes and low morbidity risk relative to open approaches
(AACE/AAES Grade C, BEL 3) 3

● for bilateral idiopathic hyperaldosteronism or patients not amenable or agreeable to surgical

intervention, selective and nonselective mineralocorticoid receptor blockers recommended (AACE/AAES
Grade A, BEL 1) 3

Malignant Disease

● rule out pheochromocytoma biochemically prior to resection of any adrenal mass (AACE/AAES Grade C,

BEL 3) 3

● resect any adrenal mass with concerning radiographic characteristics and most lesions ≥ 4 cm due to

increased risk of adrenal cancer (AACE/AAES Grade C, BEL 3) 3

⚬ consider performing laparoscopic adrenalectomy in patients with unilateral masses ≤ 6 cm and
suspicion of malignancy, but without evidence of local invasion (ESE/ENSAT Weak recommendation,
Very low quality evidence) 1
⚬ perform open adrenalectomy if adrenal cortical carcinoma is suspected (AACE/AAES Grade C, BEL

3) 3
⚬ open adrenalectomy is recommended for unilateral adrenal masses with suspicion of malignancy

and signs of local invasion (ESE/ENSAT Strong recommendation) 1

● for patients with extra-adrenal malignancy

⚬ adrenal metastasectomy is rarely indicated but should be considered for patients with isolated

adrenal metastatic lesions (AACE/AAES Grade C, BEL 3) 3

 ⚬ consider surgical resection for indeterminate lesions (ESE/ENSAT Weak recommendation) 1

Bilateral Adrenal Incidentalomas

● indications for surgery and follow-up for patients with bilateral incidentalomas may be considered the
same as those for patients with unilateral adrenal incidentalomas (ESE/ENSAT Weak
recommendation) 1

● bilateral adrenalectomy should not be performed in patients with bilateral adrenal masses for
adrenocorticotropic hormone-independent autonomous cortisol secretion unless patient has clinical
signs of overt Cushing syndrome (ESE/ENSAT Weak recommendation) 1

● in select patients with bilateral adrenal masses, consider unilateral adrenalectomy of dominant lesion

based on individualized approach, taking into consideration (ESE/ENSAT Weak recommendation) 1

⚬ age
⚬ degree of cortisol excess
⚬ general condition
⚬ comorbidities
⚬ patient preference

Pheochromocytoma

● perform surgical resection for all pheochromocytomas (AACE/AAES Grade C, BEL 3) 3

● give alpha-adrenergic blocking agent preoperatively to reduce risk of intraoperative hemodynamic

instability (AACE/AAES Grade C, BEL 3) 3

Follow-up Monitoring
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons
(AACE/AAES) Recommendations

● monitoring 3

⚬ hormonal evaluation should be performed at diagnosis and then annually for 5 years for all adrenal
tumors (AACE/AAES Grade C, BEL 3)
⚬ if no surgical resection performed, reevaluate radiographically in 3-6 months, then annually for 1-2
years (AACE/AAES Grade C, BEL 3)

● consider excision if lesion grows > 1 cm or becomes hormonally active during follow-up 3

● long-term biochemical follow-up should be conducted after resection of pheochromocytoma due to

reported 10%-15% risk of recurrence (AACE/AAES Grade B, BEL 2) 3

European Society of Endocrinology (ESE)/European Network for the Study of Adrenal Tumors
(ENSAT) Recommendations

● follow-up of patients not having surgery 1

⚬ further imaging may not be required for follow-up of patients with adrenal lesions < 4 cm in
diameter and benign characteristics (ESE/ENSAT Weak recommendation, Very low quality evidence)
⚬ consider repeat noncontrast computed tomography or magnetic resonance imaging after 6-12
months for patients with indeterminate adrenal mass who choose not to have adrenalectomy after
initial assessment (ESE/ENSAT Weak recommendation, Very low quality evidence)
⚬ consider surgical resection if lesion enlarges by > 20% and diameter increases by ≥ 5 mm 6-12
months after initial assessment; consider performing additional imaging (noncontrast CT or MRI) if
 there is growth below this threshold (ESE/ENSAT Weak recommendation)
⚬ consider refraining from repeat hormonal testing for patient with normal hormonal work-up at initial
evaluation unless signs of endocrine activity appear or comorbidities worsen (ESE/ENSAT Weak
recommendation, Very low quality evidence)
⚬ consider annual clinical reassessment for signs of cortisol excess and comorbidities potentially
related to cortisol excess in patients with autonomous cortisol secretion (dexamethasone
suppression test result between 1.8 and 5) without signs of overt Cushing syndrome (ESE/ENSAT
Weak recommendation, Very low quality evidence)
⚬ consider surgery if signs of cortisol excess or comorbidities potentially related to cortisol excess are
present at reassessment (ESE/ENSAT Weak recommendation)

● in patients with a history of extra-adrenal malignancy, follow-up imaging recommended to assess

potential growth of lesion at the same time interval as imaging of the primary malignancy, or consider
fluorodeoxyglucose-positron emission tomography/computed tomography, surgical resection, or
biopsy (ESE/ENSAT Strong recommendation) 1

American College of Radiology Recommendations

● imaging follow-up for adrenal masses that appear to be benign 5

⚬ no follow-up imaging or additional workup is required for adrenal masses with typical features of
benign lesion (such as lipid-rich adenoma or myelolipoma)
⚬ if adrenal mass had nondiagnostic imaging features and lesion is stable for ≥ 1 year, lesion can be
deemed benign without further imaging follow-up
⚬ if adrenal mass is enlarging (growth of > 5 cm) after 1 year of follow-up, consider adrenal biopsy or
resection
⚬ if features appear benign on routine postcontrast computed tomography (CT) but unenhanced CT or
adrenal-specific imaging are unavailable, assume the lesion is benign and consider follow-up 1 year
later with unenhanced CT or magnetic resonance imaging (MRI) with chemical-shift imaging (CSI)
⚬ if imaging features are suspicious, proceed with unenhanced CT or MRI with CSI followed by adrenal
CT protocol with washout calculations if required

Complications
● complications of adrenal incidentaloma are typically due to local mass effect, excess hormone

secretion, or malignancy 2

● complications due to local mass effect may include back pain, abdominal discomfort, nausea, vomiting,
and abdominal fullness (Case Rep Surg 2013;2013:132726 full-text )

● complications in functioning adrenal masses include

⚬ hypercortisolism (specifically adrenocorticotropin hormone-independent Cushing Disease);

complications of Cushing Disease may include
– infertility (in men, in women)
– early osteoporosis (in men, in premenopausal women, in postmenopausal women)
– obesity
– hypertension
– new onset or worsening diabetes
– heart failure
– deep vein thrombosis
– myocardial infarction
– immunosuppression with recurrent or atypical infections
 ⚬ hyperaldosteronism; complications of hyperaldosteronism may include

– hypertension
– hypokalemia
– mild hypernatremia

⚬ excess catecholamines due to pheochromocytoma; complications of pheochromocytoma may

include
– cardiac arrhythmias (Med Clin (Barc) 2018 Nov 21;151(10):e57 )
– myocardial infarction (Adv Exp Med Biol 2017;956:239 )
– dissecting aortic aneurysm (Adv Exp Med Biol 2017;956:239 )
– hypertensive crisis (Adv Exp Med Biol 2017;956:239 )
– dilated cardiomyopathy or hypertrophic cardiomyopathy (Adv Exp Med Biol 2017;956:239 )
– heart failure (due to toxic cardiomyopathy) (Adv Exp Med Biol 2017;956:239 )
– stroke (Med Clin (Barc) 2018 Nov 21;151(10):e57 )
– retinal bleeding (Best Pract Res Clin Endocrinol Metab 2020 Mar;34(2):101354 )
– intestinal ischemia (Best Pract Res Clin Endocrinol Metab 2020 Mar;34(2):101354 )
– constipation (Adv Exp Med Biol 2017;956:239 )
– mass-effect complications if tumor continues to grow and compresses or extends into adjacent
tissue and organs (J Clin Endocrinol Metab 2014 Jun;99(6):1915 )
– see Pheochromocytoma and Paraganglioma for additional information

● adrenal cortical carcinomas

⚬ approximately 33% of adrenal cortical carcinomas will reportedly be functional and patients can
present with hypercortisolism, hyperandrogenism, or both, and rarely hyperaldosteronism
⚬ bleeding can occur due to hemorrhage of adrenocortical carcinoma
⚬ Reference -Nat Rev Endocrinol 2011 Jun;7(6):323

Prognosis
Adrenal Cortical Adenoma

● among patients with nonfunctioning adrenal incidentalomas 1

⚬ autonomous cortisol secretion (subclinical Cushings syndrome) reported in 0%-11%

⚬ overt Cushing syndrome reported in 0.3%
⚬ aldosterone-producing adenoma reported in 0%-2%
⚬ pheochromocytoma reported in 0%-2%

● malignancy reported to develop in 0.2% of patients initially thought to have adrenal cortical adenoma 1

● adrenal cortical adenoma with autonomous cortisol secretion is reported to be associated with

increased mortality 1 , 2 , 3

● autonomous cortisol secretion (subclinical Cushing syndrome) rarely progresses to overt Cushing

syndrome 1

● conservatively treated incidentalomas generally grow slowly and have low risk of malignancy or
progression to overt Cushing disease
⚬ based on systematic review of observational studies
⚬ systematic review of 32 observational studies evaluating natural history of nonfunctioning adrenal
tumors and adenomas causing mild autonomous cortisol excess in 4,121 adults (mean age 60 years)
receiving conservative management
⚬ mean follow-up 50.2 months
 ⚬ new adrenal cancer in 0% in analysis of 26 studies with 2,854 patients
⚬ new clinically apparent hormone excess in 0.2% in analysis of 23 studies with 2,745 patients
⚬ resolution of mild autonomous cortisol excess in < 0.1% in analysis of 17 studies with 840 patients
⚬ tumor growth ≥ 10 mm in 2.5% in analysis of 14 studies with 2,023 patients
⚬ mean tumor growth 2 mm over 52.8 months in analysis of 8 studies with 1,105 patients
⚬ mild autonomous cortisol excess in 4.3% of patients with nonfunctioning adrenal tumors in analysis
of 19 studies with 2,083 patients
⚬ Reference - Ann Intern Med 2019 Jul 16;171(2):107

STUDY
● SUMMARY
5- and 10-year survival reported to be about 96% in patients with Cushings due to adrenal cortical
adenoma

COHORT STUDY: Eur J Endocrinol 2013 Nov;169(5):715

Details

⚬ based on retrospective cohort study

⚬ 418 patients (median age 41 years) with endogenous Cushing syndrome were included

– Cushing disease in 311 patients (74.4%) with median follow-up 9 years (range 0.1-46 years)
– adrenal cortical adenoma in 74 patients (17.7%) with median follow-up 3 years (range 0.1-21
years)
– ectopic adrenocorticotropic hormone syndrome in 33 patients (7.9%) with median follow-up 4
years (range 0.1-18 years)
⚬ death in 2 patients (3%) with adrenal cortical adenoma during follow-up due to cardiovascular events
⚬ survival in patients with adrenal cortical adenoma

– 95.5% at 5 years
– 95.5% at 10 years

⚬ Reference - Eur J Endocrinol 2013 Nov;169(5):715

STUDY
● SUMMARY
post-dexamethasone cortisol > 1.8 mcg/dL associated with increased mortality in patients with
benign adrenal cortical adenoma

COHORT STUDY: J Clin Endocrinol Metab 2014 Dec;99(12):4462 | Full Text

Details

⚬ based on retrospective cohort study

⚬ 272 patients with lipid-rich benign adrenal cortical adenoma (precontrast density < 10 Hounsfield
units or increased contrast washout) were included
⚬ all patients had work-up for incidental adrenal mass with dedicated diagnostic protocol, including 1
mg dexamethasone overnight test for hypercortisolism
⚬ 21 patients (7.7%) lost to follow-up
⚬ 206 patients (75.7%) included in survival analysis after exclusion of patients taking steroids and
patients with pheochromocytoma, hyperaldosteronism, intra-adrenal malignancy, size increase at 6-
month follow-up, incidentaloma > 4 cm, or metabolic deterioration
⚬ death in 18 patients (8.7%) during mean 4.2 years follow-up

– mean 3.2 years from diagnosis to death

– cause of death

● circulatory in 9 patients (50%)

 ● respiratory/infectious in 6 patients (33.3%)
● malignancy in 1 patient (5.6%)
● other in 2 patients (11.1%)

⚬ compared to post-dexamethasone cortisol level < 1.8 mcg/dL, increased mortality in patients with

– post-dexamethasone cortisol level 1.8-5 mcg/dL (hazard ratio12, 95% CI 1.6-92.6)

– post-dexamethasone cortisol level > 5 mcg/dL (hazard ratio 22, 95% CI 2.6-188.3)

⚬ Reference - J Clin Endocrinol Metab 2014 Dec;99(12):4462 full-text

● see also Adrenal Cortical Adenoma

Aldosteronism

● blood pressure usually normalizes or reaches the nadir at 1-6 months after unilateral adrenalectomy,
but may decrease further in ≤ 1 year

● persistent hypoaldosteronism necessitating mineralocorticoid replacement therapy (fludrocortisone)

reported in up to 5% of patients after adrenalectomy

● Reference - Endocrine Society clinical practice guideline on detection, diagnosis, and treatment of
primary aldosteronism (J Clin Endocrinol Metab 2016 May;101(5):1889 )

● see Primary Aldosteronism for additional information

Adrenocortical Carcinoma
Survival

● patients with adrenocortical carcinoma have poor prognosis with tumor stage at presentation and

curative resection being two determinants of long-term survival 3

● reported European Network for the Study of Adrenal Tumors (ENSAT) stage-dependent survival at 5
years
⚬ 66%-82% in patients with stage 1 disease
⚬ 58%-64% in patients with stage 2 disease
⚬ 24%-50% in patients with stage 3 disease
⚬ 0%-17% in patients with stage 4 disease
⚬ Reference - Front Cell Dev Biol 2015;3:45 full-text

● reported 5-year mortality rate of approximately 75%-90% and average overall survival in patients with
adrenal cortical carcinoma 14.5 months (Endocrinol Metab Clin North Am 2015 Jun;44(2):399 )

● median survival for metastatic disease (stage IV) at time of diagnosis is < 1 year (Crit Rev Oncol Hematol
2014 Nov;92(2):123 full-text )

● prognostic factors associated with worse overall or recurrence-free survival include

⚬ higher disease stage at initial diagnosis and presence of distant metastasis

⚬ older age at diagnosis
⚬ greater extent of disease and higher rate of tumor growth
⚬ greater number of organs involved at time of first metastasis
⚬ site of first metastasis - patients with tumor recurrence in peritoneum outside tumor bed have
worse survival
⚬ incomplete resection of primary tumor
⚬ functional tumors, especially cortisol-producing tumors
⚬ presence of tumor necrosis and atypical mitotic figures
⚬ Weiss score > 6 and specifically high mitotic rate
 – > 5 per 50 high-power fields (HPF) in patients with complete resection
– > 9 per 50 HPF in patients with ENSAT stage 3/4 disease
– ≥ 20 per 50 HPF in patients with ENSAT stage 4 disease

⚬ Ki-67 proliferation index > 10%

⚬ genetic and molecular markers including

– inactivating mutations in TP53

– activating mutations in CTNNB1
– nuclear overexpression of steroidogenic factor 1 (SF-1)
– high levels of miR-485-5p and low levels of miR-195
– combined expression of BUB1B and PINK1

⚬ Reference - J Endocrinol Invest 2016 Jan;39(1):103

STUDY
● SUMMARY
Ki-67 proliferation index may help predict overall and recurrence-free survival in patients with
European Network for the Study of Adrenal Tumors stage 1-3 adrenocortical carcinoma
DynaMed Level 1

COHORT STUDY: J Clin Endocrinol Metab 2015 Mar;100(3):841

Details

⚬ based on prognostic cohort study with independent derivation and validation cohorts
⚬ derivation cohort included 319 patients from German registry with European Network for the Study
of Adrenal Tumors (ENSAT) stage 1-3 adrenocortical carcinoma who had initial complete (R0) tumor
resection
– factors associated with overall mortality in multivariate analysis

● Ki-67 index (adjusted hazard ratio [HR] 1.06 per 1%, 95% CI 1.04-1.08)
● ENSAT stage 3 (adjusted HR 2.16, 95% CI 1.02-4.56)
● presence of venous tumor thrombus in renal vein or vena cava (adjusted HR 2.14, 95% CI 1.08-
4.26)
● adjuvant mitotane therapy (adjusted HR 0.41, 95% CI 0.21-0.8)

– factors associated with decrease in recurrence-free survival in multivariate analysis

● Ki-67 index (adjusted HR 1.05 per 1%, 95% CI 1.03-1.06)

● ENSAT stage 3 (adjusted HR 1.78, 95% CI 1.03-3.06)
● tumor size 15-20 cm (adjusted HR 1.6, 95% CI 1.03-2.48)

⚬ validation cohort included 250 patients from ENSAT registry with ENSAT stage 1-3 adrenocortical
carcinoma who had initial R0 tumor resection
– factors associated with increased overall mortality in multivariate analysis

● Ki-67 index (adjusted HR 1.03 per 1%, 95% CI 1.01-1.04)

● tumor size (adjusted HR 1.83, 95% CI 1.07-3.13)

– factors associated with decreased recurrence-free survival in multivariate analysis

● Ki-67 index (adjusted HR 1.02 per 1%, 95% CI 1.01-1.03)

● ENSAT stage 3 (adjusted HR 2.68, 95% CI 1.27-5.65)
● presence of venous tumor thrombus in renal vein or vena cava (adjusted HR 1.83, 95% CI 1.11-
3.01)
⚬ Reference - J Clin Endocrinol Metab 2015 Mar;100(3):841

STUDY
● SUMMARY
cortisol excess and higher tumor stage associated with increased risk of recurrence and
complications, and decreased overall and recurrence-free survival after surgical resection

Am J Surg 2016 Jun;211(6):1106 | Full Text

Eur Urol 2014 Apr;65(4):832

Details

⚬ based on 2 retrospective cohort studies

⚬ 234 adults who had surgical resection of adrenocortical carcinoma between 1993 and 2014 were
included
– complete (R0) resection in 68.4%
– tumor stage T3/T4 according to American Joint Committee on Cancer seventh edition staging
system in 52.8%
– functional tumors in 40.6%
– cortisol-secreting tumors in 22.6%
– recurrence at last follow-up in 50.4%
– recurrence-free survival in 61% at 1 year and 28.8% at 5 years
– comparing patients with cortisol-secreting tumors vs. nonfunctional tumors

● median overall survival 18.6 months vs. 50.4 months (p < 0.001)
● median recurrence-free survival 10.5 months vs. 26 months (p = 0.001)
● metastatic disease in 34% vs. 10.8% (p < 0.001)
● length of hospital stay 7 days vs. 5.5 days (p < 0.05)
● postoperative need for mitotane therapy in 62.2% vs. 31.1% (p < 0.001)
● presence of complications including

⚬ postoperative adrenal insufficiency in 50% vs. 13.2% (p < 0.001)

⚬ leg edema in 41.2% vs. 9.6% (p < 0.001)

– in multivariate analysis, cortisol secretion associated with increased

● recurrence (adjusted hazard ratio 2.05, 95% CI 1.16-3.6)

● major postoperative complications within 30 days of surgical resection (adjusted odds ratio
3.09, 95% CI 1.1-8.7)
– Reference - Am J Surg 2016 Jun;211(6):1106 full-text
⚬ 524 adults who had complete resection of histologically confirmed adrenocortical carcinoma were
included
– median follow-up 50 months
– mortality in 38.9%
– clinical signs of cortisol excess with or without other hormone excess in 37.6%
– nonfunctional tumors in 47.2%
– disease recurrence during follow-up in 64.7%
– cortisol excess associated with decreased

● overall survival (adjusted hazard ratio [HR] 1.55, 95% CI 1.15-2.09)

● recurrence-free survival (adjusted HR 1.3, 95% CI 1.04-1.62)

– higher tumor stage associated with decreased

● overall survival (adjusted HR 2.64, 95% CI 1.97-3.55)

● recurrence-free survival (adjusted HR 1.63, 95% CI 1.31-2.03)

– Reference - Eur Urol 2014 Apr;65(4):832

STUDY
● SUMMARY
metastatic disease, presence of functioning tumor, and older age at diagnosis associated with poorer
overall survival in patients with adrenocortical carcinoma

COHORT STUDY: Eur J Endocrinol 2013 Dec;169(6):891 | Full Text

Details

⚬ based on retrospective cohort study

⚬ 330 patients (median age 48 years) with adrenocortical carcinoma diagnosed between 1998 and
2011 were included
– hormonal excess (including cortisol, aldosterone, and/or androgens) in 138 patients (41.8%)
– other malignancies in 38 patients (11.5%)

⚬ treatments included

– resection of primary tumor in 275 patients (83.3%) with negative resection margins in 153 patients
(55.6%)
– mitotane (either alone or in combination with other chemotherapy) in 235 patients (71.2%)
– radiation therapy (mostly palliative) in 58 patients (18%)

⚬ median overall survival 3.2 years

⚬ factors significantly associated with poorer increased survival in multivariate analysis

– functioning tumor compared with non-functioning tumor

– older age at diagnosis
– European Network for the Study of Adrenal Tumors stage 3-4

⚬ Reference - Eur J Endocrinol 2013 Dec;169(6):891 full-text

Recurrence

● two-thirds of patients who present with localized adrenal cortical carcinoma experience recurrence that
often requires systemic therapy (Curr Opin Endocrinol Diabetes Obes 2017 Jun;24(3):208 )

● Ki67 is a marker of cell proliferation widely used as an important prognostic marker of adrenocortical
carcinoma behavior (Curr Opin Endocrinol Diabetes Obes 2017 Jun;24(3):208 )

● risk of recurrence after adrenalectomy is determined by tumor stage, resection status, and Ki-67 index

⚬ patients at low risk meet all of the following criteria

– stage 1-2
– R0 resection
– Ki-67 index < 10%

⚬ patients at intermediate risk meet all of the following criteria

– stage 3
– R0 resection
– N0 category
– Ki-67 index < 10%

⚬ patients at high risk have stage 3 tumor and meet any of the following criteria

– R1 or R2 resection
– N1 category
– Ki-67 index > 10%
– tumor spillage

⚬ Reference - Br J Surg 2017 Mar;104(4):358

Metastatic Disease
● more than half of patients with adrenocortical carcinoma will develop distant metastases despite
complete initial resection of primary tumor (Br J Surg 2017 Mar;104(4):358 )

● metastases of adrenocortical carcinoma reported in

⚬ liver (48%-85%)
⚬ lung (30%-60%)
⚬ lymph nodes (7%-20%)
⚬ bone (7%-13%)
⚬ Reference - Endocrinol Metab Clin North Am 2015 Jun;44(2):399

● metastatic adrenocortical carcinoma is heterogeneous

⚬ overall 5-year survival rate in patients with metastatic disease reported to be < 20%, with median
survival 6-20 months
⚬ longer survival has been reported in some patients following resection and repeated surgery
⚬ extremely long survival reported in some patients with resectable oligometastatic disease with long
intervals among recurrences
⚬ Reference - Br J Surg 2017 Mar;104(4):358

● see Adrenocortical Carcinoma for additional information

Adrenal Metastasis

STUDY
● SUMMARY
synchronous metastasis and tumor size ≥ 4 cm may be associated with shorter overall survival in
adults with solid adrenal metastasis

COHORT STUDY: Asia Pac J Clin Oncol 2020 Apr;16(2):e86

Details

⚬ based on retrospective cohort study

⚬ 25 adults (median age 67 years, 68% men) with solid adrenal metastasis were included

– laparoscopic adrenalectomy in 14 adults (56%)

– open adrenalectomy in 11 adults (44%)

⚬ median follow-up 32 months (range 2–144 months)

⚬ progression-free survival in 53% at 1 year and 24% at 2 years
⚬ median progression-free survival 14 months
⚬ median overall survival 63 months
⚬ factors associated with shorter overall survival in adults with adrenal metastasis

– synchronous metastasis compared to metachronous metastasis (adjusted hazard ratio 7.5, 95% CI
1.1-73.8)
– tumor size ≥ 4 cm (adjusted hazard ratio 17.7, 95% CI 2.7-237.1)

⚬ no significant associations found between patient age, primary malignancy site, or type of surgery
and overall survival in adjusted analysis
⚬ Reference - Asia Pac J Clin Oncol 2020 Apr;16(2):e86

STUDY
● SUMMARY
no previous metastasectomy and adrenalectomy for cure may be associated with increased survival
in adults with adrenal metastasis

COHORT STUDY: Eur J Surg Oncol 2010 Jul;36(7):699

 Details

⚬ based on retrospective cohort study

⚬ 30 adults (mean age 60 years) having adrenalectomy for metastasis to the adrenal gland were
included
⚬ median overall survival 23 months
⚬ median disease-free survival 6 months
⚬ independent factors associated with increased survival

– no previous metastasectomy compared with previous metastasectomy (HR 5.8, p = 0.02)

– adrenalectomy for cure achieved compared to not achieved (HR = 4.9, p = 0.01)

⚬ non-small cell lung cancer associated with decreased survival compared with colorectal cancer (HR
37.6, p = 0.008)
⚬ no significant associations found between other types of tumors (renal cell carcinoma, malignant
melanoma, or other), synchronous or metachronous presentation, size of metastasis, or surgical
technique and overall survival in adjusted analysis
⚬ Reference - Eur J Surg Oncol 2010 Jul;36(7):699

Pheochromocytoma

● surgery with removal of nonmetastatic solitary tumor achieves biochemical cure (N Engl J Med 2019 Nov
7;381(19):1882 )

● following tumor resection, patients may be at risk for

⚬ tumor persistence due to incomplete tumor resection or tumor spillage during surgery
⚬ new tumoral events or recurrences which may be local or metastatic
⚬ Reference - Eur J Endocrinol 2016 May;174(5):G1

● mortality can occur in patients with pheochromocytoma or paraganglioma who undergo any surgery
without preoperative medication management
⚬ most common causes of surgical mortality include hypertensive crisis, malignant arrhythmias, and
multiorgan failure
⚬ mortality can occur even in normotensive and asymptomatic patients due to the release of high
levels of circulating catecholamines during surgery
⚬ Reference - Adv Exp Med Biol 2017;956:239

● see Pheochromocytoma and Paraganglioma for additional information

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