Incidental Adrenal Mass

Incidental Adrenal Mass – 9 Interesting Facts

Incidental adrenal masses or adrenal incidentalomas are defined as adrenal masses 1 cm or larger identified on imaging performed for indications other than suspected adrenal disease or workup of an underlying malignancy ¹
Approach to a patient with an incidentally discovered adrenal mass involves assessment of malignant potential with radiologic imaging and evaluation of adrenal hormonal secretion with biochemical testing
Adrenocortical adenomas account for approximately 80% of adrenal incidentalomas ²
Adrenocortical adenomas are benign neoplasms arising from the adrenal cortex; the majority are nonfunctional and are identified on imaging performed for unrelated indications
A small proportion of adrenocortical adenomas secrete hormones in excess, most often at a subclinical level; overt symptoms may be identified in unusual cases
Functional adrenal adenomas most often secrete excess cortisol, leading to subclinical or overt Cushing syndrome; oversecretion of other adrenal steroid hormones is possible
Management options include adrenalectomy or observation; selection depends on several factors including likelihood of malignancy, secretory profile, and general health status of patient
Unilateral laparoscopic adrenalectomy is recommended for adrenocortical adenomas associated with clinical syndromes of hormone excess
Medical therapy for hormone excess may be required before surgery or as primary therapy for patients who are not surgical candidates

Pitfalls

Patients with the incidental finding of an adrenal tumor on imaging should undergo a thorough clinical and hormonal evaluation to determine whether the mass is malignant and/or functional ³
- Inadequate evaluations put patients at increased risk for a missed cancer diagnosis or development of adverse cardiometabolic outcomes ⁴
Although size is historically thought to predict a malignant adrenal neoplasm, there is no safe absolute tumor size threshold to rule out malignancy because adrenal carcinomas can be smaller than 4 cm ⁵
Management of subclinical hypercortisolism is controversial and challenging. Because hypertension, diabetes, osteoporosis, and obesity are common diseases, establishing whether these are directly related to the low-grade excess cortisol secretion in a given individual is not straightforward ⁶
- Consequently, it is difficult to predict whether surgical resection of the adrenal adenoma in a given individual will reduce the risk of these complications

Introduction

Incidental adrenal mass (also known as adrenal incidentaloma) is defined as an adrenal mass of 1 cm or larger ⁸ identified on imaging performed for indications other than suspected adrenal disease (eg, Cushing disease, pheochromocytoma) or workup of an underlying malignancy ¹⁷
- Found serendipitously on approximately 4% of abdominal CT scans ⁷
  - In light of technological improvements in imaging, their frequency is expected to increase
Adrenocortical adenomas ²
- Account for approximately 80% of adrenal incidentalomas ²
- Benign neoplasms arising from the adrenal cortex
- Most are nonfunctional, but a small proportion of adrenocortical adenomas secrete hormones in excess (most often at a subclinical level)
  - Mild autonomous cortisol secretion is the most common hormone abnormality found with adrenal incidental masses if an abnormality occurs at all
    - In some cases, the condition of low-grade, mild autonomous cortisol secretion may be associated with certain comorbidities (eg, hypertension, type 2 diabetes mellitus) ⁹ ¹⁰
    - State of clinically unapparent, mild autonomous cortisol secretion and associated comorbidities typically progress over time but rarely develop into overt Cushing syndrome ⁹ ¹⁰
  - Overt signs and symptoms of adrenal hormone excess may be observed/elicited at the time an adrenal mass is discovered in highly unusual cases
Framework for evaluating and managing incidental adrenal masses is based on a body of evidence that is derived from data extracted from cohort studies, retrospective studies, and expert opinion

Classification

Primary adrenal tumors
- Adrenocortical adenoma ¹¹
  - Benign tumor arising from adrenal cortex; majority are nonfunctioning
  - Common: prevalence of approximately 6% in autopsy studies and approximately 4% in CT radiology series ⁴ ¹²
- Adrenocortical carcinoma
  - Malignant tumor arising from cells of the adrenal cortex
  - 60% are functional and most secrete multiple hormones ¹³
  - Very rare: annual incidence is estimated to be 1 to 2 per million ¹¹
- Pheochromocytoma ¹⁴
  - Tumor arising from chromaffin cells of the adrenal medulla
  - Secretes catecholamines and catecholamine metabolites
  - Annual incidence of approximately 2 to 8 per million ¹⁴
    - Approximately 60% of pheochromocytomas were discovered in presymptomatic stage during evaluation of adrenal incidentaloma in a retrospective study ¹⁵
    - Pheochromocytomas account for up to 5% of adrenal incidentalomas ¹⁶
Classification of adrenocortical tumors according to biological activity
- Nonfunctioning/hormonally inactive
- Functioning
  - Glucocorticoid secreting
  - Mineralocorticoid secreting
  - Androgen secreting
  - Estrogen secreting

Diagnosis

Clinical Presentation

History

In most cases of an incidentally discovered adrenal mass, no symptoms are attributable to the mass
- Nonfunctioning adrenal incidentalomas that are adenomas usually do not produce symptoms
Symptoms related to excess adrenal hormones with incidentally discovered functioning adrenal masses (either adenomas, carcinomas, or pheochromocytomas) can be elicited with directed questioning on review of systems in unusual cases
- Cortisol-secreting tumors (subclinical or overt Cushing syndrome)
  - Patients with hypercortisolism resulting from adrenal adenomas, including those discovered incidentally, usually do not acknowledge overt cushingoid symptoms but instead most often exhibit subclinical hypercortisolism ¹⁷
    - Subclinical hypercortisolism is a pathologic condition defined as biochemical evidence of glucocorticoid secretory autonomy in patients who do not display overt signs or symptoms of Cushing syndrome
    - Also referred to as mild autonomous cortisol secretion
  - Symptoms of overt Cushing syndrome, when they occur, could indicate an adenoma or carcinoma and include:
    - Weight gain with central redistribution of body fat
    - Excessive facial or bodily hair in females
    - Proximal muscle weakness
    - Easy bruising
    - Depressed mood
    - Fatigue
  - Slowly evolving symptoms of overt Cushing syndrome are more likely to represent an adenoma, whereas rapidly progressive symptoms are concerning for carcinoma
- Aldosterone-secreting tumors (aldosteronoma)
  - Symptoms could include muscle weakness, muscle cramping, fatigue, headache, and nocturia
  - May be a history of hypertension that requires multiple medications to control
- Androgen-secreting tumors
  - Symptoms in female patients could include:
    - Oligomenorrhea
    - Amenorrhea
    - Excessive facial or bodily hair growth (hirsutism)
    - Deepening of voice
    - Male pattern scalp hair loss
  - Note that slowly evolving symptoms are more likely to represent an adenoma, whereas rapidly progressive symptoms of true virilization are concerning for carcinoma
- Estrogen-secreting tumors
  - Symptoms in males could include gynecomastia or reduced size of testes
- Catecholamine-secreting tumors (pheochromocytomas)
  - Incidentally discovered pheochromocytomas are uncommon and are usually not associated with the classic triad of episodic headaches, palpitations, and diaphoresis ¹⁶
  - Some patients might report a history of hypertension or recent onset of glucose intolerance or diabetes
  - Some patients might report a family history of multiple endocrine neoplasia type 2, von Hippel–Lindau disease, neurofibromatosis 1, or pheochromocytoma ⁵
In cases of adrenal metastases, there is usually a history of a nonadrenal primary malignancy (eg, breast, lung, renal)
- Among these, there may be constitutional symptoms of weight loss or fatigue
For adrenal hemorrhage, there may be a history of anticoagulant medication use and an episode of abrupt-onset flank pain
For adrenocortical carcinoma, some patients might report a family history of Li-Fraumeni syndrome or Lynch syndrome ¹⁸
- Very rarely, patients may (on questioning) admit to nonspecific symptoms from an abdominal mass, such as abdominal discomfort (ie, nausea, vomiting, or abdominal fullness) or back pain; however, this is unusual with an incidentally discovered mass ¹⁹

Physical examination

Findings are often normal; they depend on nature of the underlying tumor
Hypersecretion of cortisol
- Patients with hypercortisolism resulting from adrenal adenomas that are discovered incidentally usually do not present with overt cushingoid stigmata (eg, facial plethora, purple-red abdominal striae, muscle weakness, moon facies) ¹⁷
  - Signs that could be attributed to subclinical hypercortisolism may be present (eg, abdominal obesity, hypertension)
  - Conditions of subclinical to overt Cushing disease range along a spectrum
- Overt signs of Cushing syndrome from chronic cortisol excess include:
  - Hypertension (shared by both subclinical and overt)
  - Centripetal obesity (shared by both subclinical and overt)
  - Wide purple-red abdominal and/or axillary striae
  - Hirsutism
  - Dorsocervical fullness (buffalo hump) and supraclavicular fat pads
  - Facial plethora (moon facies)
  - Unusual number of ecchymoses
  - Proximal muscle weakness
Hypersecretion of aldosterone (aldosteronoma)
- Hypertension with or without spontaneous hypokalemia
Hypersecretion of sex steroids (rare)
- Female patients with androgen-secreting tumors may show signs of virilization (eg, hirsutism, deepening of voice, male pattern temporal balding)
- Male patients with estrogen-secreting tumors may have gynecomastia and atrophy of testes
Hypersecretion of catecholamines
- Hypertension, which may be labile ²⁰

Causes and Risk Factors

Causes

Benign ⁵
- Adrenocortical adenoma
- Pheochromocytoma
- Infections
  - Fungal: histoplasmosis, coccidioidomycosis, blastomycosis
  - Bacterial: tuberculosis, syphilis
  - Parasitic: echinococcosis
  - Viral: cytomegalovirus
- Adrenal hemorrhage or hematoma
- Adrenal infiltration or granulomatous disease
  - Sarcoidosis
  - Amyloidosis
- Myelolipoma
- Cyst
- Accessory spleen
- Rarer tumors:
  - Lymphangioma
  - Ganglioneuroma
  - Hemangioma
  - Schwannoma
Malignant ⁵
- Adrenocortical carcinoma
- Adrenal metastasis from nonadrenal primary malignancy
  - Most common are renal, lung, breast, and melanoma
- Pheochromocytoma
- Neuroblastoma

Risk factors and/or associations

Age

Can occur at any age; prevalence increases with increasing age

Sex

No difference in prevalence between sexes

Genetics

Some cortisol-secreting adenomas are associated with activating mutations in PRKACA ²¹
Loss-of-function mutations of the glucocorticoid receptor gene (NR3C1) may be associated with bilateral adrenal incidentalomas ²² ²³
Several additional genetic mutations can be associated with adrenal tumors, which can initially manifest as incidental adrenal masses ²⁴

Other risk factors/associations

Congenital adrenal hyperplasia (often bilateral masses) ²⁵

Diagnostic Procedures

Algorithm for evaluation of an incidentally detected adrenal mass. – (1) Consider biochemical assays to determine functional status and exclude pheochromocytoma before biopsy/resection. (2) “No enhancement” applies if an examination without and with IV contrast is available. (3) “Isolated” defined as no other metastatic disease identified. (4) May consider chemical shift MRI. APW, absolute percentage washout. Ca++, calcification. CS-MR, chemical shift MRI. F/U, follow-up. HU, Hounsfield units. Hx, history. NCCT, CT without IV contrast. RPW, relative percentage washout. +, positive.From Mayo-Smith WW et al: Management of incidental adrenal masses: a white paper of the ACR incidental findings committee. J Am Coll Radiol. 14(8):1038-44, 2017, Figure 1.

Primary diagnostic tools

Evaluation of an incidental adrenal mass consists of 2 fundamental issues: ⁴
- Assessment of malignant potential, and
- Determination of autonomous (excess) adrenal hormone secretion
Sequence of diagnostic tests in this evaluation may be variable, depending on the specific circumstances
- An incidentally discovered adrenal mass smaller than 1 cm may not need to be pursued ²⁶
Evaluation of malignant potential begins with assessment of radiographic appearance of the mass
- Determination of malignant potential is usually a function of radiographic characteristics and size of the adrenal mass
- In addition to size, specific features to consider include:
  - Lipid content
    - Attenuation values on unenhanced CT; assessment may be aided by imaging protocols that measure contrast avidity and washout on CT and chemical shift on MRI
  - Shape
  - Margins
  - Invasion
  - Heterogeneity
  - Necrosis
  - Calcifications
- The malignancy assessment may be complemented by procuring additional imaging with an adrenal protocol CT or MRI, or (in unusual indeterminate cases) fluorodeoxyglucose F 18 PET ²⁷
  - Adrenal protocols use thin cuts (2-3 mm) through the adrenal glands with 4 phases of image capture:
    - Noncontrast
    - Early arterial
    - Venous
    - Delayed washout
  - Fluorodeoxyglucose F 18 PET or PET-CT is possible depending on local availability and radiologic expertise
- Even when radiographic characteristics support an adrenal mass as being benign, perform a biochemical evaluation for adrenal hormone excess ⁴

Radiographic characteristics of adrenal masses.

Characteristics	Favors benign pathology	Favors malignant pathology
Size	Less than 4 cm	4-6 cm or greater
Margins or shape	Regular, smooth, with no invasion	Irregular
Homogeneous or heterogeneous interior content	Homogeneous	Heterogeneous
Necrosis	No necrosis	Necrosis present
Rate of growth (if serial examinations available)	Less than 1 cm per year	1 cm per year or greater
Attenuation on unenhanced CT	Less than 10 HU	10 HU or greater
Contrast washout on CT	Absolute, greater than 60%; relative, greater than 40%	Absolute, 60% or less; relative, 40% or less
MRI chemical shift	Yes	No
FDG avidity on PET	Not FDG avid	FDG avid (high SUV)

Caption: HU, Hounsfield units; FDG, fluorodeoxyglucose; SUV, standardized uptake value.

Citation: Data from Sahdev A: Recommendations for the management of adrenal incidentalomas: what is pertinent for radiologists? Br J Radiol. 90(1072):20160627, 2017; Zeiger MA et al: Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab. 96(7):2004-15, 2011; Vaidya A et al: The evaluation of incidentally discovered adrenal masses. Endocr Pract. 25(2):178-92, 2019; Lee JM et al: Clinical guidelines for the management of adrenal incidentaloma. Endocrinol Metab (Seoul). 32(2):200-18, 2017; Dinnes J et al: Management of endocrine disease: imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis. Eur J Endocrinol. 175(2):R51-64, 2016; Hamrahian AH et al: Clinical utility of noncontrast computed tomography attenuation value (Hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol Metab. 90(2):871-7, 2005; Marty M et al: Diagnostic accuracy of computed tomography to identify adenomas among adrenal incidentalomas in an endocrinological population. Eur J Endocrinol. 178(5):439-46, 2018; Iñiguez-Ariza NM et al: Clinical, biochemical, and radiological characteristics of a single-center retrospective cohort of 705 large adrenal tumors. Mayo Clin Proc Innov Qual Outcomes. 2(1):30-9, 2018; Mantero F et al: A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 85(2):637-44, 2000; Kim SJ et al: Diagnostic accuracy of 18F-FDG PET or PET/CT for the characterization of adrenal masses: a systematic review and meta-analysis. Br J Radiol. 91(1086):20170520, 2018; and Akkus G et al: Diagnostic efficacy of 18F-FDG PET/CT in patients with adrenal incidentaloma. Endocr Connect. 8(7): 838-45, 2019.

All patients with an incidental adrenal mass require evaluation for excess cortisol secretion; evaluation for excess secretion of aldosterone, catecholamines, and sex steroids is recommended for select patients with certain clinical or radiographic findings ⁷²⁶

Start assessment with history and physical examination to inquire about symptoms and signs of adrenal hormone excess (ie, clinical features of Cushing syndrome, hyperaldosteronism, or pheochromocytoma)
- Suspect hypercortisolism when an adrenal incidentaloma is identified in patients with poorly controlled diabetes, hypertension, or unexplained osteoporosis (particularly when multiple features are present and progressive) ¹⁷
- Patients without overt Cushing syndrome but elevated cortisol levels (mild autonomous cortisol secretion or MACS) have increased risk for morbidity and mortality and require identification by cortisol testing ²⁶
Initial laboratory testing ¹³²⁶
- Evaluate for cortisol excess in all patients with either 1 mg overnight dexamethasone suppression test, 2 to 3 late-night salivary cortisol levels, or 24-hour urinary free cortisol level ²⁶ ²⁸
- Evaluate for aldosterone excess in patients with hypertension or hypokalemia with measurement of serum aldosterone and plasma renin activity
- Evaluate for catecholamine excess in all patients with imaging features not typical for benign adenoma with plasma free or 24-hour urinary fractionated metanephrine and normetanephrine levels
  - Also consider serum or 24-hour urine catecholamines and methoxytyramine
- Evaluate for sex steroid excess: in symptomatic females, with measurements of testosterone and dehydroepiandrosterone sulfate; in symptomatic males, with measurement of 17β-estradiol
  - Imaging features suggestive of adrenocortical carcinoma are also an indication for measurement of sex steroids
Finding that multiple hormones are secreted in excess increases probability of malignancy ¹³

Biochemical evaluation of incidental adrenal masses.

Adrenal entity	Testing indications	Preferred initial test	Interpretation
Cortisol-secreting adenoma	All adrenal incidentalomas †	1 mg overnight dexamethasone suppression test (alternatives are 2–3 midnight salivary cortisols or 24-hour urinary free cortisol)	Cortisol > 1.8 mcg/dL (> 50 nmol/dL) in those without overt Cushing syndrome indicates mild autonomous cortisol secretion (MACS); confirm with repeat DST and ACTH
Aldosterone-secreting adenoma	Hypertension or hypokalemia	Serum aldosterone and serum aldosterone level to plasma renin activity ratio	Aldosterone to renin ratio greater than 20:1 or 30:1 Plasma aldosterone level greater than10 ng/dL
Pheochromocytoma	Lipid-poor adrenal mass with 10 HU or greater on CT; be sure to exclude with biochemical measurements before needle biopsy of any adrenal mass	Plasma or 24-hour urinary fractionated metanephrines and normetanephrines	Greater than 2- to 4-fold above the reference range
Androgen-secreting adenoma	Hirsutism or virilization in a female or imaging features suspicious for adrenocortical carcinoma	DHEA-S and total testosterone	Greater than upper reference limit for the assay performed
Estrogen-secreting adenoma	Feminization signs in a male or imaging features suspicious for adrenocortical carcinoma	Estradiol	Greater than male-specific upper reference limit for the assay performed

Caption: DST, dexamethasone suppression test; HU, Hounsfield units; DHEA-S, dehydroepiandrosterone sulfate. † May not be warranted in frail patients with limited life expectancy

Citation: Data from National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Neuroendocrine and Adrenal Tumors. Version 1.2023. Updated August 2, 2023. Accessed November 29, 2023. https://www.nccn.org/; Berruti A et al: Adrenal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 23(Suppl 7):vii131-8, 2012; Pappachan JM et al: Cushing’s syndrome: a practical approach to diagnosis and differential diagnoses. J Clin Pathol. 70(4):350-9, 2017; Funder JW et al: The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 101(5):1889-916, 2016; and Jason DS et al: Evaluation of an adrenal incidentaloma. Surg Clin North Am. 99(4):721-9, 2019.

Adrenal biopsy has a limited role in the evaluation of an incidental adrenal mass
- Biopsy of an adrenal mass may be considered in the following circumstances:
  - Patient has a known extra-adrenal malignancy, metastasis is the suspected cause of the adrenal mass, and results of the biopsy are likely to influence management of the primary malignancy (eg, surgery for limited disease or chemotherapy for metastatic disease) ²⁹
    - Suspect extra-adrenal metastasis in patient with either of the following:
      - History of nonadrenal cancer
      - Bilateral adrenal masses and radiographic appearance of the mass that is dense, vascular, and/or has an irregular shape
  - An infectious cause is likely (eg, mycobacterium, fungal organisms including histoplasmosis) and there are no other means of confirming the diagnosis
    - Patients with AIDS or other diseases associated with immunosuppression or patients living in endemic regions of fungal diseases may be at risk
  - An adrenal mass is deemed indeterminate, measures 1 to 4 cm, and has either grown or remains indeterminate after all additional imaging options are exhausted ³⁰ ³¹
- Biopsy of adrenal mass is not recommended to distinguish adrenocortical carcinoma from benign adrenal adenomas ³¹³²
  - Sampling bias may cause a false-negative result; sensitivity of biopsy for detecting adrenocortical carcinoma is approximately 70% ²⁹ ³¹
  - Theoretical risk of tumor seeding the needle tract

Laboratory

Serum cortisol
- Random serum cortisol testing is not helpful, but a morning serum cortisol test is obtained as part of overnight dexamethasone suppression test
  - Overnight dexamethasone suppression test is preferred to evaluate for asymptomatic autonomous cortisol secretion ²⁸ ³³
- With most cortisol-secreting adrenal adenomas, cortisol levels will not be suppressed after oral dexamethasone
24-Hour urinary free cortisol
- Urinary free cortisol measures cortisol excretion over 24 hours to encompass a complete circadian rhythm; results of this assay reflect amount of unbound cortisol
- Usually used as a second line test or confirmatory test to assess for excess cortisol secretion in patients with adrenal incidentalomas ¹⁷
- Patients are instructed to discard the first void of the day and then collect all urine over the course of 24 hours, with the final collection being the first void of the next day
- Cortisol levels are measured by either an antibody-based immunoassay or liquid chromatography with tandem mass spectroscopy (reference values depend on the specific test used) ¹⁷
- Elevated levels may result from any cause of hypercortisolemia, including cortisol-secreting adrenal tumor
  - 24-Hour urinary free cortisol result that is 4 times the reference value is considered diagnostic of Cushing syndrome
- High fluid intake, incomplete urine collection, certain drugs, and reduced GFR (less than 60 mL/minute) may affect accuracy of this test ¹⁷
Late-night (midnight) salivary cortisol
- Usually used as a second line or confirmatory test to assess for excess cortisol secretion in patients with adrenal incidentalomas
  - Only use late-night salivary cortisol if cortisone levels can also be reported ²⁸
- Based on the premise that states of hypercortisolism have disrupted normal circadian rhythm
- Salivary sample is collected by patient at home between 11 PM and midnight, then brought or mailed to the laboratory for analysis
- Late-night values above 145 ng/dL suggest hypercortisolism ¹⁷
- For patients with overt cortisol excess, this test sensitivity ranges from 92% to 100%, and specificity ranges from 93% to 100% ¹⁷
  - However, for patients with hypercortisolism associated with adrenal incidentalomas, salivary cortisol levels have poor sensitivity; therefore, this test is better used as a confirmative test if the first results of cortisol levels after overnight dexamethasone results are abnormal
- Not an appropriate test for patients with altered sleep and work patterns
Serum ACTH level
- Indicated if initial test result for hypercortisolemia is positive, to localize or confirm adrenal gland as cause of excess cortisol ¹³
  - ACTH level is necessary to differentiate ACTH-dependent (pituitary Cushing disease or ectopic ACTH) from ACTH-independent (adrenal) hypercortisolism
  - Even in the face of an adrenal mass, do not assume that adrenal gland is the cause
- Very low or undetectable ACTH levels and abnormal findings from screening test (ie, overnight dexamethasone suppression test, 24-hour urinary free cortisol, or midnight salivary cortisol) indicate that a primary adrenal gland abnormality is likely the source of excess cortisol secretion
- Hypercortisolism is considered to be ACTH independent (a primary adrenal cause) when serum ACTH levels are less than 5 pg/mL ³⁴
- A serum ACTH level above 20 pg/mL is likely to indicate an ACTH-dependent form of hypercortisolism ³⁴
Serum electrolytes
- Obtain for evaluation of hyperaldosteronism
- Hypokalemia may be found in states of aldosteronism (excess aldosterone secretion)
  - Hypokalemia occurs in 9% to 37% of patients with aldosteronism ³⁵
Plasma aldosterone level and plasma renin activity
- Indicated when manifestations of hyperaldosteronism are present (hypertension or hypokalemia with incidentaloma) ²⁶
- Both the biochemical and radiologic evaluation of aldosteronism can be complex; refer uncertain cases to endocrinologists with expertise in diagnosing and managing this condition
- Patients should have unrestricted dietary salt intake before laboratory testing and should be potassium replete ³⁵
- Mineralocorticoid receptor antagonists should be withdrawn for at least 4 weeks before testing ³⁵
- Use individual serum aldosterone and plasma renin activity values to calculate the plasma aldosterone level to plasma renin activity ratio
- Cutoff values for plasma aldosterone level to plasma renin activity ratio depend on assay used for renin and the units used for reporting ³⁵
  - Most common adopted value for a positive plasma aldosterone level to plasma renin activity ratio (using units of ng/dL for aldosterone and units of ng/mL/hour for plasma renin activity) is 30 or higher, which suggests hyperaldosteronism ¹³
  - The combination of an elevated plasma aldosterone level, low plasma renin activity, and plasma aldosterone level to plasma renin activity ratio above 20 is consistent with a diagnosis of hyperaldosteronism ³⁵
- If the ratio of plasma aldosterone level to plasma renin activity is abnormal, perform confirmatory testing to verify or exclude the diagnosis for most patients
  - There are several types of confirmatory tests, usually involving salt loading followed by an adrenal venous sampling procedure
  - Confirmatory testing is unnecessary for patients with all the following: ³⁵
    - Spontaneous hypokalemia
    - Plasma renin level below detection
    - Plasma aldosterone level of more than 20 ng/dL
  - Once a diagnosis is considered, most patients should be referred to an institution with expertise in interventional radiology adrenal venous sampling procedure
Catecholamines and catecholamine metabolites
- Plasma free or 24-hour urine fractionated metanephrines and normetanephrines with or without 24-hour urinary fractionated metanephrines and catecholamines ¹³
  - Indicated to screen for pheochromocytoma in patients with an incidental adrenal mass with imaging features not typical of a benign adenoma (eg, unenhanced Hounsfield units of more than 10) ²⁶
  - Plasma free metanephrines have high sensitivity (96%-100%), are easy to obtain, and are convenient for the patient, but they have less than ideal specificity (85%-90%) ³⁶
  - Levels greater than 3-fold above reference range are usually considered diagnostic ¹³
Sex steroids and precursors
- The following are indicated for patients with manifestations of hormone excess or when adrenocortical carcinoma is suspected based on imaging or clinical findings: ²⁶
  - Serum dehydroepiandrosterone sulfate ¹⁴
    - Often low when ACTH level is chronically suppressed
  - Testosterone
  - 17-Hydroxyprogesterone
  - 17-Hydroxypregnenolone
  - 17β-Estradiol (males and postmenopausal females)
  - Androstenedione
Urine steroid metabolites
- 24-Hour urinary levels of 11-deoxycortisol and dehydroepiandrosterone are useful tumor markers; may help differentiate adrenocortical carcinoma from benign adenoma ¹⁴ ³⁷
Genetic testing ¹³
- Consider for patients who have 1 or more neuroendocrine tumors

Imaging

Adrenal protocol CT or MRI ³⁸
- Dedicated adrenal protocol imaging can delineate characteristics that may reveal underlying pathology to determine the size, heterogeneity, lipid content, contrast washout (CT), local invasion, and margin characteristics of adrenal gland tumors
  - High-quality evidence that demonstrates the most effective imaging test and techniques is lacking; recommendations are based on expert opinion and reasonable clinical judgment ³⁹
- CT is most commonly used, and most data and experience with radiologic analysis of adrenal masses have been acquired with CT ⁵
  - Noncontrast CT is generally recommended as initial imaging test ¹³²⁶
    - If more than 10 Hounsfield units seen, immediately follow with contrast CT with washout ¹³
- MRI, with and without contrast, is an alternative that has the advantage of no radiation exposure and is appropriate for children and pregnant patients ⁸
- Benign adrenocortical adenomas
  - Homogeneous low-density masses
  - Smooth margins
  - No necrosis or calcifications
  - Regular shape ²⁷
  - Rate of growth less than 1 cm per year if serial images available ⁴
  - Contain significant amounts of intracellular lipid, noted by low unenhanced CT attenuation (less than 10 Hounsfield units) or signal loss on opposed-phase chemical shift MRI ³⁹ ⁴⁰
  - Rapid contrast washout on adrenal CT protocol (greater than 60% at 15 minutes) if contrast is used ¹ ⁴¹
  - Size smaller than 4 cm ⁴² ⁴³
- Malignant adrenocortical carcinomas
  - Features of heterogeneity
  - Irregular shapes or margins ²⁷
  - May have necrosis or calcifications
  - Rate of growth greater than 1 cm per year if serial images available ⁴
  - Unenhanced CT attenuation is greater than 10 Hounsfield units ³⁹
  - Slow contrast washout on adrenal CT protocol (60% or less at 15 minutes) ¹ ⁴¹
  - Size 4 to 6 cm or larger ⁴²
- Generally, an incidental adrenal mass can be attributed to an adrenocortical adenoma if there is unenhanced CT attenuation of less than 10 Hounsfield units and mass is smaller than 4 cm ¹⁸
  - An adrenal mass is suggestive of a malignant tumor if unenhanced CT attenuation is greater than 10 Hounsfield units and other benign characteristics are not present
- If the adrenal mass is indeterminate on unenhanced noncontrast CT (greater than 10 Hounsfield units) and results of hormonal workup do not indicate significant hormone excess, 3 options exist: ⁸⁴⁴
  - Obtain additional imaging using another modality (contrast-enhanced CT, MRI chemical shift analysis, or fluorodeoxyglucose F 18 PET)
    - In contrast-enhanced CT imaging, contrast is administered with 15-minute delayed imaging to calculate contrast washout; adenomas display rapid contrast washout at 15 minutes ¹; less than 60% washout in 15 minutes indicates tumor is possibly malignant
  - Perform interval imaging in 6 to 12 months (noncontrast CT or MRI)
  - Proceed to surgery (adrenalectomy)
    - Probably safest option for indeterminate masses greater than 4 cm to avoid missing malignancy ⁴
Fluorodeoxyglucose F 18 PET or PET-CT ⁴⁵⁴⁶
- May be useful for distinguishing potentially malignant lesions from benign tumors if indeterminate on initial imaging
- Although highly heterogeneous in terms of design and statistical results, the sensitivities, specificities, and overall diagnostic accuracy for characterization of adrenal lesions using fluorodeoxyglucose F 18 PET or PET-CT reported among the majority of studies are greater than 90% ⁴⁶
- Negative PET-CT findings are generally valid for predicting that an adrenal mass is benign ³⁸

Functional testing

1 mg overnight dexamethasone suppression test ¹³
- Preferred test to screen for hypercortisolemia in patient with adrenal incidentaloma ³³ ⁴⁷
- Patient takes 1 mg of dexamethasone orally between 11 PM and midnight, and serum cortisol level is measured at 8 AM the next morning ³³
- Interpretation of results:
  - Postdexamethasone morning cortisol level of 1.8 mcg/dL or less excludes autonomous cortisol secretion ³³ ⁴⁷
  - Postdexamethasone morning cortisol level more than 1.8 mcg/dL in patients without overt signs and symptoms of Cushing syndrome is diagnostic of MACS (mild autonomous cortisol secretion) and does not require further stratification based on degree of cortisol nonsuppressibility ²⁶
    - Conditions that may affect test results should be considered (eg, false-positive results may occur in patients receiving medications that accelerate dexamethasone metabolism) ¹⁷ ⁴⁸
    - Confirmation of cortisol secretory autonomy is recommended by repeat dexamethasone suppression test along with ACTH level ²⁶
    - Patients with MACS should be screened for hypertension, type 2 diabetes mellitus, and vertebral fractures ²⁶
    - In consultation with an expert multidisciplinary group, the option of surgery should be discussed with the patient; patient age, sex, general health, severity of comorbidities, and patient preferences are all relevant factors ²⁶
- Further evaluation after results:
  - If the result falls within the borderline range, additional biochemical tests to confirm or refute cortisol secretory autonomy are required ²⁷ ⁴⁷
  - Additional biochemical tests include 24-hour urinary free cortisol or late-night salivary cortisol levels and an ACTH level ¹⁷ ²⁷
  - It is common to perform several tests (either sequentially or simultaneously) to diagnose any degree of hypercortisolism, and endocrinologist consultation is routinely required for a proper evaluation ¹⁷
  - Presence of other pertinent associated conditions that could be related to excess cortisol (eg, diabetes mellitus, hypertension, obesity, osteoporosis) may be considered when determining whether to conduct additional biochemical testing ⁴⁷

Procedures

Collection of tissue specimen for histopathologic examination, performed percutaneously under CT guidance
Exclude pheochromocytoma with biochemical testing before biopsy ²⁹
To rule out metastasis from a known extra-adrenal malignant neoplasm ⁴
To confirm an infectious cause of adrenal infiltration from pathogens such as mycobacterium or fungal organisms ⁴
Uncorrectable coagulopathy ⁴⁹
Absence of biochemical laboratory testing documenting that pheochromocytoma has been excluded ²⁹
- Biopsy of a pheochromocytoma can precipitate numerous cardiovascular complications, including hypertensive crisis, myocardial infarction, stroke, or death ⁵⁰
Suspected adrenocortical carcinoma ²⁹
Adrenal hemorrhage ²⁹
Pneumothorax ²⁹
Needle tract seeding ⁴⁹
Pancreatitis
Main limitation of adrenal biopsy is the difficulty in distinguishing adrenocortical carcinoma from benign adrenal tumors
- Overall nondiagnostic rate is approximately 9% ²⁹
Diagnostic performance of cytology from a specimen obtained via adrenal biopsy, based on limited data: ²⁹
- Adrenocortical carcinoma: sensitivity 70%, specificity 98%
- Metastases: sensitivity 87%, specificity 96%
- Malignancy (nonadrenal): sensitivity 87%, specificity 100%
The Weiss score is the standard for differentiating benign adenoma from adrenal malignancy ¹⁴
- Includes the following features:
  - Atypical mitotic figures
  - Mitotic figures (more than 5/50 high-power field)
  - Necrosis
  - Vascular invasion
  - Sinusoidal invasion
  - Capsular invasion
  - Nuclear atypia
  - Diffuse architecture
  - Eosinophilic cytoplasm
- Weiss scoring system use is restricted to complete surgical specimens
- Scoring is as follows:
  - 0 to 2 features defines adrenocortical adenoma
  - 3 to 6 features is suggestive of malignancy ³⁷
  - More than 6 features defines adrenocortical carcinoma

Differential Diagnosis

Most common

Adrenocortical adenoma
- Benign tumor of the adrenal cortex
- Adenomas may be an incidental finding or can present with symptoms and signs related to hormone hypersecretion
- Designated as adenomas primarily on basis of imaging characteristics
  - Adrenal tumor is usually benign if:
    - Less than 4 cm in diameter
    - Homogeneous
    - Has smooth margins
    - Appears lipid rich on CT or MRI
  - Can be presumed to be benign if radiographic characteristics are uniformly benign and the unenhanced CT attenuation is less than 10 Hounsfield units or if there is signal loss on opposed-phase chemical shift MRI ¹
Adrenal metastases ¹
- The adrenal glands are a common site of metastases from breast, lung, and renal cell carcinomas; melanoma; and lymphoma
- Like some adrenocortical carcinomas, metastatic disease to the adrenals may present with symptoms or signs secondary to local tumor growth or, more commonly, be discovered as an incidental finding
- Differentiated primarily with imaging characteristics; however, cannot be reliably characterized with the use of imaging alone ¹
  - On CT, adrenal metastases can appear as nodular masses or diffuse enlargement ³⁸
    - Metastases are generally heterogeneous with unenhanced images measuring more than 10 Hounsfield units ³⁸
    - Contrast washout is usually less than 60% absolute and less than 40% relative ³⁸
  - On MRI, adrenal metastases have low signal intensity on T1-weighted images and variably high intensity on T2-weighted images ³⁸
  - When metastasis to the adrenal is very likely based on clinical context and this determination affects selection of therapy for the primary cancer, percutaneous CT-guided fine-needle aspiration biopsy may be performed once pheochromocytoma is excluded
Adrenocortical carcinoma
- A very rare malignant tumor arising from cells of the adrenal cortex
- Most tumors are functional and may present with symptoms related to excess adrenal steroid hormones (eg, Cushing syndrome, hyperaldosteronism, androgen excess); nonfunctioning tumors may be associated with nonspecific symptoms (eg, abdominal pain, back pain, early satiety, weight loss) or may be asymptomatic and discovered incidentally
- Like adrenocortical adenomas, may be an incidental finding during surgery or imaging for another medical issue or may present with symptoms and signs related to hormone hypersecretion
- Differentiated primarily on basis of imaging characteristics; however, cannot always be reliably characterized with the use of imaging alone
  - Malignancy is suspected when tumor is larger than 4 cm or is inhomogeneous and has irregular margins and/or local invasion ¹³
  - CT is suggestive of malignant tumor if unenhanced CT attenuation is more than 10 Hounsfield units and if washout is less than 60% in 15 minutes on adrenal protocol CT ¹³
  - Fluorodeoxyglucose F 18 PET can accurately differentiate benign adenoma from malignant adrenal masses ¹
Pheochromocytoma
- Catecholamine-secreting tumor of chromaffin cells of the adrenal medulla that appear as adrenal masses on abdominal imaging procedures
- Pheochromocytomas can be found incidentally during surgery or imaging for other medical issues ¹⁵¹⁶⁵¹
  - Signs and symptoms of pheochromocytomas are classically reported as palpitations, headache, sweating, and labile hypertension; this presentation may be changing with increased use of imaging techniques in general
- Differentiated on basis of history, physical examination findings, and biochemical testing showing elevated plasma free metanephrines or 24-hour urinary fractionated metanephrines ¹
  - Most imaging features are nonspecific, and a pheochromocytoma cannot be reliably discerned from other adrenal masses with the use of an imaging study
  - Pheochromocytomas do appear hyperintense on T2-weighted MRI ³⁸
Adrenal myelolipoma
- Benign adrenal tumors composed of adipose and hematopoietic tissue ⁵²
- Like many adrenal masses, myelolipomas are often asymptomatic and found incidentally on imaging for another medical issue
- Differentiated on basis of specific imaging findings on CT and MRI, although formal diagnosis requires histopathology ¹
  - On CT, myelolipoma appears as a round mass with well-defined borders ¹
    - Myelolipoma is easily diagnosed because macroscopic fat, with attenuation values less than −30 Hounsfield units, is almost always detectable ¹
  - On MRI, the fat macroscopic components are hyperintense on T1- and T2-weighted images, whereas the hematopoietic parts are hypointense on T1-weighted images and moderately hyperintense on T2-weighted images ¹
Other lesions or apparent masses within or adjacent to the adrenal
- Adrenal infection (tuberculosis or histoplasmosis)⁵³
  - Usually occur in states of immunocompromise
  - On CT, findings are nonspecific and usually bilateral; they include: ³⁸
    - Enlargement of the glands
    - Cystic changes
    - Calcifications
  - Formal diagnosis requires histopathology
- Adrenal lymphoma ⁵³
  - Lymphoma that metastasizes to the adrenal is common, but primary adrenal lymphoma is rare
  - On CT, a primary lymphoma appears as homogeneous adrenal enlargement ³⁸
  - On MRI, lymphoma shows low signal intensity on T1-weighted images and high intensity on T2-weighted images ³⁸
  - Formal diagnosis requires histopathology
- Adrenal hemorrhage (from trauma, anticoagulant therapy, sepsis, surgery) or hemorrhage within adrenal lesions (eg, adenoma, myelolipoma, metastasis, adrenocortical carcinoma)⁵³
  - Acute hemorrhage on CT is seen as a round to ovoid mass with high attenuation values (more than 50 Hounsfield units) ³⁸
    - In cases due to trauma, there may be hemorrhagic suffusion of periadrenal fat and retroperitoneal bleeding ⁵³
    - Acute hemorrhage on MRI shows as a mild T1 hypointensity and marked T2 hypointensity ³⁸
  - Chronic hematoma on CT appears as a mass with a hypoattenuating center, with or without calcifications; also called adrenal pseudocyst
    - Hematomas usually decrease in size over time and may spontaneously disappear
    - On MRI, a chronic hematoma develops a hypointense rim known as a blooming artifact ³⁸
- Adrenal cysts ⁵³
  - Adrenal cysts can be pseudocysts, endothelial cysts, epithelial cysts, or parasitic cysts and can range from 1 to 20 cm in diameter ⁵³ ⁵⁴
  - On CT, adrenal cysts appear as well-demarcated, nonenhancing, hypoattenuating lesions with water attenuation (less than 20 Hounsfield units) and thin walls
  - On MRI, cysts are usually hypointense on T1- and hyperintense on T2-weighted images ⁵⁴
  - Septations, blood products, or a soft-tissue component and calcifications may be observed in pseudocysts
  - Certain features on ultrasonography can support a diagnosis of cyst, such as well-circumscribed hypoechoic or anechoic areas with thin walls
  - Comprise 1% to 2% of adrenal incidentalomas ⁵⁴
- Hemangioma⁵³
  - Hemangiomas are uncommon incidental adrenal lesions, often found in females aged 40 to 70 years
  - On CT, small hemangiomas are usually homogeneous, whereas larger ones contain calcifications due to previous hemorrhages
  - On MRI, hemangiomas are hypointense on T1-weighted images but show bright hyperintensity on T2-weighted images
- Ganglioneuroma
  - Ganglioneuroma is a benign tumor arising from the sympathetic nerves
  - This lesion is more frequently detected in the mediastinum or retroperitoneum than in the adrenal medulla
  - A ganglioma appears as a small round mass with well-defined smooth margins and a homogeneous interior
  - On CT, a ganglioneuroma is solid and may display calcifications, necrosis, and hemorrhagic areas
  - On MRI, a ganglioneuroma is hypointense on T1-weighted images and hyperintense on T2-weighted images
- Schwannoma⁵³
  - Schwannoma is a rare tumor arising from nerve sheaths that is most often asymptomatic but occasionally can cause abdominal pain if it hemorrhages
  - On CT, a schwannoma appears as a hypodense lesion with inhomogeneous contrast enhancement
  - On MRI, schwannomas have a nonspecific appearance; they may appear isointense on T1-weighted images and slightly hyperintense on T2-weighted images
- Lymphangioma ⁵³
  - Lymphangiomas are rare adrenal lesions, but when they occur, they are almost always an incidental finding
  - Lymphangiomas are completely asymptomatic and occur at any age
  - On CT, lymphangiomas are well-encapsulated hypodense lesions (8-20 Hounsfield units) with an average size of 3 cm ⁵³
  - They contain intralesional septations showing contrast enhancement and calcifications that appear punctate or thick and curvilinear
Other causes of Cushing syndrome
- As with a cortisol-secreting adrenal adenoma, presents with physical stigmata of Cushing syndrome (centripetal obesity, hirsutism, proximal muscle weakness, easy bruising, and wide purple-red striae)
- Various causes include:
  - Iatrogenic; caused by medically prescribed corticosteroids
  - Pituitary adenoma that secretes ACTH
  - Ectopic ACTH-secreting neoplasm (eg, small cell lung carcinoma, bronchial or thymic carcinoids, pancreatic neuroendocrine tumors)
  - Ectopic corticotropin-releasing hormone syndrome
  - Bilateral adrenal hyperplasia
- Differentiated on the basis of serum ACTH, inferior petrosal sinus sampling, and diagnostic imaging findings
  - Elevated levels of ACTH indicate that hypercortisolism is likely the result of ACTH-secreting pituitary tumors or ectopic ACTH-secreting neuroendocrine tumors (ie, not caused by adrenocortical tumors)

Treatment Goals

For functioning adrenal neoplasms, normalize relevant adrenal hormone levels
- For glucocorticoid-secreting adenomas:
  - Restore normal function of the hypothalamic-pituitary-adrenal axis
  - Recover from the disorders associated with chronic hypercortisolism (eg, weight gain, proximal muscle weakness, diabetes mellitus, hypertension)

Disposition

Recommendations for specialist referral

Guidelines recommend patients with adrenal incidentalomas be discussed in a multidisciplinary expert team meeting (including a radiologist, endocrinologist, and surgeon) if any of the following criteria are met: ²⁶
- Imaging not consistent with a benign lesion
- Evidence of excess hormone secretion
- Adrenal surgery is being considered
- Evidence of significant tumor growth during follow-up imaging

Treatment Options

Treatment depends on the suspected underlying cause

Nonfunctioning adrenocortical tumors that appear benign

Observation with surveillance imaging is an option for patients with an incidental adrenal mass not suggestive of malignancy and not hormonally active ⁴
- These include asymptomatic individuals with a nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies (presumed adrenocortical adenoma) ⁴⁷
Surveillance recommendations are variable and have evolved over time: NCCN (National Comprehensive Cancer Network) guidelines recommend either of the following approaches ¹³
- American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons recommendations ⁵⁵
  - Observation with repeated imaging at 3 to 6 months and then annually for 1 to 2 years for patients with nonfunctioning adrenal tumors smaller than 4 cm in diameter and benign appearing
  - Hormonal evaluation annually for 5 years
  - Adrenalectomy for enlarging tumors; procedure may be performed laparoscopically if tumor is small and likelihood of malignancy is low
- European Society of Endocrinology recommendations ⁴⁷
  - No further imaging for follow-up of patients with an adrenal mass smaller than 4 cm with clear benign features (presumed adrenocortical adenoma)
  - Repeating imaging in 6 to 12 months is recommended for indeterminate lesions ⁴⁷
  - Adrenalectomy for tumors that have increased in size by more than 20% in this interval ⁴⁷

Functioning adrenocortical tumors

Unilateral adrenalectomy is recommended for tumors associated with clinically significant excess of glucocorticoid, mineralocorticoid, or adrenal sex hormone ⁴⁷⁵⁶
- Laparoscopic approach may be offered when imaging phenotype strongly suggests an adrenocortical adenoma (ie, tumor is less than 4 cm and other benign imaging characteristics are present) ¹³
- Open adrenalectomy and resection of adjacent lymph nodes is recommended when imaging phenotype is suggestive of carcinoma, including tumor that: ¹³
  - Is larger than 4 cm
  - Is inhomogeneous
  - Has irregular margins
  - Shows local invasion
  - Shows other imaging characteristics suggestive of malignancies
Preoperative medical therapy for hormone excess may be beneficial in some cases; primary medical therapy is appropriate for patients who are not surgical candidates
- Medical therapy should be prescribed in consultation with an endocrinologist
  - Treat electrolyte abnormalities or hypertension caused by mineralocorticoid excess with spironolactone or eplerenone
  - Treat hypercortisolism with pharmacotherapy to reduce cortisol secretion or action
    - Management is complex; options include inhibitors of adrenal cortex steroidogenesis or glucocorticoid receptor antagonist ²⁸
  - Treat mild hyperandrogenemia with spironolactone
  - Treat estrogen excess with aromatase inhibitors (eg, anastrozole) or with a selective estrogen receptor modulator (eg, tamoxifen) ¹¹
Consider perioperative corticosteroid supplementation for all patients who undergo adrenalectomy for Cushing syndrome until recovery of the hypothalamic-pituitary-adrenal axis is complete ⁴⁷
- Degree of adrenal insufficiency depends on severity of cortisol excess, but it occurs even among those with biochemically identified subclinical Cushing syndrome caused by contralateral gland atrophy ⁵⁷
- Duration of adrenal insufficiency is approximately 6 months for subclinical primary adrenal Cushing syndrome and approximately 18 months for overt primary adrenal Cushing syndrome ⁵⁸
Subclinical Cushing syndrome (mild autonomous cortisol secretion)
- Whereas surgical resection of cortisol-secreting adenomas to cure overt Cushing syndrome is advisable in most cases, surgical intervention to resect a unilateral adenoma for subclinical Cushing syndrome is controversial
  - Because hypertension, diabetes, osteoporosis, and obesity are common diseases, it is difficult to establish whether these are directly related to low-grade excess cortisol secretion in a patient
- Individualized treatment plan is recommended for patients with evidence of mild autonomous (or subclinical) hypercortisolism ⁴⁷
- Patients likely to benefit from unilateral adrenalectomy include younger patients and those whose conditions may improve on removal of excess glucocorticoid secretion (eg, patients with hypertension, diabetes, obesity, osteopenia, osteoporosis) ⁵⁹
- Observational data show that surgical adrenalectomy may lead to cardiometabolic improvements in some instances of mild autonomous cortisol secretion (subclinical Cushing syndrome) ⁶⁰
  - Small series show that weight loss, better glycemic control, improved lipid profile, lower blood pressure, and normalization of bone turnover markers occur after unilateral adrenalectomy in patients with mild autonomous cortisol secretion (subclinical Cushing syndrome) ⁶¹ ⁶² ⁶³
- Long-term medical therapy to decrease cortisol secretion or action is usually fraught with complications and is not advisable for either subclinical or overt hypercortisolism
Adrenocortical carcinoma
- All patients with suspected adrenocortical carcinoma should undergo prompt adrenalectomy because of the rapidly progressive nature of the disease
Pheochromocytoma
- All patients with documented pheochromocytoma should undergo adrenalectomy because untreated pheochromocytoma may result in significant cardiovascular complications ⁵¹
- A period of preoperative high-sodium diet, generous fluid intake, and pharmacologic α-adrenergic blockade is required before surgical resection of pheochromocytomas; some patients may also require β-adrenergic blockade to attenuate reflex tachycardia after α-adrenergic blockade is complete ⁵¹ ⁶⁴

Drug therapy

Medical treatment (including management of postoperative adrenal insufficiency) of functioning adrenocortical tumors is complex and individualized, especially for subclinical Cushing syndrome
The following drug classes are sometimes used preoperatively (consult an endocrinologist for dosing recommendations):
- Adrenal steroidogenesis inhibitors (eg, metyrapone)
- Glucocorticoid receptor antagonists
- Mineralocorticoid receptor antagonists
- Selective estrogen receptor modulators
- Aromatase inhibitors
Corticosteroids are used postoperatively (consult an endocrinologist for dosing recommendations): ⁶⁴

Nondrug and supportive care

Procedures

Unilateral adrenalectomy

General explanation

Surgical removal of the affected adrenal gland via transperitoneal or retroperitoneal approach ⁶⁵
- Open adrenalectomy is standard for patients with large or potentially malignant adrenal masses
- Laparoscopic adrenalectomy is the usual approach for most smaller adenomas ⁶⁶
  - The exact dimensional limit for laparoscopy is a subject of debate; most favorable data have been published in multiple series for lesions 6 cm or less, but some flawed studies show good outcomes with lesions larger than this ⁴⁷ ⁶⁷
  - Laparoscopic adrenalectomy for smaller adrenocortical carcinomas is controversial
- Robotic adrenal surgical techniques, which provide the advantage of 3-dimensional surgical vision, are becoming more common
  - Occasionally, conversion from a minimally invasive to open approach is necessary to facilitate en bloc tumor resection, regional lymphadenectomy, and resection of any involved organs
- Regardless of approach, the surgery should ideally be performed by an endocrine surgeon with expertise in adrenal operations ⁴⁷
Institute preoperative treatment of manifestations of hormonal excess as necessary (eg, correction of serum potassium levels, control of blood pressure, reduction of cortisol levels) ¹¹ ³⁷
For resection of most cortisol-secreting adenomas, perioperative replacement of steroids is required to prevent adrenal insufficiency ¹⁴

Indication

Functional adrenal adenomas
Suspected adrenocortical carcinoma ⁶⁸

Contraindications

Absence of biochemical evaluation to exclude pheochromocytoma

Complications

Adrenal insufficiency
Hemorrhage
Injury to nearby organs or structures

Interpretation of results

Minimally invasive surgical techniques have been shown to be associated with greater patient satisfaction, shorter postoperative hospitalization, and reduced surgical pain compared with open surgical techniques

Comorbidities

Comorbidities specifically associated with adrenal adenomas that secrete cortisol include: ⁶⁹
- Hypertension
- Type 2 diabetes
- Obesity
- Osteoporosis
- Dyslipidemia

Special populations

Bilateral adrenal incidentalomas
- For patients with bilateral adrenal masses, assess each adrenal lesion at the time of initial detection (according to the same imaging protocol used for unilateral adrenal masses) to establish whether either or both masses are benign or malignant ⁴⁷
- The clinical, radiographic, and hormonal assessments are identical to those for patients with unilateral adrenal incidentaloma
- For patients with bilateral adrenal incidentalomas and without autonomous cortisol secretion, measure serum 17-hydroxyprogesterone level to exclude congenital adrenal hyperplasia ²⁶
- For patients with bilateral metastases, lymphoma, infiltrative inflammatory disease, or hemorrhages, testing for adrenal insufficiency is recommended ²⁶

Monitoring

Patients with nonfunctioning adrenal masses presumed to be benign adenomas should undergo longitudinal clinical, biochemical, and radiographic surveillance at intervals depending on the initial imaging characteristics and patient-specific factors ¹⁷⁵⁶
- There is a lack of large prospective studies that evaluate the ideal time interval for repeating a hormonal and radiographic evaluation
- Patients aged 65 years or older and possibly those with poor general health are less likely to benefit from additional surveillance ²⁷
Longitudinal surveillance
- Clinical
  - For patients who are initially identified as having mild autonomous cortisol secretion but no signs of overt Cushing syndrome, perform annual reassessment for comorbidities related to cortisol excess ⁴⁷
    - Measure blood pressure and serum lipid levels
    - Test for diabetes mellitus and assess glycemic control
    - Consider performing DXA biannually, depending on bone mineral density values found at diagnosis
- Imaging
  - For nonfunctioning masses that are 4 cm or larger and have a benign imaging phenotype, repeating imaging after 3 to 6 months is reasonable to determine if there have been interval changes concerning for malignancy ²⁷
    - Annual examinations for 1 to 2 years are suggested ⁵⁵
  - Some experts suggest that further imaging is not necessary for follow-up of patients with a nonfunctioning adrenal mass smaller than 4 cm with clearly benign features on imaging studies ⁴⁴⁷
    - Available data from retrospective series show that small nonfunctioning lipid-rich adrenal masses are unlikely to represent a malignancy or to develop into adrenocortical carcinomas ⁹ ¹²
  - If biological behavior of an adrenal mass is indeterminate because imaging phenotype is inconclusive:
    - Repeat noncontrast CT or MRI after 6 to 12 months to exclude significant growth ⁴⁷
    - Consider surgical resection if the lesion enlarges by more than 20% (at least a 5-mm increase in maximum diameter) during this period; if there is growth of the lesion below this threshold, pursue additional imaging in another 6 to 12 months ⁴⁷
- Hormonal testing
  - For patients who are initially identified as having mild or borderline autonomous cortisol secretion but do not have signs of overt Cushing syndrome, whether to perform serial biochemical evaluations over time is controversial
  - American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons recommends annual hormonal evaluation for 5 years ⁵⁵
  - Some experts suggest that the decision to repeat the hormone evaluation after an initial evaluation with normal findings should be individualized, depending on the development of clinical signs of adrenal endocrinopathy or worsening comorbidities ⁴
    - Potential triggers include new or unexpectedly worsening: ⁴
      - Hyperglycemia
      - Diabetes
      - Hypertension
      - Hypokalemia
      - Weight gain
      - Low bone mineral density
      - Fractures
  - Other experts suggest that repeated hormonal workup is not necessary for patients with normal initial hormone evaluation results ⁴⁷

Complications

Cushing syndrome/subclinical Cushing syndrome
- Both overt and mild (subclinical) hypercortisolism increase risk for adverse cardiac events and poor skeletal health ¹⁰⁷⁰⁷¹⁷²
  - Hypertension
  - Impaired glucose tolerance and diabetes mellitus
  - Hyperlipidemia
  - Osteoporosis and vertebral fractures
Hyperaldosteronism
- Hypokalemia
- Hypertension

Prognosis

Prognosis depends on the underlying cause and associated comorbidities
Natural history of incidentally discovered nonfunctioning adrenal tumors
- Clinically significant tumor enlargement (1 cm or more) occurs in a minority (approximately 2.5%) of patients after a mean of 4 years ⁹
- Among patients initially found to have nonfunctioning (biochemically silent) tumors, subclinical (mild) autonomous cortisol excess develops in approximately 4.3% after 4 years ⁹
  - Overt cortisol excess is unlikely to develop in patients initially found to have nonfunctioning adrenal tumors after 4 years ⁹ ¹⁰
- Preexisting subclinical (mild) autonomous cortisol secretion rarely resolves, and associated cardiometabolic conditions (hypertension, obesity, and type 2 diabetes) generally worsen over time ⁹¹⁰
  - Retrospective data show that among patients with incidental adrenal masses, patients with subclinical (mild) autonomous cortisol secretion have a lower survival rate than those with nonsecreting adrenal tumors as a result of cardiovascular events and infectious complications ⁷² ⁷³
- Malignant transformation of adrenal masses identified incidentally is unlikely to occur over time ⁹
Successful surgical resection of a functioning adrenal adenoma (usually in conjunction with the involved ipsilateral adrenal gland) normalizes hormone levels in patients with clinical syndromes resulting from hormone excess

References

1.Garrett RW et al: Adrenal incidentalomas: clinical controversies and modified recommendations. AJR Am J Roentgenol. 206(6):1170-8, 2016

Incidental Adrenal Mass – 9 Interesting Facts

Pitfalls

Introduction

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Sex

Genetics

Other risk factors/associations

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Imaging

Functional testing

Procedures

Differential Diagnosis

Most common

Treatment Goals

Disposition

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Procedures

Unilateral adrenalectomy

Comorbidities

Special populations

Monitoring

Complications

Prognosis

References

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