Evaluation of the Adrenal Mass in Urologic Practice
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Jackson Schmidt, MD*, Marshall Strother, MD
KEYWORDS
. Adrenal mass . Incidentaloma . Adrenocortical carcinoma . Pheochromocytoma . Adenoma
KEY POINTS
· Adrenal lesions are relatively common, with prevalence as high as 1 in 25 adults, 1 in 10 elderly patients.
· The majority of these masses are benign adenomas; however, all lesions greater than 1 cm in diam- eter require evaluation to rule out malignancy and excess hormone secretion.
· Noncontrast computed tomography (CT) is the initial diagnostic tool for mass workup. Low atten- uation on unenhanced CT (<10 Hounsfield Units is highly specific for benign adrenal adenoma.
· A complete hormonal workup consists of laboratory testing for hypercortisolism and catecholamine excess. Tests for aldosterone excess should be performed if hypertension or hypokalemia are pre- sent. Tests for sex steroid excess should be performed if imaging is suggestive of malignancy.
· Surgical resection is standard treatment for most hormonally active or malignant masses.
INTRODUCTION
Most adrenal masses will present as adrenal “inci- dentalomas,” noted because the patient under- went imaging for an unrelated issue. With the high frequency of computed tomography (CT) imaging, incidentalomas have become a common diagnosis and prevalence seems to increase with age. The practicing urologist should therefore expect to see an increasing incidence of adrenal masses in the context of an aging population.1,2 The ques- tions that must be answered regarding any adrenal mass >1 cm in diameter are as follows:
· Is the mass malignant?
· Is the mass causing a hormone excess?
The first question can be addressed primarily with imaging, the second with laboratory testing. If the answers to both of these questions are defin- itively “no,” then no further testing or intervention is required, as there is very little risk of progression to malignancy or hormonal activity.3-5 Otherwise,
resection, surveillance, or referral to another specialist may be indicated.
BACKGROUND
Incidentalomas are defined as lesions that are at least 1 cm in size and any adrenal lesion >1 cm in size, whether found incidentally or not, requires hormonal workup.6-9 Nonfunctioning adenomas make up the majority of incidentalomas, approxi- mately 75%. Other potential benign adrenal masses include myelolipomas, cysts, lymphangio- mas, and ganglioneuromas.1º Fig. 1 shows relative occurrence of different lesions. Incidentaloma prevalence increases significantly with age:
· < 20 years of age = 0.5%
· General adult population: 4%
· >70 years of age = 7 to 10% risk10,11
Adrenal lesions in older patients are more likely to be benign, and a lesion in a younger patient should raise concern for malignancy and be
* Corresponding author.
E-mail address: schmjack@ohsu.edu
https://doi.org/10.1016/j.ucl.2025.01.011
Abbreviations
ACC adrenocortical carcinoma
ACTH adrenocorticotropic hormone
ARR aldosterone-to-renin ratio
CT computed tomography
HU Hounsfield Units
MACS mild autonomous cortisol secretion
followed closely, if not surgically resected. Impor- tantly, more than 10% of adrenal lesions cause hormonal excess and up to 20% of incidentalomas may need surgical resection.
HISTORY AND PHYSICAL EXAMINATION
A detailed description of the signs and symptoms associated with different types of adrenal lesions is given in Table 1. While a thorough history and physical is always to be encouraged, in practice, urologists may find attention to the following ele- ments to be particularly useful as they are rela- tively easy to assess and are specific to adrenal pathology:
· History of paroxysmal tachycardia/hyperten- sion or of “panic attacks”-associated with pheochromocytoma
. History of refractory hypertension, especially requiring 3 or more antihypertensive agents- associated with aldosterone-secreting lesions
. Family history of malignancy or adrenal pathology
. Personal history of malignancy-associated with metastasis to the adrenal gland
. Examination of skin of the face, chest, and abdomen-may reveal acne, hirsutism, or gynecomastia (sex-steroid excess); cushingoid fat distribution or abdominal striae (cortisol excess), or neurofibromas (pheochromocytoma)
RADIOLOGIC EVALUATION
Imaging is the best method for distinguishing be- tween benign and malignant adrenal lesions. Fig. 2 shows our simplified imaging algorithm to aid with clinical decision making. It is consistent with the European Society of Endocrinology Guidelines and the American College of Radiology White paper.5,15
Unenhanced Computed Tomography
Unenhanced CT scan is first test to perform for any patient with an adrenal lesion, as it captures the 2 most powerful predictors of risk of malignancy: lesion size and CT attenuation. The majority of ad- renal masses in clinical practice can be correctly diagnosed using these 2 features alone.
Computed Tomography Attenuation
Benign adenomas generally have high intracellular lipid content which results in low attenuation on noncontrast CT.5,8 Numerous studies have shown a 0% risk of malignancy in masses which are
Benign, Non Functional (75%)
Benign, Hormonally Active (10-15%)
Malignant (up to 10%)
Adenoma (70-75%)
Cortisol Secreting (10-12%)
Adrenocortical Carcinoma (8-11%)
Myelolipoma (8%)
Aldosterone Secreting (2- 6%)
Ganglioneuroma (4%)
Pheochromotoma (Catecholamine Secreting) (7-10%)
Extra-adrenal Metastasis (5- 7%)
Cyst (5%)
Rare lesions, infilatrative disorders, infections (<1%)ª
Pheochromocytoma (7- 10%)
Sex steroid secreting (<1%)
| Table 1 Signs/Symptoms of adrenal lesions | ||
|---|---|---|
| Adrenal Pathology | History Symptoms | Physical Examination Findings |
| Excess cortisol (Cushing syndrome) | Weight gain, easy bruising, new diabetes, proximal muscle weakness, depression, sleep disturbances, menstrual irregularities and virilization for females, and frailty with fractures | Central obesity, hypertension, supraclavicular fat accumulation, a dorsocervical fat pad (buffalo hump), facial plethora, skin discoloration, thinned skin, striae, acne, bruising, hirsutism, and muscle wasting (proximal) |
| Excess aldosterone (Conn syndrome) | Muscle cramping and weakness, headaches, intermittent or periodic paralysis | Hypertension, volume overload, electrolyte abnormalities, specifically hypokalemia |
| Excess catecholamine (pheochromocytoma) | Headaches, panic/anxiety attacks, palpitations, genetic syndromes (family history of von Hippel- Lindau disease, multiple endocrine neoplasia type 2, familial paraganglioma syndrome, or neurofibromatosis type 1) | Paroxysmal severe hypertension, tachycardia, arrhythmias, heart failure, excessive sweating, and pallor |
| Adrenocortical carcinoma (ACC) | Flank pain, abdominal pain, any symptom of a functional adenoma from any of the 3 functional regions of the adrenal cortex (hypercortisolism, hyperaldosteronism, sex steroid excess) | Weight loss or gain, hirsutism, gynecomastia, signs of hypercortisolism or hyperaldosteronism as above |
| Extra-adrenal malignancy (metastases) | History of malignancy, B symptoms (weight loss, unexplained fevers, night sweats), lack of adherence to routine cancer screening, and smoking history (increased risk for lung and kidney cancer) | Lymphadenopathy, lung mass, breast mass, renal mass or skin lesion suspicious for melanoma, as well as other cancer-specific findings |
Data from Refs. 10,14
predominantly <10 Hounsfield Units (HU) on non- contrast CT, and we are not aware of any study contradicting these findings.1 As a result, a white paper from the American College of Radiology and guidelines released by the European Society of Endocrinology has stated that such lesions can be called benign based on this criterion alone and that these require no further workup.15 Guide- lines from other societies are less definitive, allow- ing for some uncertainty in lesions greater than 4 cm in diameter.
Of course, many lesions >10 HU on CT may still be benign adenomas. Only 0.5% of incidentalo- mas between 10 to 20 HU and 6.3% of those >20 HU will eventually be found to be adrenocortical carcinoma.1,10 Additionally, it is important to note that metastasis from other malignancies can occa- sionally present as a lesion <10 HU on CT, so these cutoffs and the algorithm above should not be applied to patients with a history of extraadre- nal malignancy (see “Special Populations” below).
Size
Size is strongly correlated with risk of malignancy. While the risk is very close to 0% in masses <4 cm, the incidence increases to 2.4% in masses be- tween 4 and 6 cm and drastically increases to 19.5% in masses >6 cm.1
Macroscopic Fat Content
Unenhanced CT can also detect macroscopic fat within adrenal lesions, which is diagnostic of a benign myelolipoma.7,15 There are not set defini- tions for macroscopic fat, though very low attenua- tion on CT ( ← 30 HU) is a reasonable definition. 16 Very tiny amounts of macroscopic fat should not be considered diagnostic of myelolipoma, as these have been occasionally seen in adrenocortical car- cinoma (ACC), and care should be taken not to misdiagnose para-adrenal lesions with microscopic fat (eg, lipoma, liposarcoma, angiomyolipoma, or teratoma) as benign adrenal myelolipomas. 16-18
Yes
Obvious fat on CT
Benign Myelolipoma
No
Yes
<10 HU on non- contrast CT
Benign Adenoma
No
Yes
Follow (repeat imaging 6 months)
<4cm
No
Further workup or surgery
Other Features
In general, large heterogenous lesions are more concerning for malignancy, and likewise, rim enhancement, necrosis, local invasion, and border irregularity are suspicious for ACC, pheochromo- cytoma, or a metastatic lesion.13,19 Calcifications are thought to be associated with benign tumors, though ACC can exhibit this feature and clinicians should be cautious to use calcification as a sole predictor. 19
When noncontrast computed tomography is indeterminate
When a lesion is neither clearly benign nor suffi- ciently high risk for malignancy that it merits imme- diate resection, additional tests can be performed as described later. However, the sensitivity and specificity of these tests are not as good as non- contrast CT, so their interpretation ideally would depend on a nuanced understanding of the test characteristics, pretest and posttest probability, and a risk threshold for malignancy individualized to the patient that would prompt intervention. Thus, referral to an expert center at this point is usually reasonable. We nonetheless present a brief overview of these studies and their support- ing data here.
Contrast Enhanced Computed Tomography Scans with Washout
In general, adenomas are lipid rich and have rapid uptake and subsequent rapid loss of contrast. Ma- lignant lesions display slower washout or loss of contrast.
CT washout studies are performed as follows:
. Noncontrast imaging with 5 mm cuts through the adrenal gland
· Contrast imaging at 1 minute following contrast bolus
· Washout phase performed at 15 minutes
Absolute and relative washout can be computed by measuring the attenuation of the lesion and inserting these numbers into online calculators (for example https://cancernomograms.com/nomo grams/57) with washout values >60% being sug- gestive of benign adenoma and washout <40% washout suggestive of malignancy.20-22
Washout studies are generally considered to be the most reliable adjunctive test to noncontrast CT, but even their value has been called into ques- tion. While sensitivity and specificity have been re- ported as high in older studies (77.5% and 70% respectively), overall data on this topic are lacking and more recent studies question what the
appropriate washout threshold should be.5,20 Notably, metastases from renal cell and hepato- cellular carcinoma may also washout similarly to benign adenomas. 10,23
Chemical-Shift MRI
MRI measures signal collected from fat and water tissue to evaluate for intracellular lipid content. Chemical-shift MRI is an acceptable alternative to adrenal washout studies according to guide- lines. 10,22,24,25 The most recent guidelines and studies suggest the sensitivity and specificity for detection of malignancy with MRI is the same or potentially slightly lower than CT.5,10,24 Primary advantages to MRI include lack of radiation and contrast exposure, and useful for young or preg- nant patients or those with renal dysfunction. Note that chemical-shift MRI is not a contrast- enhanced study. Gadolinium MRI is not utilized in the workup of adrenal masses.
Growth
Repeat imaging to assess growth kinetics can also help differentiate benign and malignant lesions.
· Adrenalectomy should be considered for tu- mors with >5 mm/year increase in size or >20% increase in diameter.8,10
· Growth rate of <3 mm/year is indicative of an adenoma, and no further follow-up is required once a lesion has demonstrated these kinetics. 10,26
PET
Fluorine-18 fluorodeoxyglucose PET (18F-FDG PET) is useful primarily in 2 clinical situations:
· As part of a complete staging workup for pa- tients with known or suspected ACC.
· To differentiate between benign adenomas and metastatic lesions in patients with a his- tory of extra-adrenal malignancy.27,28
HORMONAL/ENDOCRINE EVALUATION
All lesions >1 cm should undergo hormonal workup in accordance with most clinical guide- lines.2,7,8 Approximately 10% to 15% of adrenal masses are hormonally active.29 Testing for hor- monal access is described below and should generally include the following:
· 1 mg Overnight Dexamethasone Suppression Test
· Plasma Renin and Aldosterone
· Plasma-Free Metanephrine and Noremeta- nephrine
Fig. 3 outlines tests to obtain in practice and their considerations.
Hypercortisolism
The 1 mg overnight dexamethasone suppression test (1ODST) is the screening test of choice for hypercortisolism in the setting of adrenal ade- noma.2,7,8 Patients are given 1 mg of dexametha- sone to take by mouth at 11 PM and then a serum cortisol level is drawn before 9:30 AM the following morning. Results can be interpreted as follows:
· < 1.8 µg/dL (50 nmol/L) rules out excess cortisol secretion
· 1.9 to 4.9 µg/dL (51-138 nmol/L) is considered equivocal
· > 5.0 µg/dL (139 nmol/L) is considered gener- ally diagnostic of cortisol excess
Important causes of erroneous results include as follows:
· CYP3A4 metabolizes dexamethasone, so CYP3A4-inhibiting medications cause false- negative results.30
· Oral contraceptives increase total cortisol levels by raising the patient’s cortisol-binding globulin, and thus can cause >50% false- pos- itive rate. Hepatitis and CYP3A4-inducing medications may also cause false-positive results.30
Alternative tests include as follows:
. Urine-free cortisol is the appropriate test for pregnant patients to avoid exposure to dexamethasone.31
. Late night salivary cortisol can be considered for epileptic patients, given many seizure med- ications affect dexamethasone clearance. 31
Once hypercortisolism is suspected/confirmed Patients testing positive should be screened for hypertension, diabetes, and vertebral fractures.8 A morning adrenocorticotropic hormone (ACTH) level must be checked and confirmed to be low to rule out ACTH excess as the cause of excess hypercortisolism. Exogenous cortisol use should of course be ruled out by patient history. If bilateral adrenal abnormalities are present, rare entities such as primary pigmented nodular adrenocortical disease should be considered.32
Note that “mild autonomous cortisol secretion” (MACS) is now the term used to describe patients who have ACTH-independent hypercortisolism on laboratory testing, but who do not have clinic symp- toms or signs of Cushing syndrome. There is no formal consensus on treating this phenomenon;
| Test | Performance | Interpretation | Preparation/Precautions | Additional Testing | |
|---|---|---|---|---|---|
| Cortisol | 1mg overnight dexamethasone suppression testing (1ODST) | -1mg dexamethasone taken at 11pm - Drawn at 8am -optional dexamethasone level at time of cortisol level | -Cortisol >5 mcg/dL considered diagnostic of hypercortisolism -Cortisol >1.8 mcg/dL considered to rule out hypercortisolism -Dexamethasone levels should be >0.18mcg/dL | Consider pausing medications which inhibit Cytochome P4503A4 (CPY3A4), as these are the only major causes of false negative results | -Repeat with oral contraceptive pills held x7 days if 1ODST abnormal. -Confirmatory testing only required if equivocal. |
| Aldosterone | Morning ARR with serum aldosterone | Draw plasma renin and aldosterone level between 8am and 10am | Serum aldosterone level > 15 ng/dL and ARR >20 have sensitivity and specificity >90%. | -Discontinue low sodium diet -Replete hypokalemia -Avoid chewing tobacco and licorice -Stop K-sparing diuretics and aldosterone inhibitors ×4 weeks (can continue if high level of suspicion for aldosteronoma, but will require repeat testing after holding medications if renin activity is detectable) -Ok to continue anti- hypertsion (HTN) medication in screening setting | In patients with hypokalemia, plasma aldosterone concentration > 20 ng/dl, and plasma renin activity below limit of detection, confirmatory testing is not required to confirm hyperaldosteronism. Otherwise, refer to endocrine for confirmatory testing. |
| Catecholamines | Plasma free metanephrines | Blood draw - Patient ideally in supine position with reference ranges based on supine patients | - Elevation of BOTH metanephrine and normetanephrine - Elevation of either >3x the upper limit of | Hold the following medications: -alpha-1 antagonists (esp phenoxybenzamine) -tricyclic antidepressants and cyclobenzaprine -caffeine (24 hours) -acetaminophen (5 days) | Confirmation only required if equivocal. Options include: - Repeat testing under strict testing conditions (i.e. supine position for 20 minutes prior to blood draw + hold full list of |
| 24-hour urinary fractionated metanephrines | 24-hour urine collection. Test: -metanephrine - | normal (ULN) Lesser elevations still > ULN should prompt confirmatory testing | medications/supplements. - Measurement of plasma catecholamines - Clonidine suppression testing | ||
| normetanephrine -total metanephrine -creatinine | |||||
| Sex Steroids | serum: DHEA-S, testosterone, estradiol, 17-OH progesterone, androstenedione | Blood Draw Only recommended to measure if high suspicion for ACC or in cases of new | Elevation of one or multiple of these is suggestive of ACC. Does not generally affect | None | |
| excessive virilization or feminization | preoperative management |
therefore, physicians may consider resection versus monitoring on a case-by-case basis.2,8,10
Hyperaldosteronism
Conn syndrome (aldosterone excess) occurs in 1% of adrenal masses, thus testing is recom- mended only for patients who have either
hypokalemia or hypertension.2,8,10,33 The morn- ing aldosterone-to-renin ratio (ARR) is the gold standard screening test. While there is no consensus on interpretation of the test, ARR >20 ng/dL per ng/ml/h is a typical cutoff indicating hyperaldosteronism. An aldosterone level of >15 ng/dL or an undetectable renin level are also suggestive of Conn syndrome.33
Important sources of error in this test include as follows:
· Potassium-sparing diuretics such as amilor- ide, and especially mineralocorticoid recep- tor blockers, such as spironolactone, alter the Renin-Angiotensin-Aldosterone System (RAAS) and should be held for at least 4 weeks prior to testing.10
· Beta blockers and Alpha-2 adrenergic ago- nists can cause false positives, but do not necessarily need to be held for testing14,34
Confirmatory testing, prior to adrenal vein sam- pling, is typically recommended (see exception in Fig. 3), with the assistance of endocrinology.33 Ad- renal vein sampling is required to confirm unilateral aldosterone excess prior to surgical resection, except in patients <35 years old with hypokalemia, marked aldosterone excess, and clear unilateral adrenal lesions consistent with an adenoma.7,10,33 Once diagnosis and laterality are confirmed, resec- tion is recommended.
Pheochromocytoma/Abnormal Catecholamines
There is some debate regarding whether patients with incidentalomas that measure <10 HU should undergo catecholamine testing. While a mass <10 HU is very unlikely to be a pheochromocytoma, cases have been reported and most guidelines recommend metanephrine workup for any adrenal mass >1 cm because the consequences of missing of pheochromocytoma could be quite significant.2,7,8,10,35 Testing is also not particularly expensive or invasive, though of course it incurs a risk of false positives and over treatment. Neverthe- less, North American and European guidelines allow for the omission of catecholamine testing in patients with lesions consistent with benign adenoma.5,10
Either free plasma metanephrines or 24-hour uri- nary fractionated metanephrines are appropriate for diagnosis of catecholamine hypersecretion. Neither test has demonstrated superiority.36
· Liquid chromatography is the best modality for free-plasma metanephrines measurement (compared to immunoassays). 36
· If both plasma metanephrines and noremeta- nephrines are elevated above the reference range, pheochromocytoma is very likely. Similarly if either is elevated >3 x the normal range, pheochromocytoma should be assumed.2,7,8,10,36
. Some medications can potentially disrupt either testing method (see Fig. 3) for medica- tion holding parameters. 36
If testing is ambiguous, clinicians should repeat the above tests with care to rule out any medica- tion contribution or perform confirmatory testing. The diagnosis of pheochromocytoma/paragan- glioma is often fairly clear on testing, and once established, should prompt surgical resection.
Adrenal Sex Steroids
The sex steroid-producing adrenal mass is very rare, and over half of these types of masses are actually ACC lesions that commonly also produce cortisol.37 Routine testing is not recommended, but should be performed in the setting of new viri- lization or feminization, or suspected ACC.8,10
The following are recommended when sex ste- roid testing is indicated: Dehydroepiandrosterone sulfate (DHEA-S), testosterone (in women), estra- diol (in men, post-menopausal women) 17-OH pro- gesterone, and androstenedione.8 When elevated, these can be used as a biochemical tumor marker for ACC follow-up. Studies have shown promise for the utility of advanced steroid profiling for diag- nosis of ACC, but these are not yet widely available or incorporated into clinical practice guidelines2,8
BIOPSY
Biopsy cannot differentiate between adrenocor- tical carcinoma and benign adenomas, nor can it determine whether an adenoma is hormonally active, and thus its role is limited in the workup of most adrenal lesions. It is now recommended only to determine if an adrenal lesion is a metas- tasis from an extra-adrenal malignancy and even in this setting, biopsy is often not needed.5 Biopsy may be indicated under following conditions:
· The lesion is suspected to be a metastasis from an extra-adrenal malignancy
· The diagnosis cannot be made on imaging alone
. The diagnosis will change management
· Pheochromocytoma has been ruled out by laboratory testing (as biopsy of a pheochro- mocytoma can lead to potential fatal hyper- tensive crisis)
Test characteristics in this setting are excellent (sensitivity 87%, specificity 100%, negative pre- dictive value approaching 100%), although 4% to 8% of biopsies will be nondiagnostic.8,10,38,39 The benefits of biopsy should be weighed against the potential risks. The most comprehensive evi- dence suggests a low complication rate of 2.5%, though some series reported rates up to 13%. These include hemorrhage (most common),
pneumothorax hemothorax, adrenal abscess, bacteremia, and pancreatitis.39-41
MANAGEMENT
Once a diagnosis has been established or sus- pected, the treatment for hormonally active or malignant lesions is surgical resection, and urolo- gists may also consider surgery in some benign masses. This section will briefly summarize surgi- cal recommendations for various masses and additional workup specific for each type of mass, though we refer readers to more detailed discus- sions in the other relevant articles in this volume. Fig. 4 summarizes management for hormonally active lesions.
Benign Lesions
Nonfunctioning and small (<4 cm) adrenal ade- nomas require no further workup. Larger benign lesions can be reimaged in 6 to 12 months, 10 though some guidelines recommend no further follow-up.5 Repeat hormonal workup is indicated only if new symptoms develop.1º The same can be said of cysts or myelolipomas if hormonal workup is negative. For myelolipoma specifically, repeat imaging is not even recommended for lesions >4 cm.10,15 This differs from adenomas
which require interval imaging to assess growth if >4 cm. Additionally, while most benign, nonfunc- tioning lesions do not need resection, urologists might consider surgery for the following:
· Myelolipoma >7 to 10 cm and causing symp- toms (mass effect, hemorrhage)9
. Cysts >5 cm or causing symptoms9
. Lesions with clinical or radiologic ambiguity
Adrenocortical Carcinoma
When clinical or radiologic evidence points toward ACC, urologists should adhere to the following management principles:
· Perform a metastatic workup.
· Perform aggressive resection with en-bloc resection of organs if involved in local inva- sion. Surgical resection is the only possible curative treatment for ACC.9
· Surgical approach can be minimally invasive or open. The priority of resection is the com- plete removal without tumor spillage or posi- tive margins; thus, an open procedure should be considered in larger >5 cm masses. 9,10,34
· Lymph node dissection is optional, though should be considered if feasible, given it can provide prognostic information. 10
| Additional workup | Management/Approach | Perioperative Care | |
|---|---|---|---|
| Cortisol-Secreting | Workup for: - Diabetes - Hypertension - Osteoporosis, including | Total or partial adrenalectomy, minimally invasive if feasible | Postop: monitor vitals for signs of Addisonian crisis, consider glucocorticoid supplementation |
| asymptomatic vertebral fractures - Urolithiasis - Hypogonadotropic hypogonadism | |||
| Aldosterone-Secreting | - Obtain echocardiogram - Consider adrenal vein sampling -Consider genetic testing | Total adrenalectomy, minimally invasive if feasible | Postop: High sodium diet, monitor for hyperkalemia |
| Pheochromocytoma | - Germline genetic testing - Rule out extra- adrenal disease: | Total or partial adrenalectomy, minimally invasive or open. - Early adrenal vein ligation - Minimize tumor manipulation | Preop: alpha blockade. - Hydration day before surgery |
| - Usually FDG-PET | Postop: usually ICU monitoring. - Blood pressure support - Blood glucose (rebound hyperinsulinemia) - Aggressive IV fluid and glucose repletion | ||
| - MIBG (metaiodoben- zylguanidine) if Multiple endocrine neoplasia type 2 germ- line mutation or excess normetanephrines w/o excess metanephriness |
. In the setting of ACC metastasis, primary resection with metastasectomy may be considered if the vast majority of suspected ACC can be removed.9,34
Follow-up
There are some discrepancies in the various guidelines for adrenal mass follow-up, but here we describe a brief overview of recom- mended or potentially feasible follow-up schedules. Follow-up recommendations pooled from multiple sources. 8-10,34,42
· Hormonally inactive masses with ambiguous or equivocal features on imaging:
o Repeat imaging 3 to 12 months depending on level of suspicion for malignancy
o Multidisciplinary care team consensus if possible
o Consider surgery based on size, growth kinetics
· After Surgical Resection:
o Benign, hormonally active lesions: No guidelines exist
Short-term hormonal testing to ensure resolution
Likely no need for imaging or long-term laboratory testing
o Pheochromocytoma
Symptom and blood pressure check, serum metanephrines
Imaging at 12 weeks, then 3 to 6 months for 1 year
Imaging every 6 to 12 months during years 1 to 5
Yearly imaging years 5 to 10, optional surveillance after 10 years43
o Adrenocortical Carcinoma: for each screening visit
Check hormone levels if tumor was hor- monally active prior to resection
Consider chest CT and/or CT abdomen or MRI abdomen
Every 3 to 12 months for 5 years, optional after year 543
DISCUSSION
There are several special populations that warrant individualized consideration in working up inci- dental adrenal lesions.
Pregnancy
Though rare, adrenal lesions in pregnancy can be more difficult to diagnose due to overlapping bio- logical processes and are associated with increased morbidity to the mother and fetus. 44
Workup of pregnant women should be expedited, with preference for MRI or low-dose CT imaging, and care by multidisciplinary team at an experience center is recommended.8,10 Note again for hyper- cortisolism workup, urine-free cortisol is the test of choice for pregnant women. Also note the cutoff values in the second and third trimesters must be raised 2-fold to 3-fold to account for physio- logic changes. 31
Bilateral Adrenal Masses
The workup for bilateral incidentalomas is no different from that of a unilateral mass. Urologists should start with a noncontrast CT ± CT washout or MRI if needed and obtain hormonal workup. 8,10 Most cases represent bilateral hyperplasia or benign adenomas; however, other more concern- ing lesions are possible including metastases, ad- renal lymphoma, or any combination of a benign lesion and a concurrent benign, functional, or ma- lignant mass.
Clinicians should test serum 17-hydroxyproges- terone in patients with bilateral masses to rule out congenital adrenal hyperplasia (recall that this dis- ease is most often caused by a mutation of 21-hy- droxylase, and 17-hydroxyprogesterone is the precursor for this enzyme).8 Thus, high levels of 17-hydroxyoprogesterone would be abnormal and require further endocrine evaluation. Testing for adrenal insufficiency may also be warranted if history or imaging is suggestive of metastases, infiltrative disease, or bilateral hemorrhage.8,10
Urologists and multidisciplinary teams should formulate surgical planning for these patients on a case-by-case basis. It is recommended to avoid bilateral adrenalectomy if possible, given the added morbidity and lifelong need for exogenous steroid. Instead, one might consider unilateral or partial adrenalectomy or cortical sparing surgery depending on the circumstance, and in the case of MACS, consider forgoing surgical intervention.8 Patients with hereditary syndromes are at higher risk of bilateral disease and an estimated 1% of the population has a poorly functioning or nonfunctioning adrenal gland due to infection, hemorrhage, auto-immunity, or neoplasia. 10,45 Given this, there is likely a role for partial adrenal- ectomy in experienced hands.
Young/Elderly Patients
As mentioned at the beginning of this article, inci- dentaloma prevalence increases significantly as patients near the age of retirement and most of these masses are benign in the elderly. Therefore, the rare mass in a young patient should be approached with a high suspicion for ACC.8,10
Expedite the workup of young adults and children and utilize MRI or low-dose CT scans if possible. 10 For frail and elderly patients, consider goals of care and weigh the likelihood of malignancy to clinical benefit and quality of life when considering surgery.8
Extra-Adrenal Malignancy
Common cancers that metastasize to the adrenal gland include those from the lung, kidney, breast, ovary, and skin (melanoma), with numerous other cancer sources described in the literature.13 In most cases, clinicians will have a high suspicion for metastases based on history and imaging, however approximately 7% of metastatic adrenal lesions can be very difficult to distinguish from ad- enomas on imaging (<10 HU).10 In patients with known extra-adrenal malignancy, up to 75% of ad- renal masses are metastases, with the vast majority demonstrating >10 HU on noncontrast scan and <60% absolute washout on adrenal protocol CT.8,39
· For more ambiguous lesions (indeterminate on imaging), clinicians can utilize adrenal bi- opsy or18 F-FDG-PET.5
· Certain guidelines have suggested metasta- sectomy for highly selected patients after multidisciplinary review.9
SUMMARY
Basic workup of most adrenal lesions is well within the capabilities of most urologists.
Hormonal and radiologic evaluations are crucial aspects of workup, with the primary goal being to distinguish benign nonfunctioning le- sions from malignant or hormonally functioning masses. Since most masses are benign and nonfunctional, testing is reassuring in the majority of cases. We generally recommend referral to expert centers for treatment or in cases of diag- nostic ambiguity.
CLINICS CARE POINTS
· Management of any adrenal lesion is driven primarily by 2 questions: (1) Is the lesion ma- lignant? and (2) Is the lesion hormonally active?
· Assessment of malignant potential is primar- ily achieved through imaging and assessment of hormonal activity is achieved through lab- oratory testing.
. Noncontrast CT imaging is the first step in workup for malignancy. < 10 Hounsfield
units = Adrenal Adenoma (100% specificity). Obvious fat = Myelolipoma.
· Larger tumors are more likely to be malig- nant. In young, healthy individuals, masses >4 cm should be resected or watched very closely.
· CT washout characteristics, MRI, or growth ki- netics can be used to help differentiate benign and malignant masses in cases where noncontrast CT is ambiguous.
· All patients with adrenal lesions >1 cm in diameter should undergo testing for hor- monal excess. This generally consists of a 1 mg overnight dexamethasone suppression test, plasma metanephrines, and often a morning aldosterone-to-renin ratio.
· Management of adrenal lesions can be complex, especially when masses are indeter- minate-it is encouraged to utilize a multidis- ciplinary team including endocrinology and radiology in instances of clinical ambiguity.
· Adrenal mass biopsy is not recommended routinely. Consider biopsy if all of the following criteria are confirmed:
o Mass is not hormonally active (especially no evidence of pheochromocytoma)
o There is evidence/history of extra-adrenal malignancy
· Imaging is nondiagnostic for benign mass
o Biopsy result would change management
· Any suspicion for pheochromocytoma is an absolute contraindication to biopsy
· Surgical resection is the mainstay of treat- ment for hormonally active lesions or sus- pected adrenocortical carcinoma.
DISCLOSURES
The authors have no disclosures.
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