6 Screening in adrenal tumors URRENT PINION
Eleonora P.M. Corssmita,b and Olaf M. Dekkersa,b,c
Purpose of review
Adrenal tumors are mostly encountered as incidentalomas in patients undergoing imaging not performed for suspected adrenal disease; although the majority are benign and nonfunctioning, malignant tumors and functioning tumors need to be excluded. The purpose of this review is to highlight recent advances in the evaluation of adrenal tumors.
Recent findings
As a consequence of increased use of technologically improved imaging techniques, the detection of adrenal incidentalomas has continued to increase. The vast majority of adrenal tumors are adrenocortical adenomas. To discriminate malignant from benign tumors and to identify clinically relevant functioning tumors, necessitating therapeutic intervention, adrenal tumors are best evaluated with unenhanced computed tomography (CT) attenuation and 1 mg dexamethasone overnight suppression test. An unenhanced CT attenuation value of 10 Hounsfield units or less excludes adrenocortical carcinoma and pheochromocytoma. Testing for hyperaldosteronism should be performed in hypertensive and/or hypokalemic patients, sex hormones, and steroid precursors in patients with clinical features suggestive of adrenocortical carcinoma. In patients with active extraadrenal malignancy and a single adrenal lesion without suspicion for metastasis elsewhere, CT-guided biopsy can be considered to rule out metastatic disease.
Summary
All patients with an adrenal tumor and without a prior history of cancer should be initially evaluated by unenhanced CT attenuation and 1 mg overnight dexamethasone suppression test, and additional hormone testing when indicated.
Keywords
adrenal incidentaloma, adrenal tumor, adrenocortical carcinoma, aldosteronoma, Cushings’ syndrome, pheo- chromocytoma
INTRODUCTION
Adrenal tumors are mostly discovered ‘incidentally,’ on imaging not performed for suspected adrenal disease. The prevalence on computed tomography (CT) scans ranges from less than 0.5% in children to 10% in the elderly [1-3]. As a consequence of improved image resolution and its increasing use, detection of adrenal ‘incidentalomas,’ defined as serendipitously discovered adrenal lesions of greater than 1 cm, has continued to increase. The cause varies from benign to malignant tumors derived from the adrenal cortex, medulla, or of extraadrenal origin; however, the vast majority are of adrenocor- tical origin, mostly adenomas [2,4,5""]. In series including patients with an adrenal mass on imaging and surgical series, 69-75% of adrenal incidentalo- mas were nonfunctioning, 10-12% cortisol secret- ing, 7-10% pheochromocytomas (PCC), 2.5-6% aldosteronomas, 8-11% adrenocortical carcinomas (ACC) and 5-7% metastasis [2,4,5”], the latter
increasing to 32-73% in patients with a history of malignancy [4]. After discovery, additional imaging and laboratory tests usually follow.
The purpose of this review is to provide an overview of the initial workup of adrenal tumors, to discriminate malignant and/or functioning tumors with therapeutic consequences from benign nonfunctioning tumors with no indication for intervention or follow-up.
ªDepartment of Medicine, Division of Endocrinology, bCenter of Endocrine Tumors Leiden (CETL), Department of Endocrinology and “Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Correspondence to Eleonora P.M. Corssmit, MD, PHD, Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. Tel: +31715263082; fax: +31715248136; e-mail: E.P.M.van_der_Kleij-Corssmit@lumc.nl
Curr Opin Oncol 2019, 31:243-246 DOI:10.1097/CCO.0000000000000528
KEY POINTS
. Adrenal masses are common lesions and are mostly detected incidentally.
. Most adrenal masses are benign and nonfunctional.
· All patients with an adrenal tumor and without a prior history of cancer should be initially evaluated by unenhanced CT attenuation and 1 mg overnight dexamethasone suppression test, and additional hormone testing when indicated.
Assessment of the risk of malignancy
Radiologic imaging
At initial detection, it is crucial to assess whether the adrenal mass is malignant or not. For this goal, CT, MRI, and PET/CT are used, a noncontrast CT rec- ommended as first-line technique [5"",6”]. If non- contrast (or ‘unenhanced’) CT shows a homogeneous tumor smaller than 4cm with a Hounsfield unit value of 10 or less, then this is consistent with a lipid-rich benign adrenal ade- noma, requiring no further imaging [5"",6”]. The reason is that in a review, no false-negative CT was found using 10 Hounsfield units as cut-off [7""]. For Hounsfield unit more than 10 lesions, an absolute and relative washout value of more than 60% and more than 40%, respectively, are sugges- tive of a lipid-poor adenoma [6”]. In Hounsfield unit more than 10 lesions different strategies can be followed: additional imaging with another modal- ity, interval-imaging after 6-12 months, or tumor resection [5""]. On MRI, adenomas show loss of signal intensity on out-phase imaging consistent with lipid-rich adenoma. MRI with chemical shift analysis can be helpful in diagnosis, especially if CT is relatively contraindicated (pregnancy and chil- dren), although the value is limited in the evalua- tion of lipid-poor adenomas [6”]. In patients with a prior history of malignancy, 18F-fluorodeoxyglu- cose (18 -FDG)-PET testing is useful. However, 16- 20% of benign lesions will also demonstrate uptake [6”]. Recent studies showed a negative 18F-FDG-PET scan being a valid indicator of benign behavior, both in low and high-risk populations with a prior history of cancer, showing that 18F-FDG-PET/CT can be valuable in the evaluation of large and/or indeter- minate adrenal masses [7"",8""]. Visual characteris- tics and size of the adrenal lesion correlate with malignancy risk, with risks increasing from 10 to 19% and 47% in tumors at least 4 cm, at least 6 cm, and at least 8 cm, respectively [9]. Even in larger tumors, Hounsfield unit is valuable to evaluate
malignancy risk. Importantly, a recent large series of the Mayo Clinic reported that all malignant adrenal lesions (ACC and metastases) in patients with adrenal tumors of more than 4 cm demon- strated unenhanced CT attenuation of at least 10 Hounsfield units (100% sensitivity) [10""]; however, Hounsfield unit density of 10 or less has been reported in adrenal metastases [11].
Adrenal biopsy
Adrenal biopsy is reserved for patients with a prior history of cancer and a single indeterminate adrenal lesion without evidence for metastases elsewhere, not in case of suspicion for ACC because of a lower diagnostic accuracy and the risk for tumor dissemi- nation [5"",12”,14""]. PCC should be excluded bio- chemically before biopsy [5"",12”].
Assessment for hormone excess
In addition to assessment of the risk of malignancy, guidelines recommend careful assessment for hor- mone excess, including clinical examination for signs and symptoms of hormone excess and laboratory assessment for autonomous cortisol secretion and PCC in all patients, hyperaldosteronism in patients with hypertension or hypokalemia, and sex hormones in case of clinical suspicion [5""]. Table 1 summarizes the suggested minimum workup for an adrenal inci- dentaloma in a patient without prior malignancy. Importantly, if hormonal screening is negative at
Table 1. Screening in an adrenal tumor in a patient without prior malignancy
Imaging: unenhanced CT scan attenuation:
≤10: benign
>10, uncertain lesion (absolute washout >60% and relative washout >40% suggestive of low fat adenoma)
Testing for hormone excess:
1. Dexamethasone (1 mg) overnight suppression testa cortisol ≤50 nmol/l: normal
50-138 nmol/l: possible autonomous cortisol secretion
>138 nmol/l: autonomous cortisol production
2. Plasma or 24 h urinary free metanephrines under standardized conditionsb
3. If hypertension present and/or hypokalemia: ARR and serum potassium under standardized conditions“
ARR, aldosterone-renin ratio.
“Serum cortisol at 8 a.m. after dexamethasone 1 mg at 11 p.m., the evening before.
bBlood taken ideally after 30 min in the supine position; after withdrawal of medication or dietary substances that interfere with catecholamine disposition. “Minimum intake of salt of 5 g daily, hypokalemia corrected if present, blood samples withdrawn in the morning and out of bed for at least 2h, withdrawal of medications that interfere with the renin-angiotensin system.
initial work-up, the likelihood that hormone excess occurs during follow-up is less than 1% [3,5”].
Autonomous cortisol production (‘subclinical Cushing’s syndrome’)
As full-blown Cushing’s syndrome is rare in a patient with an adrenal incidentaloma, the goal of testing is to detect mild autonomous cortisol pro- duction with or without subtle signs of Cushing’s syndrome. Urinary cortisol excretion is frequently normal in mild autonomous hypercortisolism, because the increased production of cortisol does not exceed the plasma-binding capacity of cortisol [13]. Serum cortisol levels of 50 nmol/l or less after dexamethasone 1 mg suppression test exclude autonomous cortisol production, more than 138 nmol/l indicate autonomous cortisol produc- tion; range of possible autonomous production is between 50 and 138 nmol/l [5"",13]. This usually requires additional tests to confirm autonomy (e.g., 24 h urinary excretion of cortisol and midnight salivary cortisol) and evaluation of the presence of potentially cortisol-related comorbidities like hyper- tension, diabetes, and asymptomatic vertebral frac- tures [13]. The degree of hypercortisolism, presence and control of comorbidities, and patient preferen- ces should guide management. Adrenalectomy can be considered for patients with high cortisol values and comorbidities, reassessment of cortisol excess and comorbidities is recommended for those with cortisol values of 51-138 nmol/l [5""].
Aldosteronomas
Screening for hyperaldosteronism is recommended in patients with hypertension, especially if hypokalemia is present [14"",15""]. For screening, measurement of the aldosterone-renin ratio is recommended under standardized conditions (minimum intake of salt of 5 g daily, corrected hypokalemia, blood samples taken in the morning and out of bed for ≥2h) and after withdrawal of interfering medications, and if positive confirmed by saline loading or another confirmation test [14"",15”]. Confirmation test may be omitted in the setting of spontaneous hypokalemia, renin below detection levels and plasma aldosterone concentra- tion more than 20 ng/dl (>550 pmol/l). In patients with an adrenal mass and confirmed hyperaldoster- onism, the critical step is distinguishing an aldoste- rone-producing adenoma (APA) from bilateral adrenal hyperplasia, of which APA is preferably corrected sur- gically and bilateral adrenal hyperplasia is treated medically (mineralocorticoid receptor antagonist). Importantly, as a unilateral adenoma is not always APA (high incidence of nonfunctional adenomas), adrenal vein sampling (AVS) should be considered
in patients of more than 35 years to confirm that an adrenal mass is the source of the hyperaldosteronism, although AVS has a failure rate of 5% [16”,17”].
Pheochromocytomas
PCC can be biochemically diagnosed by checking plasma free metanephrines, or urinary free or decon- jugated metanephrines, after withdrawal of medica- tion and dietary substances that interfere with catecholamine disposition [18,19,20""]. Diagnostic sensitivity is higher for plasma free than for urinary free and deconjugated metanephrines (97.9, 93.4, and 92.9%, respectively) with similar specificities (92-94%). Additional measurements of methoxytyr- amine in urine show limited diagnostic utility [20""]. Plasma free metanephrines provide a high sensitivity for the diagnosis of PCC; however, false-positive results, mostly drug associated, remain a problem. To distinguish true results from false-positive results, a clonidine suppression test can be considered [21].
In a recent international cohort study, attenua- tion of more than 10 Hounsfield units was found in 374 of 376 PCCs (99.5%), with Hounsfield unit of exactly 10 in the two exceptions, making it reason- able to abstain from biochemical testing for pheo- chromocytoma in adrenal tumors with Hounsfield unit of 10 or less. Contrast washout was shown to be unreliable to rule out PCC [22""].
Sex hormone-secreting tumors are rare and routine screening for them is not advised in the absence of clinically obvious symptomatology of feminization or virilization [5""]
CONCLUSION
Adrenal masses are common lesions and are mostly detected incidentally. Although most adrenal masses are benign and nonfunctional, every patient should undergo imaging and testing to assess malignancy and hormonally active lesions. Even with the present high-resolution imaging techniques, a high percent- age of operations in preoperatively uncertain lesions appear to have been performed unnecessarily for nonfunctioning benign lesions. In the future, unnec- essary adrenalectomies might be reduced by the use of urine steroid metabolomics, which showed a high diagnostic accuracy for distinguishing ACC from benign tumors in a proof-of-concept study [23,24”], validation studies being underway.
Acknowledgements
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Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
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