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Adrenal Incidentalomas A Disease of Modern Technology Offering Opportunities for Improved Patient Care
Adriana G. Ioachimescu, MD, PhDª, Erick M. Remer, MDb, Amir H. Hamrahian, MDC,*
KEYWORDS
. Adrenal incidentaloma . Noncontrast CT attenuation . Percentage washout
. Tumor size . Pheochromocytoma
KEY POINTS
· Noncontrast computed tomography attenuation is superior to adrenal tumor size in differ- entiating benign adenomas from malignant tumors.
· Absolute and relative percentage washout may be used to further characterize lipid-poor adrenal tumors.
· Pheochromocytoma is extremely unlikely in patients with lipid-rich adrenal tumors.
· Any degree of increase of plasma or urinary metanephrine fraction in a patient with adrenal incidentaloma should prompt a careful evaluation for an underlying pheochromocytoma.
Since the initial report of an adrenal incidentaloma (AI) in 1941, the diagnosis of AI has become increasingly prevalent contemporaneously with advances in imaging tech- niques.1,2 The two main questions that should be answered are the secretory and malignant potential of the mass. A practical approach in the investigation and follow-up of adrenal incidentalomas incorporating authors’ experience is presented in this review.
DEFINITION
Adrenal incidentalomas (AIs) are adrenal masses discovered serendipitously by radio- logical evaluation in the absence of clinical features suggestive of adrenal disease. The definition usually encompasses lesions larger than 1 cm that are detected outside the work-up for staging of known cancers. Adrenal diseases inadvertently missed on clin- ical evaluation are not under the strict definition of AIs.
Disclosure: The authors have nothing to disclose.
a Emory University School of Medicine, 1365 B Clifton Road, Northeast, B6209, Atlanta, GA 30322, USA; b Imaging Institute, Cleveland Clinic, 9500 Euclid Avenue, A21, Cleveland, OH 44195, USA; ” Endocrinology, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
* Corresponding author.
E-mail address: hamraha@clevelandclinicabudhabi.ae
EPIDEMIOLOGY Autopsy Studies
Autopsy studies have shown a wide range of prevalence of 1.1% to 32% for adrenal nodules, which reflects the heterogeneity of published data, especially with regard to age at death and inclusion of metastatic lesions.3-5 A summary of 25 autopsy studies indicates a prevalence of 6%. AIs are detected with increased prevalence at older ages. One study identified AIs in 7% of those who died after the age of 70 years. In contrast, only 1% of those younger than 30 years had AIs.6 Other investigators confirmed the age-dependent occurrence of adrenal cortical adenomas.2 No gender difference was observed in autopsy studies.
Computed Tomography Studies
Earlier computed tomography (CT) studies from 1980s reported a prevalence of 0.9%.2 However, as CT resolution improved over time, the prevalence of AIs also increased. Further, the increasing use of CT imaging for nonspecific symptoms has likely contributed to the increased identification of AIs. AIs were detected in 4.4% of chest CT scans performed as part of a high-resolution lung cancer screening program in Italy in 2006.7 Because only 1 metastasis of lung cancer was identified in this study of 520 subjects, it is unlikely that the prevalence of AIs was overestimated. In contrast, a 2011 study conducted in a routine clinical practice setting indicated a prevalence of only 0.98% for abdominal CT and 0.81% for chest CT scans.8 However, the preva- lence may have been underestimated, because only radiology reports and not the films were reviewed in this study.
The diagnosis of AI identified on CT peaks in the sixth and seventh decades of life. However, based on autopsy studies, it is expected that the prevalence of AIs con- tinues to increase after age 70 years. Some studies showed a higher prevalence of AIs in women, which may be the result of referral bias caused by higher frequency of abdominal complaints in women than in men.º An equal prevalence between the genders is supported by autopsy studies.
Differential diagnosis of adrenal incidentaloma
At least 38 different diagnoses have been identified in patients with incidentally detected adrenal masses.2 The main categories are nonfunctioning cortical adenomas (70%-80%), pheochromocytomas (PHEOs) (1.1%-11%), subclinical Cushing syn- drome (5%-20%), primary aldosteronism (1%-2%), primary adrenocortical carci- nomas (ACCs) (<5%), and metastases (2.5%).2,4,10-14 A list of disorders that may present as Als is shown in Box 1. Als are bilateral in about 10% to 15% of cases. 15,16 Nonadrenal lesions may also present as AIs (Fig. 1).17
CLINICAL EVALUATION
A thorough clinical evaluation is of paramount importance in patients with AIs, because identification of an AI may provide an opportunity for clinicians to detect an underlying secretory tumor. History should assess manifestations of hypercortisolemia, primary aldosteronism, catecholamine excess, hyperandrogenism, and abdominal complaints. New-onset or worsened hypertension, impaired glucose metabolism, and bone loss may suggest excess cortisol secretion. A history of new-onset sustained or paroxysmal hypertension, blood pressure fluctuations during general anesthesia, syncopal events, and orthostatic blood pressure changes may suggest an underlying PHEO.
Several cancers, including lung, breast, renal, and melanoma, have potential to metastasize to the adrenal glands, so history of malignancy and weight loss should
Box 1 Adrenal abnormalities that can present as AIs
1. Adrenal cortical masses.
Benign: adenoma, nodular hyperplasia,a congenital adrenal hyperplasia.ª
Malignant: primary ACC.
2. Adrenal medullary tumors: PHEO,ª ganglioneuroma, neuroblastoma.
3. Other adrenal tumors.
Benign: myelolipoma,a teratoma, hamartoma, lipoma, hemangioma, lymphangioma, adrenal adenomatoid tumor.
Malignant: metastases,a primary adrenal lymphoma,a primary adrenal melanoma.
4. Infectionsª: fungal (Histoplasma, coccidioidomycosis, blastomycosis), viral (cytomegalovirus), parasitic (echinococcosis), bacterial (tuberculosis, syphilis).
5. Infiltrationª: sarcoidosis, amyloidosis.
6. Cysts and pseudocysts.
7. Hemorrhage,ª hematoma.
8. Nonadrenal disorders such as schwannoma, leiomyosarcoma, retroperitoneal lipoma.
ªMay present as bilateral adrenal masses.
be obtained (Figs. 2 and 3). A combination of features reflecting cortisol and androgen excess in the setting of an adrenal mass should alert for the possibility of underlying primary ACC. A history of smoking and medication use including anticoagulants needs to be established.
Family history should be ascertained for components of multiple endocrine neoplasia type 2, von Hippel-Lindau syndromes, neurofibromatosis type 1, Carney complex, and Carney triad. Although genetic syndromes are usually rare in patients with AI, their detection has important implications in patients with bilateral adrenal le- sions and silent PHEOs. Unilateral or bilateral adrenal masses may be seen in patients with homozygous or heterozygous congenital adrenal hyperplasia.18 However, such an association may be related to the increased volume of adrenal tissue or intratu- moral functional impairment of enzyme activity, rather than a true enzymatic defect. 19
RADIOLOGICAL CHARACTERISTICS
After the detection of an AI, a decision must be made about whether further dedicated adrenal studies are necessary. For example, postcontrast CT studies may not provide sufficient information about the risk of malignancy and may need to be repeated by doing a noncontrast CT study with or without contrast (adrenal protocol). In addition, AIs detected by abdominal ultrasonography or nuclear medicine studies have to be further investigated.
Choice of Adrenal Imaging Studies
Adrenal CT is the cornerstone of imaging for AIs, establishing the size, lipid content, and imaging phenotype, including heterogeneity, calcifications, irregular borders, local invasion, and areas of necrosis. All of these imaging characteristics can help
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to assess the risk of malignancy. MRI scans can also be used to establish the risk of malignancy, but they are more expensive and are generally reserved for selected cases in which CT imaging is contraindicated or equivocal to delineate the malignancy risk. Functional imaging studies of the adrenal glands have a limited role in evaluation of selected patients with AIs.
Size of the Adrenal Incidentalomas
The risk of malignancy traditionally relied heavily on the size of the adrenal masses. In a retrospective study by Musella and colleagues,20 the proportion of ACCs among 282 surgically resected AIs was 25% in adrenal masses with a maximal diameter greater than 6 cm, 1.2% for tumors measuring 4 to 6 cm, and 0% in lesions smaller than 4 cm. The likelihood ratios derived from a large cohort of ACCs yielded probabilities of 10%, 19%, and 47% for malignancy in adrenal cortical tumors greater than or equal to 4 cm, greater than or equal to 6 cm, and greater than or equal to 8 cm, respectively.21 Note that there is no safe absolute tumor size cutoff to rule out malignancy because there are reports of ACCs less than 4 cm in size.22
The tumor size should be evaluated in the context of other radiological features because the risk of malignancy for a homogeneous mass greater than 4 cm with no areas of necrosis or calcification and a noncontrast CT less than 10 Hounsfield units (HU) is close to 0% (Fig. 4).23-25 In addition, myelolipoma, a benign fat-containing tu- mor, can reach sizable dimensions with negative HU typically in a range -40 HU or less (Fig. 5).
Metastatic lesions to the adrenal glands are usually smaller than ACCs. However, in most cases a history of prior malignancy is present, which can direct further work-up and management.23
Computed Tomography Scan
The CT scan is the primary tool for evaluation of adrenal masses. It provides informa- tion on the adrenal tumor size and density, as well as calcification, areas of necrosis, and local invasion (Figs. 6 and 7).
Noncontrast computed tomography attenuation coefficient
A low attenuation value measurement of an adrenal nodule is secondary to high fat concentration in the sterol-producing adrenal cortical tissue and has a specificity close to 100% for diagnosing adenoma and, thus, in differentiating benign from
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potentially malignant lesions (Fig. 8).18,23-29 In addition, a combination of adrenal mass size less than 4 cm and an attenuation value less than or equal to 20 HU had 100% specificity to predict a benign lesion.23 The unenhanced CT attenuation value is a better predictor of benign tumors than adrenal tumor size.23,24
ACCs and PHEOs typically have attenuation values greater than 30 HU. In our expe- rience the lowest attenuation value for adrenal PHEO has been 17 HU.30 There has
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been a report of unenhanced CT attenuation values less than 10 HU in 2 patients with symptomatic adrenal PHEO.31 However, these tumors were very small, less than 1.5 cm, and one of the reported patients had adrenal medullary hyperplasia on pathol- ogy. In other cases in which a low attenuation value for PHEO has been reported, the measurement technique has been questioned.32 The region of interest during mea- surement of attenuation value should encompass two-thirds of the largest axial diam- eter of the mass and should avoid boundaries to prevent volume averaging with tissue outside the nodule. Only homogeneous regions of the tumor should be selected, avoiding areas with cystic and necrotic changes. The highest CT attenuation values in mixed tumors should be used for clinical decision making (Fig. 9) with the exception of myelolipomas in which a small fat-containing area ( ← 40 HU) would establish the diagnosis. Based on the accumulating data in the literature and our own experience, we only perform biochemical investigation for PHEO in patients with AIs in whom the CT attenuation value is greater than 10 HU.30,32,33
Computed tomography washout and enhancement patterns
Although an unenhanced CT attenuation value less than or equal to 10 HU is an excel- lent predictor of benign histology, 20% to 30% of adrenal adenomas are lipid poor (Fig. 10).34 That is, there is insufficient sterol content to diminish the overall attenuation of the adrenal nodule below the diagnostic threshold. In such cases additional imaging is needed diagnose an adenoma and to avoid unnecessary surgery. If unenhanced CT shows an attenuation value greater than 10 HU, postcontrast images should be
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HU 9
HU 47
obtained at 1 and 15 minutes in order to calculate the washout percentage (Fig. 11). An absolute percentage washout greater than 60% and/or a relative percentage washout greater than 40% at 15 minutes suggests an adenoma. 35-37
Studies with shorter postcontrast time delays have been done; however, a 15-min- ute delayed scan seems to have the best sensitivity (87%) and specificity (94%) in dis- tinguishing between adenomas and nonadenomas. 35-39 Note that PHEOs may display washout characteristics similar to adenomas. 33,40
The enhancement pattern of an adrenal lesion after contrast administration may also be used as a clue to differentiate adenomas from nonadenomatous lesions. In a recent study by Northcutt and colleagues,41 comparing 41 adenomas with 12 PHEOs, none of the adenomas had an enhancement attenuation greater than 85 HU within 60 sec- onds after contrast administration compared with more than 50% of PHEOs that enhanced more than 110 HU.
Chemical shift T1-weighted MRI can reliably identify lipid-rich lesions by a reduction in signal intensity during out-of-phase compared with in-phase images (Fig. 12).42 Chemical shift MRI may further characterize adrenal tumors with borderline
1
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Precontrast CT attenuation 13 HU
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Postcontrast CT attenuation at 1 minute 80 HU
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Delayed CT attenuation at 15 minutes 26 HU
unenhanced CT attenuation values or washout characteristics.43,44 However, there are rare reports of ACC, PHEO, and clear cell renal and hepatocellular carcinoma me- tastases showing a signal loss on out-of-phase images.22 Very high signal intensity on T2-weighted MRI is characteristic but not pathognomonic for PHEO. However, it may be absent in up to 35% of cases (Fig. 13).45,46 The criteria used for defining hyperin- tensity may have an impact on its prevalence in patients with PHEO.47
Quantitative analysis of chemical shift MRI and diffusion-weighted imaging may help to characterize the hyperattenuating adrenal lesions, especially differentiating lipid-poor adenomas and benign PHEOs from malignant tumors. 48
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Functional Imaging
There is a limited role for functional imaging in the diagnostic work-up of patients with AIs. Scintigraphic studies with iodine-meta-iodobenzylguanidine (123I-MIBG), and PET studies using 18F-fluoro-2-deoxy-D-glucose (18F-FDG), 18F-3,4-dihydroxyphenylala- nine (18F-DOPA), and 18F-fluorodopamine (18F-FDA) may be used if an underlying multifocal or metastatic PHEO is suspected.49 18F-FDA and 18F-FDG have higher sensitivity than MIBG. 50,51
18F-FDG-PET and PET-CT scans may be useful to detect extra-adrenal disease in patients suspected to have an underlying malignancy. The study relies on trapping of 18F-FDG by metabolically active malignant cells. In a study of 165 adrenal lesions in 150 patients, all 139 benign lesions had a quantitative standardized uptake value of 0.54 to 3.34 SUV. A 2.31 SUV threshold provided 100% sensitivity to detect all 29 ma- lignant lesions and was associated with an approximately 5% false-positive rate for benign lesions (Fig. 14).52 There is small false-negative result in patients with small, hemorrhagic, or necrotic metastatic lesions.
Adrenal scintigraphy with radioiodinated 1311-6b-iodomethyl-19-norcholesterol (NP- 59) highlights the adrenocortical hyperfunctioning lesions, but has limited clinical avail- ability. We do not recommend it for routine evaluation of AIs. A recent small study showed that positive 19-iodocholesterol scintigraphy in patients with AI had better predictability for development of prolonged postoperative hypoadrenalism than
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# Pix 201.1
7 Perim 4 49 cm
Area 1,60 cm2
7
-Avg 2,989 HU
Dev 37.99
hormonal work-up for subclinical Cushing syndrome. It was able to predict the meta- bolic outcome, identifying the patients who could benefit from adrenalectomy irre- spective of hormonal diagnosis.53
Imaging phenotypes of the most frequent types of AIs are summarized in Table 1. An unenhanced adrenal CT scan reliably identifies benign tumors based on noncontrast attenuation values less than or equal to 10 HU. For lipid-poor adrenal masses, we sug- gest delayed contrast-enhanced CT studies for washout calculation. MRI should be considered when CT is inconclusive or iodinated CT contrast cannot safely be admin- istered. Functional scans should be considered for selected cases to detect extra- adrenal PHEOs or malignant lesions.
BIOCHEMICAL EVALUATION AND MANAGEMENT IMPLICATIONS
Up to 30% of patients with AIs harbor excess cortisol, catecholamine, or aldosterone secretion depending on the criteria used to define excess hormone secretion. Screening for subclinical excess is indicated in all patients with AIs. Patients with lipid-poor adrenal masses need to be evaluated for PHEO. Primary aldosteronism should be ruled out in patients with hypertension and/or hypokalemia. Measurement of testosterone and dehydroepiandrosterone sulfate (DHEAS) should be considered in women with virilization, new-onset symptoms suggestive of hyperandrogenism, or adrenal masses suspicious for ACCs. Although several guidelines have been released over the years,13,54,55 only 50% to 82% of patients diagnosed with AI un- dergo hormonal evaluations in clinical practice.8,56,57
Subclinical Cushing Syndrome
The first reports on subclinical Cushing syndrome (SCS) were published by Beier- waltes and colleagues58 in 1972 and subsequently by Chabonnel and colleagues59 in 1981. SCS is best defined as the subtle autonomous production of cortisol from an adrenal mass, which is usually associated with suppression of cortisol production from the contralateral gland, but no overt clinical features of Cushing syndrome.6,55 Based on the criteria used, prevalence of up to 20% in patients with AIs has been reported.2,60
At present, there is a large body of literature linking SCS to comorbidities including hypertension, abnormal glucose metabolism, obesity, dyslipidemia, vertebral frac- tures, and osteoporosis.61-65 There are emerging data on the long-term conse- quences of SCS, including a higher rate of cardiovascular events and all-cause
| Type | Size (cm) | Attenuation Nonenhanced | CT Washout >60% (Absolute) | Loss of Signal Intensity on T1-weighted Out-of-phase MRI |
|---|---|---|---|---|
| Cortical adenoma | Small (<4) | Low in 70% (<10 HU) | Yes | Yes |
| Primary cortical carcinoma | Large (>4) | High (>30 HU) | No | No |
| Metastasis | Variable | High (>10 HU) | No, except RCC, HCC | No, except RCC, HCC |
| PHEO | Large (>3) | High (>17 HU) | variable | No |
Abbreviations: HCC, hepatocellular carcinoma; RCC, renal cell carcinoma.
mortality compared with patients with normal cortisol levels.66 A full review of biochemical evaluation and management of SCS is discussed in Adrenal Mild Hyper- cortisolism by Goddard and colleagues.
Primary Aldosteronism
The estimated prevalence of primary aldosteronism among patients with AI is up to 2%.2,12-14,19,67 Evaluation for primary aldosteronism is recommended in patients with Als in the presence of hypertension regardless of their potassium levels. 55,68-70 A few patients with well-documented primary aldosteronism had hypokalemia in the absence of hypertension, therefore evaluation for primary aldosteronism in such pa- tients is also indicated.71 A detailed review of biochemical evaluation and manage- ment of patients with primary aldosteronism is discussed in another article in this issue.
Pheochromocytoma
Patients with AIs should be evaluated for PHEO regardless of their blood pressure sta- tus, because up to 50% of patients with incidentally discovered PHEO are normoten- sive. 67,72-74 The prevalence of PHEO in patients with Als is about 3%, but a prevalence ranging from 1.1% to 11% has been reported.4,11,12,60 There are accumulating data in the literature that evaluation for PHEO in AIs with a noncontrast CT attenuation less than or equal to 10 HU is not needed.23,30,32 Accordingly the authors only evaluate for PHEO in patients with lipid-poor AIs.
Biochemical evaluation
Both plasma and 24-hour urine metanephrine levels are reasonable initial screening tests in patients with AIs. Normal plasma metanephrine level rules out a diagnosis of PHEO in almost all patients except very rare dopamine-secreting tumors, which are usually extra-adrenal.75 When normotensive reference ranges are used for plasma and urine metanephrines, the diagnostic specificity of plasma metanephrines is similar to or better than that of urine metanephrines. 30 Accordingly, the authors prefer plasma metanephrines as the first-line diagnostic test because of its excellent diagnostic sensitivity and convenience. 55,75,76
Modest plasma and urine normetanephrine level increases (<4-fold above upper normal limit) in adrenal masses greater than 5 cm are almost always false-positive.30 However, any degree of increase in plasma or urinary metanephrine fraction in pa- tients with AIs should be carefully evaluated for an underlying adrenal PHEO.30
Management
PHEOs should be surgically removed after medical preparation to reduce the risk of a cardiovascular event during the surgery. All patients with PHEO should be treated with an alpha adrenoceptor blocker for at least 7 to14 days preoperatively.77-79 Calcium channel blockers may be used for better control of hypertension or in those patients who cannot tolerate adequate alpha-blockade. ß-Blockers are often required to con- trol the tachycardia that may occur during alpha-blocking receptor treatment. Preop- erative volume repletion by increased salt intake is recommended before surgery. Patients who continue to be symptomatic on alpha-blockade and beta-blockade may require a brief preoperative course of metyrosine to block catecholamine synthesis. 80
Patient should be monitored for hypotension or hypoglycemia postoperatively. Because there are no definitive pathologic diagnostic criteria for malignancy, patients with apparently benign PHEO should be followed annually for at least 5 years and then intermittently afterward.81,82
Primary Adrenocortical Carcinoma
ACC is a rare malignancy that usually carries a grave prognosis unless complete sur- gical resection can be achieved early in the course of the disease. A large series of pa- tients with ACC identified cortisol overproduction and advanced tumor stage and tumor grade as negative prognostic factors.83 ACC comprised less than 5% of all AIs in a pooled analysis from 26 international studies.19 Most ACCs have noncontrast CT HU values greater than 30.23 Concerning features for malignancy include microcal- cification, irregular shape and border, necrosis, and a heterogeneous enhancement pattern (Fig. 15).
Close follow-up by a multidisciplinary team consisting of an endocrinologist, oncol- ogist, and surgeon is recommended. Postoperative treatment with mitotane is asso- ciated with longer recurrence-free survival.83
Adrenal Metastases
Adrenal metastases are common in patients with carcinoma of lung, breast, renal cell, and ovary, and in patients with melanoma, but have been described in many other ma- lignant diseases (see Figs. 2 and 3). In cases of bilateral metastases, adrenal function needs to be evaluated. Adrenal biopsy may be of value in selected patients in whom the diagnosis of a metastatic lesion to the adrenal gland would change the treatment plan or prognosis. Any biopsy attempt should be preceded by biochemical exclusion of PHEO. Surgical treatment may improve survival in cases of solitary metastases, but the management should be decided after a thorough oncologic evaluation.84
Follow-up of Patients with Adrenal Incidentalomas
The management of patients with AIs is summarized in Fig. 16.
In a recent large Italian prospective study, 8.2% of patients developed new SCS af- ter greater than or equal to 5 years of follow-up.85 Autonomous cortisol secretion usu- ally correlates with adenoma size; adenomas larger than 2.4 cm are more likely to be associated with worsening of hypercortisolemia.85 Accordingly, patients managed conservatively should have clinical and biochemical evaluation for up to 5 years until further studies define the optimal follow-up period in such patients. A through initial diagnostic approach can be the basis of a subsequent tailored approach. 86
Repeat imaging of adrenal masses with borderline characteristics in 3 to 6 months and then annually for 2 years is reasonable. There is no good evidence supporting continued radiological surveillance in patients with AIs, which is associated with increased radiation exposure, higher health care expenditures, and potentially signif- icant emotional impact.60
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Adrenal Incidentaloma
Noncontrast CT attenuation value ≤ 10 HU
Noncontrast CT attenuation value > 10 HU
< 4 cm
1mg DST ARR if hypertensive
1mg DST and plasma METs ARR if hypertensive
≥ 4 cm or concerning radiological features
Non-functional
Functional
Non-functional
Calculate percentage washout at 15 min
Hormonal wok up including plasma METs
No routine follow up imaging required
Surgically remove
≥ 60%
< 60%
Surgery
Follow up imaging in 3-6 mon & annually for 2 years
Annual hormonal evaluation for 5 years particularly in tumors > 2.4 cm in size
< 8 mm change in size in 3-12 months
≥ 8 mm change in size in 3-12 months
A
B
7
7
Changes in adrenal mass size
AIs can increase (up to 10%), decrease (up to 5%), or remain unchanged in size over the years.87 A decrease in the size and the attenuation value of an adrenal mass on noncontrast CT studies may be a clue to the presence of an adrenal hematoma (Fig. 17). An adrenal mass growth cutoff that can reliably confirm or exclude malig- nancy has not been identified. Surgical resection may be considered for an increase greater than or equal to 0.8 cm in maximal diameter of an adrenal mass, if corrobo- rated by other imaging and clinical findings.88
SUMMARY
The incidence of AI is expected to increase because of improved resolution of CT im- aging and its use for nonspecific symptoms. Increased awareness among practi- tioners is necessary for the best cost-effective approach to AIs. We recommend dedicated adrenal imaging to assess the potential for malignancy. Noncontrast CT attenuation characteristics of AIs is the most important radiological characteristic to differentiate between benign adenomas, hyperplasia, or cysts and malignant adrenal tumors. Screening for subclinical excess is indicated in all patients with AIs. Patients with lipid-poor tumors need to be evaluated for PHEO regardless of their blood pres- sure status. Primary aldosteronism should be ruled out in patients with hypertension and/or hypokalemia. Adrenal androgens are measured in patients with clinical signs of androgen excess. Identification of AIs should be considered as an opportunity because there is growing literature linking AIs to several cardiovascular risk factors, and may be associated with increased mortality. Surgery is indicated for most secre- tory tumors and those with radiological features concerning for malignancy.
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