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adiología. 2011;53(6):516---530

www.elsevier.es/rx

PDATE IN RADIOLOGY

iagnosis and management of adrenal incidentaloma�

. Oliveira Caiafa ∗, R. Salvador Izquierdo, L. Bunesch Villalba, M.C. Sebastià Cerqueda,

. Nicolau Molina

entro de Diagnóstico por la Imagen, Hospital Clínic, Barcelona, Spain

eceived 27 October 2010; accepted 15 June 2011

KEYWORDSAdrenalincidentaloma;Computedtomography;Magnetic resonanceimaging;Positron emissiontomography/computedtomography;Algorithm

Abstract The growing demand for imaging tests and the progressive aging of the populationhave led to a progressive increase in the detection of indeterminate adrenal lesions. Oncean adrenal incidentaloma is detected, clinical and hormone tests together with a battery ofimaging techniques (CT, MRI, PET/CT. . .) make it possible to determine the cause in most cases.In this article, we discuss the advantages and limitations of each technique. We show the imagingcharacteristics of the most common adrenal lesions and propose a diagnostic algorithm to enabletheir diagnosis.© 2010 SERAM. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVEIncidentalomasuprarrenal;Tomografíacomputarizada;Resonancia

Manejo y diagnóstico del incidentaloma suprarrenal

Resumen La creciente demanda de pruebas radiológicas y el envejecimiento progresivo de lapoblación ha llevado al aumento progresivo en la detección de lesiones suprarrenales indeter-minadas. Una vez detectado el incidentaloma suprarrenal, disponemos actualmente de pruebasclínicas y hormonales y de una batería de técnicas de imagen (TC, RM, PET/TC. . .) que hacen

ded from http://zl.elsevier.es, day 03/02/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

magnética;Tomografíapor emisión depositrones/tomografía

posible el diagnóstico etiológico de la mayoría de estos incidentalomas. En este artículo pre-sentamos las ventajas y limitaciones de cada técnica, las características por imagen de laslesiones suprarrenales más frecuentes y proponemos un algoritmo diagnóstico que permita eldiagnóstico de las mismas.© 2010 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.
computarizada;
Algoritmo

� Please cite this article as: Oliveira Caiafa R, et al. Manejo y diagnóst∗ Corresponding author.

E-mail address: [email protected] (R. Oliveira Caiafa).

173-5107/$ – see front matter © 2010 SERAM. Published by Elsevier Esp

ico del incidentaloma suprarrenal. Radiología. 2011;53:516---30.

aña, S.L. All rights reserved.

dx.doi.org/10.1016/j.rxeng.2011.06.003

http://www.elsevier.es/rx

mailto:[email protected]

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Document downloaded from http://zl.elsevier.es, day 03/02/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Diagnosis and management of adrenal incidentaloma

Introduction

Adrenal incidentalomas are clinically silent adrenal massesthat are discovered during the study, treatment or follow-up of unrelated clinical conditions. This definition excludespatients imaged for cancer staging or follow-up.1,2

In autopsy studies, the mean prevalence of adrenalincidentalomas is approximately 2.3%, with no significantdifferences between men and women, and higher rates inolder patients.3 In the current setting of increasing demandand use of high-resolution diagnostic imaging techniques,there has been a significant increase in the detection ofthese lesions. Adrenal lesions are found in 4---5% of com-puted tomography (CT) studies performed for unrelatedreasons.3---7

Seventy per cent of all adrenal incidentalomas arenon-functioning adenomas; 5---16% are functioning adeno-mas; 6% are pheochromocytomas; 5% are adrenocorticalcarcinomas; 2% are metastatic carcinomas, and the rest,other types of lesions (myelolipomas, hematomas, cysts orlymphoma).3,8,9

When an adrenal incidentaloma is discovered during animaging examination, the major issues are whether thelesion is hormonally functional and whether the lesion islikely to be benign or malignant. The results from thesetests will determine whether lesion resection or conserva-tive management is indicated.

Although the majority of adrenal incidentalomas are non-functioning, a fair number of these patients present with asubclinical form of hormonal dysfunction and may representa population at higher risk of metabolic disorders and car-diovascular disease. For this reason, when an incidentalomais found, a complete medical history and physical examina-tion, a hormonal evaluation and, in some cases, additionalradiologic studies are required. Screening for pheochromo-cytoma, primary hypercortisolism and hyperaldosteronismis routinely recommended for hypertensive patients, unlessthere are unequivocal features of myelolipoma, hemorrhageor adrenal cyst.1,10,11

Radiologists have at their disposal a variety of imag-ing techniques for characterizing adrenal incidentalomas,from CT and magnetic resonance (MR), which allow for thediagnosis of most adrenal lesions, to more sophisticatedtechniques such as positron emission tomography/computedtomography (PET/CT) and MR-spectroscopy, the latter stillat an experimental stage. However, a small proportion ofadrenal lesions remain undetermined and often represent amajor diagnostic and therapeutic challenge given that thereis no consensus in the literature as to when fine needle aspi-ration (FNA), surgery or follow-up (clinical, biochemical, andradiologic) is indicated.

This article examines the advantages and limitationsof the different imaging techniques used in the characteriza-tion of incidentalomas and proposes a diagnostic algorithmthat includes clinical, biochemical and, especially, imag-ing parameters.Although the definition of incidentalomaexcludes patients undergoing imaging procedures as a partof staging or follow-up for cancer,1,2 we have included infor-
mation on the diagnosis and management of adrenal lesionsin oncologic patients, given that 50% of adrenal lesions inthese patients are metastatic.12 Additionally, the character-ization of these lesions is important for noninvasive tumor
str

517

taging and for formulating a therapeutic plan and predict-ng the prognosis.8

maging techniques

omputed tomography

t CT, parameters such as a size larger than 6 cm, rapidrowth, irregular or nodular margins and heterogeneityay be suggestive of a malignant adrenal incidentaloma,

lthough these features are not very specific.13,14 However,he unenhanced CT attenuation measurements, the his-ogram analysis and the values of contrast-enhancementashout allow for adrenal lesion characterization in a highercentage of cases.6,15,16

The appropriate technique for the evaluation of adrenalodules involves a study without intravenous (IV) contrastbaseline) in all patients, followed if necessary by a contrast-nhanced CT (portal phase at 60 s and delayed phase at5 min). A thin slice thickness (2---3 mm) is required, as wells attenuation measurements obtained through regions ofnterest covering a significant portion of the lesion (1/2 to/3 of the lesion area), but avoiding the peripheral edges ofhe mass to prevent partial volume artifacts.14,17

The quantification of the mean attenuation values onnenhanced (baseline) CT is a simple and highly sensitiveask to detect fat within the tumor, which makes it theost useful parameter in the initial assessment of adrenal

esions.18,19

Other tool that may be useful in the characterization ofdrenal lesions is the histogram analysis, that is, a graph-cal representation that displays the individual analysis ofhe attenuation values for each pixel in a given area. Thisethod is highly sensitive for the detection of fat, repre-

ented as pixels with negative attenuation values.8,17,20,21

The most commonly used parameters in contrast-nhanced CT are:

Absolute washout: quantifies the delayed washout com-pared to portal-phase enhancement.

Absolute washout = Portal AC − Delayed ACPortal AC − Baseline AC

× 100

where AC is the attenuation coefficient (HU).Relative washout: is an estimated calculation of the abso-lute washout when an adrenal lesion is discovered onenhanced CT (portal and delayed phase) and no previousbaseline study is available.

Relative washout = Portal AC − Delayed ACPortal AC

× 100

Washout values are of little use in the characterization ofdrenal masses with heterogeneous areas of low attenuationnecrosis or cystic areas).

The recent emergence of dual energy CT allows us toubtract, using a postprocessing algorithm, the iodine con-rast agent from the abdominal images obtained after cont-ast administration and generate a virtual unenhanced study

518

Figure 1 Adrenal adenoma. Abdominal CT scan in a72-year-old patient investigated for infrarenal abdominal aor-tl-

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ic aneurysm. Unenhanced CT scan shows a hypodense nodularesion in the left adrenal gland, with attenuation values of-- 13 HU, compatible with an adenoma.

hat can be used to estimate the baseline attenuation valuesf an adrenal lesion.22

agnetic resonance

hemical shift imaging is the mainstay of MR evaluationf solid adrenal lesions and is based on the detection

tai

Fusion V

igure 2 Adrenal adenoma. Abdominal dual energy CT scan in a

nenhanced study was performed. The portal-phase enhanced CT scdrenal gland of 39 HU. With the dual energy technique, a virtual uttenuation of the lesion was 3 HU, compatible with an adenoma.

R. Oliveira Caiafa et al.

f cytoplasmic lipid using in-phase and opposed-phaseradient-echo T1-weighted Images.23---26 This method reliesn the differences in resonance frequency of lipid and waterolecules. On opposed-phase images, the phase of the lipid

ignal is opposite to that of the water, resulting in a dropf signal in those voxels containing both elements, whichicroscopically correlates with the presence of intracellular

ipid.27

The chemical shift phenomenon can be assessed eitherualitatively, by visual comparison of the adrenal lesionntensity with that of the spleen, or quantitatively, throughne of the following formulas28,29:

drenal/spleen ratio

= Adrenal SI OP/Spleen SI OPAdrenal SI IP/Spleen SI IP

× 100

ercentage of SI loss

= Adrenal SI IP − Adrenal SI OPAdrenal SI IP

× 100

here SI is the signal intensity; IP the in-phase; and OP thepposed-phase.

Additionally, the protocols may include T1-, T2- andat-suppressed T1-weighted sequences obtained beforend after contrast administration, providing data on theorphology and behavior of the adrenal lesions com-arable to those provided by CT.

Gadolinium-enhanced dynamic MR imaging involveshe IV administration of gadolinium contrast media and thecquisition of consecutive fast sequences at variable timentervals, depending on the protocol of each institution, in

irtual baseline

63-year-old patient with a history of colorectal carcinoma; noan (fusion 140 kVp + 100 kVp) shows a nodular lesion in the leftnenhanced study could be obtained and this showed that the

Diagnosis and management of adrenal incidentaloma 519

Baseline Portal‐phase Delayed phase

23 HU 88 HU 43 HU

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Figure 3 Adrenal adenoma. A 72-year-old patient with an incian attenuation of 23 HU on the unenhanced CT study; however,

order to obtain a curve representing the absolute or relativevariation in signal within a specific time frame.30,31

MR-spectroscopy has proved potentially useful in the dif-ferential diagnosis of adrenal lesions based on metaboliteratios, and has proved particularly useful in the character-ization of pheochromocytomas32 and in the differentiationof adenomas and pheochromocytomas from carcinomas andmetastases.33,34

Thus far, diffusion MR imaging has not proved useful todifferentiate benign from malignant lesions.31

Ultrasonography

Ultrasonography does not allow for the characterization ofmost adrenal incidentalomas. It has been recently reportedthat the use of contrast-enhanced ultrasonography mayimprove the diagnostic accuracy since malignant lesionsare usually hypervascular. This would translate into earlycontrast enhancement in the arterial phase and rapidwashout.35

Nonetheless, its systematic use is limited by the difficultvisualization of the adrenal glands with this technique.

Positron emission tomography/computed
tomography
18F-fluorodeoxyglucose PET/CT (18F-FDG PET/CT) protocolsvary among institutions. This technique is highly sensitive

dmaa

lly discovered adrenal nodule in the left adrenal gland that hasbsolute washout is 69%, which is compatible with an adenoma.

or differentiating benign from malignant lesions,28,36 beingarticularly useful in the identification of metastatic adrenalasses in the workup of oncologic patients.37

The metabolic activity can be evaluated by qualitativenalysis, that is, visual comparison between the uptakef the adrenal lesion and that of the liver, or by quan-itative analysis based on the determination of the meannd maximum SUVs (Standardized Uptake Values) andURs (Standardized Uptake Ratios), obtained through thedrenal/liver ratio.

The usefulness of 11C-metomidate (MET) PET/CT imagingn the detection of non-necrotic primary adrenal tumors38

s being validated, as well as that of 11C-hydroxyephedrinend of 18F-dihydroxyphenylalanine in the detection ofheochromocytomas.8

MIBG (a radiotracer taken up by chromaffin cells) scintig-aphy allows pheochromocytoma detection in a significantercentage of cases.28,36

ine needle aspiration

n the algorithms for the management of adrenal inciden-alomas, FNA is indicated for the characterization of activelyrowing lesions, in cases of equivocal radiologic findings
epending on the clinical setting and of high suspicion ofetastasis27 (in patients with a known primary cancer),
nd only if the definitive diagnosis changes the treatmentpproach.

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et al.

Table 1 Imaging findings of the most common adrenal lesions.

Size Appearance Shape Margins Enhancement Necrosis Calcifications Other characteristics

Adenoma Usually ≤4 cm Homogeneoushypodense

Round or oval Smooth andwell-defined

Homogeneous Absent Very rare - Chemical shift- Contrast washout

Small metastases ≤4 cm Homogeneous Round or oval Smooth andwell-defined

Homogeneous Rare Rare ---

Large metastases >4 cm Heterogeneous Irregular Ill-definedand nodular

Ring Central Rare - Local invasion- Metastasis in distantorgans

Myelolipoma Variable Variable Round Smooth andwell-defined

Variable Absent 20% of cases - Variable amountsof macroscopic fat

Lymphoma Large mass Heterogeneous Irregular Ill-defined Heterogeneous Very common Very rare - Infiltration of adjacentstructures

Small pheochro-mocytoma

≤4 cm Homogeneous Round or oval Smooth andwell-defined

Homogeneous Rare <5% of cases ---

Large pheochro-mocytoma

>4 cm Heterogeneous Irregular May be ill-defined Heterogeneous Common <5% of cases - Presence of areasof hemorrhage

Carcinoma (lesscommonpresentation)

≤5 cm Homogeneous Round or oval Smooth andwell-defined

Homogeneous Rare Uncommon ---

Carcinoma (morecommonpresentation)

>5 cm Heterogeneous Irregular Ill-definedand nodular

Heterogeneous Very common 20---30% of cases - Presence of areasof hemorrhage- Displaces and invadesadjacent structures ---adenopathy- Distant metastases



Portal-phase

15 HU 0 HU

Delayed phase

Area: 0.44 cm2

Mean: 15.54Standard deviation: 14.79

Area: 0.47 cm2


Figure 4 Adrenal adenoma. A 56-year-old patient investigated for a left renal mass. Intravenous contrast-enhanced abdominalCT scans, portal phase at 60 s and delayed phase at 15 min, show a nodular lesion in the left adrenal gland. No unenhanced scanis available and, therefore, the absolute washout cannot be estimated. Nonetheless, the relative washout of 96% is suggestive of

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adenoma.

FNA is particularly useful in the differentiation betweenadrenal and non-adrenal tissue (metastasis or infection).Nonetheless, FNA cytology has low or no diagnostic yield inthe differentiation of adenomas from adrenal carcinomas.FNA can be performed under CT, MR or ultrasound guidanceand its diagnostic accuracy varies from 83% to 93%, witha complication rate of approximately 3% (most commonlypain, hemorrhage and pneumothorax).39,40 Hormonal evalu-ation must be done before FNA is undertaken in order to ruleout the possibility of pheochromocytoma, as the puncturemay precipitate a hypertensive crisis.

Most common adrenal incidentalomas

Adenomas

One of the key points in the diagnosis of adenomas isthe presence of a variable proportion of intracellular lipid,whose detection allows a highly accurate diagnosis. A max-imum threshold of 10 HU at unenhanced CT for adenoma
characterization (Figs. 1 and 2) yields a sensitivity of 71%and a specificity of 98%. These parameters are close to100% when size, growth and shape are also taken intoaccount.16,18,19
cAofi

Most adenomas, even lipid-poor adenomas, supposedlyontain enough amounts of cytoplasmic lipid to allow forheir characterization.20 Histogram analysis may be usefuln the characterization of lipid-poor adenomas. At unen-anced CT, the histogram analysis with a cutoff of 10%egative pixels yields a specificity of 100% and a sensitivityf 46---91%.17,20,21,41 When using an unenhanced CT attenu-tion threshold of 10---20 HU, the finding of more than 10%egative pixels yields a sensitivity of 92% for the diagno-is of adenoma. For unenhanced CT attenuation values of0---30 HU and >30 HU, the sensitivity drops to 10% and 0%,espectively.21 The combination of values ≤10 HU or >10%f negative pixels yields a sensitivity of up to 91% comparedith 68% sensitivity when attenuation values are used alone,hile the specificity remains at 100%.20

Therefore, the histogram analysis of unenhanced CTmproves the overall sensitivity for the characterization ofdenomas, particularly in lesions with attenuation valuesf 10---20 HU on unenhanced CT.

Approximately 70% of adenomas are lipid-rich42---44 and0% are lipid-poor. Both types show a more rapid washoutf contrast medium than malignant tumors, therefore the
alculation of the washout may be useful.6,15,16,42,43,45,46
bsolute washout ≥60% (88% sensitivity and 96% specificity)r relative washout ≥40% (96% sensitivity and 100% speci-city) are suggestive of adenoma16,42,43,45---47 (Figs. 3 and 4).

522 R. Oliveira Caiafa et al.

Phase Opposed ‐phase

Area: 0.36 cm2


Area: 0.64 cm2


Area: 0.42 cm2


Area: 0.80 cm2


Figure 5 Adrenal adenoma. Abdominal MRI in a 52-year-old patient investigated for an incidentally discovered adrenal noduleon CT in the left adrenal gland. Opposed-phase gradient echo sequence shows a significant signal loss of the nodule in comparisonw al ad

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ith the in-phase sequence, which is highly suggestive of adren

t should be noted that these values are set for delayedmages obtained 15 min after contrast administration. Parkt al.48 analyzed the relative washout values of adrenalesions at 3 min after contrast administration and reportedhat values >25% were diagnostic for adenoma, and val-es ≤5% were compatible with non-adenomatous lesions.esions with values between 5% and 25% were considerednspecific. However, the study had some methodologicalimitations and further research is thus required to validatehese results.

At MRI, on gradient-echo in- and opposed-phaseequences, the signal loss on opposed phase (knowns chemical shift) is indicative of cytoplasmic lipidontent,24---26 which yields a sensitivity of 81---100% and

specificity of 94---100% for the characterization ofdenomas.24,26,49 In quantitative terms, an adrenal/spleenatio ≤70%50,51 or a signal intensity loss >16.5 is compati-le with adenoma.52 However, visual analysis of chemicalhift imaging compared with splenic intensity is an easierethod of adrenal lesion analysis and has been reported toe comparable to quantitative assessments28,29 (Fig. 5).

Chemical shift imaging is not effective in adenomasith unenhanced CT attenuation >30 HU and is as effective
s unenhanced CT in adenomas ≤10 HU.23,25,50,52 Althoughhe sensitivity for adenomas with attenuation 10---30 HU isower than the calculation of contrast washout on CT, chem-cal shift imaging is indicated for these attenuation values
s

Fa

enoma.

ecause it yields a higher sensitivity than unenhanced CTnd avoids the radiation associated with the three contrast-nhanced CT sequences.

After administration of gadolinium contrast media, ade-omas show mild enhancement and rapid washout, whilealignant lesions and pheochromocytomas show marked

nhancement with slower washout.53 There is no consensusn the usefulness of the quantitative assessment of contrastnhancement curves30,53; nonetheless, significant differ-nces in the time-to-peak have been described betweendenomas and malignant lesions.31

etastasis

arge adrenal metastases are usually accompanied by datauggestive of malignancy on CT and MR imaging (Table 1),hile the appearance of small lesions makes them fre-uently indistinguishable from adenomas.6,13,15

Metastases show low values of absolute washout (<0.6%)nd relative washout (<0.4%) on dynamic contrast-enhancedT studies (Fig. 6), and no signal loss on opposed-phaseequences in chemical shift MR imaging, but these are con-
idered non-specific findings.
A recent meta-analysis37 has demonstrated that 18F-DG PET/CT has a sensitivity and specificity of 97%nd 91%, respectively, for differentiating between benign


Porta phase

98 HU 79 HU 69 HU 68 HU

Delayed phase

Area: 0.25 cm2


Area: 0.34 cm2


Area: 0.34 cm2


Area: 0.45 cm2


Figure 6 Adrenal metastasis. IV contrast-enhanced CT scan, portal phase at 60 s and delayed phase at 15 min, in a patient witha history of breast cancer shows round/oval homogeneous nodules with smooth, well-defined margins in both adrenal glands.

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The lesions show unspecific relative washout of 28% (right) anof the lesions, which confirmed the diagnosis of metastasis.

and malignant lesions, and that the qualitative analysis(visual comparison between adrenal and splenic uptake)is more accurate than quantitative analyses. The studysuggests that PET/CT provides high diagnostic accuracyin lesions >1 cm for distinguishing benign from malignantadrenal disease, particularly in the setting of oncologicpatients, making the use of additional imaging studiesunnecessary in this subgroup of patients.

However, PET/CT is not without limitations: false posi-tive results have been reported in 9%37 of benign lesions,54,55

and 3% of false negative findings37 may be seen inadrenal metastatic lesions with hemorrhage or necro-sis, small-sized (<10 mm) lesions or hypometabolic tumors(bronchioloalveolar carcinoma or carcinoid tumors).54 Addi-tionally, PET/CT is a costly technique with limitedavailability.28,54

MET PET/CT, still not in widespread use, can dif-ferentiate adrenal lesions (adenomas, carcinomas) fromnon-adrenal lesions (adrenal metastases, pheochromocy-tomas, lymphomas) with a sensitivity of 89% and specificityof 96%.38

Growth of an adrenal lesion over a period of less than
3---6 months or the presence of new lesions is suggestive ofmalignancy.
When dealing with an incidentaloma in a patientthat presents without an identifiable primary tumor and

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(left). CT follow-up at 4 months demonstrated enlargement

on-conclusive imaging findings, FNA is rarely indicatediven the low frequency of metastases, the risk ofomplications and the significant rate of false negativeesults. Surgical treatment or CT follow-up are thus recom-ended based on the characteristics of the mass and other

linical characteristics (patient’s age, comorbidity).1,10,28,56

f the mass enlarges during the follow-up period, FNA cane performed before surgical planning.27

The primary indication for FNA is a known primary tumornd high suspicion of metastasis, provided that the definitiveiagnosis changes the therapeutic approach.27

yelolipoma

yelolipomas are tumors composed of varying amounts ofature adipose tissue and hematopoietic cells.The key CT finding is the identification of macroscopic fat

<−20 HU), a characteristic finding that makes unnecessaryhe use of additional techniques6,57,58 (Fig. 7).

FNA is rarely indicated and it is only used in doubtfulases for the characterization of malignant fatty tumors,
specially liposarcomas.
The malignant transformation of myelolipomas hasot been reported, and therefore follow-up or surgicalreatment is not required. However, large myelolipomas

524

Figure 7 Myelolipoma. IV contrast-enhanced portal-phaseabdominal CT examination in a 61-year-old-patient investigatedfor evaluation of complications after radical prostatectomy. Thescan shows bilateral lesions with a predominance of fat density,compatible with myelolipomas.

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Portal phase

Figure 8 Pheochromocytoma. Multiphasic abdominal CT scan shosmooth and well-defined margins that enhances intensely during the



>10 cm) are usually removed because of the risk ofemorrhage.57

ymphoma

rimary adrenal lymphoma is extremely uncommon, withnly about 100 cases reported in the literature.59 Early diag-osis and intervention might dramatically affect patients’urvival.60

Most adrenal lymphomas are bilateral and adrenal insuf-ciency occurs in 50% of cases.

CT and MRI findings (Table 1) are not sufficiently specifico establish a correct diagnosis. Primary adrenal lymphomahows increased 18F-FDG uptake on PET/CT, characteristic ofalignancy.60 Given the low number of cases reported, there

s no consensus on the preferred method for establishing aefinitive diagnosis (surgery versus FNA).

heochromocytoma

n CT, small-sized pheochromocytomas appear as homo-eneous, oval and well-defined masses.6,61 Larger lesions
>4---5 cm) have a higher probability of containing areasf necrosis or hemorrhage, reflecting the hypervascular-ty of these tumors62 with heterogeneous enhancementhat makes them indistinguishable from other adrenal
Arterial

Delayed phase

ws a heterogeneous solid lesion in the left adrenal gland with portal phase, suggestive of pheochromocytoma.


Figure 9 Pheochromocytoma (same patient as Fig. 8). MRI with intravenous contrast material shows a heterogeneous massous

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with hypersignal areas on T2-weighted images, and heterogenesuggestive of pheochromocytoma.

neoplasms; biochemical correlation is thus required for diag-nosis (Fig. 8).

Most pheochromocytomas do not contain lipid; however,a small fraction of cases may contain sufficient intracellularlipid to have attenuation values <10 HU, making them indis-tinguishable from adenomas.44,62---64 Absolute and relativecontrast washout are <60% and <40%, respectively, in 84---89%of cases,43,45,64,65 and pheochromocytomas have attenuationcoefficients on portal-phase CT usually higher than those ofadenomas (up to 110---120 HU), but there is overlap.45

Traditionally, the administration of iodinated contrastmaterial to a patient with pheochromocytoma has beenreported to precipitate a hypertensive crisis, if alpha-receptor blockade has not been instituted.66 However,Mukherjee67 suggests that non-ionic iodinate contrast agentswith low osmolality are safe in these patients, even withoutalpha blockade. Current clinical practice would generallyavoid the use of iodinated contrast material in a patientwith suspected pheochromocytoma.62

T2-weighted imaging is more specific than CT forthe diagnosis of pheochromocytoma62 because of thehyperintensity secondary to the cystic component.68,69

Pheochromocytomas do not lose signal on opposed-phase
T1-weighted sequences,44,62---64 with the exception of thefew cases that contain microscopic fat. Intense and per-sistent enhancement appears after IV administration ofgadolinium70 (Fig. 9).
Mmes

areas of hyperintensity on arterial-phase T1-weighted images,

At MR spectroscopy, pheochromocytomas show a uniquepectral signature with a 6.8 ppm peak that may bettributed to the presence of catecholamines and cat-cholamine metabolites.32 However, further research isequired to validate MR spectroscopy as a diagnostic toolor the characterization of pheochromocytoma.

MIBG scintigraphy and 18F-FDG PET/CT are usedn the localization of biochemically suspectedheochromocytomas,28,36 but their use in incidentalo-as is limited as lesions are already localized. Since METET/CT can differentiate adrenal metastases and pheochro-ocytomas from adrenocortical lesions,38 it could be usefulhen dealing with a suspected pheochromocytoma.

arcinoma

he prevalence of adrenal carcinoma is clearly related tohe size of the tumor (2% of tumors ≤4 cm; 6% of tumors.1---6 cm; and 25% of tumors >6 cm), with larger tumorsaving a worse prognosis. Most studies report <50% 5-yearurvival, and many even report <50% at 2 years.2

Carcinomas usually appear as large masses on CT and
R imaging (Fig. 10) accompanied by findings suggestive ofalignancy (Table 1). Adrenocortical carcinomas may also
xtend directly into the vena cava and identification ofuch invasion is essential for surgical planning.71,72 Small

526

Figure 10 Adrenal carcinoma. A 32-year-old patient investi-gated for hypercortisolism and hyperaldosteronism. Intravenouscontrast-enhanced delayed-phase CT scan shows a largeretroperitoneal mass in the right suprarenal area, with somecalcifications and heterogeneous enhancement and pseudon-odular areas of enhancement interspersed with low-attenuationap

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reas. Cranial sections show signs of infiltration of the liverarenchyma, all compatible with adrenal carcinoma.

arcinomas (<5 cm) may have an appearance similar to thatf adenomas,71 without invasion of adjacent structures.

Since adrenal carcinomas have no fat content, theseesions do not lose signal intensity on opposed-phase chemi-al shift MR imaging. However, it has been reported one casef functioning adrenal carcinoma with intracellular lipid thatontributed to the signal loss on opposed phase.73

The role of PET/CT has been already discussed in theetastasis section.

Adrenal carcinomas are fast growing lesions and veryarely remain stable for more than 6 months if untreated.he stability of the lesions in serial follow-up (depending onhe phenotype of the lesion) is usually useful to rule out aarcinoma.7,28

anagement of adrenal incidentalomas

creening for pheochromocytoma and for autonomous cor-isol secretion is recommended in patients with adrenalncidentaloma and no history of malignant disease. Screen-ng for hyperaldosteronism is recommended in hypertensiveatients. The exception to this includes those patients withnequivocal findings of myelolipoma.1,2,11 Routine screen-ng for hypersecretion of androgens or estrogens is notndicated.1

Patients with asymptomatic or oligosymptomaticheochromocytoma must undergo adrenalectomy. For theest of subclinical functioning lesions, the surgical option
ill be based on the age (patients younger than 40 usuallyndergo surgery) and on the potential medical effectsssociated with excessive hormonal secretion.2,11
ifm


Although resection of non-functioning incidentalomas6 cm is the norm, there are some exceptions (acuteematomas, tuberculosis, myelolipomas and, possibly, non-unctioning masses in the elderly). Conversely, resection ofesions <4 cm with low risk of malignancy on imaging studiess usually not indicated. The strategy for lesions 4---6 cm inize is not well established, and follow-up or resection cane considered.2,11

The mean attenuation values on unenhanced CT shoulde determined for non-functioning incidentalomas ≤6 cmith no radiological evidence of malignancy. A lesion withttenuation values <10 HU is diagnosed as adenoma.16,18,19

or attenuation values of 10---20 HU, a histogram anal-sis can be performed, where a finding of >10% ofegative pixels is diagnostic for adenoma.17,20,21,41 Inases of unenhanced attenuation values of 20---30 HU oron-conclusive histogram, an MRI examination will be per-ormed, where the loss of signal intensity on opposed-phaseradient-echo images is characteristic of adenoma.23,25,50,52

or lesions with attenuation >30 HU, unenhanced andnhanced CT examinations (portal phase at 60 s and de-ayed phase at 15 min) and absolute washout determina-ion are recommended. Values ≥60% are compatible withdenoma.16,42,43,45---47

A small amount of adrenal masses remains indeterminatefter CT and MRI examinations, including atypical ade-omas, metastases, adrenocortical carcinomas, lymphomand pheochromocytomas. In these cases, 18F-FDG PET/CTand MTO PET/CT in the future) is recommended; how-ver, although this technique cannot provide accurate tissueharacterization, it does help differentiate benign fromalignant disease.28,36---38

If the lesion still remains indeterminate, follow-up isndicated in order to identify growth or possible hormonalypersecretion. There is no consensus on the appropriateollow-up: for small (<3 cm) non-functioning masses withenign appearance most authors1,2,11 recommend to repeatiochemical screening annually for 4 years and to performwo imaging studies with at least 6-month interval. For inde-erminate lesions, in addition to the annual screening during

years, an early imaging study at 3---6 months is also recom-ended as well as subsequent studies based on the degree

f suspicion.11 Lesions that have a rapid growth are usuallyonsidered malignant.7,28

Priority should be given to adrenalectomy in case of sus-ected malignancy (rapid growth, low lipid content, reducedashout values, heterogeneity, irregular margins).2,11

FNA is rarely indicated for an incidentaloma foundn a patient without a history of malignancy and non-onclusive imaging findings.1,10,28,56 If the mass enlargesuring follow-up, FNA may be performed before surgicalecision-making.27

The use of 18F-FDG-PET is warranted as the initial imag-ng study for evaluation in oncologic patients because of theigh risk of metastasis.37 A positive result is highly sugges-ive of metastasis, and FNA is indicated for confirmationafter hormonal testing to rule out pheochromocytoma),nly if the definitive diagnosis could change the therapeutic

t is recommended to follow the same approach suggestedor adrenal incidentalomas in patients with no history ofalignancy.


ADRENAL INCIDENTALOMA a

History of cancer?

Yes

PET/CT b

Positive

Suspected metastasis/Consider FNA if

appropriate c

Negative

Hormonal testing

Unenhanced CT

Adenoma

Hormonalscreeningannually

Consider FNA

Surgery

Indeterminate lesion/suspected malignancy

Low suspicionof malignancy

Hormonal screening for 4 years+

2 imaging studies at intervalsof at least 6 months

PET/CT b

OEnlargement

Hormonal screening for 4 years +

Imaging studies over shorter intervals dependingon the degree of suspicion of malignancy

Indeterminate adrenal lesion

≥10% negativepixels

<10% negative pixels

Signal loss onopposed phase

No signal loss onopposed phase

Histogram analysis Chemical shift MRIWashout CT (unenhanced

phase, portal phase at60 sec and delayed at 15 min)

Hormonal testingand surgery d

Absence of excessivehormonal secretion

Subclinical hormonalsecretion

Surgery or medicaltreatment e

≤6 cm

≤10 HU >10 HU and ≤20 HU >20 HU and ≤30 HU >30 HU

>6 cm

≥60 % >60%

Lesion size

No

Figure 11 Algorithm for the management of adrenal incidentalomas. aNo additional examination is required in case of unequivocalcharacteristics of myelolipoma; bAdrenal uptake values greater than those of the liver on 18F-FDG PET/CT (visual analysis) aresuggestive of malignant disease. cPrior to FNA, hormonal testing is recommended to rule out pheochromocytoma. dSome authorsrecommend resection of lesions 4---6 cm in size, especially those with characteristics suggestive of malignancy (heterogeneity andirregular margins). ePatients with pheochromocytomas should undergo resection. For the rest of lesions, surgical decision-makingwill be based on the patient’s age and on the potential medical effects associated with excessive hormonal secretion.


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28

The algorithm for diagnosis and management of adrenalncidentaloma is shown in Fig. 11.

onclusions

adiologists should participate actively in the diagnosis ofndeterminate lesions by using the appropriate imaging tech-iques. They have to be able to reach a conclusive diagnosisased on the behavior of the lesions, but also, they shouldive advice on the subsequent steps that a non-conclusivedrenal lesion requires based on the experience in the dif-erent techniques available at their institutions. Having anlgorithm is essential as this allows for an appropriate mana-ement of adrenal incidentalomas.

uthorship

1. Responsible for the integrity of the study: ROC, RSI,CNM.

2. Conception of the study: ROC, RSI, LBV, MCSC, CNM.3. Design: ROC, RSI, LBV, MCSC, CNM.4. Acquisition of data: ROC, RSI, LBV, MCSC, CNM.5. Analysis and interpretation of data: ROC, RSI, LBV,

MCSC, CNM.6. Statistical analysis: ROC, RSI, CNM.7. Bibliographic search: ROC, RSI, CNM.8. Drafting of the manuscript: ROC, RSI, CNM.9. Critical review of the manuscript with intellectually rel-

evant contributions: ROC, RSI, LBV, MCSC, CNM.0. Approval of the final version: ROC, RSI, LBV, MCSC, CNM.

onflict of interest

he authors declare not having any conflict of interests.

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