The optimal imaging of adrenal tumours: a comparison of ...erc.endocrinology-journals.org/content/14/3/587.full.pdf · The optimal imaging of adrenal tumours: a comparison of different

REVIEWEndocrine-Related Cancer (2007) 14 587–599

The optimal imaging of adrenal tumours: acomparison of different methods

Ioannis Ilias, Anju Sahdev1, Rodney H Reznek1, Ashley B Grossman2

and Karel Pacak 3

Department of Endocrinology, Elena Venizelou Hospital, Athens GR-11521, Greece

Departments of 1Radiology and 2Endocrinology, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK3Section on Medical Neuroendocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human

Development, National Institutes of Health, Building 10, CRC, 1 East, Room 1-3140, 10 Center Drive, MSC-1109, Bethesda,

Maryland 20892-1109, USA

(Correspondence should be addressed to K Pacak; Email: [email protected])

Abstract

Computed tomography (CT; unenhanced, followed by contrast-enhanced examinations) is thecornerstone of imaging of adrenal tumours. Attenuation values of !10 Hounsfield units on anunenhanced CT are practically diagnostic for adenomas. When lesions cannot be characterisedadequately with CT, magnetic resonance imaging (MRI) evaluation (with T1- and T2-weightedsequences and chemical shift and fat-suppression refinements) is sought. Functional nuclearmedicine imaging is useful for adrenal lesions that are not adequately characterised with CT andMRI. Scintigraphy with [131I]-6-iodomethyl norcholesterol (a labelled cholesterol analogue) candifferentiate adrenal cortical adenomas from carcinomas. Phaeochromocytomas appear as areasof abnormal and/or increased uptake of [123I]- and [131I]-meta-iodobenzylguanidine (a labellednoradrenaline analogue). The specific and useful roles of adrenal imaging include thecharacterisation of tumours, assessment of true tumour size, differentiation of adenomas fromcarcinomas and metastases, and differentiation of hyperfunctioning from non-functioning lesions.Adrenal imaging complements and assists the clinical and hormonal evaluation of adrenal tumours.

Endocrine-Related Cancer (2007) 14 587–599

Introduction

The endocrine oncologist frequently has to assess adrenal

tumours, and many problems may arise in defining

whether lesions are primary to the adrenal or represent

other tissue, they are benign or malignant and they are

functioning or not. Improvements in imaging modalities

and their interpretation have increased dramatically over

the past few years, and can now offer a considerable

amount of material to help inform clinical decision

making. The purpose of this review is to summarise the

use of various imaging modalities in the assessment of

adrenal tumours in order to allow the clinician to make a

precise diagnosis and customise treatment accordingly.

The normal adrenals have an inverted Y-shape, are

located supero-medial to the kidneys and each weigh

4–5 g (Mayo-Smith et al. 2001). On computed

tomography (CT), the maximum width of the right

adrenal limb is 0.28 cm and the left adrenal limb is

0.33 cm (Vincent et al. 1994). In neonates and young


1351–0088/07/014–587 q 2007 Society for Endocrinology Printed in Great

children, the glands are proportionately much larger than

in the adult. By conventional cross-sectional imaging, the

adrenal cortex and medulla cannot be distinguished.

There are three cortical zones, glomerular, fascicular and

reticular, producing aldosterone, cortisol and androgens

respectively. The glands’ medulla produces adrenaline

and noradrenaline. Tumours in the adrenals are common

in humans, being present in 3%of autopsies performed in

persons older than 50 years (Grumbach et al. 2003).

Primary tumours in the adrenals can be hyperfunctioning

(producing excess hormones from the cortex or the

medulla and accompanied by clinical symptoms) or non-

functioning (Ilias et al. 2004). Often adrenal tumours are

incidentally detected with abdominal ultrasound (sensi-

tivity is reported at 96 and 100% for tumours smaller and

larger than 2 cm respectively; Trojan et al. 2002).

Thorough imaging of such tumours is performed by

anatomical imaging modalities (such as CT or magnetic

resonance imaging (MRI) and functional imaging

modalities (i.e. nuclear scintigraphy).

Britain

DOI:10.1677/ERC-07-0045

Online version via http://www.endocrinology-journals.org

I Ilias et al.: Imaging of adrenal tumours

Computed tomography

The cornerstone of adrenal imaging is CT, performed

before and after i.v. injection of contrast medium and

acquired as 3–5 mmscans through the adrenal glands.The

advent of multi-detector CT (MDCT) has allowed post-

processing of the acquired data to narrow slice intervals

and provides detailed reformatted images in any plane.On

CT scanning the normal adrenals appear homogeneous

and symmetric, with a density approximately equal to that

of the kidney (Lockhart et al. 2002). Unenhanced CT is

important to provide densitymeasurements of lesions; it is

usually followed by a, preferably delayed, contrast-

enhanced study that can quantify the percentage of

absolute or relative contrast enhancement washout and

shows the vessels in the region of the adrenal glands

(Lockhart etal.2002,Slatteryetal.2006,Heinz-Peeret al.

2007). Visual assessment of the vascularity of a lesion and

the homogeneity of its enhancement can also be helpful in

characterising a lesion. The combination of unenhanced

CT and contrast washout values of adrenal masses can

assist in characterisation and distinguishing adenomas

from other adrenal tumours with 98% sensitivity and 92%

specificity (Korobkin et al. 1998, Caoili et al. 2002,

Sahdev & Reznek 2004).

Magnetic resonance imaging

MRI of the adrenal glands should include T1- and T2-

weighted images, plus chemical shift imaging (CSI)

which consists of in-phase and out-of-phase imaging. T1-

fat-suppressed imaging before and after i.v. gadolinium

administration is optional. Multi-planar MRI allows

precise localisation and separation of adrenal masses

from the surrounding structures, particularly the liver,

spleen, stomach, pancreas and kidneys. Normal adrenal

glands have T1 and T2 signal intensity equal or slightly

lower than that of the normal liver (Lockhart et al. 2002).

Figure 1 Lipid-rich adenoma. (A) Unenhanced CT of theabdomen showing a left adrenal mass with a HU measurementof K6 HU (arrow). (B) Contrast-enhanced CT acquired 60 safter administration of i.v. contrast shows enhancement of theadrenal mass to 50 HU. (C) On delayed CT, acquired 15 minafter administration of i.v. contrast, the mass measures 15 HU.These measurements provide an absolute contrast enhance-ment washout of 63% and a relative contrast washout of 70%proving a lipid-rich adenoma.

Adrenal adenomas

CT can detect adrenal masses O5 mm in diameter. Of

these, non-functioning adrenocortical adenomas are

the most common. They are usually homogeneous,

round and small, have smooth borders and well-

delineated margins that separate them from adjacent

structures (Thompson & Young 2003). Larger adeno-

mas may distort the body, medial or lateral limbs of the

adrenal. Lipid-rich adenomas have an unenhanced CT

attenuation !10 Hounsfield units (HU; Thompson &

Young 2003; Fig. 1). However, some 25–30% of

adenomas are lipid poor and have unenhanced CT

attenuation values O10 HU (Fig. 2).

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Figure 2 Lipid-poor adenoma. (A) Unenhanced CT of theabdomen showing a right adrenal mass with a HU measure-ment of 15 HU (arrow). (B) Contrast-enhanced CT acquired60 s after administration of i.v. contrast shows enhancement ofthe adrenal mass to 75 HU. (C) On delayed CT, acquired15 min after administration of i.v. contrast, the mass measures25 HU. These measurements provide an absolute contrastenhancement washout of 83% and a relative contrast washoutof 67% proving a lipid-poor adenoma.


Although adenomas may show the same density as

normal adrenal tissue on unenhanced CT, they show

greater enhancement on contrast-enhanced CT than

the surrounding normal adrenal tissue (Dunnick &

Korobkin 2002). Contrast-enhanced CT utilises the

unique property of adenomas of early enhancement

after contrast administration and early washout of the

contrast from the adenoma. Non-adenomas have a

slower contrast washout phase than adenomas. Two

criteria exist for the calculation of washout thresholds,

absolute and relative. Calculation of the absolute

washout requires a Hounsfield value from unenhanced

CT but relative washout does not (Table 1). An

absolute contrast washout of O60% and a relative

contrast washout of O40% characterise an adenoma

with a sensitivity and specificity of 98 and 92%

respectively (Dunnick & Korobkin 2002, Sahdev &

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Reznek 2004, Szolar et al. 2005). This technique is

very valuable in lipid-poor adenomas (Fig. 2).

On MRI, adenomas appear homogeneous on all

sequences. Their contrast enhancement is mild; they

have low or equal signal intensity to the liver on T2-

weighted images and may appear of lower signal

intensity than the rest of the adrenal gland (Thompson

& Young 2003). As on CT, characterisation of

adenomas is dependent on the presence of intracellular

lipid. Therefore, on CSI adenomas lose at least 30% of

their signal intensity on the out-of-phase images when

compared with the in-phase images (Fig. 3). This loss

of signal can be appreciated visually but can also be

measured using the adreno-splenic ratio (ASR) and the

signal intensity index (SII). An ASR ratio of !70%

has been shown to be highly specific for adenomas and

has a 78% sensitivity (Mayo-Smith et al. 2001). Using

the SII, a minimum of 5% signal loss characterises an

adrenal adenoma with an accuracy of 100% (Table 1).

Non-adenomatous benign adrenocorticaltumours

Myelolipomas

Myelolipomas are heterogeneous and contain mature

adipose tissue and haemopoietic tissue. They are

characterised by detecting fat on CT and MRI. On

CT, the presence of low attenuation fat in the lesion

which has a density %30 HU is a specific and

diagnostic finding (Dunnick & Korobkin 2002, Lock-

hart et al. 2002; Fig. 4). On MRI, the fat components in

the lesion demonstrate high signal on T1- and T2-

weighted images and lose signal on T1-fat-saturated

images resembling intra-abdominal fat. It is important

to appreciate that myelolipomatous tissue can coexist

with other tumours, such as adenomas or carcinomas.

Haemangiomas

Haemangiomas in the adrenals are usually large and

well-definedmasses.OnunenhancedCT, they showsoft-

tissue attenuation and calcification. On contrast-

enhanced CT, they can be inhomogeneous, enhancing

peripherally with central low attenuation (Dunnick &

Korobkin 2002, Lockhart et al. 2002). Haemangiomas

have a lower signal when comparedwith that of the liver,

on T1-weighted images, although higher signals can be

seen centrally, caused by haemorrhage and/or necrosis

(Dunnick & Korobkin 2002, Lockhart et al. 2002). On

T2-weighted views, their signal is typically moderate or

high (Dunnick & Korobkin 2002, Lockhart et al. 2002).

Foci of low signal on T1- and T2-weighted images are

caused by calcification or haemorrhage.

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Table 1 Non-specific findings of anatomical imaging that may help in differentiating benign from malignant adrenal masses

(modified in part from Ilias et al. 2004)

Benign mass

Malignant tumour (primary adrenal

carcinoma or metastasis)

Size !4 cm O4 cm

Shape/margins Round/smooth Thick/irregular

Homogeneity CT or MRI Homogeneous Heterogenous

Lipid content High (except lipid-poor adenomas) Low

Growth rate Slow Rapid

CT density !10 HU (lipid-rich adenomas) O10 HU

O10 HU (lipid-poor adenomas)

CT enhancement after contrast administration Early enhancement and early washout Variable enhancement with slow washout

% Absolute enhancement washout (AEW)a O60% !60%

% Relative enhancement washout (REW)b O40% !40%

MRI signal on T2-weighted sequences Low High

CSI signal loss on out-of-phase O30% !30%

Adreno-splenic ratio (ASR)c !70% O70%

Signal intensity index (SII) signal lossd O5% !5%

a% AEWZ100!enhanced attenuation valueKdelayed attenuation value=enhanced attenuation valueKunenhanced attenuationvalue; (Sahdev & Reznek 2004).b% REWZ100!enhanced attenuation valueKdelayed attenuation value=enhanced attenuation value. Enhanced attenuationvalue (HU)Zattenuation value of the mass 60 s post-contrast administration. Delayed attenuation value (HU)Zattenuation value ofthe mass, 15 min post-contrast administration (Sahdev & Reznek 2004).cASRZ100!ðSA=SSÞout � of � phase=ðSA=SSÞin � phase. SAZsignal intensity of the adrenal mass. SSZsignal intensity of thespleen.dSIIZ100!ðSIP adrenalKSOP adrenalÞ=SIP adrenal. SIP adrenalZsignal intensity of adrenal mass on in-phase images. SOP adrenalZsignalintensity of adrenal mass on out-of-phase images.


Ganglioneuromas

Adrenal ganglioneuromas are benign solid masses that

may be of considerable size (range 4–22 cm). They

have a soft-tissue density less than that of muscle on

unenhanced CT. Contrast-enhanced views can show

them to be homogeneous or mildly heterogeneous

(Dunnick & Korobkin 2002). Ganglioneuromas are

homogeneous and have a lower T1 signal intensity than

liver (Dunnick & Korobkin 2002). On T2-weighted

images, ganglioneuromas show non-specific hetero-

geneity, depending on their content of myxoid stroma;

the more stroma there is the higher is the T2 signal,

while cellular and fibrous components lower the T2

signal intensity (Rha et al. 2003).

Malignant adrenocortical tumours

Adrenal carcinomas

At the time of discovery, the majority of primary adrenal

carcinomas tend to be larger than adenomas, usually

5–10 cm in diameter. Approximately 50% are hyper-

functioning (Lockhart et al. 2002, Thompson & Young

2003). Inmany of these, themargins are irregular and the

contents inhomogeneous with areas of necrosis, haemor-

rhage and calcification (Fig. 5). Nevertheless, smaller

lesions may be homogeneous on unenhanced CT

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(Lockhart et al. 2002). For carcinomas, the attenuation

on unenhanced studies is higher than 10 HU (Young

2007). On contrast-enhanced studies, carcinomas

enhance avidly due to their vascularity. The pattern of

enhancement canbehomogeneous, unless there is central

necrosis (Dunnick & Korobkin 2002, Lockhart et al.

2002, Young 2007). The relative percentage washout of

carcinomas is !40% (Slattery et al. 2006). On MRI,

adrenal carcinomas are noted for heterogeneity, with

intermediate to high signal intensity, on T1-weighted

images. Heterogeneity is also noted on T2-weighted

images due to haemorrhage and/or necrosis. As with CT,

contrast-enhanced studies enable the assessment of

retroperitoneal lymph nodes, vascular extension and

thrombosis, and encroachment of adrenal and renal veins

or the inferior vena cava (Dunnick & Korobkin 2002).

Angiosarcomas and leiomyosarcomas

Adrenal angiosarcomas and leiomyosarcomas are very

rare tumours. On CT, they have irregular margins and

are inhomogeneous, and calcification may also be

prominent (Pasqual et al. 2002). Leiomyosarcomas and

their imaging characteristics are indistinguishable from

those of adrenal cortical carcinomas or metastatic

cancers (Lee et al. 2006). Leiomyosarcomas show low

intensity on T1-weighted images, high intensity on


Figure 3 Adenoma on MR chemical shift imaging. (A) AxialT1-weighted in-phase image of a left adrenal mass (arrow).(B) Axial T1-weighted out-of-phase image demonstrating visualloss of signal intensity within the mass. This visible loss of signalintensity is characteristic of an adenoma.

Figure 4 Myelolipoma. Contrast-enhanced CT of the abdomendemonstrating a large right adrenal mass containing a largeamount of low attenuation tissue of fatty density (arrow). Thislow attenuation is characteristic of myelolipomas. The attenu-ation value of myelolipomas is usually between fat and waterand in this example the attenuation value was K15 HU.


T2-weighted images and marginal enhancement after

i.v. gadolinium administration (Lee et al. 2006).

Figure 5 Left adrenal carcinoma. Contrast-enhanced CT of theabdomen demonstrating the characteristic large heterogeneousmass with areas of calcification (arrows), suggesting thediagnosis of a carcinoma.

Adrenal lymphomas

Secondary adrenal lymphomatous involvement occurs

in up to 25% of patients with lymphoma at some stage

of their disease (Lerttumnongtum et al. 2004) and may

present as bilateral adrenal masses (Ogilvie et al.

2006). Primary lymphoma of the adrenal glands is rare,

and !100 cases have been reported in the world

literature. It most commonly affects elderly men, is

bilateral, and 50% present with symptoms of adrenal

insufficiency, fever and weight loss (Kumar et al.

2005). On CT, they are usually large solid masses with

variable necrosis and enhancement after contrast

administration. On MRI, they have intermediate soft-

tissue signal intensity and a high T2 signal intensity.

On CSI, no loss of signal intensity is demonstrated on

the out-of-phase imaging. Their appearance is there-

fore indistinguishable from that of other malignant

adrenal tumours and biopsy of the mass is required to

establish the diagnosis (Li et al. 2006).


Adrenal medullary tumours

Phaeochromocytomas

Most sporadic adrenal phaeochromocytomas are at least

2–3 cm in diameter and can be readily visualised with

CT. Smaller (1–2 cm in diameter) phaeochromocytomas

are usuallyhomogeneous in appearance,with a density of

40–50 HU on unenhanced CT (Sohaib et al. 2001).

Larger phaeochromocytomas, however, can be inhomo-

geneous with areas of haemorrhage, and low attenuation

necrosis may be present (Mayo-Smith et al. 2001).

Adrenal phaeochromocytomas have signal intensity on

MRI T1 sequences equal to or higher than that of the

liver, kidney and muscle (Mayo-Smith et al. 2001;

591


Fig. 6). Phaeochromocytomas have a higher signal

intensity than that of fat on T2-weighted sequences.

This characteristic finding is due to the hypervascularity

of the tumours. On CSI, there is no signal loss on

opposed-phase images (Mayo-Smith et al. 2001; Fig. 4).

After contrast administration, phaeochromocytomas

enhance avidly and have a prolonged contrast washout

phase. In heterogeneous tumours, the viable areas of the

tumour enhance whilst necrotic areas do not.

Neuroblastomas

Two-thirds of neuroblastomas arise from the adrenals

and occur in infants and children. Most are of irregular

shape, lobulated and are usually unencapsulated with

variable amounts of amorphous or mottled calcification

(Rha et al. 2003). Extension to the liver, adjacent

lymph nodes and vessels is not uncommon. Necrosis

and/or haemorrhage within the tumour leads to an

inhomogeneous appearance on CT. Neuroblastomas in

the adrenals give a heterogeneous low-intensity signal

on T1-weighted sequences and high signal on T2-

Figure 6 Adrenal phaeochromocytoma on MR chemical shiftimaging. (A) Axial T1-weighted in-phase image of a leftheterogeneous adrenal mass (arrow). (B) Axial T1-weightedout-of-phase image demonstrating no loss of signal intensitywithin or in the periphery of the mass. The adrenal mass ishence an indeterminate mass (non-adenoma) on MR chemicalshift imaging. This is an example of a surgically confirmedphaeochromocytoma.

592

weighted views (cystic changes may also be observed;

Elsayes et al. 2004). MRI is the modality of choice for

imaging neuroblastomas as intra-spinous extension and

hepatic metastases are better demonstrated using MRI

when compared with CT.

Adrenal metastases

The adrenal gland can be the site of metastatic disease

from carcinoma of the lung, breast, lymphoma or

melanoma (Rajaratnam & Waugh 2005). Adrenal

metastases can have irregular margins and are often

bilateral (Thompson & Young 2003). On unenhanced

CT, adrenal metastases usually have attenuation values

O10 HU (Young 2007). In patients with metastases

from melanoma, attenuation values may be lower

(Rajaratnam & Waugh 2005). Contrast-enhanced

examinations can be variable: larger metastatic lesions

may be inhomogeneous if necrosis is present, whereas

smaller lesions may be homogeneous (Dunnick &

Korobkin 2002; Fig. 7). Metastases have !60%

absolute and !40% relative contrast washout after

contrast-enhanced CT. On MRI, metastases are

homogeneous with T1-weighted signal intensity

equal to that of the liver. Adrenal metastases usually

have a higher signal on T2-weighted images

(Thompson & Young 2003). Larger lesions can be

inhomogeneous due to the presence of areas of necrosis

and haemorrhage, with high signal intensity on both

T1- and T2-weighted sequences (Lack 1995, Dunnick

& Korobkin 2002).

Figure 7 Adrenal metastases. Contrast-enhanced CT of theabdomen demonstrating a large right-sided adrenal metastasis(arrowhead) and multiple liver metastases (arrows) in a patientwith disseminated breast cancer.



Functional imaging

Patients that harbour adrenal masses, which are not

adequately characterised with CT orMRI, can be further

evaluated with functional nuclear medicine modalities.

These modalities are based on physiological and

pathophysiological processes (cellular metabolism,

tissue perfusion and local synthesis, uptake and storage

of hormones and their receptors) and assist the

preoperative staging of tumours. Furthermore, they can

be of use in the evaluation of suspicious lesions and the

identification of metastatic or recurrent tumours.

Nuclear medicine modalities that are available for the

study of adrenal disease include conventional planar or

single photon emission computed tomographic (SPECT)

scintigraphy with various radionuclide tracers, and

positron emission tomographic (PET) scintigraphy with

various short-lived radionuclides. With PET, higher

doses of radionuclides can be administered for a similar

radiation exposure to SPECT. Imaging with PET has

higher spatial resolution than conventional SPECT.

Hyperfunctioning adrenal tumours

Functional imaging modalities specific for

cortical tumours

Cholesterol is the basicmolecule for steroid biosynthesis.

[131I]-6-iodomethyl norcholesterol (NP-59) is a radio-

pharmaceutical that resembles cholesterol, binds speci-

fically to low-density lipoproteins, and after receptor-

mediated uptake is stored in the adrenocortical

intracellular lipid droplets. Conventional NP-59 exami-

nations are planar, although recently SPECTwith NP-59

has been assessed (Imperiale et al. 2005). Normal

adrenals are visualised at R5 days after injection of

NP-59 (Mayo-Smith et al. 2001). Unilateral adrenal

uptake seen before day 5 suggests a functioning steroid-

synthesising adenoma (Mayo-Smith et al. 2001), inclu-

ding aldosteronomas (Thompson & Young 2003). The

minimum size of the adrenal mass to be evaluated with

NP-59 isO2 cm. Its practical use is further hampered by

limited availability (Ruffini et al. 1992). [11C]-metomi-

date is a PET ligand with inhibitor properties for the

synthesis of adrenocortical steroids. It has been assessed

in small series of adrenal masses, showing indiscrimi-

nately high uptake in adenomas and carcinomas (the

latter with irregular uptake; Eriksson et al. 2005).

Functional imaging modalities specific for

medullary tumours

Most phaeochromocytomas express the noradrenaline

transport system (NET; Schulz et al. 2004). This

system is responsible for the uptake of noradrenaline


and adrenaline from the synaptic cleft into sympathetic

presynaptic neurons, terminating neural transmission.

This uptake process also enables specific functional

imaging with various radioligands that depend upon

NET for transport into phaeochromocytoma cells.

The alkylguanidine meta-iodobenzylguanidine

(MIBG) is a noradrenaline analogue that is taken up

by phaeochromocytoma cells. Initially, MIBG was

labelled with [131I] but [123I]-MIBG has become more

common because it permits better quality SPECT

imaging with low radiation exposure. The half-life of

[123I] is much shorter, though, compared with that of

[131I] (13.2 h vs 8 days). Phaeochromocytomas appear

as areas of abnormal increased [131I]- or [123I]-MIBG

uptake (Fujita et al. 2000). For phaeochromocytomas,

scintigraphy with [131I]-MIBG has 77–90% sensitivity

and 95–100% specificity (Bravo & Tagle 2003), while

with [123I]-MIBG it has 83–100% sensitivity and

95–100% specificity (van der Harst et al. 2001).

False-negative MIBG examinations may be caused

by non-compliance not only with instructions to stop

medications that interfere with MIBG uptake but also

occurs with phaeochromocytomas that have undergone

necrosis or dedifferentiation (Figs 8 and 9).

[11C]-metahydroxyephedrine is a positron-emitter-

labelled PET ligand that resembles noradrenaline but is

not susceptible to intracellular degradation by mono-

amine oxidase (MAO). Excellent PET imaging studies

of phaeochromocytomas (better than with [123I]-

MIBG) have been obtained with it (Mann et al.

2006); however, the 20-min half-life of [11C] precludes

widespread application. [11C]-labelled adrenaline is a

PET radioligand that is a substrate for the catechol-

amine catabolic enzymes catechol-O-methyl-

transferase and MAO. PET with [11C]-adrenaline

localises fewer phaeochromocytomas than MIBG

scintigraphy and the very short half-life of [11C] is

again a deterrent to widespread use (Shulkin et al.

1995). Dopamine (DA) labelled with [18F] is substrate

specific for the NET and is an excellent PET agent

(better than [131I]-MIBG) to localise adrenal and extra-

adrenal phaeochromocytoma (Pacak et al. 2001,

Ilias et al. 2003). Dihydroxyphenylalanine (an amino

acid that is converted by aromatic amino acid

decarboxylase to DA) labelled with [18F] has also

been evaluated with success in imaging mainly adrenal

phaeochromocytomas (Hoegerle et al. 2002).

Non-specific functional imaging modalities

[18F]-fluorodeoxyglucose (FDG) is a PET glucose

analogue. It shows the metabolic activity of glucose in

tumours. [18F]-FDG PET studies have not shown

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Figure 9 Phaeochromocytoma. (A) Whole-body single-photon emission computed tomography with [123I]-meta-iodobenzyl-guanidine ([123I]-MIBG) (anterior and posterior views). Radionuclide uptake is seen in the right adrenal (arrow). (B) Reprojectedimage obtained with [18F]-fluorodopamine (FDA) positron emission tomography (PET) of the same patient (anterior view). Highhomogeneous uptake is seen in a large tumour in the right adrenal (arrow).

Figure 8 Phaeochromocytoma. (A) Whole-body single-photon emission computed tomography) with [123I]-meta-iodobenzyl-guanidine ([123I]-MIBG) (anterior and posterior views). No abnormal radionuclide uptake is seen. (B) Reprojected image obtainedwith [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) of the same patient (anterior view). High heterogeneousuptake is seen in a large tumour in the right adrenal (arrow).


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uptake in adrenal adenomas (Tenenbaum et al. 2004)

but they have shown uptake in adrenal metastases

(Dunnick & Korobkin 2002). Phaeochromocytomas

have been imaged with [18F]-FDG PET (Shulkin et al.

1999). [18F]-FDG PET is useful for the localisation of

phaeochromocytomas that do not accumulate MIBG or

other specific radionuclides (mainly dedifferentiated

and/or rapidly growing phaeochromocytomas;

Mamede et al. 2006; Fig. 6).

Phaeochromocytomas may express somatostatin

receptors (in decreasing rate of occurrence SST-2A, -3,

-4, -5 and -1; Ueberberg et al. 2005). Octreotide is a

synthetic octapeptidic analogue of somatostatin that is

chelated with diethylenetriaminepentaacetate (DTPA)

and is usually labelled with 111Indium ([111In]) for

diagnostic imaging. Studies with [111In]-DTPA-octreo-

tide did not show it to be of use in the evaluation of

neuroendocrine tumours that were limited to the

adrenals. In particular, most patients (66–75%) with

benign phaeochromocytoma had negative [111In]-

DTPA-octreotide scans (despite positive [123I]-MIBG

or [131I]-MIBG imaging results; van der Harst et al.

2001). Furthermore, normal intense uptake is noted in the

liver, spleen and kidneys, and excretion into the

gastrointestinal tract.However, [111In]-DTPA-octreotide

studies have been positive in patients with malignant/

metastatic phaeochromocytomas and paragangliomas,

where their sensitivity was w90% (Tenenbaum et al.

1995, van der Harst et al. 2001, Ilias et al. 2004).

Functional imaging modalities for

non-hyperfunctioning tumours

Usually, no NP-59 uptake is seen with carcinomas

(Thompson & Young 2003). Rarely, false-positive

[131I]-MIBG examinations have been reported with

adrenal carcinomas (Maurea et al. 2002). Adrenal

adenomas have shown false-positive [123I]-MIBG

uptake as well as false-positive [18F]-FDG PET uptake

(Al-Hawary et al. 2005).

Important points in imaging the adrenalglands

Characterising adrenal tumours

MDCTis the singlemost usefulmodality for identification

and characterisation of adrenal tumours. Unenhanced thin

section images of the adrenal glands are essential. If an

adrenal mass is demonstrated, the attenuation value

should be measured using a region of interest cursor that

includes most of the mass. Small, solid homogeneous

masses that have an attenuation value of!10 HU can be

considered to be benign lipid-rich adenomas (Hamrahian


et al. 2005); no further imaging is necessary. In the

presence of bilateral disease, heterogeneous masses or a

mass of O10 HU, a contrast-enhanced CT should be

performed. Thin section CT is performed at 60 s and

15 min after i.v. contrast administration (delayed views

are more informative). The absolute contrast washout can

then be calculated to distinguish between adenomas

(O60% contrast washout) and non-adenomas (!60%

contrast washout). If the mass is detected only on post-

contrast scans, then the relative contrast washout criteria

can be calculated. Non-adenomas include metastases,

phaeochromocytomas and carcinomas (Mayo-Smith et al.

2001, Dunnick & Korobkin 2002).

If a lesion cannot be characterised as an adenomawith

CT, then further assessment can be done with MRI

(particularly using chemical shift sequences). CSI will

identify an additional small group of adenomas in which

the intracellular lipid content is minimal (thereforeO10

HU on unenhanced CT) but sufficient to be detected on

CSI (Korobkin et al. 1996). Mostly lipid-poor masses

that are characterised as non-adenomas on imaging and

are biochemically not phaeochromocytomasmay require

biopsy (provided the mass does not give the impression

of being a carcinoma; in such a case, biopsy is

contraindicated) or surgical resection (Grumbach et al.

2003). Nuclear medicine modalities can add information

on adrenal lesions and assist anatomical imaging with

functional information (Mayo-Smith et al. 2001).

Nuclear medicine studies may assist in the character-

isation of phaeochromocytomas and may also provide

information on coexistent metastases or multiple

tumours elsewhere. This is particularly relevant for

adrenal tumours larger than 5–6 cm and extra-adrenal

phaeochromocytomas or in patients with familial

phaeochromocytomas (since all these tumours have a

higher potential for metastases or multiple tumours). It is

also important in case of distorted, post-operative

anatomy. Thus, as outlined above, for most of

biochemically proven phaeochromocytomas CT or

MRI examinations should be followed by specific

functional modalities ([123I]-MIBG SPECT and [18F]-

DA PET) and then by non-specific functional imaging

modalities ([111In]-DTPA-octreotide SPECT and [18F]-

FDGPET) in case specific functional imaging studies are

negative. However, the precise place of such nuclear

medicine scintigraphywith awell-imaged and biochemi-

cally proven tumour remains unclear.

Differentiating adenomas from metastases

In a patient with cancer, it is often critical to distinguish

between an adenoma and metastases. Adenomas are

typically smaller than metastases on unenhanced CT

595


imaging (Table 1). Metastases are more heterogeneous

than adenomas and their margins are not well defined.

However, small metastases may be homogeneous and

with well-defined margins. Approximately 70% of

adenomas can be identified using CT with no contrast

enhancement (Mayo-Smith et al. 2001). The remaining

30% of adenomas are lipid poor and cannot be reliably

differentiated from metastases with this technique

(Mayo-Smith et al. 2001). Most adenomas have

attenuation values lower than metastases on unenhanced

CT examinations (Dunnick & Korobkin 2002). With a

cut-off attenuation value of 10 HU, sensitivity has been

reported to be 71%with a specificity of 98% (Dunnick&

Korobkin 2002, Lockhart et al. 2002). On contrast-

enhanced CT images, lesions with attenuation values

!30–40 HU (taken with a 15-min delay) are almost

always adenomas, whereas metastases may show a thick

enhancing peripheral rim (Dunnick & Korobkin 2002,

Lockhart et al. 2002). Adenomas can be differentiated

from metastases with a specificity of 97% using

percentage of enhancement washout (Dunnick &

Korobkin2002).More rapidwashout of contrastmedium

is seen in adrenal adenomaswhen comparedwith adrenal

metastases (Dunnick & Korobkin 2002).

The signal intensity of an adenoma on MRI T2-

weighted sequences is usually low, but this finding is

not very useful for differentiating adenomas from

metastases because there is a 20–30% overlap in the

range of signal intensity between them (Dunnick &

Korobkin 2002). Chemical shift MRI can differentiate

adrenal adenomas from metastases (Dunnick &

Korobkin 2002). The signal intensity loss on

opposed-phase images compared with in-phase images

shows mixed lipid and non-lipid tissue in adenomas,

which is absent in metastases (Dunnick & Korobkin

2002). Chemical shift MRI enables the calculation of

the adreno-splenic ratio (ASR)Zlesion intensity

relative to spleen on in-phase images/signal ratio of

lesion to spleen on opposed-phase images. An ASR

!70% indicates an adenoma with 78% sensitivity and

100% specificity (Lockhart et al. 2002).

FDG PET scanning has been used in several studies

to distinguish benign from malignant adrenocortical

lesions and O95% accuracy has reported (Becherer

et al. 2001), along with excellent sensitivity and

specificity (both approaching 100%) for primary and

secondary adrenal cortical tumours.

Differentiating adenomas from carcinomas

On axial imaging alone, large adrenal masses may be

difficult to differentiate from exophytic renal tumours

arising from the upper pole (Lockhart et al. 2002).

596

MDCT with accurate multi-planar reformations has

effectively solved this problem. Analysis with receiver

operated characteristics of O1000 adrenal incidenta-

lomas has pointed to a lesion diameter of 4 cm as a

reasonable cut-off to differentiate benign from malig-

nant lesions. Using 4 cm, the sensitivity, specificity and

negative predictive value of detecting a malignant

lesion is 93, 42, and 98%, specifically. If larger size

criteria are used to diagnose malignant masses, the

sensitivity falls to 81% for 5 cm and 74% for 6 cm

lesions (Mantero et al. 2000). Hence, in order to

maintain a good sensitivity for malignant masses, the

4 cm size cut-off has been advocated to select patients

for surgery (Bertherat et al. 2002). With increasing

size, the probability of malignancy becomes higher

(Table 1). For lesions O6 cm, the ratio of benign to

malignant tumours is 1:8 (Bertherat et al. 2002).

Because size is important in the assessment and

management of adrenal lesions, it is important to

point out that CT is known to underestimate the size of

adrenal tumours (Fajardo et al. 2004). To improve the

performance of CT against histological size, a formula

has been proposed by Linos (2000). The finding of a

unilateral adrenal mass either on CT or MRI with a

diameter O4 cm is suggestive of adrenal cortical

carcinoma, especially in those patients without

signs and symptoms of catecholamine, cortisol or

aldosterone excess (Dunnick & Korobkin 2002;

Table 1). The presence of necrosis, haemorrhage or

calcification leans more to the diagnosis of carcinoma

(Rockall et al. 2004). On MRI examination, if the

entire lesion loses signal on the out-of-phase images

the mass is an adenoma. Adrenal carcinomas have no

or only partial loss of signal intensity on out-of-phase

images. Nevertheless, the data on adrenal cortical

carcinoma and CT or chemical shift MRI are limited,

and at present no firm conclusions can be formulated

(Dunnick & Korobkin 2002). Some reports indicate

that FDG PET has 100% sensitivity and 80–100%

specificity for differentiating malignant from benign

adrenalmasses (Mayo-Smith et al. 2001, Dunnick &

Korobkin 2002).

Differentiating hyperfunctioning from

non-functioning lesions

Anatomical cross-sectional imaging concentrates on

differentiating solid adrenal masses into benign

adenomas and non-adenomas. It cannot reliably

differentiate between functioning and non-functioning

adenomas and relies on the biochemical profile (Israel

& Krinsky 2003). In ACTH-independent Cushing’s

syndrome, adrenal adenomas and carcinomas account



for 92% of the cases. Other rare causes included

collision tumours with adenomas and primary

pigmented nodular adrenal dysplasia (PPNAD). In

PPNAD, uni- or bilateral small (2–5 mm) adrenal

nodules have been reported (Rockall et al. 2004).

There have also been reports of normal CT scans and a

report of myeloid metaplasia of the nodules (with very

high lipid content; Courcoutsakis et al. 2004). Older

subjects with PPNADmay have macronodulesO1 cm.

In 70% of patients with ACTH-dependent Cushing’s

disease, the adrenal glands are enlarged bilaterally. The

adrenal glands are larger in patients with ectopic

ACTH source when compared with pituitary-depen-

dent disease (Sohaib et al. 1999). Cortical hyperplasia

can be distinguished from focal tumours with

sensitivity O95% using CT. In a study of 34 patients

with primary hyperaldosteronism (17 due to bilateral

adrenal hyperplasia and 17 due to adenomas), CT was

shown to detect aldosteronomas with a sensitivity and

specificity of 87 and 93% respectively (Lingam et al.

2004). In patients with aldosteronomas, the adrenal

glands may be normal, show minimal unilateral

adrenal thickening, uni- or bilateral solitary or multiple

adenomas (ranging in size from !1 to O1 cm; Young

2003). Nevertheless, most aldosteronomas are uni-

lateral and small (with a median size!2 cm). Usually,

they are encapsulated and the remaining adrenal cortex

does not show any atrophy. However, some have

recommended that, regardless of CT/MRI findings,

when localisation of a putative aldosteronoma is

attempted all patients should undergo selective adrenal

venous sampling (pre- and post-corticotrophin infu-

sion) to precisely locate the tumour (Rossi 2007).

Non-hyperfunctioning adenomas of the adrenal cortex

synthesise and secrete hormones like normal adrenal

cortical tissue. These lesions show uptake of NP-59, but

so does the surrounding normal adrenal tissue (Dunnick

& Korobkin 2002). NP-59 scintigraphy can complement

biochemical and radiological imaging results to identify

abnormal adrenal function in an adenoma (Maurea et al.

2004). It has a high specificity (100%) and reasonable

sensitivity (about 70% for tumours O2 cm in diameter)

for distinguishing benign functioning adrenal adenomas

from other space-occupying adrenal lesions (Maurea et

al. 2004).The positive predictive value ofNP-59 is 100%

for lesions R2 cm in diameter. Nevertheless, well-

differentiated adrenal cancer may show NP-59 uptake

(Gross et al. 2007). Moreover, the scarcity of NP-59, its

limited spatial resolution and the prolonged necessary

examination time, in light of the results obtained with

other modalities, may lead to its eventual abandonment.

Because 40–50% of primary adrenal carcinomas are

hyperfunctioning and 50–60% are not, it is apparent that


further biochemical diagnostic work-up is necessary in

cases of doubtful diagnosis (Lockhart et al. 2002).

Acknowledgements

The authors declare that there is no conflict of interest

that would prejudice the impartiality of this scientific

work.

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