Imaging the Adrenal GlandsR.H.Reznek

Introduction

Clinically, one can distinguish two major settings of adrenal disorders: a small group of patients with clinical and laboratory findings of adrenal endocrinopathy, and a second, much larger group of patients, with an inciden- tally found enlargement of the adrenal glands. The diag- nostic approach to these two groups is totally different;

in the first category imaging methods are used for local- ization of an adrenal pathology, while in the second group the lesion is found in the course of a routine imag- ing examination or while staging a malignant primary tu- mor [1-5].

Adrenal masses are seen at autopsy in 2-10% of all pa- tients and metastases are found postmortem in the adren- al glands in up to 26% of patients with primary extra- adrenal malignancies. It is thus not surprising that adren- al mass lesions are quite common incidental findings during imaging of the abdomen. However, even in an on- cologic setting, many adrenal lesions are benign, mostly non-hyperfunctioning adenomas, resulting in the need for a reliable method to discriminate between these lesions and malignant masses [6-7].

Normal Radiological Anatomy of the Adrenal Glands

The adrenal glands are enclosed within the perinephric fascia and are usually surrounded by a sufficient amount of fat for identification on computed tomography (CT) or magnetic resonance imaging (MRI). The right adrenal gland lies immediately posterior to the inferior vena cava (IVC). The left adrenal gland lies anteromedial to the up- per pole of the left kidney and posterior to the pancreas and splenic vessels. The shape of the adrenals can vary, depending on the orientation of the gland and the level of the image, but the normal adrenal gland has an arrowhead configuration, with a body and medial and lateral limbs.

The normal adrenals extend over 2-4 cm in the cranio- caudal direction, and on CT the thickness of the normal adrenal body and limbs does not exceed 10-12 and 5-6 mm, respectively [8].

Computed Tomography Unenhanced CT

At CT, certain imaging findings indicate a higher likeli- hood of lesion malignancy. Lesions greater than 5 cm in diameter tend to be either metastases or primary adrenal carcinomas. However, size alone is poor at discriminating between adenomas and non-adenomas. Using 3.0 cm as the size cut-off, the specificity of such a discrimination is only 79% and the sensitivity is 84% [9].

Rapid change in size suggests malignancy because adenomas are slow-growing lesions. Although it has been suggested that adenomas have a smooth contour, where- as malignant lesions have an irregular shape, there is a very large overlap between the two groups, and shape is therefore not a helpful differentiating feature.

Adenomas have a high intra-cellular lipid content, which lowers their attenuation value. If an adrenal mass measures 0 HU or less (with a threshold attenuation val- ue of 0 HU), the specificity of the mass being an adeno- ma is 100%, but the sensitivity is an unacceptable 47%.

Boland et al. [9] performed a meta-analysis of ten stud- ies, and demonstrated that if a threshold attenuation val- ue of 10 HU was adopted, the specificity was 98% and the sensitivity increased to 71%. Therefore, in clinical practice, 10 HU is the most widely used threshold atten- uation value for the diagnosis of an adrenal adenoma [9].

Contrast-enhanced CT

Contrast-enhanced CT is a CT scan acquired after the ad- ministration of intravenous contrast medium. CT contrast media contain iodine with a very high density and hence a high attenuation value. The contrast medium is usually ad- ministered into an antecubital vein and injected at variable rates. The CT images are acquired at variable time intervals after the administration of contrast medium, and uptake of the contrast medium is termed ‘contrast enhancement’.

Contrast enhancement is directly proportional to the vascu- larity of the enhancing structure. The increase in attenuation values of adrenal masses after contrast administration is a di- rect measurement of their contrast enhancement properties.

Imaging the Adrenal Glands

R.H. Reznek

, G.P. Krestin

1

Cancer Imaging, St Bartholomew’s Hospital, West Smithfield, London, United Kingdom

2

Department of Radiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Nederlands

On non-contrast-enhanced CT, up to 30% of benign adenomas have an attenuation value greater than 10 HU and are considered to be lipid poor. Malignant lesions are also lipid poor. Characterization of adrenal masses using contrast-enhanced CT utilizes the different physiological perfusion patterns of adenomas and metastases. Adenomas enhance rapidly after contrast administration and also demonstrate a rapid loss of contrast medium – a phenom- enon termed contrast washout. Metastases also enhance rapidly but show a slower washout of contrast medium (Fig. 1). In a standard abdominal CT obtained for staging patients with cancer, the CT images are acquired 60 sec- onds after contrast administration. Attenuation values of adrenal masses obtained 60 seconds after contrast medium injection show too much overlap between adenomas and malignant lesions to be of clinical value. Adrenal masses with CT attenuation value measuring less than 30 HU, on delayed images obtained 10-15 minutes after contrast en- hancement are almost always adenomas. However, the per- centage of contrast washout between initial enhancement (at 60 seconds) and delayed enhancement (at 15 minutes) can be used to differentiate adenomas from malignant le- sions. Measurement of the attenuation value of the mass before injection of contrast medium, at 60 seconds after injection of contrast medium and then again at 10-15 min- utes, are made using an electronic cursor. These absolute contrast medium enhancement washout values are only applicable to relatively homogeneous masses without large areas of necrosis or hemorrhage. It has been shown that washout of contrast from adenomas occurs much faster than from metastases. Both lipid-rich and lipid-poor ade- nomas behave similarly, because this property of adeno- mas is independent of their lipid content [10-15].

The percentage of absolute enhancement washout can be thus calculated:

% washout =

enhanced attenuation value – delayed attenuation value

enhanced attenuation value – non-enhanced attenuation value × 100 The enhanced attenuation value is the attenuation val- ue of the mass, measured in HU, 60 seconds after contrast administration. The delayed attenuation value is the at- tenuation value of the mass, measured in HU, 10-15 min- utes after contrast administration [10-11].

If the percentage absolute enhancement washout is 60% or higher, this has a sensitivity of 88% and a speci- ficity of 96% for the diagnosis of an adenoma. However, the measurement of this absolute contrast medium en- hancement washout requires an unenhanced image.

Frequently in clinical practice, only post-contrast images are available. In these patients, the percentage ‘relative’

enhancement washout can be thus calculated:

% relative washout =

enhanced attenuation value – delayed attenuation value enhanced attenuation value × 100 The enhanced and delayed attenuation values are mea- sured as described previously.

b a

c

Fig. 1. Adrenal metastasis. (a) A 3 cm left adrenal mass measures 34

HU on the unenhanced scan. (b) After contrast administration it en-

hances to 64 HU. (c) The mass measures 59 HU on delayed images

At 15 minutes, if a relative enhancement washout of 40% or higher is achieved, this has a sensitivity of 96- 100% and a specificity of 100% for the diagnosis of an adenoma. Therefore a combination of unenhanced CT and enhancement washout characteristics correctly separates nearly all adrenal masses as adenomas or metastases [15].

Magnetic Resonance Imaging Conventional Spin-echo Imaging

Early reports were enthusiastic about the ability of MRI to differentiate benign from malignant adrenal masses on the basis of signal intensity (SI) differences on T2- weighted spin-echo images. In general, metastases and carcinomas have a higher fluid content than adenomas and therefore are of higher SI on T2-weighted images than the surrounding normal adrenal gland. Adenomas are homogeneously iso- or hypo-intense compared with the normal adrenal gland. However, considerable overlap exists between the signal intensities of adenomas and other lesions, and up to 31% of lesions remain indeter- minate [16-18].

Gadolinium-enhanced Magnetic Resonance Imaging

The accuracy of MRI in differentiating benign from ma- lignant masses can be improved after intravenous gadolinium injection on gradient echo sequences. As with CT, adenomas show enhancement after administration of gadolinium with quick washout, whereas malignant tu- mours and pheochromocytomas show strong enhance- ment and slower washout. Uniform enhancement (capil- lary blush) on post-gadolinium capillary phase has been reported in up to 70% of adenomas, but is rare in other masses. In addition, adenomas often show a thin rim of enhancement in the late phase of gadolinium-enhanced images. Metastases frequently have heterogeneous en- hancement. However, as with signal characteristics, there is considerable overlap in the characteristics of benign and malignant masses, limiting the clinical applicability of this technique to distinguish adenomatous from malig- nant masses [19-20].

Chemical-shift Imaging

Chemical-shift imaging (CSI) relies on the fact that, within a magnetic field, protons in water molecules os- cillate or precess at a slightly different frequency than the protons in lipid molecules. As a result, water and fat pro- tons cycle in- and out-of-phase with respect to one an- other. By selecting appropriate sequencing parameters, images can be acquired with the protons oscillating in and out of phase. The SI of a pixel on an in-phase image is derived from the signal of water plus fat protons, if wa- ter and fat are present in the same pixel. On out-of-phase sequences, the SI is derived from the difference of the

signal intensities of water and fat protons. Therefore, ade- nomas that contain intracellular lipid lose SI on out-of- phase images compared with in-phase images (Fig. 2), whereas metastases that lack intracellular lipid remain unchanged [21-23].

There are several ways of assessing the degree of loss of SI. Quantitative analysis can be made using a variety of ratios, essentially comparing the loss of signal in the adrenal mass with that of liver, paraspinal muscle or spleen on in-phase and out-of-phase images. However, fatty infiltration of the liver (particularly in oncology pa- tients receiving chemotherapy) and iron overload make the liver an unreliable internal standard. Fatty infiltration might also affect skeletal muscle, although to a lesser ex-

a

b

Fig. 2. Left adrenal adenoma in a patient with lung cancer.

Chemical-shift MRI shows significant signal decrease on opposed

phase (b), compared to the in-phase image (a)

tent. The spleen has been shown to be the most reliable internal standard, although this might also be affected by iron overload [21].

To calculate the adrenal lesion to spleen ratio (ASR), regions of interest are used to acquire the SI within the adrenal mass and the spleen from in-phase and out-of- phase images. The ASR reflects the percentage signal drop-off within the adrenal lesion compared with the spleen and it can be calculated as follows:

ASR =

SI lesion (out-of-phase) / SI spleen (out-of-phase) SI lesion (in-phase) / SI spleen (in-phase) × 100 An ASR ratio of 70 or less has been shown to be 100%

specific for adenomas but only 78% sensitive [21-23].

Simple visual assessment of relative signal intensity loss is just as accurate, but quantitative methods might be useful in equivocal cases. A signal intensity loss within an adrenal mass on out-of-phase images of greater than 20% is diagnostic of an adenoma [24].

The combination of spin-echo signal characteristics, gadolinium enhancement and CSI is currently 85-90%

accurate in distinguishing adenomas from non-adenomas.

There are few direct comparisons between CT and MRI. Evidence from one histological study showed that because both non-contrast CT alone and CSI rely upon the same property of adenomas, namely their lipid con- tent, the techniques correlate.

Positron Emission Tomography

Whole body positron emission tomography (PET) with 18-F-fluorodeoxyglucose (18-FDG) allows malignant adrenal lesions to be recognized. The contribution of 18- FDG PET has been well evaluated in large studies in re- lation to lung cancer, and is highly accurate in differenti- ating benign non-inflammatory lesions from malignant disease. Using 18-FDG PET, these studies have shown a 100% sensitivity and specificity for the diagnosis of ma- lignant adrenal mass when CT or MRI identify enlarged adrenal glands or a focal mass. Recent studies have re- ported false positive results as a result of 18-FDG uptake by pheochromocytomas and benign adenomas. For the diagnosis of a malignant adrenal tumour, the positive pre- dictive value of 18-FDG PET was 100% and the negative predictive value (NPV) to rule out malignancy was also 100%. Within these study populations, 18-FDG PET al- so has the ability to detect metastatic lesions in non-en- larged adrenal glands, but its accuracy in this situation has not been fully evaluated. In addition, 18-FDG PET has the advantage of simultaneously detecting metastases at other sites. However, in some countries, PET is not readily available. Nevertheless, it is a useful tool for eval- uating masses that are indeterminate by both CT and MRI. PET can substitute for percutaneous biopsy and has the advantage of being non-invasive and therefore a safer investigation for the patient [25].

Percutaneous Adrenal Biopsy

With improved imaging and recent techniques, such as contrast medium washout measurement on CT and chem- ical-shift MRI, only a small proportion of adrenal mass- es cannot be characterized accurately and require percu- taneous biopsy for diagnosis. However, before percuta- neous biopsy, the possibility of a pheochromocytoma must be excluded because of the risk of an adrenal crisis induced by the biopsy. In a recent study by Harisinghani et al. [26], the NPV of adrenal biopsies was shown to be between 98% and 100%. In this study, 225 CT-guided biopsies were evaluated, where no malignant lesion was missed on the first biopsy. It was concluded that a single negative biopsy for malignancy can be regarded as a true negative, and there is no necessity to repeat the biopsy.

Percutaneous CT-guided adrenal biopsy is a relatively safe procedure in patients with a known extra-adrenal malignancy. Minor complications of adrenal biopsy in- clude abdominal pain, hematuria, nausea and small pneu- mothoraces. Major complications, generally regarded as those requiring treatment, occur in 2.8-3.6% of cases and include pneumothoraces requiring intervention, and hem- orrhage. There are also isolated reports of adrenal ab- scesses, pancreatitis and seeding of metastases along the needle track [26].

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