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Clinical Radiology
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clinical ŘADÍOLOGY
Pictorial Review
Adrenal neoplasms
G. Lowª,*, H. Dhliwayo ª, D.J. Lomas b
a Department of Radiology & Diagnostic Imaging, University of Alberta Hospital, Edmonton, Alberta, Canada
b Department of Radiology, Addenbrooke’s Hospital, University of Cambridge, UK
ARTICLE INFORMATION
Article history: Received 18 November 2011 Received in revised form 31 January 2012 Accepted 13 February 2012
Adenoma, myelolipoma, phaeochromocytoma, metastases, adrenocortical carcinoma, neuro- blastoma, and lymphoma account for the majority of adrenal neoplasms that are encountered in clinical practice. A variety of imaging methods are available for evaluating adrenal lesions including ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine techniques such as meta-iodobenzylguanidine (MIBG) scintigraphy and positron-emission tomography (PET). Lipid-sensitive imaging techniques such as unenhanced CT and chemical shift MRI enable detection and characterization of lipid-rich adenomas based on an unenhanced CT attenuation of ≤10 HU and signal loss on opposed-phase compared to in-phase T1-weighted images, respectively. In indeterminate cases, an adrenal CT washout study may differentiate adenomas (both lipid-rich and lipid-poor) from other adrenal neoplasms based on an absolute percentage washout of >60% and/or a relative percentage washout of >40%. This is based on the principle that adenomas show rapid contrast washout while most other adrenal neoplasms including malignant tumours show slow contrast washout instead. 18F-2-fluoro-2-deoxy-D-glucose-PET (18FDG-PET) imaging may differentiate benign from malignant adrenal neoplasms by demonstrating high tracer uptake in malignant neoplasms based on the increased glucose utilization and metabolic activity found in most of these malignancies. In this review, the multi-modality imaging appearances of adrenal neoplasms are discussed and illustrated. Key imaging findings that facilitate lesion charac- terization and differentiation are emphasized. Awareness of these imaging findings is essential for improving diagnostic confidence and for reducing misinterpretation errors.
@ 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction
Adrenal neoplasms are commonly encountered in routine clinical practice with incidental adrenal lesions detected in up to 10% of the general population on imaging.1,2 Accurate radiological evaluation is essential for formulating appropriate diagnoses and for differentiating benign from malignant neoplasms. A variety of imaging
methods are available for evaluating adrenal neoplasms including ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine techniques such as meta-iodobenzylguanidine (MIBG) scintigraphy and positron-emission tomography (PET). In this review, the imaging appearances of adrenal neoplasms are discussed with emphasis on key findings that facilitate lesion charac- terization and differentiation.
Adrenal anatomy and physiology
The adrenal glands are suprarenal retroperitoneal organs situated within the perirenal fat and enclosed by Gerota’s fascia. On axial cross-sectional imaging, the right adrenal
* Guarantor and correspondent: G. Low, Department of Radiology & Diagnostic Imaging, University of Alberta Hospital, 2A2.41 WMC, 8440-112 Street, Edmonton, Alberta T6G 2B7, Canada. Tel .: +1 780 407 6907; fax: +1 780 407 3853.
E-mail address: timgy@yahoo.com (G. Low).
has an inverted “V”-shaped configuration and the left adrenal an inverted “Y” or “lambda”-shaped configuration. The adrenals are each composed of a body and medial and lateral limbs. Both adrenals are approximately located at the axial level of the T12 vertebral body, with the right adrenal situated the more cephalad of the two organs. The following anatomical relationships are observed: the right adrenal is located posterior to the inferior vena cava (IVC), medial to the liver and lateral to the right diaphragmatic crus; while the left adrenal is located posterior to the splenic vein and pancreas, partly anterior-medial to the superior pole of the left kidney and lateral to the left diaphragmatic crus.
The adrenals glands are categorized by their zonal anatomy into the outer adrenal cortex and inner adrenal medulla. The adrenal cortex, derived embryologically from mesoderm, is composed histologically of three layers: zona glomerulosa (responsible for mineralocorticoid secretion), zona fasiculata (responsible for glucocorticoid secretion), and zona reticularis (responsible for androgen secretion). The adrenal medulla, derived embryologically from neural crest tissue, is responsible for secretion of the sympathetic hormones adrenaline and noradrenaline.
Adenoma
Adenomas represent 80% of all adrenal neoplasms and are found in 0.2% of 20-29-year-olds and in 7-10% of elderly patients on CT.1,2 Most adenomas are non- functioning, while functioning adenomas account for approximately 6% (5% cortical-secreting, 1% aldosterone or sex-hormone secreting).1 On imaging, adenomas are typi- cally 1-3 cm, well-circumscribed, ovoid-shaped, homoge- neous lesions.1,3,4 These benign neoplasms show stable size on interval imaging assessment. Large size, calcifications, haemorrhage, or cystic appearance are rare findings.4 Ten to 20% of adenomas are bilateral.5 Adenomas typically show low attenuation on unenhanced CT and may be categorized as lipid-rich (70%) or lipid-poor (30%) depending on the intracytoplasmic fat content. Functioning and non- functioning adenomas cannot be differentiated based on the lipid content. In a pooled analysis of 10 studies, Boland et al.6 found that a 10 HU unenhanced CT threshold had 71% sensitivity and 98% specificity in diagnosing adenomas (Fig 1). This threshold has been widely adopted clinically. Chemical shift imaging is a lipid-sensitive MRI technique that exploits the resonance frequency differences of fat and water. Adenomas that possess significant intracytoplasmic fat show signal loss on the opposed-phase compared to the in-phase with 81-100% sensitivity and 94-100% spec- ificity reported (Fig 2).1 The percentage signal loss can be calculated using the adrenal signal intensity (SI) index, [(SIIn phase - SIopposed phase)/SIIn phase x 100%] with a value ≥16.5% considered diagnostic for an adenoma.1 Provided matched measurement regions are used this method avoids problems related to surface coil intensity variation. Alter- natively, the adrenal-to-spleen chemical shift ratio may be calculated, with a value of <0.71 indicative of a lipid-rich adenoma.1 This is performed by dividing the lesion-
to-spleen signal intensity ratio on the in-phase images by the lesion-to-spleen signal intensity ratio on the opposed- phase images. At our institutions, signal loss on chemical shift imaging is determined in most cases by qualitative visual analysis using an internal reference organ such as the spleen or muscle, with quantitative analysis reserved for select cases. This practice reflects the general radiological practice in most centres. Chemical shift imaging and unenhanced CT show comparable performance in charac- terizing lipid-rich adenomas.7-9 However, chemical shift imaging may be superior for characterizing lipid-poor adenomas with attenuations between 10-30 HU.7-9 At our institutions, unenhanced CT is preferred to chemical- shift MRI as the first-line imaging technique for character- izing adenomas. This is because we have shorter waiting times and better local access to CT compared to MRI and because in our experience both techniques are fairly comparable in most cases.
Adenomas (regardless of lipid content) show pathogno- monic rapid enhancement and corresponding rapid washout following contrast medium administration. Given its high diagnostic accuracy, an adrenal CT washout study may be considered the imaging test of choice for determining whether an adrenal lesion is an adenoma.1 This examination typically involves performing a triphasic adrenal CT (unen- hanced phase/60-s enhanced phase/15-min delayed enhanced phase) at a 5 mm minimum collimation utilizing approximately 150 ml non-ionic iodinated contrast medium administered intravenously by pump injection at a rate of 2-3 ml/s. A region of interest (ROI) ≥50% of the area of the adrenal lesion being assessed is placed on representative targets on the unenhanced image, the 60-s enhanced image and the 15-min delayed enhanced image. The HU attenua- tions of these ROIs are recorded and permit adrenal CT washout formulas to be calculated as follows10
RPW = [(enhanced HU60s-delayed HU15 min)/ enhanced HU60 s] × 100
APW = [(enhanced HU60 s - delayed HU15 min)/ (enhanced HU60 s - unenhanced HU)] x 100
(a)
(b)
where RPW is the relative percentage washout and APW the absolute percentage washout.
An APW >60% or RPW >40% has close to 100% sensitivity and specificity for adenomas (Fig 3).1,5,9,10 In contrast, an APW <60% or RPW <40% is almost always associated with malignancy. Both APW and RPW calculations are equally valid for adrenal characterization. The advantage of calcu- lating the RPW over the APW is that the RPW calculation does not require an unenhanced CT phase. If an incidental adrenal lesion is detected at the time of a routine 60-s contrast-enhanced CT examination, the radiologist can elect to proceed to performing a 15-min delayed post- contrast phase to obtain an RPW calculation. This reduces the recall rate for further imaging (which would be neces- sary if an APW was required instead).
Dynamic contrast-enhanced MRI has been evaluated for adrenal characterization. In a study of 48 adenomas and 16 malignant adrenal neoplasms, Inan et al.11 suggested that the combination of the visual enhancement pattern on
dynamic contrast-enhanced MRI, time-to-peak, and wash- in rates, derived from signal intensity-time curves on dynamic contrast-enhanced MRI, may provide additional value beyond that of chemical shift imaging in character- izing lipid-poor adenomas. However, the exact contribution of dynamic contrast enhanced MRI requires further vali- dation in larger studies. Adrenal neoplasms of differing aetiologies may show overlap in imaging enhancement patterns. Furthermore, unlike CT, MRI has a non-linear relationship between dose of contrast medium and signal intensity values making MRI-derived calculations more complex.
PET imaging is a valuable technique for evaluating adrenal lesions. 18F-2-fluoro-2-deoxy-D-glucose (18FDG) is the most widely used PET tracer employed in clinical practice. 18FDG is a glucose analogue that is preferentially taken up by metabolically active malignant adrenal neoplasms as a result of upregulation of glucose trans- porters (Glut 1-7) and intracellular tracer trapping due
(a)
(b)
(c)
to phosphorylation by hexokinase. Malignant adrenal neoplasms typically show greater 18FDG uptake than the background liver with a standardized uptake value (SUV) ≥3.1, a useful cut-off for differentiating malignant from benign lesions.1,12,13 However, occasional false-positive cases exist as a small proportion of benign adrenal lesions such as functional adenomas and phaeochromocytomas may rarely show some 18FDG uptake. The use of combined PET/CT is superior to PET alone as it enables the co- acquisition and synthesis of both anatomical and func- tional data. In a study of 175 adrenal masses in 150 oncology patients, Metser et al.12 evaluated the performance of 18FDG-PET/CT in differentiating adenomas from malignant lesions. Using a SUV cut-off of 3.1, for combined PET/CT data there was 100% sensitivity, 98% specificity, 97% positive predictive value, and 100% negative predictive value. For PET alone, there was 98.5% sensitivity, 92% specificity, 89.3% positive predictive value, and 98.9% negative predictive value. Overall, specificity was higher for PET/CT than for PET alone (p < 0.01). A new PET tracer, 11C-metomidate shows exclusive uptake in adrenocortical neoplasms, such as adenomas and adrenocortical carcinomas. A recent study showed that 11C-metomidate-PET was able to differentiate subcentimetre functioning adenomas from other adrenal incidentalomas.14
Myelolipoma
Adrenal myelolipomas are benign neoplasms composed of macroscopic fat and haematopoietic tissue. Originally described by Gierke in 1905, these were termed “formations myelolipomatoses” by Oberling in 1929.15,16 Adrenocortical metaplasia secondary to necrosis, infection, or stress is postulated to be a precipitating factor.17 Myelolipomas are typically asymptomatic and incidentally discovered on post-mortem (0.08-0.2% prevalence) or imaging (repre- senting 5-10% of adrenal incidentalomas).2,18 Most patients present in the 5-7th decade of life and both sexes are equally affected.19 Myelolipomas may co-exist with adenomas, phaeochromocytomas, or adrenal hyperplasia.20
Myelolipomas are typically 1-4 cm, well-circumscribed, heterogeneous neoplasms.2º Less commonly, myelolipomas may reach a large size and become symptomatic from mass effect or spontaneous haemorrhage. Akamatsu et al. re- ported a case of a 31 cm myelolipoma.21 The imaging appearance of myelolipomas is dependent on the relative proportion of macroscopic fat and myeloid present in the tumours. At ultrasound, most myelolipomas have a hetero- geneous echogenicity with macroscopic fat appearing echogenic and myeloid tissue appearing hypoechoic.22,23 The presence of macroscopic fat in an adrenal mass is pathognomonic for myelolipoma (Fig 4). At CT, macroscopic fat has an attenuation of -30 to -100 HU.22 On MRI, macroscopic fat shows high T1 and T2 signal intensities with signal loss following fat suppression.22 On chemical shift imaging, “india ink” artefact is seen in a myelolipoma at the boundary between macroscopic fat and myeloid tissue on opposed-phase images (Fig 5).23,24 Myeloid tissue
Spin: - 0 Tilt: 0
MYELOID
FAT
A
typically enhances and shows soft-tissue attenuation on CT and low T1 signal intensity and intermediate T2 signal intensity on MRI.22 Haemorrhage may cause a rapid increase in tumour size and can obscure typical imaging findings. High T1 signal intensity may be seen in haemor- rhage due to methaemoglobin (Fig 5). Calcifications (found in 27%) are best assessed on CT.25
Phaeochromocytoma
Originally described by Frankel in 1886, phaeochromo- cytomas are catecholamine-secreting neuroendocrine tumours of the adrenal medulla.26 A 0.8 per 100,000 annual incidence, a 0.02% post-mortem prevalence, and a 0.6% prevalence in patients with hypertension is reported.26-31 Phaeochromocytomas account for 5% of all adrenal inci- dentalomas, being incidentally discovered on imaging in 25% of cases.26,32,33 While most phaeochromocytomas are sporadic in origin, recent discoveries suggest that familial phaeochromocytomas account for 30% of cases. Multiple endocrine neoplasia type 2 (MEN 2), Von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF 1), and succi- nate dehydrogenase (SDH) mutations are responsible for the majority of familial cases. Phaeochromocytomas are detected in 30-50% of patients with MEN 2, 15-20% of patients with VHL, and 1-5% of patients with NF 1.34 While bilateral phaeochromocytomas occur in 10% of sporadic cases, 50-80% of phaeochromocytomas in MEN 2 and 40-80% in VHL patients are bilateral. Sporadic phaeochro- mocytomas present most frequently in the 4th and 5th decades of life, while familial phaeochromocytomas generally present before 40 years of age.26,35 Approximately 90% of phaeochromocytomas secrete catecholamines and are associated with elevated serum and urinary meta- nephrines (catecholamine metabolites).
Phaeochromocytomas have variable imaging features that may mimic both benign and malignant adrenal neoplasms. Size may range from 1.2-15 cm with a mean size
(a)
(b)
(c)
of 5.5 cm reported.36 Smaller neoplasms may be homoge- neous and large neoplasms heterogeneous in appearance.36 On MRI, 65% of phaeochromocytomas show intermediate or high T2 signal intensity. The classic “light bulb” bright appearance - high T2 signal intensity comparable to cere- brospinal fluid is found in only 34% (Fig 6).36 In contrast, 35% of phaeochromocytomas may show low T2 signal inten- sity.37 A cystic appearance, haemorrhage, or calcifications (in 20%) may be additional findings (Fig 7).38 Rarely,
phaeochromocytomas may possess intra-cytoplasmic fat and mimic adenomas showing ≤10 HU attenuation on unenhanced CT and signal loss on chemical shift imaging.37,39 Although earlier studies suggested that iodin- ated contrast media could precipitate hypertensive crises in phaeochromocytomas, recent experience suggests this does not occur with non-ionic contrast media.39 Most phaeochromocytomas show rapid contrast enhancement and slow washout - characteristics that overlap with
(a)
(b)
(a)
(b)
adrenocortical carcinomas and adrenal metastases.40 Rarely, phaeochromocytomas may also show a washout pattern (APW >60%, RPW >40%) that overlaps with adenomas (Fig 8).37 Malignancy is found in 11% of sporadic and 35% of familial phaeochromocytomas.35,41,42 Imaging is essential for determining malignancy in phaeochromocytomas as histopathological analysis is non-discriminatory. Detection of metastases (most commonly to the bones, lymph nodes, lungs, or liver) is the only reliable criterion of malignancy. 123/1311-MIBG scintigraphy is the technique of choice for evaluating phaeochromocytomas with 95-100% specificity and 83-100% and 77-90% sensitivities for 1231-MIBG and 131I-MIBG, respectively (Fig 9).43 An MIBG-positive adrenal mass in a patient with elevated serum or urinary meta- nephrines is highly suggestive for a phaeochromocytoma.
Metastases
Metastases are the most frequently encountered malig- nant adrenal neoplasms with the adrenals being the fourth most common site of metastases overall.44 Approximately 27% of cancer patients have adrenal metastases at post- mortem.45 Furthermore, an adrenal mass in a cancer patient has a 50-75% probability of being a metastasis.46 Mela- noma, breast, lung, colon, and kidney cancers are the most common neoplasms that metastasize to the adrenals. Breast cancer and lung cancer have a 39% and 35% incidence of adrenal metastases, respectively.45 In comparison, the incidence of adrenal metastases is very low in patients with no history of cancer. A study of 1049 consecutive incidental adrenal masses (mean size 2 cm, range 0.4-8.2 cm) in
(a)
(b)
patients with no history of cancer did not find a single malignancy.47
Adrenal metastases may show an overlap in imaging findings with adenomas.44 In general, adrenal masses >4 cm are more likely to be malignant, while masses <4 cm are more likely to be benign.48-50 However, metastases detec- ted an early stage may be <4 cm, while atypical adenomas may rarely be >4 cm. An ill-defined outline and heteroge- neous density are more common in metastases (Fig 10), while a well-defined outline and homogeneous density are more common in adenomas. 44,51 However, small metastases may appear homogeneous, while atypical adenomas may appear heterogeneous.51 Bilateral adrenal involvement is more common in metastases than adenomas (50% versus 10-20%; Fig 11). Unlike lipid-rich adenomas, metastases are typically >10 HU on unenhanced CT and do not show signal
LIVER
+
×
×
+
loss on chemical shift imaging.51 However, these features overlap with lipid-poor adenomas. On MRI, metastases show low T1 signal intensity and heterogeneous high T2 signal intensity.51 CT washout studies are very accurate in differentiating benign from malignant adrenal neoplasms, with metastases typically showing APW <60% and RPW <40%. Unlike adenomas, metastases show significant growth on interval imaging performed at 6 months. Adrenal metastases typically show high uptake on 18F-2-fluoro-2- deoxy-D-glucose-PET (18FDG-PET) with PET-CT showing 100% sensitivity and 98% specificity for differentiating malignant from benign adrenal neoplasms (Fig 12).12 Image- guided biopsy can be performed in indeterminate cases.
Adrenocortical carcinoma (ACC)
ACC is the most common primary malignant neoplasm of the adrenal cortex accounting for <5% of all adrenal inci- dentalomas. It has a one to two cases per million annual incidence and is responsible for 0.2% of all cancer deaths.52,53 A bimodal distribution in the 4th and 5th decades of life and in children <5 years of age is recog- nized.53,54 A female to male ratio of 1.5:1 is reported.52,53 Sixty percent of ACCs are functional and may secrete cortisol, aldosterone, or sex-hormones. Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, Carney syndrome, and MEN 1 are associated conditions.52,55,56
ACCs are typically large, ill-defined, complex neoplasms with heterogeneous density and enhancement (Figs 13 and 14).57-59 A median size of 11-12 cm with a size range of 2-40 cm is reported. Cystic appearance and haemor- rhage are common and calcifications are found in 30%.58 ACC preferentially affects the left adrenal gland while bilateral neoplasms are found in 10%.58,60 ACCs show >10 HU on unenhanced CT and typically exhibit slow contrast medium washout (APW <60% and RPW <40%).61 On MRI, ACCs show low T1 and heterogeneous high T2
O
D
signal intensities. Haemorrhage may show high T1 signal intensity. Rarely, ACCs may show signal loss on chemical shift imaging due to the presence of intracytoplasmic fat.58,62 Aggressive features may be seen such as local invasion, vascular involvement, or metastases. Neoplasms may show contiguous intraluminal growth into the renal vein, IVC and right atrium. IVC involvement is found in 9-19% and is more frequent with right-sided ACCs.58,63 Vascular involvement is best evaluated by multi-planar enhanced MRI. Metastases occur most frequently to the lungs, liver, lymph nodes, and bones. ACCs typically show high uptake on 18FDG-PET with 100% sensitivity and 88% specificity for differentiating ACCs from adenomas (Fig 15).64
LIVER
KIDNEY
Neuroblastoma
Neuroblastomas are embryonal malignancies of the sympathetic nervous system and the most common solid extra-cranial neoplasms of childhood representing 8-10% of all paediatric neoplasms and 15% of paediatric cancer mortality.65 Approximately 10.5 per million children younger than 15 years of age are affected.65 The adrenal medulla is the site of origin in 35%. At presentation, 50% of children are under age 2 years, 75% under age 4 years, and 90% under age 10 years.66 A more favourable prognosis is recognized for children younger than 15-18 months of age than for older children.67 67
A large, suprarenal mass showing heterogeneity and calcifications (30% on radiographs, 85% on CT) in a young child is characteristic for an adrenal neuroblastoma (Figs 16 and 17). Typically, mass effect from the neuroblastoma causes displacement of the ipsilateral kidney inferiorly and the aorta and IVC anteriorly. Neuroblastomas have
IVC
a propensity to cross the midline and to encase adjacent arteries, such as the celiac axis and superior mesenteric artery (Fig 18). Metastases are common, with the bones and liver most frequently affected. MIBG scintigraphy is the imaging technique of choice in neuroblastomas facilitating tumour localization, assessment of metastases, and disease staging (Fig 19). MIBG has 88-93% sensitivity and 83-92% specificity for neuroblastomas.67 In MIBG-negative tumours (10%), 99Tc-diphosphonate scintigraphy and 18FDG-PET may be performed to assess for metastases.
Lymphoma
Secondary adrenal lymphoma is found in 25% of post- mortems and 4% of CT examinations in patients with disseminated non-Hodgkin’s lymphoma.68,69 In compar- ison, primary adrenal lymphoma (PAL) accounts for 3% of extra-nodal lymphoma with <100 cases reported.70 PAL has an uncertain aetiology but is postulated to arise from hae- matopoietic tissue within the adrenal glands.71 Diffuse large B-cell lymphoma subtype accounts for 70%.72 PAL has a mean age at presentation of 65 years, a 2:1 male to female ratio and is bilateral in 70% of cases.72,73 In over 50%, significant adrenocortical tissue destruction leads to Addi- son’s disease.72,73
The presence of bilateral large adrenal masses without extra-adrenal disease should raise the suspicion for PAL (Fig 20).74 Neoplasms have a median size of 8 cm and may have a round, oval, or nodular configuration.70,72 Adrenal enlargement without shape distortion is also recognized.75 Variable echogenicity is reported sonographically although most tumours are hypoechoic.76 CT or MRI typically show a complex, heterogeneous mass containing cystic change or haemorrhage.75 Similar to other forms of lymphoma, PALs
may infiltrate around adjacent organs and vessels without intervening tissue destruction.7º Calcifications are rare.51,75 Most PALs are hypovascular and show mild contrast
CHA
CA
SA
enhancement.51 On MRI, PALs typically show low T1 signal intensity and intermediate to high T2 signal intensity.51,75 PALs also typically show high uptake on 18FDG-PET. Given the rarity of the tumour, image-guided biopsy is generally recommended for definitive diagnosis.
Algorithm for evaluating patients with adrenal incidentalomas
An adrenal incidentaloma is an adrenal mass (≥1 cm) discovered incidentally on a cross-sectional imaging examination performed for another reason.77 In most cases, this would include solid adrenal lesions detected but not
adequately characterized on previous CT studies performed. A proposed diagnostic algorithm for evaluating adrenal lesions is discussed in this section and included in Fig 21. This is based on the authors’ own preferences and is adapted from the American College of Radiology’s Inci- dental Findings Committee White Paper.77
There are four specific clinical scenarios that need to be considered: (1) symptomatic versus asymptomatic patients. In general, the majority of benign asymptomatic adrenal lesions can be managed conservatively. In this scenario, the main objective of imaging is to characterize an adrenal lesion accurately as benign or malignant. In contrast, symptomatic adrenal lesions (regardless of whether benign or malignant) generally require surgery. An example is adrenergic excess in a phaeochromocytoma. In this scenario, the main objectives of imaging are to detect and stage the disease accurately and to suggest appropriate referral to a surgeon/endocrinologist. (2) Young versus elderly patients. Young patients and older patients that are good surgical candidates will generally benefit from a more detailed imaging assessment of their adrenal incidentalo- mas. In contrast, elderly patients with significant co- morbidities and that are poor surgical candidates may be more appropriately managed with less extensive imaging investigations. (3) Low versus high-risk patients. Patients with a past history of cancer or a genetic predisposition for the development of adrenal neoplasms (e.g., VHL, MEN 2, and NF 1 predispose to phaeochromocytomas) are consid- ered high-risk patients. A higher index of radiological suspicion is required in these patients and diagnostic imaging tests should be considered as a part of routine surveillance for patients with a known genetic predisposi- tion. In contrast, patients that do not have a past history of cancer or a genetic predisposition have a statistically very low risk of possessing a malignant adrenal neoplasm. (4) Discovery of adrenal incidentaloma at time of imaging. Most adrenal incidentalomas are originally discovered during routine contrast-enhanced CT examinations. If an adrenal lesion is detected at the time of initial examination
ADRENAL INCIDENTALOMA
UNENHANCED CT/ CS-MRI
DIAGNOSTIC FEATURES - Adenoma - Myelolipoma
INDETERMINATE FEATURES
SUSPICIOUS FEATURES FOR MALIGNANCY
CE-CT / CE-MRI, if still suspicious BIOPSY OR RESECTION
NO HISTORY OF CANCER
HISTORY OF CANCER
STABLE ( ≥ 1 year) BENIGN
ENLARGING presumed malignant BIOPSY OR RESECTION
ADRENAL CT WASHOUT
PET
BIOPSY
while the patient is undergoing the CT examination, the radiologist can elect to perform an adrenal CT washout study (RPW) at the same sitting for lesion characterization. This reduces the need to recall some patients for additional imaging tests.
The local institutional resources and expertise available will determine the range of diagnostic tests on offer and the waiting times for these investigations. For example, smaller centres may have limited or no access to specialist imaging, such as PET, while waiting times may be shorter for CT compared to MRI examinations. Taking these factors into account, the main objective of adrenal imaging is to char- acterize and differentiate benign from malignant adrenal lesions accurately. At our institutions, unenhanced CT is used as the first-line examination in most cases due to the greater accessibility and shorter waiting times for CT. Unenhanced CT provides reliable characterization of the majority of adenomas and myelolipomas, the two most common benign adrenal neoplasms. Lipid-rich adenomas (accounting for 70% of adenomas) and myelolipomas may be characterized based on an unenhanced attenuation of ≤10 HU and the presence of foci of macroscopic fat, respectively. Chemical shift MRI is a credible alternative investigation and may be used either for confirming the findings of an unenhanced CT or for characterizing lesions detected incidentally on contrast-enhanced CT. However, in our experience it does not offer significantly noticeable additional value over an unenhanced CT.
Cases that cannot be characterized on unenhanced CT and/or chemical shift MRI maybe divided into lesions with suspicious imaging findings for malignancy (e.g., size
>4 cm, irregular margins, intratumoural necrosis, invasive features, enlarged adenopathy, etc.) and lesions that are indeterminate but with no overt suspicious imaging find- ings. Cases with suspicious imaging findings should undergo further characterization with contrast-enhanced CT or contrast-enhanced MRI. If suspicion persists, biopsy or surgical resection should be considered. Indeterminate cases with no overt suspicious features on unenhanced CT and/or chemical shift MRI maybe stratified into two groups based on whether these patients have a past history of cancer. Patients with no history of cancer have a very low statistical probability of having a malignant adrenal lesion.47 Therefore, these patients may be appropriately managed by diagnostic follow-up (with unenhanced CT and/or chemical shift MRI) performed at 6 and 12 months, with a minimum length of follow up of 12 months recom- mended.77 Benign lesions, such as adenomas, are typically stable in size, while malignant neoplasms generally show significant increase in size during follow-up. Previous imaging studies, if available, are very helpful for deter- mining whether an adrenal lesion has demonstrated significant interval growth. In patients with a history of cancer and indeterminate findings on unenhanced CT and/ or chemical shift MRI, additional imaging tests may be appropriate, as these patients have a statistically higher risk of malignancy (e.g., an adrenal mass in a cancer patient has a 50-75% probability of being a metastasis).46 A CT washout study or 18FDG-PET are diagnostic options for consideration, depending on the local resources. A CT washout study is a technically undemanding test that can be performed in almost any centre that possesses a CT machine, while PET
imaging requires specific infrastructure and radiopharma- ceuticals and physicians that are familiar with interpreting PET examinations. On CT washout studies, adenomas generally show an APW of >60% and RPW of >40% while most adrenal malignancies show an APW <60% and RPW <40%. On 18FDG-PET, most benign adrenal lesions show no significant tracer uptake, while most malignant lesions show high uptake greater than the background liver. An added advantage of PET imaging over CT washout studies is that it also enables the detection of foci of malignancy elsewhere in the body and so permits more accurate disease staging. In our experience, we have found that the use of CT washout studies and PET imaging have reduced the clinical demand for image-guided biopsy to obtain definitive diagnosis.
Conclusion
Neoplasms of the adrenal glands encompass a heteroge- neous group of benign and malignant diseases that may present with variable imaging findings. Advances in imaging have enhanced the ability of radiologists to char- acterize adrenal lesions and to differentiate benign from malignant neoplasms. Some tumours show characteristic imaging appearances. In others, imaging findings may overlap between different diseases. Knowledge of the imaging findings of adrenal neoplasms is essential for improving diagnostic confidence and for reducing misin- terpretation errors.
References
1. Boland GW, Blake MA, Hahn PF, et al. Incidental adrenal lesions: prin- ciples, techniques, and algorithms for imaging characterization. Radi- ology 2008;249:756-75.
2. Kloos RT, Gross MD, Francis IR, et al. Incidentally discovered adrenal masses. Endocr Rev 1995;16:460-84.
3. Mayo-Smith WW, Boland GW, Noto RB, et al. State-of-the-art adrenal imaging. RadioGraphics 2001;21:995-1012.
4. Johnson PT, Horton KM, Fishman EK. Adrenal mass imaging with mul- tidetector CT: pathologic conditions, pearls, and pitfalls. RadioGraphics 2009;29:1333-51.
5. Johnson PT, Horton KM, Fishman EK. Adrenal imaging with multi- detector CT: evidence-based protocol optimization and interpretative practice. RadioGraphics 2009;29:1319-31.
6. Boland GW, Lee MJ, Gazelle GS, et al. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roent- genol 1998;171:201-4.
7. Haider MA, Ghai S, Jhaveri K, et al. Chemical shift MR imaging of hyperattenuating (>10 HU) adrenal masses: does it still have a role? Radiology 2004;231:711-6.
8. Park BK, Kim CK, Kim B, et al. Comparison of delayed enhanced CT and chemical shift MR for evaluating hyperattenuating incidental adrenal masses. Radiology 2007;243:760-5.
9. Blake MA, Holalkere NS, Boland GW. Imaging techniques for adrenal lesion characterization. Radiol Clin North Am 2008;46:65-78. vi.
10. Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002;222:629-33.
11. Inan N, Arslan A, Akansel G, et al. Dynamic contrast enhanced MRI in the differential diagnosis of adrenal adenomas and malignant adrenal masses. Eur J Radiol 2008;65:154-62.
12. Metser U, Miller E, Lerman H, et al. 18F-FDG PET/CT in the evaluation of adrenal masses. J Nucl Med 2006;47:32-7.
13. Wong KK, Arabi M, Zerizer I, et al. Role of positron emission tomog- raphy/computed tomography in adrenal and neuroendocrine tumors: fluorodeoxyglucose and nonfluorodeoxyglucose tracers. Nucl Med Commun 2011;32:764-81.
14. Burton T, Bird N, Soloviev D, et al. 11C-Metomidate PET-CT scan: A non- invasive method to lateralise aldosterone secretion in patients with primary hyperaldosteronism and small adrenal adenomas. J Hypertens 2010;28:e216-7.
15. Gierke E. Uber Knochenmarksgewebe in der Nebenniere. Beitr Pathol Anat 1905;7:311-25.
16. Oberling C. The formation of myelolipomas. Bull Assoc Fr Etud Cancer 1929;18:234-46.
17. Plaut A. Myelolipoma in the adrenal cortex; myeloadipose structures. Am J Pathol 1958;34:487-515.
18. Olsson CA, Krane RJ, Klugo RC, et al. Adrenal myelolipoma. Surgery 1973;73:665-70.
19. Ketelsen D, von Weyhern CH, Horger M. Diagnosis of bilateral giant adrenal myelolipoma. J Clin Oncol 2010;28:e678-9.
20. Cha JS, Shin YS, Kim MK, et al. Myelolipomas of both adrenal glands. Korean J Urol 2011;52:582-5.
21. Akamatsu H, Koseki M, Nakaba H, et al. Giant adrenal myelolipoma: report of a case. Surg Today 2004;34:283-5.
22. Cyran KM, Kenney PJ, Memel DS, et al. Adrenal myelolipoma. AJR Am J Roentgenol 1996;166:395-400.
23. Rao P, Kenney PJ, Wagner BJ, et al. Imaging and pathologic features of myelolipoma. RadioGraphics 1997;17:1373-85.
24. Pereira JM, Sirlin CB, Pinto PS, et al. CT and MR imaging of extrahepatic fatty masses of the abdomen and pelvis: techniques, diagnosis, differ- ential diagnosis, and pitfalls. RadioGraphics 2005;25:69-85.
25. Daneshmand S, Quek ML. Adrenal myelolipoma: diagnosis and management. Urol J 2006;3:71-4.
26. Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet 2005;366:665-75.
27. Beard CM, Sheps SG, Kurland LT, et al. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58:802-4.
28. Platts JK, Drew PJ, Harvey JN. Death from phaeochromocytoma: lessons from a post-mortem survey. J R Coll Physicians Lond 1995;29:299-306.
29. McNeil AR, Blok BH, Koelmeyer TD, et al. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auck- land. Aust N Z J Med 2000;30:648-52.
30. Anderson Jr GH, Blakeman N, Streeten DH. The effect of age on preva- lence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 1994;12:609-15.
31. Omura M, Saito J, Yamaguchi K, et al. Prospective study on the preva- lence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 2004;27:193-202.
32. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidenta- loma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000;85:637-44.
33. Mansmann G, Lau J, Balk E, et al. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004;25:309-40.
34. Renard J, Clerici T, Licker M, et al. Pheochromocytoma and abdominal paraganglioma. J Visc Surg 2011 Aug 19 [Epub ahead of print].
35. Whalen RK, Althausen AF, Daniels GH. Extra-adrenal pheochromocy- toma. J Urol 1992; 147:1-10.
36. Jacques AE, Sahdev A, Sandrasagara M, et al. Adrenal phaeochromocy- toma: correlation of MRI appearances with histology and function. Eur Radiol 2008; 18:2885-92.
37. Blake MA, Kalra MK, Maher MM, et al. Pheochromocytoma: an imaging chameleon. RadioGraphics 2004;24(Suppl. 1):S87-99.
38. Lee TH, Slywotzky CM, Lavelle MT, et al. Cystic pheochromocytoma. RadioGraphics 2002;22:935-40.
39. Bessell-Browne R, O’Malley ME. CT of pheochromocytoma and para- ganglioma: risk of adverse events with i.v. administration of nonionic contrast material. AJR Am J Roentgenol 2007;188:970-4.
40. Szolar DH, Korobkin M, Reittner P, et al. Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT. Radiology 2005;234:479-85.
41. Waguespack SG, Rich T, Grubbs E, et al. A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and para- ganglioma. J Clin Endocrinol Metab 2010;95:2023-37.
42. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 2004;89:479-91.
43. Havekes B, King K, Lai EW, et al. New imaging approaches to phaeo- chromocytomas and paragangliomas. Clin Endocrinol (Oxf) 2010;72:137-45.
44. Krebs TL, Wagner BJ. MR imaging of the adrenal gland: radiologic- pathologic correlation. RadioGraphics 1998;18:1425-40.
45. Abrams HL, Spiros R, Goldstein N. Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer 1950;3:74-85.
46. Lenert JT, Barnett Jr CC, Kudelka AP, et al. Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 2001;130:1060-7.
47. Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1049 consecutive adrenal masses in patients with no known malignancy. AJR Am J Roentgenol 2008;190:1163-8.
48. Lee MJ, Hahn PF, Papanicolaou N, et al. Benign and malignant adrenal masses: CT distinction with attenuation coefficients, size, and observer analysis. Radiology 1991;179:415-8.
49. Korobkin M, Brodeur FJ, Yutzy GG, et al. Differentiation of adrenal adenomas from nonadenomas using CT attenuation values. AJR Am J Roentgenol 1996;166:531-6.
50. Sahdev A, Reznek RH. The indeterminate adrenal mass in patients with cancer. Cancer Imaging 2007. 7 Spec No A: S100-9.
51. Lockhart ME, Smith JK, Kenney PJ. Imaging of adrenal masses. Eur J Radiol 2002;41:95-112.
52. Dackiw AP, Lee JE, Gagel RF, et al. Adrenal cortical carcinoma. World J Surg 2001;25:914-26.
53. Wajchenberg BL, Albergaria Pereira MA, et al. Adrenocortical carcinoma: clinical and laboratory observations. Cancer 2000;88:711-36.
54. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effects of mitotane therapy. N Engl J Med 1990;322:1195-201.
55. Roman S. Adrenocortical carcinoma. Curr Opin Oncol 2006;18:36-42.
56. Phan AT. Adrenal cortical carcinoma - review of current knowledge and treatment practices. Hematol Oncol Clin N Am 2007;21:489-507.
57. Zini L, Porpiglia F, Fassnacht M. Contemporary management of adre- nocortical carcinoma. Eur Urol 2011 Aug 4 [Epub ahead of print].
58. Bharwani N, Rockall AG, Sahdev A, et al. Adrenocortical carcinoma: the range of appearances on CT and MRI. AJR Am J Roentgenol 2011;196:W706-14.
59. Belldegrun A, Hussain S, Seltzer SE, et al. Incidentally discovered mass of the adrenal gland. Surg Gynecol Obstet 1986;163:203-8.
60. Wooten MD, King DK. Adrenal cortical carcinoma: epidemiology and treatment with mitotane and a review of the literature. Cancer 1993;72:3145-55.
61. Fassnacht M, Libe R, Kroiss M, et al. Adrenocortical carcinoma: a clini- cian’s update. Nat Rev Endocrinol 2011;7:323-35.
62. Schlund JF, Kenney PJ, Brown ED, et al. Adrenocortical carcinoma: MR imaging appearance with current techniques. J Magn Reson Imaging 1995;5:171-4.
63. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003;169:5-11.
64. Groussin L, Bonardel G, Silvera S, et al. 18F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients. J Clin Endocrinol Metab 2009;94:1713-22.
65. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am 2010;24:65-86.
66. Bagatell R. Chapter 22: Neuroblastoma. In: Lanzkowsky P, editor. Manual of Pediatric Hematology and Oncology. 5th ed. Oxford, UK: Elsevier; 2011. p. 671-93.
67. Sharp SE, Gelfand MJ, Shulkin BL. Pediatrics: diagnosis of neuroblas- toma. Semin Nucl Med 2011;41:345-53.
68. Rosenberg SA, Diamond HD, Jaslowitz B, et al. Lymphosarcoma: a review of 1269 cases. Medicine (Baltimore) 1961;40:31-84.
69. Paling MR, Williamson BR. Adrenal involvement in non-Hodgkin lymphoma. AJR Am J Roentgenol 1983;141:303-5.
70. Zhou L, Peng W, Wang C, et al. Primary adrenal lymphoma: Radiological; pathological, clinical correlation. Eur J Radiol 2010 Dec 10 [Epub ahead of print].
71. Dutta P, Bhansali A, Venkatesan R. Primary adrenal lymphoma. Endo- crinologist 2005;15:340-2.
72. Aziz SA, Laway BA, Rangreze I, et al. Primary adrenal lymphoma: differential involvement with varying adrenal function. Indian J Endo- crinol Metab 2011;15:220-3.
73. Zhang LJ, Yang GF, Shen W, et al. Imaging of primary adrenal lymphoma: case report and literature review. Acta Radiol 2006;47:993-7.
74. Li Y, Sun H, Gao S, et al. Primary bilateral adrenal lymphoma: two case reports. J Comput Assist Tomogr 2006;30:791-3.
75. Guo YK, Yang ZG, Li Y, et al. Uncommon adrenal masses: CT and MRI features with histopathologic correlation. Eur J Radiol 2007;62:359-70.
76. Yoon JH, Lee YY, Park CG, et al. A case of primary adrenal gland lymphoma. Korean J Intern Med 2003; 18:122-4.
77. Berland LL, Silverman SG, Gore RM, et al. Managing incidental findings on abdominal CT: white paper of the ACR incidental findings committee. J Am Coll Radiol 2010;7:754-73.