Practical Approach to Adrenal Imaging
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Khaled M. Elsayes, MDa,*, Sally Emad-Eldin, MDb, Ajaykumar C. Morani, MDª, Corey T. Jensen, MDª
KEYWORDS
. Adrenal . Adenoma . Pheochromocytoma . Adrenocortical carcinoma . Computed tomography
· Magnetic resonance
KEY POINTS
. Noncontrast attenuation less than 10 Hounsfield units is most compatible with a lipid-rich adenoma.
· CT enhancement washout technique is the most sensitive and specific technique for evaluation of adrenal masses exhibiting an attenuation higher than 10 Hounsefield units on noncontrast CT.
· MR imaging is helpful in the setting of a heterogeneous mass or when there is contraindication of iodinated contrast medium (allergy or renal insufficiency).
· Adrenal adenoma is the most common adrenal mass containing intracytoplasmic lipid. Rarely, me- tastases can contain intracytoplasmic lipid, thus can mimic adenoma on MR imaging.
· Diffuse bilateral gland thickening with preserved adreniform configuration in patients with hypercor- tisolism is consistent with adrenal hyperplasia.
INTRODUCTION
The adrenal gland can be affected by a variety of pathologies, the majority of which are benign. Ad- renal lesions tend to be encountered incidentally when performing imaging for other purposes. Diagnosis of adrenal masses can be challenging, but the imaging characteristics of morphologic and physiologic features can be used to appropri- ately guide the identification and management of adrenal lesions. This review describes an array of pathologic adrenal conditions discovered through imaging and illustrates their imaging characteris- tics with the implications for management.
IMAGING TECHNIQUES Computed Tomography
Computed tomography (CT) is the imaging method most often used to detect and characterize adrenal
masses. When an adrenal mass is found inciden- tally on imaging, a dedicated CT protocol is usually performed to further evaluate the mass. This is particularly true for patients with a history of malignancy. The adrenal mass protocol includes densitometry of the mass on noncontrast CT. Measuring the unenhanced attenuation value of an adrenal mass is crucial for accurate diagnosis of lipid-rich adenoma. An unenhanced attenuation value of less than 10 Hounsfield units (HU) is char- acteristic. If the mass fits this criterion, no further imaging is required.1
Adrenal masses with attenuation values of greater than 10 HU often have a unique contrast enhancement and washout pattern. Adenomas behave differently from other masses, enhancing rapidly after contrast administration and then rapidly washing out. Although most malignant le- sions also enhance rapidly, they show a slower
This article was previously published in March 2017 Radiologic Clinics, Volume 55, Issue 2. None of the authors have conflict of interest or financial disclosure.
a Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1473, Houston, TX 77030, USA; b Department of Diagnostic and Intervention Radiology, Cairo Uni- versity, Kasr Al-Ainy Street, Cairo 11652, Egypt
* Corresponding author. Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX 77030. E-mail address: KMElsayes@mdanderson.org
washout pattern owing to leaky capillaries.2 The absolute percentage of enhancement washout is calculated by measuring the unenhanced value, the enhanced attenuation at 60 seconds, and enhancement 15 minutes after contrast injection and applying them in the following formula:
Enhanced attenuation value - delayed attenuation value × 100
Enhanced attenuation value unenhanced attenuation value
Absolute washout measurement requires an unenhanced HU measurement, which is not usu- ally acquired in daily practice. Relative washout can be obtained as an alternative formula when noncontrast phase is not available. Relative enhancement washout is calculated as:
Enhanced attenuation value - delayed attenuation value × 100
Enhanced attenuation value
Absolute washout threshold values of greater than or equal to 60% and relative washout threshold values of greater than or equal to 40% have been reported to be highly
sensitive (88%-96%) and highly specific (96%- 100%) for diagnosing adrenal adenomas (Fig. 1).1,3,4
Dual-energy computed tomography
Recent technologic advances in dual-energy CT permit nearly simultaneous acquisition of the tar- geted region at 2 different tube voltages (usually 80 and 140 kVp) during a single breath-hold acqui- sition. Using a 3-material decomposition algo- rithm, virtual unenhanced CT images can be reconstructed from contrast-enhanced CT images.5,6
Because adrenal lesions display different atten- uations at different voltage settings, they are suited for characterization by dual-energy CT.7 The use of virtual unenhanced images may permit characterization of some adrenal lesions as ade- nomas, which would be characterized as indeter- minate if enhanced images were the only images available.8
Lower attenuation of an adrenal lesion at 80 kVp than at 140 kVp has been shown to be a highly specific sign of adrenal adenoma, the diagnostic equivalent of the presence of intracytoplasmic lipid. However, because some adenomas and ad- renal metastases show higher attenuation at 80 kVp, the sensitivity of this test is low. Gupta and
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41 HU
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colleagues9 have reported a sensitivity of 50% and a specificity of 100%, whereas Shi and col- leagues10 have reported a sensitivity of 78.6% and a specificity of 100% for dual-energy CT diag- nosis of adenoma. The variable presentation of ad- renal adenomas on dual-energy CT is likely owing to varying amounts of intracytoplasmic lipid.
Computed tomography perfusion imaging
The application of CT perfusion imaging in adrenal gland tumors is currently undergoing investiga- tion.11 CT perfusion imaging has been shown to quantitatively differentiate adrenal adenomas from nonadenomas.11 The CT perfusion parame- ters (blood flow, blood volume, mean transit time, and permeability surface area product), which reflect adrenal nodule angiogenesis, are quantified.12 Although adenomas have a higher permeability surface value than nonadenomas, only the blood volume parameter has been shown to have prognostic significance. Blood volume is significantly higher in adenomas than in nonade- nomas, with reported sensitivity of 76.9% and specificity of 73.2%.11,12
MR Imaging
Chemical shift MR imaging
Chemical shift MR imaging (CS-MR imaging) is the essential MR technique in the evaluation of adrenal lesions. CS-MR imaging uses in-phase (IP) and opposed-phase (OP) T1 gradient-recalled echo pulse sequences.2 A decrease in signal intensity of the adrenal lesion on OP compared with IP im- ages is characteristic of the presence of intracyto- plasmic lipid. Visual analysis of this signal drop is accurate in the diagnosis of most lipid-rich ade- nomas (Fig. 2).13 The signal intensity drop from IP to OP images is assessed quantitatively through calculation of the signal intensity index (SII). The SII is calculated as:
SI on IP - SI on OP SI on IP
× 100
Where SI is the signal intensity. Using a SII cutoff value of 16.5%, the reported accuracy of CS-MR imaging in distinguishing adenomas from metastatic tumors has been reported as 100% (see Fig. 2).13 Another quantitative chemical-shift method of distinguishing adenomas from malignant tumors is calculation of the adrenal-to-spleen ratio (ASR). The ASR is calcu- lated as:
SI adrenal OP/spleen OP SI adrenal IP/SI spleen IP × 100
An ASR of less than or equal to 70 showed 78% sensitivity and 100% specificity for identifying ad- enomas. However, SII has been found to be a more valid measure than ASR in identifying lipid containing adrenal adenomas. 13-15
MR imaging has a limited role in characterizing lipid-poor adenomas. Israel and colleagues 16 have reported that CS-MR imaging can identify 60% of adenomas (8/13) that demonstrated greater than 10 HU on unenhanced CT.16 One study showed that CS-MR imaging is most limited when the unenhanced CT attenua- tion of the lesion is greater than 30 HU.17 Sahdev and colleagues14 reported a sensitivity of 89% for CS-MR imaging in diagnosing lipid-poor adenomas of 10 to 30 HU. Rarely, adrenal metastases, such as those from clear cell renal cell carcinoma or hepatocellular carcinoma, may contain intracytoplasmic lipid and thus show a significant decrease in signal intensity on OP compared with IP images (Fig. 3).18
Diffusion-weighted MR imaging
The effectiveness of diffusion-weighted imaging (DWI) for the diagnosis of adrenal tumors has been investigated.15,19 Normal adrenal glands
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show high signal intensity with nonpathologic restricted/embedded diffusion on DWI.20 There is considerable overlap of apparent diffusion co- efficient (ADC) values between adenomas and metastatic lesions (Figs. 4 and 5). DWI is not useful in the further differentiation of potentially lipid-poor adenomas, indicating that its utility for indeterminate lesions is limited. 15,19,21
However, pheochromocytomas have relatively higher ADC values than adenomas and metasta- tic lesions.22
MR spectroscopy
Few studies have evaluated the use of MR spec- troscopy (MRS) in the characterization of adrenal lesions. The deep location of the adrenal glands
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and proximity to regions with significant suscep- tibility artifact, together with the heterogeneous nature of adrenal masses, limit the feasibility of MRS techniques.23 On visual analysis of MRS re- sults for the characterization of adrenal lesions, adenomas have only positive lipid peaks in the spectra. There is no difference in metabolic peaks between lipid-rich and lipid-poor adenomas. The presence of a high choline peak supports malignancy.24
Quantitative analysis of the metabolic ratios has shown better results. The metabolic ratios are calculated include choline:creatine of 4.0 to 4.3 ppm:creatine, choline:lipid, and lipid:creatine. The first 2 ratios offer the most effective discrimi- nation of adrenal lesions, with the highest sensi- tivity and specificity.23,24
Using a cutoff value of 1.20 for the choline:crea- tine ratio, adenomas and pheochromocytomas can be distinguished from carcinomas and metas- tases (92% sensitivity, 96% specificity). In addi- tion, pheochromocytomas and carcinomas can be differentiated from adenomas and metastases by a 4.0 to 4.3 ppm:creatine ratio of greater than 1.50 (87% sensitivity, 98% specificity).24
One small series demonstrated that MRS is use- ful for characterizing pheochromocytomas. These tumors are characterized by a unique spectral peak at 6.8 ppm that may be attributed to the pres- ence of catecholamines.25
PET Computed Tomography with 18FFluorodeoxyglucose
PET with 18Ffluorodeoxyglucose combined with CT (FDG PET-CT) has shown merit in differenti- ating adrenal masses, identifying the origin of the mass as adrenal versus nonadrenal, and deter- mining the staging of malignant lesions.26 It is not, however, used as the primary imaging modal- ity to characterize adrenal lesions.27 The degree to which qualitative or quantitative PET analysis should be used in the characterization of adrenal lesions remains uncertain. The findings of qualita- tive PET analyses are interpreted as positive if the FDG uptake of an adrenal lesion is greater than or equal to that of the liver and as negative if lesion uptake is less than that of the liver (Figs. 6 and 7).27 Other reports using quantitative PET analysis to identify adrenal lesions have
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suggested that a maximum standardized uptake value (SUVmax) of greater than or equal to 3.1 is useful for differentiating malignant from benign ad- renal lesions. 28,29
The measurement of SUV is subject to variability owing to features such as patient body weight, scanner resolution, image reconstruction method, and time between FDG injection and scan acquisi- tion.30 Thus, a method that quantifies the ratio of adrenal mass SUV to liver SUV (tumor:liver SUVmax ratio) was created to correct some of the variables that affect SUV measurements. 31
The implementation of a mean CT attenuation threshold greater than 10 HU, with either SUVmax greater than 3.1 or tumor:liver SUV ratio greater than 1.0, increases the specificity of FDG PET- CT for identifying metastases without decreasing the sensitivity. Because some adrenal adenomas have moderate FDG uptake above the PET thresh- olds, both the CT and PET thresholds are applied to improve the overall diagnostic accuracy and decrease the false-positive rate.28,29 Greater
FDG activity in the tumor than in the liver in some benign adrenal adenomas, adrenal endothelial cysts, and inflammatory lesions (sarcoidosis, tuberculosis) leads to a 5% false-positive rate for PET-CT in the identification of adrenal lesions. 32
Causes of false-negative results are small (<10 mm) metastatic nodules, adrenal metastatic lesions with hemorrhage or necrosis, and metasta- ses from non-FDG-avid malignancies, including bronchoalveolar carcinoma and carcinoid.33 PET cannot differentiate between malignant adrenal le- sions, such as metastases, adrenocortical carci- noma (Fig. 8), or malignant pheochromocytoma, and lymphoma.2
ADRENAL MASSES AND SPECTRUM OF IMAGING FEATURES
Adrenal masses can be characterized on the basis of their morphologic features into the following spectrum: intracytoplasmic lipid, fat cells, hemorrhagic, cystic, markedly enhancing,
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large lobulated heterogeneous mass, calcified, or bilateral adrenal masses.
Adrenal Adenoma
Adrenal adenoma is the most common adrenal lesion, found in 2% to 9% of autopsies.7 Most ad- enomas are nonfunctioning; differentiation from functioning adenomas requires clinical and labora- tory evaluation in conjunction with imaging. How- ever, other atypical features may provide useful clues. For example, an atrophic contralateral adre- nal gland suggests a functioning adenoma, since such atrophy may be owing to suppression of pitu- itary adrenocorticotropic hormone (ACTH) secre- tion by elevated cortisol levels. 34
Adenomas vary in size, with most lesions measuring less than 3 cm in greatest dimension. They are typically well-circumscribed round or oval masses with homogeneous attenuation/ signal intensity and enhancement patterns. How- ever, overlap with characteristics of malignant le- sions may make these morphologic features insufficient for confirming a diagnosis of adrenal adenoma.35 Furthermore, some adenomas have an atypical appearance that may include large size, calcification, cystic degeneration, or hemor- rhage, thus mimicking the appearance of nonade- nomas and making the diagnosis more challenging. 36
The classic diagnostic feature of adrenal ade- noma is the presence of intracytoplasmic lipid. However, 10% to 40% of adenomas are lipid poor, occasionally rendering them almost indistin- guishable from other adrenal pathologies.37 The attenuation of adrenal adenomas on precontrast CT varies according to the amount of intracyto- plasmic lipid.38 The mean attenuation of lipid-rich adenomas ranges from -2 to 16 HU, whereas that of lipid-poor adenomas is higher, measuring 20 to 25 HU.1,3,16,39 An unenhanced attenuation value of less than 10 HU is characteristic of a lipid-rich adenoma, with reported 71% sensitivity and 98% specificity.40 When this threshold is not met, washout criteria can be helpful in the identifi- cation of these lipid-poor adenomas. Threshold values of greater than 60% for absolute enhance- ment washout and greater than 40% for relative enhancement washout have been found to be highly sensitive and specific for diagnosing adre- nal adenoma, irrespective of lipid content (see Fig. 1).3,41
Chemical shift IP and OP pulse sequences is the most reliable MR technique for evaluation of adrenal adenoma. This differentiates adrenal ade- nomas from metastases with a high sensitivity (81%-100%) and specificity (94%-100%).42,43
With CS-MR imaging, most adrenal adenomas demonstrate drop of signal intensity on OP compared with IP images. A decrease in signal in- tensity of more than 16.5% is diagnostic of an ad- enoma (see Fig. 2).13 Rarely, foci of fat cells have been reported in adrenal adenomas that were pre- operatively diagnosed as myelolipoma on the ba- sis of radiologic findings. The lipomatous tissue may represent fatty degeneration in adrenocortical adenoma or may be an additional neoplastic component of the tumor. 44
Mimics of Adrenal Adenoma
Various adrenal masses can mimic adrenal ade- nomas. Although this is not common, misinterpre- tation may occur mainly because of low attenuation on CT or drop of signal intensity on OP when compared with IP sequence. Simple cyst with attenuation values of less than 10 HU can mimic adrenal lipid-rich adenoma on unen- hanced CT. However, they do not enhance on postcontrast series and exhibit markedly increased signal intensity on T2-weighted MR images.
Some metastatic deposits can contain intracy- toplasmic lipid, such as those occurring second- ary to hepatocellular carcinoma, and clear cell renal cell carcinoma (see Fig. 3), and thus can mimic adenoma on MR imaging as they demon- strate drop of signal intensity on OP compared with IP pulse sequences. 18
Adrenal Metastases
Adrenal metastases are the most common malig- nant lesions involving the adrenal gland. Although only 2% of adrenal incidentalomas are metasta- ses, the rate is much higher in patients with known malignancy (26%-73%).2,45 The adrenal gland is a common site of metastasis; common primary tu- mors that metastasize to the adrenal glands include the lung, breast, kidney, pancreas, and gastrointestinal tract.46 Isolated adrenal metas- tasis is less common than bilateral metastases but, if unilateral, they occur more on the left side.47,48
On routine CT or MR imaging, the diagnostic features of adrenal metastases can be nonspe- cific. Metastases tend to be heterogeneous with irregular margins, particularly when large. Howev- er, small metastatic lesions may be homogeneous with smooth margins, mimicking benign lesions. 49 Therefore, further evaluation is often needed, especially in cancer patients with no other sites of metastases, given the significant impact on management. 50
Metastases typically have attenuation values of higher than 10 HU on unenhanced CT. They usually do not demonstrate significant enhancement washout on delayed phase, with absolute enhancement washout less than 60% and relative enhancement washout less than 40% (Fig. 9).1,38,51 One study suggested that any nonhemorrhagic, noncalcified adrenal lesion with an unenhanced CT attenuation 43 HU or greater should be suspicious for metastasis regardless of its contrast washout characteristics.51
On MR imaging, metastases usually exhibit low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, with het- erogeneous enhancement after administration of contrast material. Metastases typically do not demonstrate signal drop on OP compared to IP pulse sequences, with the exception of metasta- ses containing intracytoplasmic lipid (Fig. 10).52,53
Collision Tumors
Collision tumors are rare consisting of 2 adjacent but histologically different neoplasms
in the same mass without significant histologic admixture.54 The most frequent adrenal collision tumor comprises an adrenal adenoma and a mye- lolipoma.55 Although rare, metastases can occur adjacent to or in an existing adrenal adenoma. In this setting, collision tumor is suspected if there are new findings suggestive of metastatic dis- ease, including an increase in size or develop- ment of a new component (Fig. 11), together with heterogeneous signal drop on OP images. 36,55
On CT, an adrenal adenoma complicated by hemorrhage may mimic collision tumor. MR im- aging and PET-CT can improve the accuracy of identification of collision tumors’ components, thereby avoiding unnecessary biopsy.54 On MR imaging, the internal component is either a hema- toma with characteristic nonenhancing blood products (in case of adrenal adenoma compli- cated by hemorrhage), or an enhancing metasta- tic component on top of the adenoma (collision tumor). On PET-CT, the hemorrhagic component of adenomas typically demonstrates no FDG up- take, so it can be distinguished from metastasis. 56,57
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There are case reports of extremely rare types of collision tumors, including adenoma and pheo- chromocytoma or hemangioma, adrenocortical carcinoma and myelolipoma, or metastases in addition to myelolipoma and lymphoma.58-60
Lymphoma
Although rare, lymphoma involving the adrenal gland is more frequently non-Hodgkin lymphoma than Hodgkin lymphoma. Primary adrenal lym- phoma is rare, whereas secondary adrenal lym- phoma is more common and is frequently associated with other sites of disease, such as the ipsilateral kidney and retroperitoneal lymph nodes. Bilateral adrenal involvement is seen in 50% of patients. 60,61
Lymphomatous involvement of the adrenal gland may manifest as extensive retroperitoneal disease owing to total engulfment of the adrenal gland, focal discrete masses, or diffuse
enlargement of the gland.42 Occasionally, in the early course of the diffuse infiltrative form, the glands maintain their adreniform configuration and mimic adrenal hyperplasia.2
The imaging characteristics of adrenal lym- phoma are nonspecific. On CT, lymphoma mani- fests as homogeneous masses (Fig. 12) with washout characteristics similar to those of other malignancies.62,63 In untreated lymphoma, calcifi- cation is uncommon.64 Lymphoma demonstrates low signal intensity on T1-weighted imaging and heterogeneous high signal intensity on T2- weighted imaging, with mild progressive enhance- ment after intravenous contrast administration (see Fig. 11).65 Distinguishing adrenal lymphoma from metastases based on imaging alone is not possible.66 Because of its high cellularity, adrenal lymphoma tends to show diffusion restriction. It also tends to be intensely FDG avid.67 The degree of FDG uptake in adrenal lymphoma is similar to that of other involved sites.2
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Myelolipoma
The most common fat cells-containing adrenal mass is myelolipoma, an uncommon benign tumor composed of fatty tissue and hematopoietic tissue that histologically resembles bone marrow.35 The quantity of fat cells is variable and can be minimal or nearly 100%.43 Calcification is identified in approximately 20% of adrenal myelolipomas.68 The overwhelming majority of these masses are asymptomatic. Rarely, large masses cause pain by inducing spontaneous hemorrhage (owing to the myeloid component), necrosis, or mass ef- fect.43,50 For this reason, surgical excision is rec- ommended for lesions greater than 7 cm in greatest dimension.69 On CT, the presence of negative-attenuation fat (-20 to -100 HU) in the lesion is virtually diagnostic of myelolipoma (Fig. 13).7 On MR imaging, fat cells are demon- strated as high signal intensity on non-fat-sup- pressed T1- and T2-weighted images, with signal loss on fat suppression images (Fig. 14).
Using CS-MR imaging, voxels containing both fat and water tissue demonstrate lower signal in- tensity on OP than on IP imaging, leading to India ink artifact at the interface of the fatty components with nonfatty components. 43
Adrenal lipoma, adrenocortical carcinoma with lipomatous metaplasia, pheochromocytoma, and adrenal teratoma are very rare adrenal lesions
that are also reported to demonstrate gross fat cells and may mimic myelolipoma. 36
In cases of long-standing or improperly treated congenital adrenal hyperplasia, prolonged stimu- lation of the adrenal cortex by elevated ACTH levels may lead to the characteristic appearance of multiple bilateral adrenal masses with substan- tial fat cells.70
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Cystic Adrenal Masses
Adrenal cysts
There are 4 pathologic subtypes of adrenal cysts: vascular or endothelial cysts, pseudocysts, epithelial cysts, and parasitic cysts.36 Endothelial cysts, also known as simple cysts, are the most common subtype (45%).71 Endothelial cysts include 2 subtypes: lymphangiomatous (42%) and hemangiomatous cysts (3%).72
Simple adrenal cysts are well-defined homoge- neous masses with thin walls. They demonstrate fluid attenuation (0-20 HU) on noncontrast CT and thus may be misinterpreted as a lipid-rich ad- enoma.73 On MR imaging, their signal is similar to that of fluid, hypointense on T1-weighted images and hyperintense on T2-weighted images. Simple cysts should not demonstrate soft tissue components or internal enhancement on postcon- trast CT and MR imaging (Fig. 15).
Adrenal pseudocysts typically arise secondary to sequela of a prior episode of hemorrhage; they do not have an epithelial lining and their wall is composed of fibrous tissue.65 Adrenal pseudo- cysts have a complex appearance on imaging. They may demonstrate high internal density on CT or blood signal intensity on MR imaging sec- ondary to hemorrhage or hyalinized thrombus, together with thick walls and internal septations. The presence of peripheral curvilinear calcification is characteristic of an adrenal pseudocyst (Fig. 16).74 Given its high sensitivity in detailing the hemorrhagic components and internal septa, MR is superior to other imaging modalities for the identification of adrenal pseudocysts, yet pe- ripheral calcification is best identified on CT.
Parasitic cysts represent 7% of adrenal cysts. For the most part, they occur secondary to echino- coccal infection. The imaging appearance depends on the stage of the infection; it varies from simple
looking cyst to complex multicystic mass with inter- nal septa. They also can have septal or mural calci- fication. The presence of daughter cysts in the lumen is characteristic on CT and MR images. Iso- lated adrenal involvement is extremely rare; the presence of extraadrenal disease is essential to make a proper diagnosis of adrenal hydatid cyst.75
Epithelial cysts comprise 9% of adrenal cysts. They lack specific diagnostic features, making them difficult to distinguish from other adrenal cystic lesions. 76
Occasionally, some adrenal tumors, including pheochromocytoma, adrenocortical carcinoma, metastases, and hemangioma, may go through cystic degeneration and seem to be cystic. Imag- ing findings that suggest an underlying tumor include an irregular thick wall or nodular septal or mural enhancement.71
Of benign cysts, 60% show interval increases in size over time. This should not be interpreted erro- neously as a sign of an underlying malignancy or a complication when identified as an isolated finding.73
Lymphangioma
Cystic lymphangioma of the adrenal gland is both extremely rare and asymptomatic. A multilocular cyst with thin septa and CT attenuation of simple fluid is most suggestive of a lymphangioma.36 On MR imaging, adrenal lymphangiomas can be visu- alized as thin-walled cystic lesions with low signal intensity in T1-weighted imaging and high signal intensity in T2-weighted images without significant postcontrast enhancement.77
Pheochromocytoma
Pheochromocytoma is an adrenal medullary para- ganglioma arising from chromaffin cells, the predominant cells in the adrenal medulla. Extraa- drenal paragangliomas can occur anywhere from
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the skull base to the pelvis along the sympathetic chain.35
Pheochromocytomas follow the rule of 10s; 10% are bilateral, malignant, extraadrenal, and occur in children.35 Pheochromocytomas can be associated with various syndromes, including mul- tiple endocrine neoplasia type 2, von Hippel- Lindau disease (Fig. 17), neurofibromatosis type 1, Sturge-Weber syndrome, tuberous sclerosis, and familial paraganglioma syndrome.78 Approxi- mately 10% of pheochromocytomas are asymp- tomatic. Most patients present with headache, flushing, and palpitations.79 Patients typically have elevated plasma-free metanephrines, 24- hour levels of urinary metanephrines, or vanillyl- mandelic acid.35
Pheochromocytomas are typically larger than adenomas, yet smaller than adrenocortical carci- nomas.39 Nonfunctioning pheochromocytomas are larger than functioning lesions at presenta- tion.80 The CT appearance of pheochromocy- tomas is nonspecific and usually overlaps with
that of other adrenal masses. Small masses are typically homogeneous, yet larger masses are usually heterogeneous and may show areas of hemorrhage or necrosis.5º After intravenous
contrast administration, most pheochromocy- tomas demonstrate intense enhancement. The washout characteristics of pheochromocytomas are variable. They typically demonstrate washout values similar to malignant lesions, regardless of whether they are benign or malignant.39 Howev- er, some pheochromocytomas demonstrate sig- nificant washout values overlapping with adenoma. 80,81
On MR imaging, most pheochromocytomas demonstrate high signal intensity on T2-weighted images, which was classically described as a “light bulb” and regarded as characteristic for pheo- chromocytoma (Fig. 18). However, recent studies found that 30% of pheochromocytomas demon- strate intermediate to low signal on T2-weighted images or are inhomogeneous secondary to hem- orrhagic, cystic, or myxoid degeneration (Fig. 19).2
Cystic pheochromocytomas are usually large, typically demonstrating a thick enhancing wall with or without septae (see Fig. 19). Some of these tumors are nonfunctioning, with negative biochemical findings.82 Less than 10% of pheo- chromocytomas show calcification. Very rarely, pheochromocytomas contain intracytoplasmic fat, with inconsistent signal drop on OP images,
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potentially mimicking adenoma.80,83 Conversely, adrenal adenoma typically demonstrates uniform and substantial signal drop. Extensive fatty degen- eration in pheochromocytoma can occur rarely and may lead to a large amount of fat cells, which may mimic features of myelolipoma. 37
Despite the variable imaging appearances of pheochromocytoma, an avidly enhancing mass (3-5 cm in size) with high signal intensity on T2-weighted images and no signal drop on CS-MR imaging is highly suspicious for pheochro- mocytoma. The presence of local invasion into adjacent structures as well as distant metastases are the only reliable imaging findings for the diag- nosis of malignant pheochromocytoma. 35
Metaiodobenzylguanidine (MIBG) can be useful in the diagnosis of pheochromocytoma. MIBG is particularly helpful in exclusion of bilateral, multi- focal, or metastatic disease as well as postopera- tive recurrence.84,85
Adrenocortical carcinoma
Adrenocortical carcinoma is a rare tumor that arises from the adrenal cortex. It shows bimodal age distribution, mainly occurring in children aged 10 years and younger and in adults in their fourth and fifth decades. Approximately 60% of adrenocortical carcinomas are functioning; the functioning form is more common in children than adults.86,87 Patients often present with Cush- ing syndrome, virilization, or a combination of both. Feminization and Conn syndrome are much less common. 87,8
Adrenocortical carcinoma is typically large at presentation, with tumor size greater than 6 cm in greatest dimension. This tumor typically demon- strates heterogeneous appearance on CT and MR
imaging because of the presence of central necro- sis and hemorrhage (Fig. 20), although smaller le- sions may be homogeneous. Calcification is found in 30% of cases.88 Adrenocortical carcinomas enhance heterogeneously, and CT washout values are similar to those of other malignant adrenal le- sions (see Fig. 20).39 The large tumor size and het- erogeneity are the most useful features for the diagnosis of these tumors.7 Very rarely, adreno- cortical carcinomas undergo fatty degeneration, producing small foci of intracytoplasmic lipid or fat cells.89 Vascular invasion of large adrenocor- tical carcinomas into the inferior vena cava and renal vein is common, particularly in right-sided tu- mors.5º Metastases are found frequently at
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presentation. The most common sites of metasta- ses are the liver, lungs, bones, and regional lymph nodes. 86,88
Bilateral Adrenal Lesions
The main differential diagnosis for bilateral adrenal masses includes metastases, lymphoma, granulo- matous disease, and hemorrhage, in addition to any other adrenal pathology occurring bilaterally, including adenoma and pheochromocytoma (which is bilateral in 10% of cases). In cortical hy- perplasia, adrenal glands can also be diffusely thickened while maintaining their shape, either in a smooth or nodular fashion.
Adrenal cortical hyperplasia
Adrenal cortical hyperplasia is found in patients with Cushing syndrome and, less commonly, in patients with Conn syndrome. It can be ACTH dependent when induced by stimulation of the ad- renal cortex by ACTH secreted by a pituitary ade- noma (Fig. 21) or a rare ectopic tumor such as bronchogenic carcinomas.90,91 On rare occasions, ACTH-independent adrenal cortical hyperplasia can result from macronodular hyperplasia with marked adrenal nodularity, also known as ACTH- independent macronodular adrenal hyperplasia (Fig. 22), which can lead to distortion and marked nodular thickening of the glands.92 Another cause is primary pigmented nodular adrenocortical dis- ease, in which the adrenal glands are of normal size or slightly enlarged and show small pigmented nodules, with atrophic intervening cortex. 69
On imaging, adrenal cortical hyperplasia typi- cally appears as smooth to slightly lobular uniform gland enlargement that maintains an adreniform configuration.90,93 Nodular hyperplasia is identi- fied only if associated with macronodules. These
macronodules appear as small hypodense-to- isodense nodules with atrophic or normal inter- vening adrenal tissue. 36
Using a thickness cutoff of 5 mm, CT is shown to have sensitivity and specificity of 47% and 100%, respectively for diagnosis. Using a 3-mm thick- ness cutoff, better sensitivity (100%) but lower specificity (54%) has been reported.94
The attenuation and signal intensity of adrenal cortical hyperplasia are usually similar to that of the normal gland. In a small percentage of cases, however, the precontrast CT attenuation may be lower. Likewise, the signal intensity may also be lower on the OP compared with IP pulse
sequence, especially in patients with adenoma- tous cortical nodules. 95
Adrenal hemorrhage
Adrenal hemorrhage can result from both trau- matic and nontraumatic causes, with trauma ac- counting for 80% of cases. Adrenal hemorrhage is frequently caused by blunt trauma and is usually associated with multiple simultaneous organ in- juries.96 It is usually unilateral (80%) and is more frequently located on the right side. In children, ad- renal hemorrhage is sometimes observed in cases of nonaccidental injuries.97 Nontraumatic adrenal hemorrhage is typically bilateral and associated with causes such as stress (eg, recent surgery, sepsis, organ failure, pregnancy); coagulopathy, including use of an anticoagulant; venous hyper- tension from adrenal vein or inferior vena cava thrombosis; or hemorrhagic tumor (myelolipoma or, less frequently, adenoma, metastasis, adreno- cortical carcinoma, or hemangioma).98 In rare cases, bilateral adrenal hemorrhage leads to adre- nal insufficiency (Addison disease).99
In the mildest form of acute adrenal hemor- rhage, the gland maintains its adreniform configu- ration, showing a “tram track” appearance (ie, preserved peripheral enhancement and central hypodensity) together with periadrenal infiltra- tion.98,100 As bleeding continues, the adrenal gland enlarges, giving the appearance of a mass. CT demonstrates an oval or rounded adrenal mass with an attenuation value greater than simple fluid (ranging from 50-90 HU) (Fig. 23).98 The size and CT density of the adrenal hemorrhage de- creases gradually over time, and the majority of cases resolve completely and become undetect- able. Chronic hematomas may, however, liquefy and persist as an adrenal pseudocyst or calcifica- tion (see Fig. 16).50,101
MR imaging is the most sensitive and specific modality for diagnosing adrenal hemorrhage. The MR imaging features vary according to the duration of the hematoma.65 In the acute stage (<7 days), deoxyhemoglobin is isointense to slightly hypointense on T1-weighted images and has low signal intensity on T2-weighted im- ages. In the subacute stage (1-7 weeks), methe- moglobin is hyperintense on T1-weighted images. Initially, methemoglobin is intracellular and has low signal intensity on T2-weighted im- ages. With red cell lysis, the methemoglobin be- comes extracellular and has high signal intensity on T2-weighted images. In the chronic stage (>7 weeks), the hemorrhage has low signal inten- sity on both T1-weighted and T2-weighted im- ages because of the presence of hemosiderin, which demonstrates “blooming” on gradient echo sequences.
The presence of an underlying hemorrhagic ad- renal tumor should be excluded in patients with no risk factor for hemorrhage. Further imaging with contrast-enhanced CT or MR imaging using a subtraction technique is useful to assess for an enhancing underlying tumor.35 If a hemorrhage is confirmed, follow-up imaging should be indi- cated to ensure its decrease in size and resolution.36
Hemangioma
Adrenal hemangioma is an extremely rare benign tumor. These tumors are highly vascular, consist- ing of 2 main types: cavernous and, less frequently, capillary hemangioma. Because of their clinically silent course, they are often very large at presentation. 43
Characteristic features of hemangiomas include phleboliths and persistent peripheral nodular enhancement either with or without delayed
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central filling.100 Dystrophic calcification may be present in areas of previous hemorrhage. 36
On MR imaging, hemangiomas are typically hyperintense on T2-weighted images and hypoin- tense on T1-weighted images. However, they may show central areas of high T1-weighted imaging signal owing to hemorrhage.93,100 Hemangiomas may be difficult to differentiate from malignant le- sions, and a correct diagnosis may be reached only after image-guided biopsy or surgical resection.36
Adrenal Masses of Neural Crest Origin
These adrenal tumors are derived from the primor- dial neural crest cells that form the sympathetic nervous system. They range from malignant (neu- roblastoma) to benign (ganglioneuroma); ganglio- neuroblastoma is of intermediate malignant potential.
Neuroblastoma
Neuroblastoma is a malignant tumor composed of primitive neuroblasts. The adrenal gland is the most common site of primary neuroblastoma, ac- counting for 35% to 40% of cases.102 These tu- mors are typically found in infants and very young children (mean presentation age, 22 months), and 95% of cases are detected in chil- dren younger than 10 years.103 Neuroblastoma can metastasize to the bones, liver, lymph nodes, and skin. Seventy percent of cases have metasta- tic disease upon presentation. 104
On CT, neuroblastoma appears as a large, irreg- ular, heterogenous mass with areas of necrosis or hemorrhage. Coarse amorphous calcification is present in 80% to 90% of cases (Fig. 24).105
Encasement and narrowing of adjacent vessels may occur. In aggressive tumors, there can be direct invasion of local soft tissues and organs. 106 Neuroblastoma usually demonstrates heteroge- neous low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, with variable and heterogeneous enhancement. Cystic changes demonstrate high signal intensity on T2-weighted images with areas of T1-hyperintense hemorrhage. 106 Gahr and col- leagues107 suggested that DWI is effective for the differentiation of neuroblastoma, ganglioneuro- blastoma and ganglioneuroma. They found that the ADC values of ganglioneuroma and ganglio- neuroblastoma are significantly higher than those of neuroblastomas. No ganglioneuroma or gan- glioneuroblastoma had an ADC value of less than 1.1 x 10-3mm2/s.
Ganglioneuroma
Ganglioneuroma is a rare benign neoplasm composed of Schwann cells and ganglion cells. These tumors grow slowly and are often discov- ered incidentally. They have a good prognosis af- ter surgical resection.104 They are most often seen in young adults; 60% of patients are younger than 20 years at the time of diagnosis. These tu- mors are more common in the posterior medias- tinum and retroperitoneum than in the adrenal gland (20%-30% of cases). 76
Adrenal ganglioneuroma is typically seen as a well-circumscribed, mildly enhancing, lobulated, hypodense mass on CT. Areas of necrosis and hemorrhage have been described. Twenty percent to 30% of cases show discrete punctate calcifica- tions. 106 On MR imaging, ganglioneuroma typically demonstrates homogenous low signal intensity on T1-weighted images and mildly to moderately high signal intensity on T2-weighted images, depend- ing on its content of myxoid stroma (Fig. 25). 104 A whorled appearance of T2 hyperintensity has been described owing to interlacing bundles of longitudinal and transverse Schwann cells or collagen fibers.108 Contrast-enhanced CT and MR imaging typically demonstrate slight enhance- ment with progressive enhancement on delayed phase. 109
Ganglioneuroblastoma
Ganglioneuroblastoma is an intermediate-grade tumor composed of mature ganglion cells and primitive neuroblasts. Ganglioneuroblastoma typi- cally occurs in the pediatric population, with a mean presentation age of 2 to 4 years, and a rare incidence in individuals older than 10 years. 110 Ganglioneuroblastomas are generally smaller and more well-defined than neuroblastoma at
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diagnosis.111 Imaging appearance vary and can be predominantly solid or cystic.108 These tumors usually demonstrate intermediate signal intensity on T1-weighted images and heterogeneously high signal intensity on T2-weighted images, with heterogeneous moderate contrast enhancement. 112
Adrenal Calcification
Adrenal calcification can be observed in a variety of lesions, including adrenal cyst, adenoma,
adrenocortical carcinoma, myelolipoma, pheo- chromocytoma, adrenal hemorrhage, and chronic granulomatous diseases. Calcification in an adre- nal mass is overall nonspecific. Ancillary CT find- ings may help to indicate an underlying etiology of calcification. For example, diffuse bilateral calcification in normal-sized or atrophic glands is suggestive of an old hemorrhage or granuloma- tous infection. The pattern of calcification can be helpful, as in the case of adrenal pseudocyst, which demonstrates peripheral curvilinear calcifi- cation. To narrow the differential diagnosis, the
pattern of calcification in an adrenal mass must be correlated with other imaging features such as size, homogeneity, enhancement pattern, and margins. 113
Tuberculosis and histoplasmosis are granulo- matous diseases that can affect adrenal glands. In the early acute stages of granulomatous dis- eases, bilateral enlargement, with or without con- tour preservation, can be seen. After intravenous administration of contrast, peripheral marginal enhancement with a nonenhancing necrotic center can be noted.114 Chronic infection is characterized typically by calcification, which may be associated with significant gland destruction and subsequent adrenal insufficiency (Addison disease). 42
Another cause of adrenal gland calcification is Wolman disease, a rare recessive autosomal inborn error of metabolism. It leads to fat accumu- lation in multiple organs such as the liver, spleen, lymph nodes, small bowel, and adrenal cortex. A characteristic of Wolman disease is the presence of dense punctuate calcifications in bilaterally enlarged adrenal glands that maintain adeniform shape. 111
Key Teaching Points and a Practical Approach to Diagnosis
· In imaging evaluation of adrenal mass, the most important utility is to differentiate be- tween adenomas and nonadenomatous adre- nal masses.
· CT washout technique is the most sensitive and specific for characterization of adrenal adenoma.
. Noncontrast attenuation less than 10 Houns- field units is most compatible with a lipid- rich adenoma.
· Absolute percentage washout of greater than or equal to 60%, and relative percentage washout of greater than or equal to 40% are highly sensitive and specific for lipid-poor adenoma.
· MR imaging is helpful in the setting of a het- erogeneous mass, or when there is contrain- dication of iodinated contrast medium (allergy or renal insufficiency).
· Chemical shift IP and OP pulse sequences are useful for diagnosing lipid-rich and most lipid- poor adenomas. It is limited at characterizing cases of lipid-poor adenomas with noncon- trast CT attenuation of greater than 30 HU.
· Various morphologic patterns can help to make a specific diagnosis, for example:
o Adrenal adenoma is the most common ad- renal mass containing intracytoplasmic lipid.
Rarely, metastases secondary to clear cell renal cell carcinoma and hepatocel- lular carcinoma can contain intracyto- plasmic lipid, thus can mimic adenoma on chemical shift MR imaging.
Simple cyst can also mimic adenoma on unenhanced CT.
o The presence of fat cells in an adrenal mass is consistent with myelolipoma.
Rarely, bilateral fatty masses can be seen in congenital adrenal hyperplasia
Very rarely, adrenocortical carcinoma contains fat cells.
· Adrenal mass with a simple fluid attenuation is consistent with a simple cyst.
o Complex features including calcification can be seen in pseudocysts. Pseudocyst can have heterogeneous complex features, thus may mimic malignancy.
· Avidly enhancing adrenal lesion with a high signal intensity of T2-weighted images raises the suspicion of pheochromocytoma. Biochemical evidence can be helpful in the majority of cases.
· Lesion with hemorrhagic CT density or MR im- aging signal intensity is suggestive of adrenal hemorrhage. However, in patients with no risk factor for nontraumatic hemorrhage, hemor- rhagic adrenal tumor has to be excluded (contrast-enhanced MR imaging with subtrac- tion technique and/or follow-up).
· Diffuse bilateral gland thickening with pre- served adreniform configuration, in patients with hypercortisolism (Cushing) is suggestive of adrenal hyperplasia. Other causes of diffuse gland enlargement include lymphoma, metastases or adrenal hemorrhage.
· Adrenal calcification can be seen in both benign and malignant lesions. Curvilinear calcification suggests an adrenal pseudocyst. Bilateral calcification in atrophic or normal sized adrenal glands is usually the sequela of previous hemorrhage or granulomatous infection.
SUMMARY
Proper imaging, combined with detailed clinical evaluation, provides robust assessment of adrenal pathologies. The small incidental adrenal nodules are overwhelmingly benign, making further evalua- tion and treatment often unnecessary. Some tu- mors such as lipid-rich adenoma and myelolipoma have characteristic features that can be diagnosed accurately, thus preventing further unnecessary workup. Many indeterminate lesions can be considered benign if stability for
greater than 1 year can be shown; if no prior im- ages are available and characteristics are indeter- minate, a 12-month follow-up evaluation is suggested. When imaging or clinical factors are more suspicious, additional noninvasive imaging such as FDG PET-CT can be a useful adjunct. Finally, when a lesion remains indeterminate, adre- nal biopsy may be considered; resection may be prudent when masses are greater than 4 cm because of the higher chance of malignancy.
REFERENCES
1. Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: characterization with combined unen- hanced and delayed enhanced CT. Radiology 2002;222(3):629-33.
2. Blake MA, Cronin CG, Boland GW. Adrenal imag- ing. AJR Am J Roentgenol 2010; 194(6): 1450-60.
3. Caoili EM, Korobkin M, Francis IR, et al. Delayed enhanced CT of lipid-poor adrenal adenomas. AJR Am J Roentgenol 2000; 175(5):1411-5.
4. Park BK, Kim CK, Kim B, et al. Comparison of de- layed enhanced CT and chemical shift MR for eval- uating hyperattenuating incidental adrenal masses. Radiology 2007;243(3):760-5.
5. Petersilka M, Bruder H, Krauss B, et al. Technical principles of dual source CT. Eur J Radiol 2008; 68(3):362-8.
6. Graser A, Johnson TR, Chandarana H, et al. Dual energy CT: preliminary observations and potential clinical applications in the abdomen. Eur Radiol 2009;19(1):13-23.
7. Korivi BR, Elsayes KM, de Castro SF, et al. An update of practical CT adrenal imaging: what physicians need to know. Curr Radiol Rep 2015; 3(4):1-11.
8. Coursey CA, Nelson RC, Boll DT, et al. Dual-energy multidetector CT: how does it work, what can it tell us, and when can we use it in abdominopelvic im- aging? Radiographics 2010;30(4):1037-55.
9. Gupta RT, Ho LM, Marin D, et al. Dual-energy CT for characterization of adrenal nodules: initial expe- rience. AJR Am J Roentgenol 2010;194(6): 1479-83.
10. Shi JW, Dai HZ, Shen L, et al. Dual-energy CT: clin- ical application in differentiating an adrenal ade- noma from a metastasis. Acta Radiol 2014;55(4): 505-12.
11. Qin HY, Sun HR, Li YJ, et al. Application of CT perfusion imaging to the histological differentiation of adrenal gland tumors. Eur J Radiol 2012;81(3): 502-7.
12. Qin HY, Sun H, Wang X, et al. Correlation between CT perfusion parameters and microvessel density and vascular endothelial growth factor in adrenal tumors. PLoS One 2013;8(11):e79911.
13. Fujiyoshi F, Nakajo M, Fukukura Y, et al. Character- ization of adrenal tumors by chemical shift fast low- angle shot MR imaging: comparison of four methods of quantitative evaluation. AJR Am J Roentgenol 2003; 180(6): 1649-57.
14. Sahdev A, Willatt J, Francis IR, et al. The indetermi- nate adrenal lesion. Cancer 2010;10:102-13.
15. Miller FH, Wang Y, McCarthy RJ, et al. Utility of diffusion-weighted MRI in characterization of adre- nal lesions. AJR Am J Roentgenol 2010;194(2): W179-85.
16. Israel GM, Korobkin M, Wang C, et al. Comparison of unenhanced CT and chemical shift MRI in evalu- ating lipid-rich adrenal adenomas. AJR Am J Roentgenol 2004;183(1):215-9.
17. 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(3):711-6.
18. Gabriel H, Pizzitola V, McComb EN, et al. Adrenal lesions with heterogeneous suppression on chem- ical shift imaging: clinical implications. J Magn Re- son Imaging 2004;19(3):308-16.
19. Sandrasegaran K, Patel AA, Ramaswamy R, et al. Characterization of adrenal masses with diffusion- weighted imaging. AJR Am J Roentgenol 2011; 197(1):132-8.
20. Morani AC, Elsayes KM, Liu PS, et al. Abdominal applications of diffusion-weighted magnetic reso- nance imaging: where do we stand. World J Radiol 2013;5(3):68-80.
21. El-Kalioubie M, Emad-Eldin S, Abdelaziz O. Diffu- sion-weighted MRI in adrenal lesions: a warranted adjunct? Egypt J Radiol Nucl Med 2016;47(2): 599-606.
22. Tsushima Y, Takahashi-Taketomi A, Endo K. Diag- nostic utility of diffusion-weighted MR imaging and apparent diffusion coefficient value for the diagnosis of adrenal tumors. J Magn Reson Imag- ing 2009;29(1):112-7.
23. Melo HJ, Goldman SM, Szejnfeld J, et al. Applica- tion of a protocol for magnetic resonance spectros- copy of adrenal glands: an experiment with over 100 cases. Radiol Bras 2014;47(6):333-41.
24. Faria JF, Goldman SM, Szejnfeld J, et al. Adrenal masses: characterization with in vivo proton MR spectroscopy-initial experience. Radiology 2007; 245(3):788-97.
25. Kim S, Salibi N, Hardie AD, et al. Characterization of adrenal pheochromocytoma using respiratory- triggered proton MR spectroscopy: initial experi- ence. AJR Am J Roentgenol 2009; 192(2):450-4.
26. Wong KK, Arabi M, Bou-Assaly W, et al. Evaluation of incidentally discovered adrenal masses with PET and PET/CT. Eur J Radiol 2012;81(3):441-50.
27. Boland GW, Dwamena BA, Jagtiani Sangwaiya M, et al. Characterization of adrenal masses by using
FDG PET: a systematic review and meta-analysis of diagnostic test performance. Radiology 2011; 259(1):117-26.
28. Metser U, Miller E, Lerman H, et al. 18F-FDG PET/ CT in the evaluation of adrenal masses. J Nucl Med 2006;47(1):32-7.
29. Brady MJ, Thomas J, Wong TZ, et al. Adrenal nod- ules at FDG PET/CT in patients known to have or suspected of having lung cancer: a proposal for an efficient diagnostic algorithm. Radiology 2009; 250(2):523-30.
30. Vikram R, Yeung HD, Macapinlac HA, et al. Utility of PET/CT in differentiating benign from malignant adrenal nodules in patients with cancer. AJR Am J Roentgenol 2008; 191(5): 1545-51.
31. Kunikowska J, Matyskiel R, Toutounchi S, et al. What parameters from 18F-FDG PET/CT are useful in evaluation of adrenal lesions? Eur J Nucl Med Mol Imaging 2014;41(12):2273-80.
32. Chong S, Lee KS, Kim HY, et al. Integrated PET-CT for the characterization of adrenal gland lesions in cancer patients: diagnostic efficacy and interpreta- tion pitfalls. Radiographics 2006;26(6):1811-24 [discussion: 1824-16].
33. Jana S, Zhang T, Milstein DM, et al. FDG-PET and CT characterization of adrenal lesions in can- cer patients. Eur J Nucl Med Mol Imaging 2006; 33(1):29-35.
34. Reznek RH, Armstrong P. The adrenal gland. Clin Endocrinol (Oxf) 1994;40(5):561-76.
35. Taffel M, Haji-Momenian S, Nikolaidis P, et al. Adre- nal imaging: a comprehensive review. Radiol Clin North Am 2012;50(2):219-43.
36. Lattin GE Jr, Sturgill ED, Tujo CA, et al. From the radiologic pathology archives: adrenal tumors and tumor-like conditions in the adult: radiologic- pathologic correlation. Radiographics 2014;34(3): 805-29.
37. Adam SZ, Nikolaidis P, Horowitz JM, et al. Chemi- cal shift MR imaging of the adrenal gland: princi- ples, pitfalls, and applications. Radiographics 2016;36(2):414-32.
38. Korobkin M, Giordano TJ, Brodeur FJ, et al. Adre- nal adenomas: relationship between histologic lipid and CT and MR findings. Radiology 1996;200(3): 743-7.
39. Szolar DH, Korobkin M, Reittner P, et al. Adrenocor- tical carcinomas and adrenal pheochromocy- tomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT. Radiology 2005; 234(2):479-85.
40. Boland GW, Lee MJ, Gazelle GS, et al. Character- ization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roent- genol 1998;171(1):201-4.
41. Johnson PT, Horton KM, Fishman EK. Adrenal im- aging with multidetector CT: evidence-based
protocol optimization and interpretative practice. Radiographics 2009;29(5): 1319-31.
42. Mayo-Smith WW, Boland GW, Noto RB, et al. State- of-the-art adrenal imaging. Radiographics 2001; 21(4):995-1012.
43. Boland GW, Blake MA, Hahn PF, et al. Incidental adrenal lesions: principles, techniques, and algo- rithms for imaging characterization. Radiology 2008;249(3):756-75.
44. Papotti M, Sapino A, Mazza E, et al. Lipomatous changes in adrenocortical adenomas: report of two cases. Endocr Pathol 1996;7(3):223-8.
45. Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J En- docrinol 2003; 149(4):273-85.
46. DeAtkine AB, Dunnick NR. The adrenal glands. Semin Oncol 1991;18(2):131-9.
47. Lee JE, Evans DB, Hickey RC, et al. Unknown pri- mary cancer presenting as an adrenal mass: fre- quency and implications for diagnostic evaluation of adrenal incidentalomas. Surgery 1998;124(6): 1115-22.
48. Lam KY, Lo CY. Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospi- tal. Clin Endocrinol (Oxf) 2002;56(1):95-101.
49. Song JH, Grand DJ, Beland MD, et al. Morphologic features of 211 adrenal masses at initial contrast- enhanced CT: can we differentiate benign from ma- lignant lesions using imaging features alone? AJR Am J Roentgenol 2013;201(6):1248-53.
50. Song JH, Mayo-Smith WW. Current status of imag- ing for adrenal gland tumors. Surg Oncol Clin N Am 2014;23(4):847-61.
51. Blake MA, Kalra MK, Sweeney AT, et al. Distin- guishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay. Radiology 2006;238(2):578-85.
52. Namimoto T, Yamashita Y, Mitsuzaki K, et al. Adrenal masses: quantification of fat content with double- echo chemical shift in-phase and opposed-phase FLASH MR images for differentiation of adrenal ade- nomas. Radiology 2001;218(3):642-6.
53. Korobkin M, Lombardi TJ, Aisen AM, et al. Charac- terization of adrenal masses with chemical shift and gadolinium-enhanced MR imaging. Radiology 1995; 197(2):411-8.
54. Otal P, Escourrou G, Mazerolles C, et al. Imaging features of uncommon adrenal masses with histo- pathologic correlation. Radiographics 1999;19(3): 569-81.
55. Schwartz LH, Macari M, Huvos AG, et al. Collision tumors of the adrenal gland: demonstration and characterization at MR imaging. Radiology 1996; 201(3):757-60.
56. Katabathina VS, Flaherty E, Kaza R, et al. Adrenal collision tumors and their mimics: multimodality im- aging findings. Cancer 2013;13(4):602-10.
57. Tappouni R, DeJohn L. AJR teaching file: enlarging adrenal mass previously characterized as an ade- noma. AJR Am J Roentgenol 2009; 192(6 Suppl): S125-7.
58. Anderson SB, Webb MD, Banks KP. Adrenal colli- sion tumor diagnosed by F-18 fluorodeoxyglucose PET/CT. Clin Nucl Med 2010;35(6):414-7.
59. Bertolini F, Rossi G, Fiocchi F, et al. Primary adrenal gland carcinosarcoma associated with metastatic rectal cancer: a hitherto unreported collision tumor. Tumori 2011;97(5):27e-30e.
60. Hagspiel KD. Manifestation of Hodgkin’s lym- phoma in an adrenal myelolipoma. Eur Radiol 2005; 15(8):1757-9.
61. Glazer HS, Lee JK, Balfe DM, et al. Non-Hodgkin lymphoma: computed tomographic demonstration of unusual extranodal involvement. Radiology 1983;149(1):211-7.
62. Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007; 356(6):601-10.
63. Sohaib SA, Reznek RH. Adrenal imaging. BJU Int 2000;86(Suppl 1):95-110.
64. Zhou L, Peng W, Wang C, et al. Primary adrenal lymphoma: radiological; pathological, clinical cor- relation. Eur J Radiol 2012;81(3):401-5.
65. Elsayes KM, Mukundan G, Narra VR, et al. Adrenal masses: MR imaging features with pathologic cor- relation. Radiographics 2004;24(Suppl 1):S73-86.
66. Rashidi A, Fisher SI. Primary adrenal lymphoma: a systematic review. Ann Hematol 2013;92(12): 1583-93.
67. Kumar R, Xiu Y, Mavi A, et al. FDG-PET imaging in primary bilateral adrenal lymphoma: a case report and review of the literature. Clin Nucl Med 2005; 30(4):222-30.
68. Rao P, Kenney PJ, Wagner BJ, et al. Imaging and pathologic features of myelolipoma. Radiographics 1997;17(6):1373-85.
69. Lack EE. Tumors of the adrenal glands and extraa- drenal paraganglia. Atlas of tumor pathology. Wash- ington, DC: American Registry of Pathology; 2007.
70. Ioannidis O, Papaemmanouil S, Chatzopoulos S, et al. Giant bilateral symptomatic adrenal myeloli- pomas associated with congenital adrenal hyper- plasia. Pathol Oncol Res 2011;17(3):775-8.
71. Sanal HT, Kocaoglu M, Yildirim D, et al. Imaging features of benign adrenal cysts. Eur J Radiol 2006;60(3):465-9.
72. Foster DG. Adrenal cysts. Review of literature and report of case. Arch Surg 1966;92(1):131-43.
73. Ricci Z, Chernyak V, Hsu K, et al. Adrenal cysts: natural history by long-term imaging follow-up. AJR Am J Roentgenol 2013;201(5):1009-16.
74. Rozenblit A, Morehouse HT, Amis ES Jr. Cystic ad- renal lesions: CT features. Radiology 1996;201(2): 541-8.
75. Polat P, Kantarci M, Alper F, et al. Hydatid disease from head to toe. Radiographics 2003;23(2):475- 94 [quiz: 536-7].
76. Guo YK, Yang ZG, Li Y, et al. Uncommon adrenal masses: CT and MRI features with histopathologic correlation. Eur J Radiol 2007;62(3):359-70.
77. Touiti D, Deligne E, Cherras A, et al. Cystic lym- phangioma in the adrenal gland: a case report. Ann Urol (Paris) 2003;37(4):170-2 [in French].
78. Mittendorf EA, Evans DB, Lee JE, et al. Pheochro- mocytoma: advances in genetics, diagnosis, local- ization, and treatment. Hematol Oncol Clin North Am 2007;21(3):509-25, ix.
79. Johnson PT, Horton KM, Fishman EK. Adrenal mass imaging with multidetector CT: pathologic conditions, pearls, and pitfalls. Radiographics 2009;29(5):1333-51.
80. Blake MA, Krishnamoorthy SK, Boland GW, et al. Low-density pheochromocytoma on CT: a mimicker of adrenal adenoma. AJR Am J Roentgenol 2003; 181(6):1663-8.
81. Park BK, Kim B, Ko K, et al. Adrenal masses falsely diagnosed as adenomas on unenhanced and de- layed contrast-enhanced computed tomography: pathological correlation. Eur Radiol 2006;16(3): 642-7.
82. Andreoni C, Krebs RK, Bruna PC, et al. Cystic phaeochromocytoma is a distinctive subgroup with special clinical, imaging and histological fea- tures that might mislead the diagnosis. BJU Int 2008; 101(3):345-50.
83. Schieda N, Alrashed A, Flood TA, et al. Compari- son of quantitative MRI and CT washout analysis for differentiation of adrenal pheochromocytoma from adrenal adenoma. AJR Am J Roentgenol 2016;206(6):1141-8.
84. Maurea S, Klain M, Mainolfi C, et al. The diagnostic role of radionuclide imaging in evaluation of pa- tients with nonhypersecreting adrenal masses. J Nucl Med 2001;42(6):884-92.
85. Tenenbaum F, Lumbroso J, Schlumberger M, et al. Comparison of radiolabeled octreotide and meta- iodobenzylguanidine (MIBG) scintigraphy in malig- nant pheochromocytoma. J Nucl Med 1995;36(1): 1-6.
86. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003; 169(1):5-11.
87. Icard P, Goudet P, Charpenay C, et al. Adrenocor- tical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001;25(7):891-7.
88. Reznek RH, Narayanan P. Primary adrenal malig- nancy. In: Husband JE, Reznek RH, editors. Hus- band & Reznek’s imaging in oncology. 3rd edition. London (UK): Informa Healthcare; 2010. p. 280-98.
89. Schlund JF, Kenney PJ, Brown ED, et al. Adreno- cortical carcinoma: MR imaging appearance with current techniques. J Magn Reson Imaging 1995; 5(2):171-4.
90. Sohaib SA, Hanson JA, Newell-Price JD, et al. CT appearance of the adrenal glands in adrenocorti- cotrophic hormone-dependent Cushing’s syn- drome. AJR Am J Roentgenol 1999;172(4):997- 1002.
91. Doppman JL, Chrousos GP, Papanicolaou DA, et al. Adrenocorticotropin-independent macronod- ular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism. Radiology 2000;216(3):797-802.
92. Dobbie JW. Adrenocortical nodular hyperplasia: the ageing adrenal. J Pathol 1969;99(1):1-18.
93. Lockhart ME, Smith JK, Kenney PJ. Imaging of ad- renal masses. Eur J Radiol 2002;41(2):95-112.
94. Lingam RK, Sohaib SA, Vlahos I, et al. CT of pri- mary hyperaldosteronism (Conn’s syndrome): the value of measuring the adrenal gland. AJR Am J Roentgenol 2003; 181(3):843-9.
95. Lumachi F, Zucchetta P, Marzola MC, et al. Usefulness of CT scan, MRI and radiocholesterol scintigraphy for adrenal imaging in Cushing’s syndrome. Nucl Med Commun 2002;23(5): 469-73.
96. Rana AI, Kenney PJ, Lockhart ME, et al. Adrenal gland hematomas in trauma patients. Radiology 2004;230(3):669-75.
97. Nimkin K, Teeger S, Wallach MT, et al. Adrenal hemorrhage in abused children: imaging and post- mortem findings. AJR Am J Roentgenol 1994; 162(3):661-3.
98. Jordan E, Poder L, Courtier J, et al. Imaging of non- traumatic adrenal hemorrhage. AJR Am J Roent- genol 2012;199(1):W91-8.
99. Ten S, New M, Maclaren N. Clinical review 130: Ad- dison’s disease 2001. J Clin Endocrinol Metab 2001;86(7):2909-22.
100. Kawashima A, Sandler CM, Ernst RD, et al. Imag- ing of nontraumatic hemorrhage of the adrenal gland. Radiographics 1999;19(4):949-63.
101. Huelsen-Katz AM, Schouten BJ, Jardine DL, et al. Pictorial evolution of bilateral adrenal haemor- rhage. Intern Med J 2010;40(1):87-8.
102. Papaioannou G, McHugh K. Neuroblastoma in childhood: review and radiological findings. Can- cer 2005;5:116-27.
103. Brossard J, Bernstein ML, Lemieux B. Neuroblas- toma: an enigmatic disease. Br Med Bull 1996; 52(4):787-801.
104. Rha SE, Byun JY, Jung SE, et al. Neurogenic tu- mors in the abdomen: tumor types and imaging characteristics. Radiographics 2003;23(1):29-43.
105. Abramson SJ. Adrenal neoplasms in children. Ra- diol Clin North Am 1997;35(6):1415-53.
106. Lonergan GJ, Schwab CM, Suarez ES, et al. Neu- roblastoma, ganglioneuroblastoma, and ganglio- neuroma: radiologic-pathologic correlation. Radiographics 2002;22(4):911-34.
107. Gahr N, Darge K, Hahn G, et al. Diffusion-weighted MRI for differentiation of neuroblastoma and gan- glioneuroblastoma/ganglioneuroma. Eur J Radiol 2011;79(3):443-6.
108. Rajiah P, Sinha R, Cuevas C, et al. Imaging of un- common retroperitoneal masses. Radiographics 2011;31(4):949-76.
109. Scherer A, Niehues T, Engelbrecht V, et al. Imaging diagnosis of retroperitoneal ganglioneuroma in childhood. Pediatr Radiol 2001;31(2):106-10.
110. Yamanaka M, Saitoh F, Saitoh H, et al. Primary retroperitoneal ganglioneuroblastoma in an adult. Int J Urol 2001;8(3):130-2.
111. Westra SJ, Zaninovic AC, Hall TR, et al. Imaging of the adrenal gland in children. Radiographics 1994; 14(6):1323-40.
112. McLoughlin RF, Bilbey JH. Tumors of the adrenal gland: findings on CT and MR imaging. AJR Am J Roentgenol 1994;163(6): 1413-8.
113. Paterson A. Adrenal pathology in childhood: a spectrum of disease. Eur Radiol 2002;12(10): 2491-508.
114. Guo YK, Yang ZG, Li Y, et al. Addison’s disease due to adrenal tuberculosis: contrast-enhanced CT features and clinical duration correlation. Eur J Radiol 2007;62(1):126-31.