ELSEVIER
Imaging of Adrenocortical Carcinoma: An Update
B. Howard,* A. Elsayed,+ S. Klimkowski,* J. Lee,+ and K. Elsayes*
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Introduction
A drenocortical carcinoma (ACC) is a rare and aggressive malignancy, representing the most common primary cancer of the adrenal gland.1 The global incidence of ACC is estimated at 0.5-2 cases per million annually, with fewer than 200,000 cases diagnosed each year in the United States.2 Historically, ACC was thought to exhibit a bimodal age distribution, with incidence peaks occurring in early childhood and between ages 30 and 50.3,4 However, recent studies have shown that ACC cases now typically present between ages 50 and 70s.5,6 ACC is associated with poor out- comes with 5-year survival rates ranging from 35% to 58% with curability rates in early-stage disease around 30%.7-9
Clinical manifestations of ACC vary; approximately half of cases present with symptoms associated with hormonal excess, such as hypercortisolism and hyperandrogenism, 10-12 which can manifest as abdominal striae, menstrual irregulari- ties, hirsutism, virilization, and male pattern baldness.13-15 About one-third of patients exhibit nonspecific symptoms due to mass effect or invasion of nearby structures,11,12 while the remaining cases are often incidentally discovered during imaging conducted for unrelated conditions.16
When ACC is suspected, the diagnostic approach com- bines biochemical laboratory assessments with anatomical and functional imaging. The biochemical diagnosis of ACC typically involves measuring steroid hormone concentrations in plasma and urine, including the assessment of diurnal rhythm of hormone levels. 17 Initial imaging often includes contrast enhanced computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomogra- phy-CT (PET/CT). 18,19
Adrenal biopsy should only be reserved in patients with suspected metastatic disease. This procedure carries
risks such as bleeding and potential tumor seeding, which may advance tumor stage, necessitate additional therapy, and reduce survival. 20 In the case of pheochromocytoma, another potential complication of biopsy may be hemody- namic instability due to catecholamine secretion.21 Fur- thermore, a retrospective review of 75 ACC patients revealed that transabdominal biopsy for ACC has a maxi- mum sensitivity of only 70%.22 The decision to perform transabdominal biopsy must carefully weigh the risks and potential benefits.
Imaging plays an essential role in diagnosis, preoperative planning, and staging ACC.23 Here, we review the up-to-date multimodal imaging approach needed for the comprehensive evaluation of adrenal masses.
Imaging Techniques
The imaging evaluation of ACC relies on a multimodality approach to assess the tumor’s morphological characteris- tics, extent, and involvement of adjacent structures. The ability to image and characterize adrenal lesions has undergone many improvements due to technological improvements in CT, MRI, and nuclear medicine. Adrenal masses are often discovered incidentally during imaging and can be further characterized on CT or MRI. Fluoro- deoxyglucose (FDG) PET/CT offers additional biologic information that is very helpful in staging and trouble- shooting. 24-28
Contrast-enhanced CT or MRI are the standard imaging modalities for diagnosis, staging, and restaging of ACC. While contrast-enhanced CT is ideal for disease staging and assessment of metastatic spread, MRI is better suited for detecting intracellular lipid and characterizing poten- tial sites of metastatic disease.29 FDG PET/CT imaging can be helpful in characterizing indeterminate adrenal lesions. However, some benign lesions such as adrenal adenomas can be radiotracer avid and ultimately careful correlation with level of suspicion, other imaging modali- ties, patient history, and laboratory results is necessary. 30 Furthermore, this technique cannot differentiate ACC
*Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX.
+Department of Abdominal Imaging, The University of Kentucky College of Medicine, Lexington, KY.
Address reprint requests to Benjamin Howard, MD. E-mail: bmhoward@mdanderson.org
https://doi.org/10.1053/j.ro.2024.11.005
from metastases, lymphoma, or pheochromocytoma, which also demonstrate high metabolic activity.3
Ultrasonography
New techniques in abdominal ultrasonography, including harmonic imaging, spatial compound imaging, and 3-dimen- sional sonography, have improved visualization of adrenal masses. However, ultrasonography remains limited in visual- izing adrenal masses and in distinguishing benign from malignant lesions. 28,32-38 Adding contrast enhancement may improve its accuracy and provide a potentially cost-effective alternative to other modalities; investigation into this option is ongoing. 25,27,28,32-39
Several sonographic imaging features of ACC have been described. The typical imaging appearance of ACC is an often large, hypervascular, hypoechoic mass, usually round or sometimes oval-shaped, with heterogeneous echotexture and sometimes displaying a partial or complete echogenic rim. The echotexture depends on the size and the internal charac- teristics of the lesion, such as presence of hemorrhage or necrosis. Smaller lesions are often homogenous but become more heterogeneous as they grow. Calcifications can appear as internal echogenic foci with posterior shadowing. Color Doppler ultrasound may demonstrate intralesional hypervas- cularity and help better delineate mass effect on adjacent vas- cular structures. 28,40,41
CT
Adrenal masses are frequently evaluated using multi-phasic CT due to its superior spatial resolution, which is crucial for assessing anatomy and preoperative planning.41,42 CT fea- tures suggesting malignancy include size (greater than 4 cm), calcifications, heterogeneous enhancement, irregular mar- gins, central necrosis or hemorrhage, and invasion into adja- cent structures (Fig. 1). 4,42-45 Large size and heterogeneous enhancement are the most reliable features to suggest malignancy.43,46 The typical adrenal CT protocol involves obtaining images in precontrast, venous, and delayed phases, with an optional arterial phase.
Precontrast imaging is important for differentiating ACC from other adrenal masses. For example, the identification of macroscopic fat within a lesion may suggest an alternative diagnosis, such as myelolipoma (Fig. 2). Unlike ACC, most adenomas contain microscopic lipid, which demonstrates low attenuation values of less than 10 HU on precontrast CT. Adenomas do not typically exhibit macroscopic fat attenua- tion, with the rare exception of some atypical adenomas and myelolipomatous transformation (Fig. 3).42,47 Of note, when assessing precontrast attenuation and evaluating enhance- ment, it is important to center the region of interest in the lesion to avoid volume averaging and beam-hardening artifacts.42,48 The region of interest should also be large enough to cover at least 2/3 of the lesion’s cross-sectional area. 42,49,50
ACCs often exhibit intense enhancement following con- trast administration due to their neovascularity. Postcontrast
images are acquired in the portal venous phase 60 seconds after injection of intravenous contrast. 42 The venous phase is important in assessing enhancement patterns and facilitates delineation of the adrenal mass from the adjacent structures, a crucial step during staging with important surgical manage- ment implications. An optional arterial phase can be acquired around 25 seconds, which may help with operative planning and in distinguishing adenomas from pheochromocytoma or hypervascular metastases, such as from renal cell carcinoma.51
The delayed phase acquired at 10-15 minutes (with 15 minutes being the most common) is particularly useful for assessing washout characteristics of adrenal lesions. 42,49 The 2 ways of measuring washout are by calculating abso- lute percentage washout (APW) and relative percentage washout (RPW). APW includes precontrast lesion attenua- tion, and RPW can be calculated using dynamic images. The following formulas are in use today: APW = 100 x (VA - DA)/(VA-PCA) and RPW = 100 x (VA - DA)/VA, where VA = venous attenuation, DA = delayed attenuation, and PCA = precontrast attenuation.42,52 Benign adenomas typi- cally demonstrate rapid washout of contrast, whereas ACC, along with other malignant masses, tend to show slower washout.42 ACCs often exhibit absolute washout values of less than 60% and relative washout values of less than 40%.53 Importantly, the use of adrenal washout characteris- tics in differentiating benign adrenal adenomas from other adrenal lesions should be reserved for homogenous, well- circumscribed lesions, as heterogeneity, significant interval growth (Fig. 4), and lesion size often outweigh the signifi- cance of washout in distinguishing between benign and malignant masses. For heterogeneous nodules, the adrenal CT protocol performs poorly in accurately distinguishing adenomas from nonadenomas. 54 Assessment of washout is also limited in the setting of hypervascular metastases, as these can often demonstrate washout that falls in the benign adenoma range (> 60% absolute washout and > 40% rela- tive washout). 55
Calcifications in ACC are not uncommon and distin- guishing ACC from adrenal hemorrhage and atypical adre- nal adenomas-particularly those containing fat, hemorrhage, iron, or heterogeneous enhancement-can be challenging (Figs. 5 and 6).47,53,56 Irregular borders are more suggestive of malignancy, as is invasion into the peria- drenal fat or adjacent structures. 43 This invasion often necessitates careful evaluation of the surrounding vascular structures, including the inferior vena cava.42 ACCs are also known for their high propensity for metastasis at the time of initial imaging. Common sites of metastasis include regional and paraaortic lymph nodes (25%-46%), lungs (45-97%, liver (48%-96%), and bones (11%-33%).43,57 While a nonenhanced central attenuation less than 10 HU is highly specific for benign adenoma, central low attenua- tion can also be seen in metastases from fat-containing pri- mary malignancies such as renal cell carcinoma or hepatocellular carcinoma, which are typically larger, more heterogenous, irregular at the margins, and invasive com- pared to adrenal adenomas.55
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MRI
MRI serves as a useful tool in evaluation of adrenal lesions in part due to its superior contrast resolution compared to CT. The standard MRI protocol for adrenal lesions includes dual-echo T1-weighted, T2-weighted, and T1/T2-weighted sequences with fat suppression. ACC
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usually displays heterogeneous signals on both T1 and T2 due to often-present internal hemorrhage and necrosis. Focal areas of hemorrhage typically show intrinsic T1 hyperintensity (T1 shortening), whereas necrosis will show up as heterogenous regions of T2 hyperintensity (T2 prolongation). 40,43
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The presence of intralesional fat on MRI using chemical- shift imaging (CSI) and other fat-suppression techniques can be useful in differentiating adrenal masses. Myelolipoma can be confidently diagnosed and differentiated from other lesions when an adrenal mass is composed of at least 50%
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macroscopic fat.55 Rarely, ACC has been reported to contain both microscopic and macroscopic fat (Fig. 7). Additionally, lesions containing a small amount of intralesional macro- scopic fat (<10%) may represent myelolipomatous transfor- mation or metaplasia in other adrenal neoplasms.55,58 Thus,
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in cases of fat containing nonadenoma lesions radiologists need to consider other imaging features and clues to correctly characterize potential ACC lesions.
Gradient echo sequences, which take advantage of the chemical shift phenomenon, are crucial in the MRI evalu- ation of adrenal lesions and are useful in assessing intra- voxel microscopic lipid content typically present in benign adenomas. CSI can be used to diagnose benign adenomas with a high level of certainty and is more effec- tive than CT in diagnosing lipid-poor adenomas, particu- larly in cases with unenhanced central lesion attenuation of 10-20 HU. 59 In cases reliably diagnosed as adrenal adenomas on CSI or precontrast CT, the use of contrast with MRI may be avoided. Also, adrenal lesions on CSI can be assessed both qualitatively, via visual inspection, and quantitatively. Chemical shift can be quantified by calculating the adrenal-to-spleen ratio or, alternatively, the adrenal signal intensity index. The adrenal-to-spleen ratio is the ratio of lesion-to-spleen signal intensity calcu- lated on in-phase images divided by the signal intensity ratio on opposed-phase images. A ratio less than 0.71 suggests a lipid-rich adenoma. The adrenal signal inten- sity index is calculated as [(Slip - SIopp)/Slip)] × 100, where SIip and SIopp are signal intensities on in-phase and opposed-phase images, respectively. A value of more than 16.5% also suggests a lipid-rich adenoma. 49,59
Adrenal glands are a common site for metastases. On CSI, intracellular lipid is specific for benign adrenal adenomas, but as with CT, there is decreased specificity when assessing metastases from primary malignancies containing intracellu- lar fat, such as renal cell carcinoma (Fig. 8) or hepatocellular carcinoma. Ancillary MRI features, such as T2 signal and sig- nal heterogeneity, can help distinguish benign adenomas from metastases in these cases. Metastases will typically dem- onstrate T2 hyperintense signal and more signal heterogene- ity compared to adenomas.55 Diffusion-weighted MRI has not been shown to be of much value in differentiating ACC from other adrenal lesions due to conflicting results and overlapping apparent diffusion coefficients.60
PET
The comprehensive staging of ACC, which commonly uses the American Joint Committee on Cancer Manual, 8th edi- tion, or the European Network for the Study of Adrenal Tumors system, benefits from not only CT and MRI, but also PET (Fig. 9).23,61 While CT and MRI allow for local staging and evaluation of distant metastatic disease, PET is a useful adjunct in evaluating viable metastatic disease and monitoring treatment response. ACC is FDG-avid, and FDG PET/CT can help identify the primary tumor, metastases, and recurrent disease by detecting increased radiotracer activity. 24,62,63 FDG activity has also been correlated with mitotic rate and overall prognosis, with higher degree and amount of FDG uptake correlating with increased tumor burden and worse prognosis.24,62 Thus, FDG PET/CT is complementary to conventional CT and MRI in staging and restaging.62
F-18 FDG PET/CT can also be useful in distinguishing metastases from benign adrenal lesions in patients with nona- drenal primary malignancies. Adrenal metastases will generally demonstrate FDG uptake higher than that of liver background, whereas benign lesions may demonstrate FDG uptake lower than liver background, although this is not always reliable. As previously mentioned, benign adrenal lesions can demonstrate variable FDG activity on FDG PET/CT. The degree of FDG uptake has not been shown to differ between lipid-rich and lipid-poor adenomas. Also, FDG uptake is not specific to either metastases or ACC. Therefore, FDG PET/CT findings should be interpreted in combination with conventional imaging fea- tures and available clinical information.24
Imaging in the Post-Treatment Period
Currently, there is no curative treatment option for ACC and surgical resection is often the best option. Patients with unre- sectable stage IV ACC have a median survival of 3 months, and the overall 5-year survival rate of all patients with ACC is 38%. Recurrence and metastatic disease are common (35%-
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85%), even in those who undergo complete surgical resec- tion.43 Due to the high rate of recurrence, close follow-up with CT or MRI should be performed with or without accompanying PET. The surgical site should be scrutinized for local recurrence on imaging (Fig. 10). Systemic recur- rence will often occur in the liver, bone, and lungs, and care- ful evaluation of these structures on imaging should be performed.64 Treatment options for recurrence depend on multiple factors including site(s) of recurrence, previous
treatments, and individual patient considerations such as functional status. Although stage IV ACC is not considered curable, palliation of symptoms with systemic agents, sur- gery, and radiotherapy can sometimes lead to survival dura- tions of 5 years.65
Emerging Imaging Techniques
11C-metomidate PET has recently shown promise, demon- strating high sensitivity and specificity for adrenocortical tumors; however, it cannot distinguish between adenomas and ACC and is limited by its 20-minute half-life. 66,67
Contrast-enhanced ultrasonography (CEUS) may play a future role in imaging. Some have found that triphasic CEUS may detect malignancy with sensitivity approaching 100%, comparable to CT and MRI. On CEUS, early arterial or arte- rial contrast enhancement and washout were commonly seen in primary or secondary malignant lesions and less frequently in patients with benign adrenal masses. ACC will typically show early contrast enhancement and washout, particularly on delayed imaging.25,27 However, CEUS may not easily dif- ferentiate ACC from other hypervascular lesions, such as pheochromocytomas.68 Additionally, large pheochromocyto- mas may demonstrate imaging features that overlap with ACC, such as internal cystic changes.69 Large, atypical ade- nomas may also demonstrate overlapping imaging features with ACC or other malignant masses, making accurate diag- nosis even more challenging.
Dual-energy CT has also been investigated as a means of evaluating adrenal lesions and can generate various images, including virtual noncontrast (VNC), virtual monoenergetic, and material density images. Several studies have explored the use of VNC attenuation measurements for characterizing adrenal lesions on contrast-enhanced dual-energy CT. Find- ings indicate that VNC attenuation has limited reliability dur- ing the portal venous phase and lower sensitivity for diagnosing adenomas compared to unenhanced images.70-75 The efficacy of fat fraction and 2-material decomposition with fat-iodine pairs has also been investigated, with one study suggesting dual-energy material density analysis may diagnose adenomas with a sensitivity and specificity approaching 96% and 100% respectively.
Magnetic resonance spectroscopy evaluates proton resonance spectra, reflecting molecular environments within tissues. This technique may prove useful in characterizing adrenal masses based on associated spectral profiles. In magnetic resonance spectroscopy, choline-a metabolite involved in cell membrane synthesis and breakdown-can be used as a potential tumor marker, and citrate may serve as a reference metabolite. The choline/creatinine ratio is the most useful metabolite ratio for distinguishing adrenal metastases and carcinomas from benign lesions. A ratio of >1.2 has demonstrated 100% sensitivity and 98.2% specificity for distinguishing benign adrenal lesions, such as adenomas and pheochromocytomas, from malignant ones, including ACC and adrenal metastases.78,7
Radiomics and artificial intelligence may also play a role in differentiating ACC from benign adrenal lesions. Radiomics
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involves extracting many quantitative features from medical images using computational algorithms. Machine learning- based quantitative CT texture analysis may aid in distinguish- ing ACC from adrenal adenomas. In one study, a texture- based predictive model demonstrated an accuracy of 82% in differentiating ACC from adrenal adenomas, surpassing the accuracy of radiologists using conventional morphologic assessment. 40,80,81
Conclusion
Although CT remains the standard for assessing most cases of ACC, MRI and functional imaging techniques prove valuable in problem solving and complex or atypical cases. FDG PET/ CT can be particularly useful for monitoring treatment response and detecting metastases. The combined applica- tion of CT, MRI, and functional imaging with laboratory work-up provides a comprehensive approach for precise diagnosis and management of ACC.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
CRediT authorship contribution statement
B. Howard: Writing - review & editing, Writing - original draft, Investigation, Formal analysis, Conceptualization. A. Elsayed: Writing - original draft. S. Klimkowski: Writing - review & editing. J. Lee: Writing - review & editing. K. Elsayes: Supervision, Conceptualization.
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