Check for updates
Adrenal cortical carcinoma: pathology, genomics, prognosis, imaging features, and mimics with impact on management
Ayahallah A. Ahmed1 . Aaron J. Thomas2 . Dhakshina Moorthy Ganeshan1 . Katherine J. Blair1 . Chandana Lall3 . James T. Lee4 . Ali I. Morshid1 . Mouhammed A. Habra5 . Khaled M. Elsayes1
@ Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Most tumors are either metastatic or locally invasive at the time of diagnosis. Differentiation between ACC and other adrenal masses depends on clinical, biochemical, and imag- ing factors. This review will discuss the genetics, pathological, and imaging feature of ACC.
Keywords Adrenal cortical carcinoma . Adrenal tumors . Ki67 . Weiss score . CT adrenal protocol . MRI . Cushing syndrome
Introduction
Adrenocortical carcinoma (ACC) is a rare malignant tumor arising from the adrenal cortex (1). Approximately 60% of ACCs are functional, producing hormones with a wide range of clinical syndromes depending upon the hormones pro- duced [2]. Many ACCs are incidentally discovered during imaging studies obtained for other reasons [3]. ACCs can occasionally be linked to other endocrine malignances and familial cancer syndromes [4]. Patients with suspected ACC should thus undergo a complete adrenal biochemical panel as well as radiological evaluation [5].
Ayahallah A. Ahmed and Aaron J. Thomas contributed equally to this work.
☒ Khaled M. Elsayes kmelsayes@mdanderson.org
1 Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX 77030, USA
2 Department of Radiology, Baylor College of Medicine, Houston, TX, USA
3 Department of Radiology, University of Florida College of Medicine, Jacksonville, FL, USA
4 Department of Radiology, University of Kentucky, Lexington, Kentucky, USA
5 Departments of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Computed tomography (CT) and magnetic resonance imaging (MRI) are the most commonly used imaging modal- ities for the initial evaluation of adrenal masses. The use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) can help in tumor staging, detection of recur- rence, and differentiation of malignant from benign lesions on initial imaging. The initial accurate characterization of ACC based on imaging features and differentiating it from other entities is critical for guiding appropriate management [6].
Epidemiology
ACC is a rare, highly malignant tumor with a reported annual incidence of 1 cases per million in the united states according to the Surveillance, Epidemiology, and End Results-18 registry (SEER) database for ACC cases identi- fied from 1974 to 2014. [7]. The previous reported annual incidence was 0.5-2 cases per million [8]. Females are affected more commonly than males. The reported female- to-male ratio is 1.34:1, and most cases are unilateral. A bimodal age distribution has been described for ACC with one peak occurring in the first decade and a second peak later in the fifth decade of life. However, this bimodal pres- entation has been questioned with a recent study suggesting a predominantly unimodal distribution with a median age of diagnosis of 55 years [7].
Generally, the diagnosis of ACC is made in one of three scenarios. The majority of patients (40-60%) present with
signs of excess hormonal synthesis. About one-third present with abdominal pain and other local compressive symptoms related to tumor growth and invasion of surrounding struc- tures [9]. A rising number of cases are discovered inciden- tally (10-15%), but the probability that an incidentally dis- covered adrenal lesion is ACC remains relatively low [10]. The most common clinical presentation for functioning ACC is Cushing’s syndrome, characterized by symptoms related to excess corticosteroid synthesis including truncal obesity, diabetes, hypertension, easy bruising, and menstrual cycle irregularities [11-13]. In females, virilization resulting from excess androgens may accompany signs of excess cortisol. A small percentage of male patients, present with signs of estrogen excess, such as gynecomastia, breast tenderness, decreased libido, and testicular atrophy. Rarely do patients present with signs of isolated hyperaldosteronism such as hypertension and hypokalemia [11]. Systemic symptoms common with other malignancies, such as weight loss, night fever, and anorexia, can also be seen in ACC [14].
Pathological features of ACC
Differentiating ACC from adrenal adenomas based on his- tological criteria is not always straightforward, especially with needle biopsy specimens. At gross examination ACCs tend to be large, lobulated, and heterogeneous, with areas of hemorrhage and necrosis [6]. The Weiss criteria (Table 1 [15]) are the most commonly applied criteria in diagnosing ACC and differentiating it from adenoma [16]. The scoring system is based on nine pathological criteria, each of which is weighted equally (one point) when present on pathologi- cal specimens. The criteria are subdivided into three main categories:
1) Related to cell cytological features
2) Related to tumor architecture, and
3) Related to tumor invasion and infiltration.
| Cytological features | High nuclear grade (3 or 4 ) High Mitotic rate > 5 per 50 high power field Atypical mitosis |
| Tumor architecture | Clear cells ≤ 25% Necrosis Diffuse architecture ( > 1/3 of tumor) |
| Infiltration | Venous invasion Sinusoidal invasion Capsular invasion |
Note Each criterion is given a score of 1. A score ≥ 3 correlates with malignant behavior
Each category has three criteria. A score ≥ 3 favors ACC, and a score of 0-2 favors adenoma, although lesions scoring 2 may still be considered suspicious. [5]. A higher Weiss score correlates with more aggressive tumor behavior [15]. In addition to conventional ACC, there are other rare histopathological subtypes including oncocytic, myxoid, and sarcomatoid variants. Oncocytic ACC is composed of oncocytic cells, with a much lower prevalence of the genetic alterations and mutations detected in comparison with the conventional and myxoid subtype. Only a few cases of myxoid subtype are reported in the literature. The clinical presentation of myxoid variant is comparable to the conven- tional ACC, and these tumors are usually hormonally active. The last subtype is sarcomatoid ACC which is characterized by more aggressive behavior than the conventional subtype. Differentiating the subtype of ACC at histology can be very challenging [17, 18].
Genomics of ACC
Although the majority of ACCs develop sporadically, many cases arise in association with various familial cancer syn- dromes [Table 2 [19-23]] including Li-Fraumeni (Fig. 1), Beckwith-Wiedemann, and Lynch syndromes. Several genetic alterations have been noted to play an important role in the pathogenesis of ACC [24]. Most of the drivers for the pathogenesis of ACC are related to mutations or downregu- lation of tumor suppressor genes, overexpression of certain growth factors, chromosomal aberrations, and dysregulation of certain important signaling pathways [25].
Tumor protein 53 (TP53) mutation and insulin growth factor II (IGF-II) overexpression are the most important genetic alterations in the pathogenesis of familial ACC. TP53 is a tumor suppressor gene responsible for control- ling cellular proliferation. Germline mutations of TP53 are observed in about 70% of patients with Li-Fraumeni syn- drome and 20-30% of sporadic ACC [26]. IGF-II is a gene located on chromosome 11p15 and encodes for fetal growth factor. This gene is maternally imprinted and expressed only by the paternal allele. Genetic alterations in the 11p15 region lead to overexpression of IGF-II. Adrenal tissue has abun- dant IGF-I and IGF-II receptors, and overexpression of this gene is frequently found in patients with ACC [27].
The Wingless iNTegration (WNT) signaling pathway is one of the most commonly involved pathways in the patho- genesis of ACC. During embryogenesis, this pathway is essential for the cell growth and renewal, but dysregulation of this pathway can lead to oncogenesis in various tissues including the adrenal glands. B-catenin and zinc and ring finger protein 3 (ZNRF3) are important regulators of WNT signaling pathway. 30-80% of patients with ACC have abnormal activation of ß-catenin, and 21% of them show abnormality of ZNRF3 [28]. c-MET overexpression is also
| Familial cancer syn- drome | Mode of inherit- ance | Genes involved | Clinical presentation | Surveillance for adrenal lesions |
|---|---|---|---|---|
| LFS | AD | TP53 (tumor suppressor) | Predisposition to multiple cancers, including breast cancer (25- 30%), sarcomas (25-30%), brain tumors, leukemia, colorectal and ovarian cancer | In children, abdominal ultrasound every 4 months until the age of 18 No screening recommendations for adults due to the lower risk of ACC in this age group |
| MEN I | AD | Menin (tumor suppressor) | Parathyroid tumors (95%), pancreatic neuroendocrine tumors (95%) and pituitary tumors (40%). Bilateral adrenal cortical hyperplasia is common, and 1-2% may develop ACC | No specific adrenal screening recommendations For newly detected adrenal lesions: If > 3 cm, surgical resection If < 3 cm, follow-up for 6 months and if stable in size; 2-year inter- val follow-up is recommended |
| FAP | AD | APC CTNNB1 | Multiple colonic adenomatous polyps, increased risk of colorectal cancer and other malignancies as sarcoma, melanoma and ACC | No evidence-based screening recommendations Suggestions of screening abdominal MRI at adolescence or referral for endocrinologist in selected cases with family history of extraco- lonic involvement |
| LS | AD | MSH2 MSH6 MLH1 PMS2 | Increased risks of colorectal, ovarian, endometrial, and lung can- cers. In addition to melanoma, sarcoma and ACC | No guidelines for ACC surveillance in LS given the rarity of the condition |
| BWS | AD | IGF2 CDKN1C KCNQ10 T1 H19 | Abdominal wall defects, macroglossia, hemihypertrophy, and exophthalmos. Increased risk of some cancers such as hepatoblas- toma, nephroblastoma, and ACC | No specific guidelines for ACC screening, yet screening of these patients for Wilms tumor and hepatoblastoma allows visualization of adrenal area |
ACC adrenocortical carcinoma, AD autosomal dominant, APC adenomatous polyposis coli, BWS Beckwith-Weidman syndrome, CDKNIC cyclin-dependent kinase inhibitor 1C, CTNB1 catenin beta 1, FAP familial adenomatous polyposis, IGF2 insulin growth factor 2 gene, KCNQ10TI potassium channel, voltage gated KQT-like subfamily Q, member 1, LFS Li-Fraumeni syndrome, LS lynch syndrome, MEN1 multiple endocrine neoplasia, MSH1-6 MutS protein homolog 2-6, PMS2 post-meiotic segregation increased 2, TP53 tumor protein 53
an important molecular change in ACC that is believed to occur as a resistance mechanism to radiation therapy and chemotherapy [29].
A number of chromosomal aberrations have been detected in ACC using comparative genomic hybridization (CGH). The most commonly detected aberrations are losses on chro- mosomes 1, 17, 22, 2, and 11, and gains on chromosomes 5, 12, 19, and 4. It is suggested that tumor suppressor genes and oncogenes might be located on the regions of chromo- somal loss and gain [25]. ACC is a heterogeneous cancer with multiple molecular and genetic drivers. Despite the recent advances in understanding the molecular and genetic elements contributing to the pathogenesis of ACC, there remain many unexplored areas. More understanding of the correlation between the molecular, clinical, and pathological profile of ACC is still needed [18].
Prognostic indicators in ACC
Clinical, molecular, and pathological features determine the prognosis of patients with ACC. Patient age and initial stage at diagnosis are considered two of the most important predictors of survival, with a poorer prognosis in patients with advanced age or metastatic disease at the time of diag- nosis. Furthermore, hormonally functioning tumors have a relatively worse prognosis, which may be related to the effects of Cushing syndrome and immunosuppressive effect of corticosteroids, which can lead to “tumor flaring” [1, 30].
Ki67 is among the most important markers in differ- entiating benign from malignant adrenal lesions. Lesions with Ki67 index greater than 5% are likely to be malignant. Moreover, Ki67 positivity is considered the single most important predictor for local recurrence after complete R0
surgical resection of ACC. Tumors with less than 10% Ki67 have significantly better clinical outcomes than those with greater than 10% Ki67 [17].
Imaging features of ACC
Imaging provides information about the malignant potential of adrenal masses, especially for localized lesions without extra-adrenal metastases. Unfortunately, even with these tools, the definitive characterization of adrenal masses remains challenging [12]. The presence of distant metasta- ses is a reliable sign of malignancy. Other radiological fea- tures suspicious for malignancy include large tumor size and heterogeneous attenuation/signal intensity and enhancement pattern; the latter two may reflect the presence of necrosis, intra-tumoral hemorrhage, and calcification [6].
Ultrasonography
Some have reported high sensitivity for detecting adrenal masses ([31] (97% for masses >20 mm and 94% for masses < 20 mm) [32], but further characterization may be limited by body habitus and operator skill [33]. By ultrasound, ACC most commonly appears as a rounded or oval well-defined hypoechoic mass (Fig. 2), with a minority displaying a thick partial or complete echogenic rim [34].
The echotexture depends on the size of the lesion and the degree of internal hemorrhage and necrosis. Small lesions are often homogeneous but demonstrate increased heteroge- neity with increasing size. Calcifications within the lesion appear as echogenic foci with posterior acoustic shadowing [35]. Color Doppler may demonstrate hypervascularity, due
to possible neovascularity [36]. Displacement of adjacent organs by larger masses can also be identified by ultrasound [33].
Computed tomography (CT)
ACCs are typically large, with roughly 70% of tumors larger than 6 cm at the time of diagnosis [6]. Size of the adrenal tumor, pattern of contrast enhancement, and degree of heter- ogeneity by CT are all important predictors of the malignant potential of the adrenal lesion [37]. ACC is typically het- erogeneous by CT and displays mixed intra-tumoral attenu- ation (Fig. 3). An attenuation value of more than 10 HU on non-contrast CT has high sensitivity for detecting malig- nancy (93%), but a specificity of only 71-73% [38]. Con- trast enhancement is heterogeneous and may be increased peripherally due to central necrosis. ACC characteristically displays less washout of contrast than benign adrenal adeno- mas (absolute washout < 60% and relative washout < 40%) (Fig. 4) [39]. However, the use of adrenal washout charac- teristics should be reserved for homogenous well-defined masses. The size of the lesion and the heterogeneity trump washout properties, which depend on the sampled region of the mass [40]. Punctate, patchy, or nodular calcifications are found in 30% of ACC [39, 41].
An irregular tumor margin is a sign of aggressiveness; however, its absence is not a reliable sign of benignity. A thin rim of well-defined enhancement commonly detected around ACC likely represents the tumor capsule [42].
Invasion of periadrenal fat and the surrounding organs or vasculature are other specific features of malignancy (Fig. 5) [6, 42]. IVC invasion is common at the time of diagnosis,
(A)
37 HU
(B)
76 HU
(C)
62 HU
and therefore, it is recommended that CT images extend to the level of the right atrium to exclude right atrial thrombus [41]. Metastases are also relatively common at time of pres- entation (Fig. 6), and the most common sites are in the liver, lung, bone, and retroperitoneal lymph nodes [43].
(A)
(B)
Magnetic resonance imaging (MRI)
ACC displays heterogeneous signal intensity on both T1 and T2 WI due to areas of hemorrhage and necrosis. Areas of intrinsic T1-shortening, most commonly indicates the presence of hemorrhage (Fig. 7). Necrosis appears as areas of T2-prolongation [6]. Rarely, ACC may demonstrate intracellular lipid, which can be appreciated on chemi- cal shift imaging, losing signal on out-of-phase imaging [39]. Generally, the area of signal loss is small (< 30% of lesion), in contrast to lipid-rich adenomas which more commonly demonstrate a more uniform drop in signal (Fig. 8) [6]. Other suspicious findings such as heterogene- ity of the lesion and large tumor size should aid in avoid- ing diagnostic error when ACCs contain intracellular fat [44]. MRI has better soft tissue resolution than CT giving it the added value of detecting venous invasion by tumor, differentiating bland from tumor thrombus, and identifying the upper limit of tumor thrombus extension [14, 45-47].
(A)
(B)
(C)
A study evaluating treatment outcomes of children with ACC reported that MRI is superior to both ultrasonogra- phy and CT in the detection of intravascular invasion with sensitivity of 100 %, compared to 50% by ultrasound and 66% by CT [48].
(A)
(A)
(B)
(B)
Diffusion-weighted imaging (DWI) is not of significant value in characterization of adrenal lesions due to the over- lapping apparent diffusion coefficient (ADC) values between benign and malignant adrenal masses [49].
Magnetic resonance spectroscopy (MRS) has been recently implemented in oncological practice for the char- acterization and post-treatment evaluation of various tumors [50]. The utility of MRS in the characterization of adrenal lesions is limited by the deep anatomical location of adrenal gland, its proximity to other organs with marked suscepti- bility artifact, and the heterogeneous nature of lesions [51]. Analysis of the metabolic profiles of various adrenal masses using MRS has shown that the metabolic fingerprint of ACC is distinct from adrenal adenoma, reflecting its malignant properties. Choline-containing compounds were higher in ACC due to the high cellular turnover. Anaerobic metabo- lism markers such as lactate were more abundant in ACC. Acetate, which is a major contributor of fatty acid synthesis through the beta oxidation pathway, is remarkably elevated
Fig. 8 A 46-year-old male patient presenting with hypertension and weight gain. a Axial in-phase MR image shows a hypointense right adrenal mass (white arrowhead). b Axial out-of-phase MR image exhibits non-uniform loss of signal in the adrenal mass (white arrow). Pathology of the mass revealed ACC
in ACC, explained by the high fatty acid content of ACC. The combination of significantly relative higher levels of choline, acetate, and lactate in ACC can aid in differentiating ACC from adenomas [52]. Another MRS study categorized adrenal lesions into four groups including adenoma, ACC, pheochromocytoma, and metastases. Distinguishing adeno- mas and pheochromocytomas from ACC and metastases using the choline-creatinine ratio, choline-lipid ratio, and lipid-creatinine ratio was possible with substantial sensitiv- ity and specificity. Also, a 4-4.3 ppm/creatinine ratio greater than 1.5 enabled the differentiation of pheochromocytomas and ACC from adenoma and metastasis with 87% sensitivity and 98% specificity [53].
Functional imaging
Fluorodeoxyglucose positron emission tomography (FDG- PET) has the potential to differentiate benign and malignant adrenal lesions by virtue of their metabolic activity. The
adrenal uptake is compared to the background activity in the liver either visually or quantitatively by measuring the standardized uptake value (SUV) within the region of inter- est. Normal adrenal glands have FDG uptake equal to or less than the liver. Multiple studies have demonstrated the utility of FDG-PET in the discrimination of benign and malignant adrenal masses to varying degrees [54-57]. The reported sensitivity and specificity of FDG-PET in the previous stud- ies ranged between 92 and 100% and 80 and 100%, respec- tively. A recent meta-analysis reported a sensitivity and specificity of 91% for FDG-PET in discriminating benign from malignant adrenal lesions [56]. FDG-PET also showed higher prognostic performance than contrast-enhanced CT (CECT) in diagnosing ACC, with an accuracy of 93.4% for FGD-PET versus 75% for CECT [58]. In general, the nega- tive predictive value and sensitivity of FDG-PET in char- acterization of adrenal masses are much higher than the positive predictive value and specificity [10]. Currently, the American College of Radiology committee on incidental findings suggest utilizing FDG-PET in patients with a prior cancer history and indeterminate adrenal masses or indeter- minate adrenal masses which are less than 4 cm [59].
FDG-PET is a complementary imaging tool to CT and MRI for the initial staging of ACC and detection of distant metastases [60]. FDG-PET was found to be more useful in the detection of ACC recurrence in the operative bed com- pared to routine anatomical imaging (Fig. 9), yet it was less sensitive in the detection of lung and liver metastasis [61]. The degree of FDG uptake by the tumor does not corre- late with the overall or disease-free survival, and it cannot be used as an independent prognostic predictor as in other malignancies like lymphoma and lung cancer [62]. Never- theless, in a more recent series of 106 ACC patients with metastatic disease, FDG-PET slightly outperformed con- ventional cross sectional imaging with respect to monitor- ing response to chemotherapy [63]. Despite the ability of FDG-PET to differentiate benign from malignant adrenal lesions, difficulty remains in discriminating primary adre- nal malignancy from metastasis. 11C-metomidate has a high affinity for key enzymes involved in steroidogenesis. There- fore, 11C-metomidate accumulates only in adrenal cortical origin tissues, such as adenomas and ACC, and thus may dif- ferentiate these entities from pheochromocytoma or adrenal metastases [64, 65].
Radiomics and texture analysis
Radiomics is a developing field of medical imaging which involves the extraction of quantitative data from routine CT and MRI studies, converting the visual information in the routine medical images into minable data. This can be further analyzed to help in decision making, especially in the field of medical oncology [66]. Radiomics has multiple
(A)
(B)
(C)
potential application including distinguishing benign from malignant lesions, prediction of treatment outcomes, assess- ment of treatment response, and prediction of cancer genet- ics and histopathological subtypes [67]. The utilization of second-order radiomic features extracted from unenhanced
MRI images may be useful for the classification of adre- nal lesions into lipid-rich adenoma, lipid-poor adenoma, or non-adenomatous lesion. In one study, texture analysis performed via a machine learning algorithm demonstrated superior diagnostic accuracy compared to an experienced radiologist in distinguishing these lesions, though the differ- ence was not statistically significant [68]. Radiomic features derived from contrast-enhanced CT have shown statistically significant differences between malignant adrenal nodules and lipid-poor adenomas, though the diagnostic accuracy was lower than that obtained with unenhanced CT attenua- tion values or chemical shift imaging on MRI [69]. A recent study assessing quantitative CT texture analysis of 54 his- topathologically proven adrenal masses looked at ACC and adenomas which were assessed by two blinded radiologists based on morphological criteria. Comparison of prediction accuracy and inter-observer agreement showed that the tex- ture predictive model had a higher mean accuracy of 82%, whereas the mean accuracy for the radiologists was less at 68.5% (p <0.0001). The study thus concluded that CT tex- ture analysis can improve differentiation of ACC and adrenal adenomas [70].
Staging of ACC
Accurate staging is a crucial step in treatment planning and in determining the prognosis of ACC [10]. Survival drops precipitously with advanced stages, with 90% 1-year sur- vival for Stage I disease plummeting to 29% 1-year survival for Stage IV disease [71]. A CT scan of the chest is a critical component for accurate staging due to its superiority to other imaging modalities in identification of pulmonary metasta- ses. Abdominal or pelvic CT or MRI covers the majority of other metastatic sites [10], although MRI is superior to CT in the detection of vascular invasion [6, 14, 45]. Unless clinically suspected, focused imaging for bony and brain metastases is not essential as both are uncommon sites of metastases [10]. The European Network for the Study of Adrenal Tumors (ENSAT) system is the most commonly used system to stage ACC [72]. According to ENSAT sys- tem, Stage I includes lesions < 5 cm and stage II lesions > 5 cm, both with no evidence of metastatic involvement of adjacent organs, periadrenal fat, or lymph nodes. Stage III includes lesions of any size with evidence of surround- ing organs, periadrenal fat, and/or lymph node involvement, but no evidence of distant metastasis. Stage IV is limited only to lesions with evidence of distant metastasis [72]. This system is also adopted in the recently published edition of AJCC staging manual (8th edition). It has been proposed that future staging schemes incorporate lymphovascular invasion, a known poor prognostic indicator, to better pre- dict survival [73].
Approach to atypically presenting ACC
Although ACCs most commonly present with features of excessive hormonal secretion or compressive symptoms due to the enlarging mass, an increasing number of cases are discovered incidentally [14]. Adrenal incidentalomas are adrenal lesions greater than 1 cm, discovered during imaging studies for unrelated reasons [74]. The majority of adrenal incidentalomas are benign. The determination of the malignant potential of an adrenal mass depends on the size of the lesion, imaging features, and hormonal sta- tus [75]. Hormonal evaluation is a fundamental step in the assessment of adrenal incidentalomas with the exception of adrenal cysts, myelolipoma, and adrenal hemorrhage [76]. All hormonally functioning lesions should be considered for surgical removal. Currently, the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons recommend biochemical assessment of all incidentally discovered adrenal lesions [59]. Inciden- tally discovered lesions greater than 4 cm are suspicious for primary or metastatic malignancy and patients should have biochemical assessment and a thorough history elicited to exclude a previous malignancy. Lesions >4 cm with benign radiological features could be considered for surgery or follow-up if the patient is not a good surgical candidate [59, 76]. With respect to an indeterminate mass, size > 4 cm is a sensitive but nonspecific indicator of malignant potential of an adrenal lesion. In general, these patients are consid- ered for surgery, taking into account age and comorbidi- ties [76]. Lesions ranging between 1 and 4 cm should have further assessment for signs of benignity. Adrenal lesions with benign features such as pre-contrast attenuation <10 HU, loss of signal on out-of-phase images compatible with intracellular lipid, and macroscopic fat do not require fur- ther imaging. Lesions with pre-contrast attenuation > 10 HU should have imaging with a dedicated adrenal protocol to quantify the degree of contrast washout. Typically, adeno- mas show absolute washout > 60% and relative washout > 40%, with high sensitivity and specificity in differentiating adenomas from non-adenomas [59]. MRI is an alternative for further characterization of indeterminate adrenal lesions due to its ability to detect intracellular lipid. There is no specific recommendation for the best imaging modality to be used. MRI is generally more expensive and time-consuming than CT, but has the advantage of not using intravenous con- trast and lack of ionizing radiation [75].
FDG-PET/CT may be an important ancillary study in indeterminate lesions, especially in patients with known extra-adrenal malignancy or inpatients with indeterminate lesions measuring < 4 cm. Indeterminate adrenal lesions are small percentage of adrenal lesions that do not show imaging features diagnostic of benignity by CT and MRI. Indeterminate adrenal lesion by imaging might represent
lipid-poor adenoma, pheochromocytoma, primary or sec- ondary malignancy [59, 77, 78]. Adrenal/liver SUV ratio > 1.8 demonstrates 87% sensitivity and 84% specificity in differentiating benign from malignant lesions [38]. If the lesion is non-functioning and indeterminate by imaging cri- teria, follow-up imaging using the same modality is recom- mended. There is no clear agreement regarding the optimum follow-up or surveillance period, ranging from 3 to 6 months for more suspicious lesions to 12 months for more benign- appearing lesions [76]. A more than 20% increase in the size of the lesion or a 5 mm increase in maximum diameter is an indication for surgery. If there is measurable growth that does not meet this threshold, continued follow-up in 6-12 months is recommended [79].
Although the presence of macroscopic fat is most com- monly seen in benign myelolipoma, ACC may show areas of macroscopic fat as well (Fig. 10). Other imaging and biochemical features should be kept in consideration to dif- ferentiate this rare manifestation of ACC from myelolipoma [80], as previously discussed. With any adrenal lesion, the appropriate workup depends on a variety of factors. Incor- porating clinical, imaging, and biochemical data allow the formulation of a proposed systematic approach (Fig. 11).
ACCs may also coexist with other adrenal neoplasms representing the so-called adrenal collision tumors. These are histologically distinct neoplasms coexisting in the same location without histological intermixing. Collision tumors have been described in the adrenal gland including adren- ocortical cancer with myelolipoma and ACC with other lesions such as adenoma.
Collision lesions pose a diagnostic dilemma owing to var- ying enhancement patterns between the two entities which may lead to inaccurate diagnosis. Hemorrhage into an ACC can also mimic a collision lesion, and it is important to dif- ferentiate these two pathologies [81].
Role of image-guided biopsy
Image-guided biopsy is seldom needed in patients with adrenal tumors. Oftentimes, in patients with large adrenal masses, surgical resection is favored over a biopsy, as sur- gery has therapeutic and diagnostic benefits [10]. There are two types of adrenal biopsies: fine-needle aspiration (FNA) and core biopsy. Both can be used depending on preference of the radiologist performing the procedure. Fine-needle aspiration is preferred in hypervascular masses and lesions that are surrounded by bowel to avoid inadvertent bowel wall injury during the procedure. If an FNA is performed, assess- ment of the FNA sample for adequacy is recommended, necessitating availability of the pathologist at the time of the procedure. Core biopsy may be performed, especially when larger tissue samples are needed for flow cytometry in the setting of suspected lymphoma [31]. Although biopsy
(A)
(B)
samples by either method have an established diagnostic role in multiple solid tumors as pancreatic and hepatic tumors, the role of biopsy in the diagnosis of ACC is less clear [82].
Multiple studies have reported a high sensitivity (81-100%) and specificity (96.3-100%) for fine-needle aspiration biopsy in adrenal masses. A study on 204 adre- nal lesions reported 86% sensitivity and 88% specificity for core-needle biopsy in diagnosing adrenal masses [83]. Rou- tine adrenal biopsy is not recommended in suspected ACC to avoid needle track metastasis [84]. It is often challeng- ing for pathologists to differentiate benign from malignant adrenal cortical masses even if the whole tumor specimen is available. The small sample size from the biopsy may not be sufficient to elaborate all Weiss score criteria which are essential in differentiating adenomas from ACC [85]. Biopsy is generally reserved for select cases, such as for staging in patients with known primary malignancy and in cases when an infiltrative process is suspected such as his- toplasmosis or tuberculosis [10, 86]. Biochemical exclusion
Clinical presentation
Incidental
· Signs of excessive hormonal secretion or
· Compressive symptoms
Hormonally active
Hormonally inactive
CT or MRI features suggestive of malignancy: Large (>4 cm), heterogeneous, peripheral enhancement, necrosis, hemorrhage, calcifications, or invasion of surrounding structures
Surgical resection
Lesion >4 cm
Lesion 1-4 cm
Less than 4 cm
Consider surgery or follow up for poor surgical candidates with lesions showing typical benign imaging features.
· Detailed Hormonal evaluation
· Staging
· Hormonal assessment
· Radiological evaluation: Morphological features / washout properties/ Complementary FDG PET in border lines cases
Pre contrast attenuation <10 HU
Pre contrast attenuation >10 HU
Management according to the clinical stage
Benign adenoma
Adrenal CT washout
Hormonally inactive
Hormonally active
Absolute washout >60% and relative washout >40%
Absolute washout <60% and relative washout <40%
Indeterminate features
Follow up/ PET CT/surgical resection according to clinical scenario.
Suspicious radiological features
Surgical resection
Resection or follow
of pheochromocytoma before biopsy is essential to avoid life-threatening hormonal surge during the biopsy procedure [87].
Mimics of adrenocortical carcinoma
Pheochromocytoma
Pheochromocytoma can have a variable imaging appearance, resulting in a diagnostic challenge (Fig. 12). Smaller lesions usually display more uniform homogenous enhancement than larger ones and show calcification in 10% of cases. Almost all pheochromocytomas have high attenuation val- ues (> 10 HU) on pre-contrast CT, though they rarely may have fatty content, resulting in attenuation values less than
10 HU. High attenuation may be attributed to intra-tumoral hemorrhage in some cases [88]. Contrast enhancement and washout properties of pheochromocytoma are vari- able. Although pheochromocytoma typically shows intense contrast enhancement, the washout properties overlap with both benign and malignant lesions. The classic MRI appear- ance of pheochromocytomas, i.e., hyperintense T2 signal, sometimes referred to as the “lightbulb sign,” is not a sensi- tive or specific feature of pheochromocytoma [83, 84]. The clinical presentation is variable among patients, with the majority presenting with signs and symptoms of excess cat- echolamine such as hypertension, diaphoresis, palpitations, anxiety, and headache. Roughly 10% of pheochromocytomas are non-functioning/poorly functioning and therefore asymp- tomatic [89]. All patients with adrenal masses should be tested for serum or urine metanephrines [90]. Biochemical
evaluation readily discriminates pheochromocytoma from ACC in most cases, yet non-functioning large lesions still represent a diagnostic challenge [6].
Adrenal adenoma
Adrenal adenoma is the most commonly encountered adre- nal mass and is typically homogenous with mild contrast enhancements. Approximately 70% of adenomas are lipid- rich, with pre-contrast attenuation < 10 HU. Lipid-poor ade- nomas generally have attenuation value ranging between 10 and 30 with a characteristic washout pattern as previously discussed [89]. Greater than 20% drop of signal during out- of-phase imaging is also a diagnosis of adenoma [91]. The average size of adrenal adenomas has been reported to be 2-2.5 cm in size, and typically they do not exceed 3 cm [40]. Larger adenomas tend to be more heterogeneous with possi- ble calcifications [92]. Differentiation of large heterogeneous adenomas from carcinomas is often not possible by imaging (Fig. 13), and lesions larger than 4 cm are generally managed as presumed malignant lesions [6, 93].
Adrenal metastasis
Adrenal metastases (Fig. 14) represent a small portion of incidentally discovered adrenal masses. Bilateral involve- ment of the adrenals with metastases is more common than unilateral involvement [39]. Isolated adrenal metastases in the absence of other systemic metastases are rare [94]. Metastases should be considered in any patient with a known
primary malignancy and bilateral adrenal lesions or when there is evidence of other metastatic sites [6]. The most com- mon primary malignancies that metastasize to the adrenals include breast, colon, lung, and renal cancers as well as melanoma [39].
Metastatic lesions usually have a CT attenuation value >10 HU and demonstrate less contrast washout when compared to adenoma [95]. FDG-PET usually shows high uptake, but this is dependent on the FDG avidity of the pri- mary tumor. Rarely metastatic adrenal lesions may show imaging overlap with adenomas including intracellular lipid and washout on CT [96].
Adrenal lymphoma
Adrenal lymphoma is most commonly secondary in the pres- ence of diffuse disease, and primary adrenal lymphoma is extremely rare. Lymphomatous involvement of the adrenals is detected by autopsy in 25% of patients with advanced lymphoma [94]. About 70% of primary adrenal lymphomas are bilateral [97]. Lymphomas are large soft tissue masses of average size 8 cm, often maintaining the triangular shape of the gland (Fig. 15). Most lesions are hypoattenuating by CT and display mild-to-moderate contrast enhancement. By MRI, they usually show low T1 signal and increased T2 signal as well as diffusion restriction due to its high cel- lularity. Calcifications are rarely seen unless the patient
(A)
(B)
has been previously treated. The presence of bilateral large adrenal masses in the absence of an extra-adrenal primary malignancy should raise concern for adrenal lymphoma [39]. Elevated serum lactate dehydrogenase is a common finding in aggressive lymphomas and may help in the differentiation of adrenal lymphomas from other large adrenal masses [98].
Ganglioneuroma and ganglioneuroblastoma
Both are uncommon tumors that can arise anywhere along the sympathetic chain and can occasionally arise from the adrenal medulla. Ganglioneuromas are benign tumors that typically display low homogenous CT attenuation and mild contrast enhancement. Calcifications are noted in 42-60% of lesions [99]. Ganglioneuromas exhibit low homogenous T1 signal intensity and heterogeneous high T2 signal intensity, likely attributable to the combination of myxoid components and ganglion cells [100]. One feature of ganglioneuroma on MRI is a whorled appearance due to bundles of collagen and Schwann cells that interlace in a characteristic manner [99]. Also, ganglioneuromas often have progressive enhancement pattern on CT that can help distinguishing ganglioneuro- mas from other adrenal tumors such as ACC and adenomas (Fig. 16) [101]. Because the mean size of adrenal gangli- oneuromas is 6.8 cm and they commonly demonstrate het- erogeneity and calcification, ganglioneuromas are usually managed surgically [102].
Ganglioneuroblastoma is a malignant lesion that has a variable CT appearance ranging from solid heterogene- ous masses to predominantly cystic ones. The variable CT appearance is likely related to differences in the percent- age of ganglion cells constituting the tumor relative to other
.0 mm
immature elements [99, 103]. By MRI ganglioneuroblas- toma usually displays low T1 and heterogeneous T2 signal intensity and marked rapid contrast enhancement [104].
Adrenal hemorrhage and pseudocyst
Adrenal hemorrhage may be due to traumatic or non-trau- matic etiologies. Non-traumatic causes include coagulopa- thy, sepsis, and venous thrombosis. Adrenal hemorrhage appears as an oval or rounded mass with surrounding fat- stranding and high CT attenuation value ranging from 50 to 90 HU. The size and attenuation value of adrenal hematoma decrease over time, and usually the lesion will eventually completely resolve (Fig. 17). Hemorrhage with an underly- ing mass should be suspected in cases with no risk factors for traumatic or non-traumatic hemorrhage, as ACC and other solid adrenal masses can present with hemorrhage. MRI with subtraction images can be essential for the detection of the enhancing solid component or for detecting venous thrombosis that might predispose to hemorrhage [105].
An adrenal pseudocyst is a sequela of chronic adrenal hemorrhage, typically appearing as a cystic structure with thin wall [106]. However, a pseudocyst may appear as a mixed solid and cystic mass or a pure solid mass by CT, which might be confused with adrenal tumors. The CT appearance depends on the age of the hematoma. The pres- ence of solid enhancement can point to a neoplastic etiology rather than pseudocyst [107]. Other features concerning for malignancy within a cystic lesion include large size, het- erogeneous appearance, and the presence of calcifications or central necrosis. These features may necessitate surgical excision [108].
Adrenal hemangioma
Hemangiomas are tumors arising from the endothelial lining of blood vessels, and the majority of these lesions involv- ing the adrenal gland are incidentally discovered. Periph- eral patchy enhancement with centripetal filling is a typical imaging feature of hemangioma by both CT and MRI, and when this is absent, hemangiomas may be confused with other masses [109]. Marked T2 hyperintensity and focal T1 hyperintensity due to hemorrhage and calcifications might be seen in hemangiomas but are nonspecific [110].
Treatment options and surgical resection
Surgical resection is the mainstay of treatment for localized disease (Stage I-III), with a 5-year survival rate of 55% in case of complete resection [111]. Open adrenalectomy is the standard surgical technique used for large lesions (> 6 cm) or for lesions with suspected loco-regional infiltration. This decreases the risk of capsular rupture and peritoneal
(A)
(B)
(C)
0
0
carcinomatosis and allows adequate resection of the tumor to avoid local recurrence. Laparoscopic resection can be con- sidered for tumors less than 6 cm in size, especially when performed by experienced surgeons. Lesions with extensive infiltration of the surrounding tissues require en bloc resec- tion of the tumor and the adjacent invaded organs [112].
Vascular invasion is not a contraindication to surgery, and complete surgical resection with free resection margin remains the only curative option for those patients. However, vascular invasion adds complexity to the surgical approach. The extent of tumor thrombus and its extension to vascular and cardiac structures are best assessed with MRI and are essential for planning the surgical approach. Extension of thrombus to the IVC and other vessels requires extensive thrombectomy, and potentially cardiopulmonary bypass if cavoatrial extension is seen [113].
Adjuvant therapy
Due to the high risk of local recurrence even with complete resection, adjuvant therapy might be needed. The most com- monly used adjuvant therapy is mitotane which is an adreno- lytic drug. There is a controversy in the literature regarding the efficacy of mitotane in preventing local recurrence. How- ever, the current guidelines recommend the use of mitotane in patients with high risk of recurrence, including stage III disease or a high proliferation index (Ki67 greater than 10%) [114].
A large retrospective cohort study in Italy and Germany reported prolonged overall survival and disease-free sur- vival in patients receiving adjuvant mitotane after surgical resection, suggesting the efficacy of mitotane in improving clinical outcomes [115]. A more recently updated series of 152 ACC patients who deemed at high risk of recurrence and adjuvant mitotane was associated with improved overall survival and prolonged recurrence-free survival [116].
Systemic therapy
Patients with advanced metastatic disease at the time of diagnosis have poor outcomes, and management is centered on the use of palliative systemic therapy. Mitotane is used alone or in association with systemic chemotherapy for that purpose [111].
Targeted therapies
There are multiple ongoing clinical trials and evolving tar- geted therapies, which aim to combat metastatic disease through the targeting of molecular pathways involved in the pathogenesis of ACC. These novel agents include drugs that target the WNT signaling pathway, vascular endothelial growth factor inhibitors, IGF-II inhibitors, and other tyrosine
kinase inhibitors. Although targeted therapies showed prom- ising preclinical results, the clinical results have been disap- pointing. This could be explained by the multiple molecular pathways involved in the pathogenesis of ACC, which may make different drug classes effective in only a small sub- group of patients. Ongoing trials and patient-directed tumor analysis may yield results in the future [25].
Surveillance guidelines
Due to the high recurrence rate of ACC, close follow-up is recommended even after complete resection. Follow-up with abdominal CT or MRI and CT of the chest every 3 months for the first 2 years is recommended. Additional monitor- ing of steroid hormones level is essential, especially in hor- monally active tumors to detect early recurrence. After 2 years of follow-up, the interval may be increased to every 6 months for 5 years [5, 117]. Approximately 90% of cases recur during the first five years after resection, so there is no clear recommendation for patient surveillance after 5 years. Annual follow-up for another 5 years might be adapted according to the clinical situation and the judgment of the physician [10].
Surveillance for more advanced disease should be tailored according to the prognostic factors, ongoing treatment, and expected treatment efficacy and is generally recommended every 2-3 months. There are no guidelines for patients with advanced metastatic disease undergoing only palliative therapy [10].
Conclusion
ACC is a rare tumor with a dismal prognosis and is best managed using a multidisciplinary approach. Knowledge of the various imaging features of ACC and differentiating it from other lesions is of utmost importance to improve treatment outcomes. Additionally, adequate staging with precise delineation of tumor extension and infiltration into surrounding tissues is the cornerstone in guiding a treatment plan. Different imaging modalities including CT, MRI, and PET are complementary to each other in evaluating adrenal masses and can be tailored according to the clinical scenario. Pathological markers such as the Weiss score and Ki67 index are important diagnostic and prognostic indicators for ACC.
References
1. Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting
tumors in a series of 202 consecutive patients. The Journal of clinical endocrinology and metabolism. 2006;91(7):2650-5.
2. Wandoloski M, Bussey KJ, Demeure MJ. Adrenocor- tical cancer. The Surgical clinics of North America. 2009;89(5):1255-67.
3. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocri- nology. The Journal of clinical endocrinology and metabolism. 2000;85(2):637-64.
4. Else T. Association of adrenocortical carcinoma with familial cancer susceptibility syndromes. Molecular and cellular endo- crinology. 2012;351(1):66-70.
5. Libé R. Adrenocortical carcinoma (ACC): diagnosis, prognosis, and treatment. Front Cell Dev Biol. 2015;3(45).
6. Bharwani N, Rockall AG, Sahdev A, Gueorguiev M, Drake W, Grossman AB, et al. Adrenocortical carcinoma: the range of appearances on CT and MRI. AJR American journal of roent- genology. 2011;196(6):W706-14.
7. Sharma E, Dahal S, Sharma P, Bhandari A, Gupta V, Amgai B, et al. The Characteristics and Trends in Adrenocortical Carci- noma: A United States Population Based Study. Journal of clini- cal medicine research. 2018;10(8):636-40.
8. Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A. Extent of disease at presentation and outcome for adrenocortical car- cinoma: have we made progress? World journal of surgery. 2006;30(5):872-8.
9. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Cao- ili EM, et al. Adrenocortical carcinoma. Endocrine reviews. 2014;35(2):282-326.
10. Fassnacht M, Dekkers O, Else T, Baudin E, Berruti A, de Krijger RR, et al. European Society of Endocrinology Clinical Practice Guidelines on the Management of Adrenocortical Carcinoma in Adults, in collaboration with the European Network for the Study of Adrenal Tumors. European journal of endocrinology. 2018.
11. Benassai G, Desiato V, Benassai G, Bianco T, Sivero L, Com- pagna R, et al. Adrenocortical carcinoma: what the surgeon needs to know. Case report and literature review. International journal of surgery (London, England). 2014;12 Suppl 1:S22-8.
12. Zini L, Porpiglia F, Fassnacht M. Contemporary man- agement of adrenocortical carcinoma. European urology. 2011;60(5):1055-65.
13. Adkins KM, Lee JT, Bress AL, Spires SE, Lee CY, Ayoob AR. Classic Cushing’s syndrome in a patient with adrenocortical car- cinoma. Radiology case reports. 2013;8(3):826.
14. Allolio B, Fassnacht M. Clinical review: Adrenocortical carci- noma: clinical update. The Journal of clinical endocrinology and metabolism. 2006;91(6):2027-37.
15. Lau SK, Weiss LM. The Weiss system for evaluating adren- ocortical neoplasms: 25 years later. Human pathology. 2009;40(6):757-68.
16. Papotti M, Libe R, Duregon E, Volante M, Bertherat J, Tissier F. The Weiss score and beyond-histopathology for adrenocortical carcinoma. Hormones & cancer. 2011;2(6):333-40.
17. Erickson LA. Challenges in surgical pathology of adrenocortical tumours. Histopathology. 2018;72(1):82-96.
18. Vatrano S, Volante M, Duregon E, Giorcelli J, Izzo S, Rapa I, et al. Detailed genomic characterization identifies high het- erogeneity and histotype-specific genomic profiles in adreno- cortical carcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2018;31(8):1257-69.
19. Angelousi A, Zilbermint M, Berthon A, Espiard S, Stratakis CA. Diagnosis and Management of Hereditary Adrenal Cancer. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 2016;205:125-47.
20. Griniatsos JE, Dimitriou N, Zilos A, Sakellariou S, Evangelou K, Kamakari S, et al. Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene. World journal of surgical oncology. 2011;9:6.
21. Gaujoux S, Pinson S, Gimenez-Roqueplo AP, Amar L, Ragazzon B, Launay P, et al. Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(21):5133-41.
22. Kratz CP, Achatz MI, Brugieres L, Frebourg T, Garber JE, Greer MC, et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clinical cancer research : an offi- cial journal of the American Association for Cancer Research. 2017;23(11):e38-e45.
23. Challis BG, Kandasamy N, Powlson AS, Koulouri O, Annamalai AK, Happerfield L, et al. Familial Adrenocortical Carcinoma in Association With Lynch Syndrome. The Journal of clinical endocrinology and metabolism. 2016;101(6):2269-72.
24. Marlon A. Guerrero EK. Adrenocortical Carcinoma and Syn- chronous Malignancies. Journal of Cancer. 2010;1(1):108-11.
25. Creemers SG, Hofland LJ, Korpershoek E, Franssen GJ, van Kemenade FJ, de Herder WW, et al. Future directions in the diagnosis and medical treatment of adrenocortical carcinoma. Endocrine-related cancer. 2016;23(1):R43-69.
26. Soon PSH, McDonald KL, Robinson BG, Sidhu SB. Molecular Markers and the Pathogenesis of Adrenocortical Cancer. Oncolo- gist. 2008;13(5):548-61.
27. Almeida MQ, Fragoso MC, Lotfi CF, Santos MG, Nishi MY, Costa MH, et al. Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. The Journal of clinical endocrinology and metabolism. 2008;93(9):3524-31.
28. Rubin B, Regazzo D, Redaelli M, Mucignat C, Citton M, Iaco- bone M, et al. Investigation of N-cadherin/beta-catenin expres- sion in adrenocortical tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2016;37(10):13545-55.
29. Phan LM, Fuentes-Mattei E, Wu W, Velazquez-Torres G, Sircar K, Wood CG, et al. Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Car- cinoma. Cancer research. 2015;75(19):4131-42.
30. Ayala-Ramirez M, Jasim S, Feng L, Ejaz S, Deniz F, Busaidy N, et al. Adrenocortical carcinoma: clinical outcomes and progno- sis of 330 patients at a tertiary care center. European journal of endocrinology. 2013;169(6):891-9.
31. Sharma KV, Venkatesan AM, Swerdlow D, DaSilva D, Beck A, Jain N, et al. Image-guided adrenal and renal biopsy. Techniques in vascular and interventional radiology. 2010;13(2):100-9.
32. Trojan J, Schwarz W, Sarrazin C, Thalhammer A, Vogl TJ, Dietrich CF. Role of ultrasonography in the detection of small adrenal masses. Ultraschall in der Medizin (Stuttgart, Germany : 1980). 2002;23(2):96-100.
33. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evalu- ation and treatment. The Journal of urology. 2003;169(1):5-11.
34. Hamper UM, Fishman EK, Hartman DS, Roberts JL, Sanders RC. Primary adrenocortical carcinoma: sonographic evalua- tion with clinical and pathologic correlation in 26 patients. AJR American journal of roentgenology. 1987;148(5):915-9.
35. Lattin GE, Jr., Sturgill ED, Tujo CA, Marko J, Sanchez-Mal- donado KW, Craig WD, et al. From the radiologic pathology archives: Adrenal tumors and tumor-like conditions in the adult: radiologic-pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 2014;34(3):805-29.
36. Albano D, Agnello F, Midiri F, Pecoraro G, Bruno A, Alongi P, et al. Imaging features of adrenal masses. Insights into imag- ing. 2019;10(1):1.
37. Fulmer B. Diagnosis and management of adrenal cortical car- cinoma. Current Urology Reports. 2007;8(1):77-82.
38. Iniguez-Ariza NM, Kohlenberg JD, Delivanis DA, Hartman RP, Dean DS, Thomas MA, et al. Clinical, Biochemical, and Radiological Characteristics of a Single-Center Retrospective Cohort of 705 Large Adrenal Tumors. Mayo Clinic proceed- ings Innovations, quality & outcomes. 2018;2(1):30-9.
39. Shin YR, Kim KA. Imaging Features of Various Adrenal Neo- plastic Lesions on Radiologic and Nuclear Medicine Imaging. AJR American journal of roentgenology. 2015;205(3):554-63.
40. Johnson PT, Horton KM, Fishman EK. Adrenal mass imaging with multidetector CT: pathologic conditions, pearls, and pit- falls. Radiographics : a review publication of the Radiological Society of North America, Inc. 2009;29(5):1333-51.
41. Zhang HM, Perrier ND, Grubbs EG, Sircar K, Ye ZX, Lee JE, et al. CT features and quantification of the characteristics of adrenocortical carcinomas on unenhanced and contrast- enhanced studies. Clinical radiology. 2012;67(1):38-46.
42. Rowe SP, Lugo-Fagundo C, Ahn H, Fishman EK, Prescott JD. What the radiologist needs to know: the role of preoperative computed tomography in selection of operative approach for adrenalectomy and review of operative techniques. Abdominal radiology (New York). 2019;44(1):140-53.
43. Gaujoux S, Mihai R. European Society of Endocrine Sur- geons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical manage- ment of adrenocortical carcinoma. The British journal of sur- gery. 2017;104(4):358-76.
44. Blake MAC, Carmel G;Boland, Giles W. Adrenal Imaging. AJR American journal of roentgenology. 2010;194.6:1450-60.
45. Jiang M, Ding H, Li C, Xiang K, Tang J, Guo Y, et al. Surgical resection of adrenocortical carcinoma with invasion into the inferior vena cava: a case report and literature review. Clin Case Rep. 2017;5(12):1934-7.
46. Elbanna KY, Khalili K, O’Malley M, Chawla T. Imaging and implications of tumor thrombus in abdominal malignancies: reviewing the basics. Abdominal radiology (New York). 2019.
47. Hricak H, Amparo E, Fisher MR, Crooks L, Higgins CB. Abdominal venous system: assessment using MR. Radiology. 1985;156(2):415-22.
48. Tucci S, Jr., Martins AC, Suaid HJ, Cologna AJ, Reis RB. The impact of tumor stage on prognosis in children with adrenocor- tical carcinoma. The Journal of urology. 2005;174(6):2338-42, discussion 42.
49. Sandrasegaran K, Patel AA, Ramaswamy R, Samuel VP, Northcutt BG, Frank MS, et al. Characterization of adrenal masses with diffusion-weighted imaging. AJR American jour- nal of roentgenology. 2011;197(1):132-8.
50. Martin Noguerol T, Sanchez-Gonzalez J, Martinez Barbero JP, Garcia-Figueiras R, Baleato-Gonzalez S, Luna A. Clinical Imaging of Tumor Metabolism with (1)H Magnetic Resonance Spectroscopy. Magnetic resonance imaging clinics of North America. 2016;24(1):57-86.
51. Melo HJ, Goldman SM, Szejnfeld J, Faria JF, Huayllas MK, Andreoni C, et al. Application of a protocol for magnetic reso- nance spectroscopy of adrenal glands: an experiment with over 100 cases. Radiologia brasileira. 2014;47(6):333-41.
52. Imperiale A, Elbayed K, Moussallieh FM, Reix N, Piotto M, Bellocq JP, et al. Metabolomic profile of the adrenal gland: from physiology to pathological conditions. Endocrine-related cancer. 2013;20(5):705-16.
53. Faria JF, Goldman SM, Szejnfeld J, Melo H, Kater C, Kenney P, et al. Adrenal masses: characterization with in vivo proton MR spectroscopy-initial experience. Radiology. 2007;245(3):788-97.
54. Guerin C, Pattou F, Brunaud L, Lifante JC, Mirallie E, Hais- saguerre M, et al. Performance of 18F-FDG PET/CT in the Characterization of Adrenal Masses in Noncancer Patients: A Prospective Study. The Journal of clinical endocrinology and metabolism. 2017;102(7):2465-72.
55. Groussin L, Bonardel G, Silvera S, Tissier F, Coste J, Abiven G, et al. 18F-Fluorodeoxyglucose positron emission tomogra- phy for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients. The Journal of clinical endocri- nology and metabolism. 2009;94(5):1713-22.
56. Kim SJ, Lee SW, Pak K, Kim IJ, Kim K. Diagnostic accuracy of (18)F-FDG PET or PET/CT for the characterization of adre- nal masses: a systematic review and meta-analysis. The British journal of radiology. 2018;91(1086):20170520.
57. Blake MA, Slattery JM, Kalra MK, Halpern EF, Fischman AJ, Mueller PR, et al. Adrenal lesions: characterization with fused PET/CT image in patients with proved or suspected malig- nancy-initial experience. Radiology. 2006;238(3):970-7.
58. Cistaro A, Niccoli Asabella A, Coppolino P, Quartuccio N, Altini C, Cucinotta M, et al. Diagnostic accuracy of (18) F-FDG PET or PET/CT for the characterization of adrenal masses: a systematic review and meta-analysis Hellenic jour- nal of nuclear medicine. 2015;18(2):97-102.
59. Mayo-Smith WW, Song JH, Boland GL, Francis IR, Israel GM, Mazzaglia PJ, et al. Management of Incidental Adrenal Masses: A White Paper of the ACR Incidental Findings Com- mittee. Journal of the American College of Radiology : JACR. 2017;14(8):1038-44.
60. Fassnacht M, Allolio B. What is the best approach to an appar- ently nonmetastatic adrenocortical carcinoma? Clinical endo- crinology. 2010;73(5):561-5.
61. Mackie GC, Shulkin BL, Ribeiro RC, Worden FP, Gauger PG, Mody RJ, et al. Use of [18F]fluorodeoxyglucose positron emis- sion tomography in evaluating locally recurrent and metastatic adrenocortical carcinoma. The Journal of clinical endocrinol- ogy and metabolism. 2006;91(7):2665-71.
62. Tessonnier L, Ansquer C, Bournaud C, Sebag F, Mirallie E, Lifante JC, et al. (18)F-FDG uptake at initial staging of the adrenocortical cancers: a diagnostic tool but not of prognostic value. World journal of surgery. 2013;37(1):107-12.
63. Takeuchi S, Balachandran A, Habra MA, Phan AT, Bassett RL, Jr., Macapinlac HA, et al. Impact of (1)(8)F-FDG PET/CT on the management of adrenocortical carcinoma: analysis of 106 patients. European journal of nuclear medicine and molecular imaging. 2014;41(11):2066-73.
64. Hahner S, Sundin A. Metomidate-based imaging of adrenal masses. Hormones & cancer. 2011;2(6):348-53.
65. Mendichovszky IA, Powlson AS, Manavaki R, Aigbirhio FI, Cheow H, Buscombe JR, et al. Targeted Molecular Imaging in Adrenal Disease-An Emerging Role for Metomidate PET-CT. Diagnostics (Basel, Switzerland). 2016;6(4).
66. Gillies RJ, Kinahan PE, Hricak H. Radiomics: Images Are More than Pictures, They Are Data. Radiology. 2016;278(2):563-77.
67. Yip SSF, Aerts HJWL. Applications and limitations of radiomics. Physics in Medicine and Biology. 2016;61(13):R150-66.
68. Romeo V, Maurea S, Cuocolo R, Petretta M, Mainenti PP, Verde F, et al. Characterization of Adrenal Lesions on Unenhanced MRI Using Texture Analysis: A Machine-Learning Approach. Journal of magnetic resonance imaging : JMRI. 2018;48(1):198-204.
69. Ho LM, Samei E, Mazurowski MA, Zheng Y, Allen BC, Nel- son RC, et al. Can Texture Analysis Be Used to Distinguish Benign From Malignant Adrenal Nodules on Unenhanced CT,
Contrast-Enhanced CT, or In-Phase and Opposed-Phase MRI? AJR American journal of roentgenology. 2019;212(3):554-61.
70. Elmohr MM, Fuentes D, Habra MA, Bhosale PR, Qayyum AA, Gates E, et al. Machine learning-based texture analysis for dif- ferentiation of large adrenal cortical tumours on CT. Clin Radiol. 2019;74(10):818.e1 -. e7.
71. Kerkhofs TM, Verhoeven RH, Van der Zwan JM, Dieleman J, Kerstens MN, Links TP, et al. Adrenocortical carcinoma: a population-based study on incidence and survival in the Nether- lands since 1993. European journal of cancer (Oxford, England : 1990). 2013;49(11):2579-86.
72. Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Clas- sification. Cancer. 2009;115(2):243-50.
73. Poorman CE, Ethun CG, Postlewait LM, Tran TB, Prescott JD, Pawlik TM, et al. A Novel T-Stage Classification System for Adrenocortical Carcinoma: Proposal from the US Adrenocor- tical Carcinoma Study Group. Annals of surgical oncology. 2018;25(2):520-7.
74. Reginelli A, Di Grezia G, Izzo A, D’Andrea A, Gatta G, Cappabi- anca S, et al. Imaging of adrenal incidentaloma: our experience. International journal of surgery (London, England). 2014;12 Suppl 1:S126-31.
75. Vaidya A, Hamrahian A, Bancos I, Fleseriu M, Ghayee HK. THE EVALUATION OF INCIDENTALLY DISCOVERED ADRENAL MASSES. Endocrine practice : official journal of the American College of Endocrinology and the American Asso- ciation of Clinical Endocrinologists. 2019;25(2):178-92.
76. Kapoor A, Morris T, Rebello R. Guidelines for the management of the incidentally discovered adrenal mass. Canadian Urological Association journal = Journal de l’Association des urologues du Canada. 2011;5(4):241-7.
77. Sahdev A, Willatt J, Francis IR, Reznek RH. The indeterminate adrenal lesion. Cancer imaging : the official publication of the International Cancer Imaging Society. 2010;10:102-13.
78. Adam SZ, Nikolaidis P, Horowitz JM, Gabriel H, Hammond NA, Patel T, et al. Chemical Shift MR Imaging of the Adrenal Gland: Principles, Pitfalls, and Applications. Radiographics : a review publication of the Radiological Society of North America, Inc. 2016;36(2):414-32.
79. Sahdev A. Recommendations for the management of adrenal incidentalomas: what is pertinent for radiologists? The British journal of radiology. 2017;90(1072):20160627.
80. Egbert N, Elsayes KM, Azar S, Caoili EM. Computed tomog- raphy of adrenocortical carcinoma containing macroscopic fat. Cancer imaging : the official publication of the International Cancer Imaging Society. 2010;10(1):198-200.
81. Katabathina VS, Flaherty E, Kaza R, Ojili V, Chintapalli KN, Prasad SR. Adrenal collision tumors and their mimics: multimo- dality imaging findings. Cancer imaging : the official publication of the International Cancer Imaging Society. 2013;13(4):602-10.
82. Saeger W, Fassnacht M, Chita R, Prager G, Nies C, Lorenz K, et al. High diagnostic accuracy of adrenal core biopsy: results of the German and Austrian adrenal network multicenter trial in 220 consecutive patients. Human pathology. 2003;34(2):180-6.
83. Villelli NW, Jayanti MK, Zynger DL. Use and usefulness of adre- nal core biopsies without FNA or on-site evaluation of adequacy: a study of 204 cases for a 12-year period. American journal of clinical pathology. 2012;137(1):124-31.
84. Phan AT. Adrenal cortical carcinoma-review of current knowl- edge and treatment practices. Hematology/oncology clinics of North America. 2007;21(3):489-507; viii-ix.
85. Bancos I, Tamhane S, Shah M, Delivanis DA, Alahdab F, Arlt W, et al. DIAGNOSIS OF ENDOCRINE DISEASE:
The diagnostic performance of adrenal biopsy: a systematic review and meta-analysis. European journal of endocrinology. 2016;175(2):R65-80.
86. Wahab NA, Mohd R, Zainudin S, Kamaruddin NA. Adrenal involvement in histoplasmosis. EXCLI journal. 2013;12:1-4.
87. Williams AR, Hammer GD, Else T. Transcutaneous biopsy of adrenocortical carcinoma is rarely helpful in diagnosis, poten- tially harmful, but does not affect patient outcome. European journal of endocrinology. 2014;170(6):829-35.
88. Blake MA, Kalra MK, Maher MM, Sahani DV, Sweeney AT, Mueller PR, et al. Pheochromocytoma: an imaging chameleon. Radiographics : a review publication of the Radiological Soci- ety of North America, Inc. 2004;24 Suppl 1:S87-99.
89. Wang F, Liu J, Zhang R, Bai Y, Li C, Li B, et al. CT and MRI of adrenal gland pathologies. Quantitative imaging in medicine and surgery. 2018;8(8):853-75.
90. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guide- line. The Journal of clinical endocrinology and metabolism. 2014;99(6):1915-42.
91. Elsayes KM, Mukundan G, Narra VR, Lewis JS, Jr., Shirkhoda A, Farooki A, et al. Adrenal masses: mr imaging features with pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 2004;24 Suppl 1:S73-86.
92. Li B, Guo Q, Yang H, Guan J. Giant non-functional adrenal adenoma: A case report. Oncology letters. 2013;5(1):378-80.
93. Newhouse JH, Heffess CS, Wagner BJ, Imray TJ, Adair CF, Davidson AJ. Large degenerated adrenal adenomas: radiologic- pathologic correlation. Radiology. 1999;210(2):385-91.
94. Herr K, Muglia VF, Koff WJ, Westphalen AC. Imaging of the adrenal gland lesions. Radiologia brasileira. 2014;47:228-39.
95. Uberoi J, Munver R. Surgical management of metastases to the adrenal gland: Open, laparoscopic, and ablative approaches. Cur- rent Urology Reports. 2009;10(1):67.
96. Alshahrani MA, Bin Saeedan M, Alkhunaizan T, Aljohani IM, Azzumeea FM. Bilateral adrenal abnormalities: imaging review of different entities. Abdominal radiology (New York). 2019;44(1):154-79.
97. Joseph FG, Cook S, Gowda D. Primary adrenal lymphoma with initial presentation concerning for bilateral adrenal pheochromo- cytomas. BMJ case reports. 2017;2017:bcr-2017-220549.
98. Toogood V, Milliken S, Morey A, Samaras K. Adrenal tumours: How to establish malignancy. BMJ case reports. 2014;2014:bcr2014203736.
99. Guo YK, Yang ZG, Li Y, Deng YP, Ma ES, Min PQ, et al. Uncommon adrenal masses: CT and MRI features with his- topathologic correlation. European journal of radiology. 2007;62(3):359-70.
100. Majbar AM, Elmouhadi S, Elaloui M, Raiss M, Sabbah F, Hrora A, et al. Imaging features of adrenal ganglioneuroma: a case report. BMC research notes. 2014;7:791.
101. Shawa H, Elsayes KM, Javadi S, Morani A, Williams MD, Lee JE, et al. Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre. Clinical endocrinology. 2014;80(3):342-7.
102. Linos D, Tsirlis T, Kapralou A, Kiriakopoulos A, Tsakayan- nis D, Papaioannou D. Adrenal ganglioneuromas: incidentalo- mas with misleading clinical and imaging features. Surgery. 2011;149(1):99-105.
103. Heidari Z, Kaykhaei MA, Jahantigh M, Sheikhi V. Adrenal Gan- glioneuroblastoma in an Adult: A Rare Case Report. International journal of endocrinology and metabolism. 2018;16(1):e63055.
104. Koike K, Iihara M, Kanbe M, Omi Y, Aiba M, Obara T. Adult- Type Ganglioneuroblastoma in the Adrenal Gland Treated by
a Laparoscopic Resection: Report of a Case. Surgery Today. 2003;33(10):785-90.
105. Taffel M, Haji-Momenian S, Nikolaidis P, Miller FH. Adrenal imaging: a comprehensive review. Radiologic clinics of North America. 2012;50(2):219-43, v.
106. Eric Jordan LP, Jesse Courtier, Victor Sai, Adam Jung, Fergus V. Coakley Imaging of Nontraumatic Adrenal Hemorrhage. AJR American journal of roentgenology. 2012;199(1):W91-W8.
107. Wang L-J, Wong Y-C, Chen C-J, Chu S-H. Imaging spec- trum of adrenal pseudocysts on CT. European Radiology. 2003;13(3):531-5.
108. Isono M, Ito K, Seguchi K, Kimura T, Tachi K, Kono T, et al. A Case of Hemorrhagic Adrenal Pseudocyst Mimicking Solid Tumor. The American journal of case reports. 2017;18:1034-8.
109. Feo CV, De Troia A, Pedriali M, Sala S, Zatelli MC, Carcoforo P, et al. Adrenal cavernous hemangioma: a case report. BMC surgery. 2018;18(1):103.
110. Zemni I, Haddad S, Hlali A, Manai MH, Essoussi M. Adre- nal gland hemangioma: A rare case of the incidentaloma: Case report. International journal of surgery case reports. 2017;41:417-22.
111. Puglisi S, Perotti P, Cosentini D, Roca E, Basile V, Berruti A, et al. Decision-making for adrenocortical carcinoma: surgical, systemic, and endocrine management options. Expert review of anticancer therapy. 2018;18(11):1125-33.
112. Gaujoux S, Weinandt M, Bonnet S, Reslinger V, Bertherat J, Dousset B. Surgical treatment of adrenal carcinoma. Journal of visceral surgery. 2017;154(5):335-43.
113. Annamaria P, Silvia P, Bernardo C, Alessandro de L, Antonino M, Antonio B, et al. Adrenocortical carcinoma with inferior vena cava, left renal vein and right atrium tumor thrombus extension. International journal of surgery case reports. 2015;15:137-9.
114. Paragliola RM, Torino F, Papi G, Locantore P, Pontecorvi A, Corsello SM. Role of Mitotane in Adrenocortical Carci- noma - Review and State of the art. European endocrinology. 2018;14(2):62-6.
115. Strosberg JR. Update on the management of unusual neuroendo- crine tumors: pheochromocytoma and paraganglioma, medullary thyroid cancer and adrenocortical carcinoma. Seminars in oncol- ogy. 2013;40(1):120-33.
116. Calabrese A, Basile V, Puglisi S, Perotti P, Pia A, Saba L, et al. Adjuvant mitotane therapy is beneficial in non-metastatic adreno- cortical carcinoma at high risk of recurrence. European journal of endocrinology. 2019;180(6):387-96.
117. Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2012;23 Suppl 7:vii131-8.
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.