Endocrine DOI 10.1007/s12020-014-0440-6

REVIEW

Metabolic and anatomic characteristics of benign and malignant adrenal masses on positron emission tomography/computed tomography: a review of literature Asha Kandathil • Ka Kit Wong • Daniel J. Wale • Maria Chiara Zatelli • Anna Margherita Maffione Milton D. Gross • Domenico Rubello

•

Received: 22 July 2014 / Accepted: 25 September 2014 Ó Springer Science+Business Media New York 2014

Abstract PET/CT with 18F-fluorodeoxyglucose (FDG) or using different radiocompounds has proven accuracy for detection of adrenal metastases in patients undergoing cancer staging. It can assist the diagnostic work-up in oncology patients by identifying distant metastases to the adrenal(s) and defining oligometastatic disease that may benefit from targeted intervention. In patients with incidentally discovered adrenal nodules, so-called adrenal ‘‘incidentaloma’’ FDG PET/CT is emerging as a useful test to distinguish benign from malignant etiology. Current published evidence suggests a role for FDG PET/CT in assessing the malignant potential of an adrenal lesion that has been ‘indeterminately’ categorized with unenhanced

A. Kandathil
K. K. Wong
D. J. Wale
M. D. Gross Nuclear Medicine/Radiology Department, University of Michigan Hospital, Ann Arbor, MI 48109, USA K. K. Wong
M. D. Gross Nuclear Medicine Service, Department of Veterans Affairs Health System, Ann Arbor, MI, USA M. C. Zatelli Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy A. M. Maffione
D. Rubello (&) Department of Services in Diagnosis and Cure, Santa Maria della Misericordia Hospital, Rovigo, Italy e-mail: [email protected] D. Rubello Department of Nuclear Medicine, Padova University, 35100 Padova, Italy D. Rubello Service of Nuclear Medicine & PET/CT Unit at Santa Maria della Misericordia Hospital, Via Tre Martiri 140, 45100 Rovigo, Italy

CT, adrenal protocol contrast-enhanced CT, or chemicalshift MRI. FDG PET/CT could be used to stratify patients with higher risk of malignancy for surgical intervention, while recommending surveillance for adrenal masses with low malignant potential. There are caveats for interpretation of the metabolic activity of an adrenal nodule on PET/CT that may lead to false-positive and false-negative interpretation. Adrenal lesions represent a wide spectrum of etiologies, and the typical appearances on PET/CT are still being described, therefore our goal was to summarize the current diagnostic strategies for evaluation of adrenal lesions and present metabolic and anatomic appearances of common and uncommon adrenal lesions. In spite of the emerging role of PET/CT to differentiate benign from malignant adrenal mass, especially in difficult cases, it should be emphasized that PET/CT is not needed for most patients and that many diagnostic problems can be resolved by CT and/or MR imaging. Keywords Incidentaloma
Adrenocortical adenoma
Pheochromocytoma
PET/CT
MRI
CT

Introduction Incidentally discovered adrenal lesions (commonly referred to as incidentalomas) are increasingly encountered on diagnostic imaging studies performed for indications unrelated to the adrenal gland, due to widespread use of computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US), and more recently positron emission tomography (PET)/CT with 18F-fluorodeoxyglucose (FDG) and other radiopharmaceuticals for cancer characterization and staging. Incidentalomas are often included also in the field of view in thoracic and spine imaging. These lesions are

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Endocrine Table 1 Classification and frequency of incidentally discovered adrenal masses Etiology

Frequency (%)

Comments

Adrenal cortical adenoma

36–94

Non-oncology and nonselected series

Adrenal cortical adenoma

7–68

Oncology patients

Macronodular hyperplasia

7–17

Adrenocortical carcinoma

0–25

Pheochomocytoma

0–11

Neuroblastoma

0–11

Ganglioneuroma

0–6

Adrenal metastases

0–21

Non-oncology and nonselected series

Adrenal metastases

32–73

Oncology patients

Myelolipoma

7–15

Lipoma

0–11

Cyst

4–22

Pseudocyst Hemorrhage

2–9 0–4

Parasitic

0–1

Rare beyond early childhood

Modified with permission from Ref. [52]

not to be ignored as an adrenal mass in a patient with a known malignancy has a 32–73 % chance of being a metastasis [1], while the risk of adrenal malignancy about 21 % [2]. When an incidental adrenal lesion is encountered, the primary goal is to distinguish malignant from benign etiology (Table 1). Although metastases comprise the majority of malignant adrenal lesions, less common primary adrenal malignancies such as adrenocortical carcinoma, primary adrenal lymphoma, melanoma, malignant pheochromocytoma, and angiosarcoma are also occasionally found. A variety of benign lesions including adrenocortical adenoma, benign pheochromocytoma, myelolipoma, ganglioneuroma, adrenal cyst, adrenal hemorrhage, and granulomatous disease should also be considered. In addition to diagnostic imaging, biochemical evaluation is important as serum and urinary markers can aid in the diagnosis of pheochromocytomas and hormonally active adrenocortical lesions [3] (Table 2). For the remaining nonfunctioning adrenal lesions, a variety of imaging modalities can be utilized to attempt to predict the histopathology [4–6]. Diagnostic strategies have classically focused on distinguishing between adrenocortical adenoma and adrenal metastasis [3–7]. Figure 1 summarizes the histopathology classification of common and uncommon benign and

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malignant adrenal masses, derived from the adrenal cortex, sympathomedullary system, and stromal tissues of the adrenal gland. Unfortunately, no single imaging modality has proven ideal for the comprehensive evaluation of incidental adrenal lesions [3–7]. Further complicating this topic is the difficulty establishing a simple universally accepted diagnostic algorithm because these adrenal lesions are initially detected over a variety of modalities (and variety of protocols/techniques within each modality) due to their incidental nature. Although CT and MRI (using adrenal lesion-specific techniques) are classically utilized in the evaluation of incidental adrenal lesions, FDG PET/CT is emerging as an adjunctive imaging test for distinguishing benign from malignant adrenal nodules [6–9]. Current evidence suggests a possible role for PET/CT in assessing the malignant potential of an adrenal mass, otherwise categorized as ‘‘indeterminate’’ by unenhanced or contrastenhanced CT, or MRI [8, 10, 11, 12]. However, adrenal lesions represent a wide spectrum of etiologies, and the typical appearances on PET/CT are still being described for rarer lesions. Our goal was to provide a summary of the current biochemical and diagnostic imaging work-up of adrenal masses and present a detailed review of the PET/ CT findings of common and uncommon adrenal lesions with a focus on differentiating benign and malignant lesions.

Functional and anatomic imaging of adrenal nodules Normal adrenal anatomy and metabolic features The adrenal glands have a unique shape that has been likened to a lambda or an inverted T, Y, or V shape on axial CT or MRI images. The limbs of the adrenals are thin with normal maximum diameter of 6 mm for the right adrenal and 8 mm for the left adrenal [13], although they are generally not considered thick until the diameter of any limb is greater than 10 mm. Benitah et al. reported in a study on 197 patients with lung cancer that normal adrenals could be seen to be smoothly enlarged ([6 mm) in 11–18 % of patients and nodular in 18–23 % [14]. Normal adrenal glands demonstrate mild FDG uptake, less than liver uptake on FDG PET/CT, with maximum standardized uptake values (max SUV) ranging from 0.95 to 2.46 [15]. A study of aging of normal organs on PET reported that the left adrenal had max SUV of 1.39 ± 0.34 (0.76–2.64) and the right adrenal gland had max SUV 1.68 ± 0.48 (0.86–3.26) [16].

Endocrine Table 2 Endocrine screening for incidentally discovered adrenal masses Syndrome

Hormone

Cushing’s syndrome

Cortisol

Conn’s syndrome

Aldosterone

Etiology

Laboratory biochemical testing

Adrenocortical adenoma,

24 h urinary cortisol, dexamethasone suppression cortisol levels

ACTH-dependent macrohyperplasia, Ectopic ACTH production, Rarely adrenocortical cancer Adrenocortical adenoma,

Hypokalemia, aldosterone:renin ratio

Macrohyperplasia, Rarely adrenocortical cancer Hyperandrogenism

Androgen

Adrenocortical adenoma, Rarely adrenocortical cancer

Progesterone and DHEA in woman, androstendione and testosterone in men, 17-b-estradiol

Catacholamine excess

Norepinephrine, epinephrine, metanephrines

Pheochromocytoma

24 h urinary catecholamines and metanephrines, plasma metanephrines

Reference [11] Lacroix A. Clinical Presentation and Evaluation of Adrenocortical Tumors. In UpToDate, UpToDate, Waltham, MA. (Accessed on 3/16/2014)

Fig. 1 Histopathology classification of benign and malignant neoplastic adrenal masses, derived from the adrenal cortex, sympathomedullary system, and stromal tissues of the adrenal gland

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CT and MRI imaging of adrenal nodules The majority of adrenal incidentalomas can be characterized and monitored with anatomic imaging modalities: unenhanced CT, contrast-enhanced CT, or chemical shift MRI. Adrenal metastases show significant interval growth on serial imaging at 6 months, therefore comparison with prior studies, if available, is important for assessing interval growth of malignant lesions. CT characteristics indicative of malignancy include size greater than 3 cm, heterogeneity, unenhanced CT attenuation value [10 HU, ill-defined margins, and concomitant metastases [6, 8, 10, 17]. Conversely, the majority of benign adrenal adenomas contain large amounts of intracellular lipid, resulting in low-attenuation values at unenhanced CT. A meta-analysis of published data showed that using a \10 HU unenhanced CT threshold resulted in diagnosis of an adrenal adenoma with sensitivity of 71 % and specificity of 98 % [18]. Lipid-rich and lipid-poor adenomas can be differentiated from nonadenomas at delayed enhanced CT examinations using percentage enhancement washout calculations [19]. All adenomas, including those without substantial lipid content, tend to have a more rapid loss of attenuation value soon after enhancement with intravenous contrast material. Absolute and relative percentage contrast washout is calculated using dedicated adrenal protocol CT performed with unenhanced (U), 1 min post contrast (E) and 15 min delayed post contrast (D) scan. Absolute % wash out (APW) is calculated as (E - D)/(E - U) 9 100, and relative % wash out (RPW) is calculated as (E - D)/E 9 100. Using APW [60 % and RPW [40 % adenomas can be differentiated from nonadenomas with near 100 % sensitivity and specificity. If the lesions demonstrate APW \60 % and/or RPW \40 %, they cannot be characterized confidently as a benign adenoma, and biopsy or follow-up is required [5, 8, 9, 10, 17–19]. Considering MRI, standard protocol for adrenal imaging includes the following sequences: (1) coronal T2-weighted imaging with half-Fourier rapid acquisition with relaxation enhancement performed during a single-breath hold; (2) fast spin-echo T2-weighted or long-echo-time inversion-recovery sequence performed during a single-breath hold; (3) axial and coronal gradient-recalled-echo T1weighted chemical shift in-phase and out-of-phase imaging in the axial and coronal planes during a single-breath hold; and (4) axial and coronal three-dimensional gradientrecalled-echo sequence (e.g., volumetric interpolated breath-hold examination), performed before and after administration of a gadolinium-based contrast agent and with breath hold. The most important characteristic feature of adrenal adenoma is the presence of intracellular lipid. Chemical shift imaging is the most reliable technique for diagnosing adrenal adenoma. Adenomas with intracellular

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lipid can be confidently identified on chemical shift MRI with sensitivity of 78 % and specificity of 87 % using an adrenal signal intensity index threshold value of more than 16.5 % [20]. Uniform enhancement on immediate contrast material-enhanced images is also typical of adenomas [21]. Adrenocortical carcinomas are usually large at diagnosis and appear heterogeneous on both T1- and T2-weighted images owing to the presence of internal hemorrhage and necrosis [22]. In summary, when evaluating an incidentally discovered adrenal nodule by CT, an initial unenhanced CT should be obtained. If the nodule demonstrates HU that \10, the lesion is confidently characterized as a benign adenoma and no further imaging is needed. If the lesion is [10 HU, an adrenal washout protocol contrast-enhanced study should be obtained to determine the APW and RPW. If the nodule demonstrates an APW [60 % and RPW [40 %, an adenoma can be confidently diagnosed. By using MRI, chemical shift imaging is the most reliable technique for diagnosing adrenal adenoma. For masses that appear to be benign (\10 HU; washout, [60 %), small (\3 cm), and completely nonfunctioning, imaging and biochemical reevaluation at 1–2 year (or more) are appropriate. Differentiating benign from malignant adrenal disease using FDG PET/CT Occasionally CT and MRI characterization of adrenal nodules are not possible, often due to heterogenous density which makes attenuation measurements unreliable and difficulty evaluating lipid-poor adenomas which comprise up to 30 % of cases [6]. Therefore, the adrenal nodule can be categorized as indeterminate based on its imaging characteristics. 18F-FDG PET has been demonstrated to help distinguish malignant adrenal masses (adrenocortical carcinoma or metastases to the adrenals) from benign adrenal masses, with high sensitivity (74–100 %) and specificity (66–100 %) [23–39] in groups of patients both with and without a history of cancer [25, 27, 29, 32, 35, 37, 40, 41]. Most benign adenomas have been described to have adrenal FDG uptake equal to or below liver background. Metser et al. found that, with adrenal max SUV cutoff of 3.1, FDG PET/CT had sensitivity of 98.5 % and specificity of 92 % for differentiating lipid-rich and lipid-poor adenomas from malignant lesions [34]. Conversely, adrenal metastases typically demonstrate high FDG uptake. Watanabe et al. found that the mean adrenal SUVmax and adrenal-to-liver SUV ratio was higher for adrenal metastases (8.4 ± 3.8 and 3.0 ± 1.3, respectively) than for adrenocortical adenomas (2.9 ± 1.0 and 0.9 ± 0.3, respectively) (P \ 0.001) [42]. In 105 patients with 132 nodules use of adrenal SUV max led to a sensitivity 90 % and specificity of 97 %, with high

Endocrine Table 3 Pitfalls for using FDG-PET/CT for distinguishing malignant from benign adrenal masses Cause (refs)

Comments

False-negative PET for adrenal malignancy Small size

Spatial resolution for PET (\8 mm)

Neoplasms with low FDG-avidity Post-chemotherapy

Neuroendocrine tumors, bronchoalveolar cancer Decreased sensitivity for detecting residual metastatic disease

Tumor necrosis or hemorrhage

May have a rim of peripheral increased FDG activity

Adrenal collision tumors Co-existing adrenal lesions with [206–208] different etiology not recognized False-positive PET for adrenal malignancy due to benign causes of increased FDG activity Adrenocortical adenoma [166–168, 176]

Hypersecretory and non-functioning adenomas may have mild FDG uptake above liver background

Macrohyperplasia [173]

ACTH-dependent and ectopic ACTH disease may have mild FDG uptake above liver background

Pheochromocytoma [127]

Benign or malignant pheochromocytomas display FDGavidity

Inflammatory granulomatous disease [210–219]

Tuberculosis, histoplasmosis, syphilis Other conditions such as sarcoidosis and HIV-related adrenalitis due to cytomegalovirus are expected to also cause increased FDG uptake, Infectious abscess are expected to also cause increased FDG uptake

Myelolipoma [177, 179, 180]

Hypermetabolic due to adenomatous and hematopoietic elements

Ganglioneuroma [199– 201]

Generally low grade FDG uptake, occasionally mildly increased FDG uptake above liver background

Oncocytoma [71, 164, 171, 204]

FDG-avid tumor that rarely involves the adrenals

Brown fat [194]

Para- or peri-adrenal adipose tissues, hibernoma [195, 196]

Autoimmune adrenal insufficiency

Autoimmune adrenalitis

Hemorrhage

Acute or subacute hemorrhage can present with mild FDG-avidity, usually bilateral Following adrenalectomy for adrenocortical cancer, the remaining normal adrenal gland may become transiently hypermetabolic, of uncertain etiology, presumed related to mitotane or other chemotherapy

Post-chemotherapy

Upper pole duplex kidney

Concern only on stand-alone PET, rather than hybrid PET/CT

inter-observer agreement (visual k was 0.79–0.90). Diagnostic performance of qualitative visual assessment and quantitative analysis was similar [43]. A recent meta-analysis of 1,217 patients from 21 studies reported that 18FFDG PET had a pooled sensitivity of 97 % and specificity of 91 % for distinguishing malignant from benign adrenal masses [9]. No difference in accuracy was seen for PET compared to PET/CT or for various interpretive methods, visual analysis, SUV measurements, or SUV ratios (adrenal:liver or adrenal:spleen). FDG PET/CT has the advantage of integrated anatomic and metabolic feature analysis in characterizing lesions. In 325 patients with adrenal lesions, the highest accuracy, sensitivity (99 %) and specificity (91 %), was found when max SUV adrenal:liver ratio [2.5 was combined with HU [ 10 [44]. FDG PET/CT metabolic measurements have been combined with CT histogram and unenhanced CT parameters (Hounsfield units, size), SUV max[2.8 with histograms and Hounsfield units \20 with excellent results [45]. However, false-negatives can occur with small tumors \10 mm, hemorrhagic or necrotic lesions, in tumors with low FDG-avidity (such as bronchoalveolar carcinoma or carcinoid) and in the immediate post-chemotherapy setting [6, 7, 46]. Despite overall high specificity of FDG PET/CT for detection of distant metastases to the adrenals, false positives are encountered and should be recognized. Pheochromocytomas, either benign or malignant, can present as large heterogenous tumors with increased FDG uptake [47]. False-positives PET/CT scans have also been reported in inflammatory/infectious processes [48], benign adrenal adenoma and hyperplasia, myelolipoma, hemorrhagic nodules, peri-renal brown fat, and following chemotherapy [6, 7]. Several studies have noted an overlap in metabolic activity between malignant and benign adrenal nodules with nearly 5 % of benign adenomas demonstrating FDG uptake greater than liver, therefore mimicking metastases. In order to further characterize adrenal lesions with metabolic activity equal to that of liver, or just slightly higher, these adrenal lesions can be evaluated with dedicated adrenal protocol contrast washout CT technique. As stated above, this technique can differentiate adenoma from metastasis with sensitivity of 98 % and specificity 97 % [20]. Table 3 summarizes pitfalls associated with FDG PET/ CT interpretation of adrenal metabolic activity. Alternative PET imaging agents to FDG There are alternative radiopharmaceuticals to FDG for PET imaging, which may be of value for characterization of a

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hyperfunctioning adrenal nodule; however, their availability is currently limited to academic centers, and they are discussed briefly for completeness. 11C-labeled metomidate (MTO) is a selective inhibitor of 11b-hydroxylase, an enzyme involved in adrenocorticotrophin-regulated biosynthesis of cortisol and aldosterone, used for imaging of tumors of adrenocortical origin. Although MIBG scanning is the most widely used catecholamine analog for radionuclide imaging of pheochromocytomas, other catecholamine precursors radio-labeled with positron emitters have been developed including 11C-labeled hydroxyephedrine (HED), 18 F-fluorodopamine (DA), and 18F-fluorodihydroxyphenylalanine (DOPA). Another major family are the somatostatin receptor analogs for imaging of neuroendocrine tumors, of which 68gallium-DOTA-Tyr-3-octreotide (DOTATOC), 68gallium-DOTA-NaI-octreotide (DOTANOC), and 68gallium-DOTA-octreotate (DOTATATE) are the most commonly used [49]. 11 C-MTO PET of incidentally discovered adrenal nodules could distinguish adrenocortical origin versus non-cortical etiology based on intensity of uptake, with reported SUV from highest to lowest: adrenocortical carcinoma (SUV = 28), functioning and non-functioning adenomas, cortical adenomas, and non-cortical lesions (median SUV = 5.7). Although 11C-MTO PET had 100 % sensitivity and specificity for identifying adrenocortical versus non-adrenocortical masses, it could not distinguish between adenoma versus carcinoma as both have high 11C-MTO uptake. 11C-MTO can detect metastatic deposits from adrenocortical carcinoma with sensitivity in one study of 8/11 (72 %). However, falsenegatives occurred due to tumor necrosis, therefore FDG PET/CT remains the radiotracer of choice for staging adrenocortical cancer. If there is biochemical evidence for a catecholaminesecreting pheochromocytoma, 18F-dopamine (DA) has high sensitivity and specificity for localization of intraadrenal and metastatic pheochromocytoma, with superior sensitivity to that of MIBG. In a similar fashion, 18 F-DOPA may be used to characterize adrenal masses suspected to represent pheochromocytoma with high specificity. In the unusual circumstance where other imaging modalities were unsuccessful for adrenal nodule characterization, 68gallium-DOTA peptide PET/CT could be performed to confirm a tumor of neuroendocrine origin and stage for metastatic disease. Although pheochromocytomas will accumulate 68Ga-DOTA-peptide, 18 F-DA or 18F-DOPA would be preferable, if available. Furthermore, 68Ga-DOTA peptides are also accumulated by somatostatin receptor expressing cells, therefore infection or chronic granulomatous inflammation processes involving the adrenals could lead to potential false-positive studies.

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Fig. 2 Imaging flow-chart for the work-up of adrenal nodules

Summary on diagnostic work-up of adrenal lesions The more widespread application of anatomic imaging in routine clinical medicine has identified an increasing number of incidental adrenal masses [50–53], which poses a diagnostic dilemma that can affect patient management. Because the overwhelming majority of these lesions are benign and non-functional, an aggressive approach is not indicated [50–53]. Given the uncertainty in diagnosis of adrenal masses, other than those minority lesions with pathognomonic imaging appearance, many diagnostic algorithms and approaches have been offered to distinguish benign from malignant adrenal lesions [52, 54]. A thoughtful approach to such patients includes an initial biochemical evaluation sufficient to exclude cortical and

Endocrine

Fig. 3 Melanoma metastases. Transaxial 18F-FDG PET (a), CT (b), fused PET-CT (c), and maximum intensity PET (d) images demonstrating a hypermetabolic right adrenal mass (arrow) with a maximum

SUV of 40.5. Additional hypermetabolic foci are demonstrated throughout the body consistent with patient’s known malignancy

medullary hyperfunctioning lesions [55] followed by anatomic and/or functional imaging evaluation with the primary goal being to exclude malignancy. Financial costs, radiation exposure, and nuances of performing numerous recommended tests in a large patient population must also be considered [56–58]. Figure 2 presents a flow-chart for the work-up of adrenal nodules; an exception to this flowchart is related to pheochromocytoma that not only can remain stable for years but also functionally grow very rapidly, therefore a strict monitoring of plasma/urinary catecholamines and metanephrines in the suspicion of pheochromocytoma is mandatory as well as an adequate functional imaging, typically the 123I-MIBG scintigraphy [59].

in 27 % of post-mortem examinations of patients with malignant neoplasms of epithelial origin [58, 59]. Melanoma, breast, lung, colon, lymphoma, kidney, thyroid, esophagus, pancreas, and stomach cancer are the malignancies that commonly metastasize to the adrenals [61]. In a study of 464 patients with adrenal metastases followed over a 30-year period, Lung cancer was the most common (35 %), then stomach (14 %), esophagus (12 %), and cancer of the liver/bile ducts (10 %) [62]. Reports of adrenal metastases in melanoma are as high as 50 % [65– 68] (Fig. 3). Small metastases may be homogeneous on contrast-enhanced CT or MRI, whereas large metastases often have regions of heterogeneous appearance due to necrosis, hemorrhage, or both. Calcification is rare in adrenal metastases. Enlarging adrenal masses are always suspicious for malignancy, even after long periods of stability [64]. There is some evidence for survival advantage for surgical intervention for oligometastatic disease of the adrenals [80–84]. Other treatment approaches to oligometastatic disease include CT-guided ablation [85], radiotherapy, and stereotactic radiation treatments [86, 87]. PET may have an advantage for detection of oligometastatic disease [88]

Malignant adrenal nodules and masses Adrenal metastases The adrenal gland is a common site of metastases and is prone to metastatic seeding due to its rich sinusoidal blood supply [57–79]. Adrenal metastases were reported to occur

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Fig. 4 Adrenocortical carcinoma. Transaxial 18F-FDG PET (a), CT (b), and fused PET-CT (c) images demonstrating a large hypermetabolic left adrenal mass (solid arrow) with a maximum SUV 8.9. The

presence of a hypermetabolic right retrocrural lymph node (dashed arrow) indicates regional nodal metastases

especially metastases from small cell lung cancer [89]. The role of performing routine fine-needle aspiration biopsy (FNAB) or tissue sampling of the adrenal gland is controversial [90] with some authors not reporting meaningful benefit and significant morbidity from the procedure [84]. Adrenalectomy may be considered for solitary adrenal disease when the mass is [4 cm, FDG PET (SUV max [3.1), SUV adrenal:liver ratio [2.5 and washout CT or chemical shift MRI is positive, and FNAB is unsafe or not possible [91].

nodules, FDG PET was used to study indeterminate adrenal tumors at CT. Investigators found that an adrenal/liver max SUV ratio [1.6 had sensitivity 100 % and specificity 90 % for malignant tumor, including 2 ACC less than 5 cm in size [99]. Intensity of FDG uptake was found to be related to survival in patients with ACC with SUV max of [10 indicating poor prognosis. However, in another study, FDG uptake did not provide prognostic information for adrenocortical cancer at 6 months [100]. Pheochromocytoma (malignant and benign)

Primary adrenocortical cancer Adrenocortical carcinoma is a rare tumor, with a reported incidence of two cases per million [92]. Patients may present with abdominal pain, a palpable mass, or Cushing’s syndrome, as about 50 % of these tumors are functional and secrete cortisol. Other endocrine manifestations include aldosteronism, virilization, and feminization. These neoplasms are large (often [6 cm), heterogeneously enhancing masses at presentation [93], with central nonenhancing areas of hemorrhage and necrosis on enhanced CT and MRI scans and they may contain foci of calcification in 20–30 % of cases [58, 94–97]. Concurrent metastases to liver, lungs, or lymph nodes are commonly seen. Venous extension of tumor into the renal veins or the inferior vena cava can be identified on contrast-enhanced images [94]. It is important to define precisely the cephalad extent of the intravenous tumor, as this defines the point where the surgeon can gain vascular control of the tumor [95]. On FDG PET/CT adrenocortical cancer shows a typical intense FDG uptake, greater than liver background [97] (Fig. 4). In 51 patients with adrenocortical cancer FDG PET had sensitivity 95 % and specificity 97 % and the degree of FDG uptake correlated with the Weiss score [98]. In this group, adrenocortical cancer had SUV max adrenal/ SUV max liver [1.7, with adrenal SUVmax mean of 7.3 (4–21.8). In another study of 23 patients with adrenal

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Pheochromocytomas are catecholamine-secreting tumors of the adrenal medulla. Although most patients present with manifestations of excess catecholamine production, approximately 8–10 % of tumors are silent and are incidentally detected by imaging studies [101, 102]. The majority are benign and managed successfully with surgical resection; however, malignant pheochromocytoma is more often associated with genetic inherited syndromes [103, 104]. Apart from the presence of metastatic lesions, there are no differentiating imaging features between benign and malignant pheochromocytomas [105, 106]. Most cases are sporadic, but are increasingly associated with multiple endocrine neoplasia (MEN) syndromes, neurofibromatosis, von Hippel-Lindau disease, or familial pheochromocytoma. Localization of a pheochromocytoma is essential because surgical resection can be curative. CT, MRI, and 131I (and 123 I)-meta-iodobenzylguanidine (MIBG) imaging all have been used to successfully localize pheochromocytomas. Most pheochromocytomas are 2–5 cm in diameter (range 1.2–15 cm) and are readily detected on CT. On unenhanced CT smaller pheochromocytomas have nonspecific findings. Although some are small and homogeneous in attenuation, many have regions of necrosis or hemorrhage and can have ‘‘fluid’’ density on unenhanced CT. Non-functioning tumors are larger and present as incidentalomas on imaging studies. Larger tumors are heterogenous and may have areas of hemorrhage, necrosis,

Endocrine

Fig. 5 Pheochromocytoma. Transaxial 18F-FDG PET (a), CT (b), and fused PET-CT (c) images demonstrating a large hypermetabolic left adrenal mass (arrow) with a maximum SUV of 17.4. This was surgically confirmed to be a benign pheochromocytoma

cystic change and fibrosis, mimicking adrenocortical carcinoma and metastasis. Most lesions demonstrate intense, rapid contrast enhancement and slow washout with contrast washout characteristic similar to malignant tumors [107]. On contrast-enhanced CT adrenal pheochromocytomas show non-specific homogeneous or, more commonly, heterogeneous, enhancement similar to that seen in adrenal metastases or adrenal cortical carcinoma. Occasionally, however, the contrast washout characteristics mimic those of a benign adenoma. Traditionally, 131I-MIBG and 123I-MIBG imaging techniques have been used to stage chromaffin NETs. In a metaanalysis, 123I-MIBG was seen to have a sensitivity of 94 % and a specificity of 95 % for imaging pheochromocytoma [108]. The presence of 123I-MIBG uptake identifies patients for consideration of high-dose 131I-MIBG therapy. However, sensitivity of 123I-MIBG is lower for extra-adrenal sites compared with that for adrenal sites and for malignant tumors compared with benign tumors. In these cases, 18FDOPA PET/CT showed higher sensitivity especially in hereditary forms. Particularly those characterized by succinate dehydrogenase mutation-related pheochromocytoma or paraganglioma [109]. Investigations correlating VMAT activity, cellular proliferative indices, and 123I-MIBG studies have shown that, in the absence of VMAT expression, 123 I-MIBG is often negative and FDG PET becomes positive (Fig. 5). In a study on 216 patients with suspected PHEO/ PGL, FDG PET/CT and 123I-MIBG SPECT/CT had similar sensitivity for detecting the primary lesion (76.8 vs. 75 %), with both being inferior to the CT/MRI sensitivity of 95.7 %. However, for imaging of metastatic disease, FDG PET had a higher sensitivity of 82.5 %, compared 123I-MIBG (50 %) and CT/MRI (74.4 %). SDH-related and von Hippel–Lindau-related tumors have higher FDG SUVmax compared with neurofibromatosis and multiple endocrine neoplasiarelated PHEO/PGL. For metastatic PHEO/PGL related to SDH germline mutations, FDG PET had a sensitivity of 100 %, which exceeded that of MIBG (80 %), and somatostatin receptor scintigraphy (SRS) (81 %) [104]. Carneys triad, a very rare condition with gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal

paragangliomas, has been evaluated with PET [103]. Unsuspected pheochromocytoma can sometimes lead to risks with surgical intervention [110]. Successful surgical treatment may lead to renal function improvement with therapeutic response seen with PET [111]. Neuroblastoma Neuroblastoma is the third most common malignancy of childhood accounting for 8–10 % of all pediatric malignancies, and it can be seen less frequently in adults. It arises from sympathetic neuroblast cells of the neural crest and may occur anywhere along the parasympathetic plexus, presenting as an adrenal tumor in 40–60 %, in the retroperitoneum in 20 %, and in the mediastinum or neck in 10 % of cases [112]. Adults are more likely than children to present with disseminated disease [113]. 123I-MIBG imaging has an overall sensitivity of 90 % and a specificity of 100 % for neuroblastoma [108] and is used to select patients for subsequent high-dose 131I-MIBG therapy [114]. Recently, FDG PET/CT was proposed for staging of neuroblastoma, based on observations that less-differentiated neuroblastoma loses the ability to concentrate MIBG [115]. FDG PET/CT appears to be more sensitive than 123IMIBG for soft-tissue disease in the neck, thorax, abdomen, and pelvis [112]. Sharp et al. reported that, although FDG PET/CT is more accurate than 123I-MIBG for stage 1 and 2 disease, 123I-MIBG is superior to FDG PET/CT for stage 3 and 4 disease [116]. This occurred because osseous metastases, the most common site of spread in neuroblastoma, are more readily detected with 123I-MIBG because of confounding FDG marrow stimulation after chemotherapy. Primary adrenal melanoma Primary melanoma of the adrenal, first reported in 1946, is extremely rare with between 20 and 30 cases reported in the world literature [117–123]. Diagnosis is difficult due to frequent adrenal metastases from melanoma. Carten established 4 criteria for diagnosis: (1) neoplastic involvement of a single gland; (2) absence of melanoma elsewhere; (3)

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confirmed absence of previous excision of cutaneous, mucosal or ocular pigmentary lesions; and (4) exclusion of occult pigmented lesion preferably by autopsy. Despite these criteria, primary adrenal melanoma may be difficult to distinguish from widely metastatic melanoma of unknown primary with unilateral adrenal involvement [123]. Primary adrenal lymphoma Secondary disease involvement of the adrenals is seen in up to 25 % of patients, more so with non-Hodgkin’s lymphoma than Hodgkin’s disease. Secondary involvement is often bilateral, and other retroperitoneal disease is usually present with disseminated non-Hodgkin’s lymphoma of which 70 % are diffuse large B cell lymphoma [124]. Disease involvement can range from bilateral small nodules to large masses with contrast washout characteristics similar to other malignant adrenal lesions (RPW \60 % and APW \40 %) [125]. Primary lymphoma of the adrenal glands is rare with only 70 cases reported in the literature [126–128] accounting for 3 % of extra-nodal lymphoma [129]. The most common presentation is with bilateral adrenal masses and symptoms of fever, weight loss, and adrenal insufficiency [129]. In one review, 56/70 cases were bilateral and the majority were of B cell origin with only 6 cases of T cell lymphoma reported [128]. On CT scan, they have a heterogenous appearance with areas of hemorrhage and necrosis. Most lesions are hypovascular with minimal contrast enhancement. They present as bilateral large intensely FDG-avid adrenal masses without extra-adrenal disease and SUV max as high as 21 [129]. Rare malignancies Other rare malignancies with adrenal involvement on FDG PET/CT include leiomyosarcoma [130], malignant fibrous histiocytoma (bilateral adrenal metastases with SUV max of 13 and 5) [131], and retroperitoneal dysgerminoma [132]. Angiosarcomas arising from the adrenals are exceedingly rare [133–136], and to date FDG PET/CT findings have not been described.

Benign adrenal masses Adrenocortical adenoma Benign adrenocortical adenoma is the most common adrenal tumor, reported as occurring in 1.4–8.7 % of postmortem examinations [137], with higher incidence in patients with hypertension or diabetes [138–140]. Adenomas large enough to be recognized on abdominal CT

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examinations are found in approximately 1–5 % of patients [141]. Benign adrenocortical adenomas represent 80 % of all adrenal neoplasms and may be non-functioning or functioning. Most adenomas are well circumscribed, homogenous lesions measuring 1–3 cm in size [51] and around 10–20 % of adenomas are bilateral [142]. Because most adenomas contain intra-cytoplasmic lipid, many have a low CT density, often approximating water on unenhanced CT [143]. Calcification is rare. Adenomas show early contrast enhancement after intravenous administration of iodinated contrast media, and although the degree of enhancement is not significantly different from that of other adrenal tumors, adenomas do show more rapid washout of contrast than do adrenal malignancies [55, 144, 145]. Chemical shift MR imaging is also used to identify the intra-cytoplasmic lipid and can distinguish many adenomas from metastases [146–148]. The endocrine work-up of adrenal masses has been discussed above. FDG PET/CT has potential to investigate adrenal masses otherwise ‘‘indeterminate’’ on CT and MRI. In one case report, FDG PET was true negative in a large right adrenal adenoma which was difficult to distinguish from a posterior right hepatic lobe mass, aiding in correct diagnosis [149] (Fig. 6). Unfortunately the utility of FDG PET/CT for adrenal mass evaluation is hampered by a small, though significant number of false positives due to adrenocortical adenomas, which may be functioning or non-functioning, with overlap between adenomas and malignancy. Several authors have described focal increased FDG uptake in a benign adrenal adenoma [150–152] and also in a rare black (pigmented) adrenal adenoma [153]. An adrenal adenoma with subclinical Cushing’s syndrome also had increased FDG uptake with max SUV of 4.8, considered higher than normally seen with benign adrenal lesions [154]. Ectopic ACTH-induced macrohyperplasia has been described with bilateral increased adrenal FDG uptake [127, 155]. A patient with paraneoplastic Cushings syndrome related to breast cancer was assessed with FDG PET and found to have SUV of 6.8 and 6.3 with enlarged adrenal limbs on diagnostic CT and elevated ACTH 2–3 times normal [156]. A novel use of FDG PET is to localize remnant and ectopic adrenal tissue after bilateral adrenalectomy with recurrence of symptoms of hyperadrenalism. The FDG PET/CT is performed after ACTH stimulation which leads to increased visibility of FDG uptake in adrenal rests [157, 158]. Primary aldosteronism is characterized by moderate to severe hypertension caused by unregulated secretion of aldosterone with elevated levels of serum and urinary aldosterone, hypokalemia, and suppressed plasma renin activity. A solitary aldosterone-producing adenoma is

Endocrine

Fig. 6 Adrenal adenoma. Transaxial 18F-FDG PET (a), CT (b), and fused PET-CT (c) images demonstrating a small right adrenal nodule (arrow) with FDG uptake that is less than the liver background with a

maximum SUV of 1.7. The lesion measures 5 Hounsfield units, which also characterizes it as an adrenal adenoma based upon CT criteria

Fig. 7 Adrenal myelolipoma. Transaxial 18F-FDG PET (a), CT (b), and fused PET-CT (c) images demonstrating a fat containing right adrenal mass (arrow) with mild FDG uptake that is less than liver

background with a maximum SUV of 2.3. The presence of macroscopic fat density is pathognomonic for a myelolipoma

present in about 70 % of patients, and surgical or laparoscopic adrenalectomy corrects hypertension and hypokalemia in 75–90 % of cases. Very rarely bilateral hyperplasia may have a predominant unilateral macronodule and contralateral gland thickening, that may lead to an erroneous diagnosis of a unilateral aldosteronoma. Bilateral adrenal incidentalomas with hyperaldosteronism have been described as positive on PET, albeit low-grade uptake with a max SUV of 2.7 [159].

contain variable amounts of macroscopic fat giving CT density of -30 to -100 HU, enhancing soft tissue and occasionally calcifications [163]. FDG PET findings were described in a patient with bilateral adrenal myelolipomas [164, 165]. These lesions usually have FDG uptake below that of liver background (Fig. 7). Myelolipoma can occasional be a false-positive finding on FDG PET/CT [127]. Lipoma

Myelolipoma Myelolipomas are rare, benign tumors composed of hematopoietic bone marrow elements and mature adipose tissue. Their incidence is 0.2 % on autopsy studies and they are more commonly unilateral [160]. They are usually slow-growing, non-functioning, and asymptomatic. Occasionally, large tumors or those undergoing tumor necrosis or spontaneous hemorrhage may cause flank pain [161, 162]. Because these tumors contain large amounts of fat, most myelolipomas are easily recognized on CT. On CT scans, the majority of myelolipomas are well defined and measure 1–4 cm in size. Lesions larger than 5 cm tend to hemorrhage, resulting in rapid increase in size [142]. They

Adrenal lipomatous tumors comprise 4.8 % of all primary adrenal tumors and include myelolipomas, lipomas, angiomyolipomas, teratomas, and liposarcomas [166–168]. They are usually composed of benign mature adipose tissue; however, unlike myelolipomas, lipomas do not have haematopoietic elements. Rarely, they can present with spontaneous hemorrhage [169]. Only 14 cases have been reported in the literature [170–174], and to date FDG PET findings have not been described. Angiomyolipomas are common in the kidney and consist of a mixture of adipose tissue, smooth muscle, epithelioid cells, and blood vessels. Rarely angiomyolipomas

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Fig. 8 Brown fat. Transaxial 18F-FDG PET (a), CT (b), and fused PET-CT (c) images demonstrating bilateral increased FDG uptake localizing to the fat adjacent to the adrenal glands (arrows) with a

maximum SUV of 12.8. The presence of additional foci of brown fat uptake in the supraclavicular and paraspinal regions (not shown) confirms the diagnosis

have been described as extra-renal and may involve the adrenal gland. FDG PET findings have not been described [175].

Hemangioma

Brown fat FDG uptake occurring on PET/CT is a well-described entity that occurs in metabolically active, mitochondriarich, brown adipose tissue, usually found in the head/neck and supraclavicular region and thoracic paraspinous soft tissues, however that can be found in retroperitoneal paraadrenal and para-renal locations, with implications for interpretative errors [176–178] (Fig. 8). FDG uptake in adjacent para-adrenal brown fat may mimic adrenal metastases, and requires careful review of the fusion PET/ CT images to determine to origin of uptake and the adjacent. Ganglioneuromas Ganglioneuromas are benign tumors composed of mature ganglion cells, Schwann cells and nerve biers that occur in young adults. These tumors arise from the neural crest and occur anywhere along the paravertebral sympathetic plexus; approximately 20–30 % arise in the adrenal medulla [180]. Because they do not secrete hormones, most ganglioneuromas are asymptomatic, detected as an incidental finding [181]. On CT, ganglioneuroma appears as a solid adrenal mass measuring up to 11 cm in diameter with homogenous or mildly heterogenous enhancement [55]. Extra-adrenal retroperitoneal tumors may be even larger [180]. FDG PET was performed in 5 cases of ganglioneuroma with a mean SUV max of 2.4 (range 1.5–2.9). In this series, one composite tumor with minor ganglioneuroma component had SUV of 7.6, noting that the ganglioneuroma was likely of low FDG-avidity [182]. Other cases of ganglioneuroma have reported low-grade FDG uptake with SUV max of 2.02 [183] and SUV max of 4 [184].

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An adrenal hemangioma is a rare, benign tumor comprising closely adjacent vascular channels lined with a single layer of endothelium [133, 134]. On CT, hemangiomas are seen as large, well-defined masses with soft-tissue density, often with calcifications due to phleboliths or prior hemorrhage on unenhanced images and demonstrate inhomogeneous contrast enhancement [185, 186]. Rare benign tumors of the adrenals Oncocytoma is a epithelial tumor characterized by loosely packed mitochondria usually arising in the salivary glands, kidneys, thyroid, parathyroids, and pituitary. Adrenocortical oncocytomas are rare with only 110 cases reported in the literature, and they have variable malignant potential [187]. Oncocytoma has been described as a FDG-avid lesion, with rare involvement of the adrenal [188]. A case of a benign solitary fibrous tumor on FDG PET has been reported [189]. Adrenal collision tumors Two separate processes affecting a single adrenal gland, so-called adrenal collison tumors are rare, with only a handful reported in the literature. A metastasis to an adrenal gland with a pre-existing adenoma (collision tumor) may result in a falsely low CT attenuation value of less than 10 HU. A case of a lung cancer metastasis within an adrenal myeolipoma detected on FDG PET has been described [190]. There was a small FDG-avid nodule centrally within a fat containing right adrenal mass. CTguided biopsy guided by FDG PET/CT confirmed metastatic disease. Another case of coexisting adrenal adenoma in the superior limb and metastatic sarcoma was proven on the biopsy guided by FDG PET/CT [191]. Another case reported a collision tumor with metastatic disease developing in a adrenal nodule previously characterized as an adenoma [192].

Endocrine

Inflammatory granulomatous disease

Adrenal hemorrhage

Tuberculosis, histoplasmosis, blastomycosis, and other granulomatous diseases affecting the adrenals usually have bilateral involvement but often asymmetrical. CT findings are variable and include the presence of soft tissue masses, cystic changes, and/or calcification [193]. Although uncommon, they should be considered in the differential diagnosis of incidental bilateral adrenal masses in the absence of a primary neoplasm or coagulopathy. Biopsy is needed to confirm the diagnosis and identify the responsible organism. Tuberculosis, the most common bacterial cause of adrenal infection, has been reported to demonstrate intensely hypermetabolic bilateral mass-like enlargement of the adrenals, acting as a potential mimic of adrenal metastases [127, 194]. There is difficulty in staging lung cancer in patient populations with endemic tuberculosis; in one study of 54 patients, 2 of whom had adrenal uptake one lesion was malignant and one benign [142, 195]. Other reports of tuberculosis affecting the adrenals confirm increased FDG uptake on PET [196, 197]. Rarely, adrenal tuberculosis may lead to adrenal insufficiency [198]. Bilateral adrenal masses due to histoplasmosis, the most common fungal cause of adrenal infection, were reported to have increased FDG uptake; SUV max of 5.7 and lesion:liver uptake ratio of 3.1 [199]. FDG PET/CT showed a treatment response to antifungals with decreasing SUV to 3.4 on the right and 3.5 on the left. Another study of bilateral adrenal histopasmosis showed SUV max of 19.7 and 24.5, respectively [200], therefore histoplasmosis is a potential mimic of adrenal malignancy in endemic countries [127, 201, 202]. Syphilis is another rare disease that may affect the adrenals causing focal FDG uptake [203].

Adrenal hemorrhage can result from blunt abdominal trauma. Non-traumatic adrenal hemorrhage may arise from stressors: bleeding diathesis, percutaneous intravenous procedures, surgery, organ failure, sepsis, pregnancy, [206– 208] and in relation to tumors such as myelolipoma, pheochromocytoma, or metastases. The adrenal gland has a rich blood supply arising from 3 arteries, with only one draining vein, predisposing to bleeding. Adrenal vein thrombosis may occur as a complication of adrenal vein catheterization leading to hemorrhage [209, 210]. Patients present with signs and symptoms of adrenal insufficiency [abdominal pain, flank pain, nausea and vomiting, hypotension, fever] and low hematocrit values [211]. The highattenuation value of a recent adrenal hemorrhage is usually readily apparent on unenhanced CT, but is indistinguishable from a solid adrenal neoplasm on contrast-enhanced CT. An adrenal mass detected on contrast-enhanced CT after trauma usually is assumed to be a hematoma, but an unrelated adrenal neoplasm can be only excluded only by serial follow-up CT. Adrenal hemorrhage may present with increased FDG uptake in the adrenals, often bilateral [212–214] (Fig. 9).

Adrenal cyst Adrenal cysts are uncommon lesions with a 3:1 female predilection and four types of cysts reported on the basis of pathologic classification: endothelial, epithelial, parasitic, and post-traumatic pseudocysts [204, 205]. True cysts are of fluid attenuation with thin enhancing walls. They may contain thin enhancing septae and calcification. A report of 13 new cystic adrenal masses and review of 26 benign adrenal cysts from the literature included one cystic adrenocortical carcinoma [105]. Features of the 37 benign cysts were mural calcification in 19, central calcification in 7, unilocular in 28, and high-attenuation values in 7. The authors concluded that a CT finding of a non-enhancing mass with or without wall calcification allows differentiation of an adrenal cyst from an adenoma. A small adrenal cyst with near-water attenuation and a thin (B3 mm) wall is likely benign. FDG PET/CT findings were described as ‘cold’ in one example of adrenal cyst [127].

Adrenal insufficiency Adrenal insufficiency is most commonly due to an autoimmune etiology causing atrophy of the adrenal glands, and imaging is usually not useful for diagnosis as the glands are small and difficult to identify on either CT or MRI. Other causes of adrenal insufficiency include granulomatous infection from tuberculosis, histoplasmosis, or blastomycosis, bilateral adrenal hemorrhage and rarely bilateral adrenal masses, as it is believed that over 90 % of the adrenal volume must be destroyed in order for adrenal insufficiency to occur [215]. Granulomatous disease involvement presents with inhomogeneous low attenuation within the adrenal mass due to caseous necrosis, best seen on enhanced CT or MRI. Unlike patients with adrenal metastases, the enlarged glands typically retain their normal shape, and in the acute and subacute phases of disease are associated with bilateral adrenal enlargement. Bilateral adrenal hemorrhage can be accompanied by adrenal insufficiency with the detection of bilateral hyperattenuating masses on unenhanced CT being the first clue to this diagnosis. Adrenal insufficiency can be caused by acquired immunodeficiency syndrome (AIDS) and the antiphospholipid antibody syndrome, with the appearance of the adrenal glands being variable. Autoimmune adrenalitis causing adrenal insufficiency has been described as having bilateral FDG uptake within adrenals that retained their normal in size and morphology, possibly related to lymphocyte infiltration and inflammation.

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Fig. 9 Adrenal hemorrhage. Coronal 18F-FDG PET (a), CT (b), and fused PET-CT (c) images demonstrating bilaterally enlarged adrenal glands with central photopenia, with a rim of peripheral mildly

increased FDG activity (arrows). The patient presented with hypotension and adrenal insufficiency after a complicated surgery

Fig. 10 Chemotherapy Effect. Transaxial 18F-FDG PET (a), CT (b), and fused PET-CT (c) images demonstrating increased FDG uptake in the structurally normal right adrenal gland (arrow) with a maximum SUV of 8.0 without an anatomic correlate. The patient was status post

left adrenalectomy due to a left adrenal cortical carcinoma and recently completed chemotherapy. This finding was a benign effect from chemotherapy

Post-adrenalectomy and chemotherapy

Conclusions

Following the observation of a case in which increased FDG uptake was seen on FDG PET/CT in the contralateral adrenal gland after adrenalectomy for adrenocortical cancer, in which the surgically removed specimen was found to be benign, a systematic investigation of this phenomenon was performed [216]. Hypermetabolic activity was found to occur in the structurally normal adrenals of between 14 and 29 % of patients with all cases resolving spontaneously within 24 months (Fig. 10). The authors postulated that it was an effect of chemotherapy and when seen should not be considered as corresponding to disease. This phenomenon has been suggested to be due to an effect of mitotane, commonly used as an adjunctive therapeutic agent with effects on cholesterol synthesis pathways [217, 218]. Physiological FDG activity within an upper pole duplex collecting system is a potential false-positive mimic of a hypermetabolic adrenal lesion on stand-alone FDG PET scans [219]. Administration of furosemide to clear radioactive urine from the pelvicalyceal systems has been suggested to improve interpretation of PET scans [220], however with the adoption of PET/CT, review of fusion images should prevent any ambiguity as to the origin of calyceal uptake.

Diagnostic work-up of incidentally discovered adrenal masses on cross-sectional imaging remains challenging. Although an aggressive approach is not indicated for all patients, early detection of adrenocortical cancer is crucial due to poor outcomes, and identification of distant metastatic or oligometastatic adrenal disease in cancer patients may change the management plan. For adrenal masses that appear to be benign on unenhanced CT (\10 HU; absolute contrast washout, [60 %), small (\3 cm), and completely non-functioning, imaging and biochemical re-evaluation at 1–2 years is appropriate. Current evidence suggests a role for FDG PET/CT in assessing the malignant potential of an adrenal mass, categorized as ‘‘indeterminate’’ by unenhanced or contrast-enhanced CT, or MRI. Interpretation of FDG PET/CT will be more accurate if the reader has knowledge of the characteristic metabolic and anatomic findings of a spectrum of benign and malignant adrenal masses, as well as an appreciation of potential pitfalls that may lead to false-negative and false-positive metabolic interpretation. Lastly, there is no doubt that PET/CT helps to differentiate benign from malignant adrenal mass. However, it should be emphasized that as point out by Pitts et al. PET/

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CT is not needed for most patients and that many diagnostic problems can be revolved by CT and/or MRI [63].

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