Online version at https://www.minervamedica.it

REVIEW NUCLEAR ENDOCRINOLOGY IN THE ERA OF PRECISION MEDICINE

Integration of molecular imaging in the personalized approach of patients with adrenal masses

Margherita LORUSSO 1, Vittoria RUFINI 2,3, Carmela DE CREA 3, 4 *, Francesco PENNESTRÌ 3, 4, Rocco BELLANTONE 3, 4, Marco RAFFAELLI 3, 4

1PET/CT Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 2Section of Nuclear Medicine, University Department of Radiological Sciences and Hematology, Università Cattolica del Sacro Cuore, Rome, Italy; 3Division of Endocrine and Metabolic Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 4Università Cattolica del Sacro Cuore, Rome, Italy

*Corresponding author: Carmela De Crea, Sacred Heart Catholic University, Rome, Italy. E-mail: carmela.decrea@unicatt.it

ABSTRACT

Adrenal masses are a frequent finding in clinical practice. Many of them are incidentally discovered with a prevalence of 4% in patients undergo- ing abdominal anatomic imaging and require a differential diagnosis. Biochemical tests, evaluating hormonal production of both adrenal cortex and medulla (in particular, mineralocorticoids, glucocorticoids and catecholamines), have a primary importance in distinguishing functional or non-functional lesions. Conventional imaging techniques, in particular computerized tomography (CT) and magnetic resonance imaging (MRI), are required to differentiate between benign and malignant lesions according to their appearance (size stability, contrast enhanced CT and/or chemical shift on MRI). In selected patients, functional imaging is a non-invasive tool able to explore the metabolic pathways involved thus providing additional diagnostic information. Several single photon emission tomography (SPET) and positron emission tomography (PET) radiopharmaceuticals have been developed and are available, each of them suitable for studying specific pathological conditions. In functional masses causing hypersecreting diseases (mainly adrenal hypercortisolism, primary hyperaldosteronism and pheochromocytoma), functional im- aging can lateralize the involvement and guide the therapeutic strategy in both unilateral and bilateral lesions. In non-functioning adrenal masses with inconclusive imaging findings at CT/MR, [18F]-FDG evaluation of tumor metabolism can be helpful to characterize them by distinguishing between benign nodules and primary malignant adrenal disease (mainly adrenocortical carcinoma), thus modulating the surgical approach. In oncologic patients, [18F]-FDG uptake can differentiate between benign nodule and adrenal metastasis from extra-adrenal primary malignancies.

(Cite this article as: Lorusso M, Rufini V, De Crea C, Pennestrì F, Bellantone R, Raffaelli M. Integration of molecular imaging in the personalized approach of patients with adrenal masses. Q J Nucl Med Mol Imaging 2022;66:104-15. DOI: 10.23736/S1824-4785.22.03449-5) KEY WORDS: Functional neuroimaging; Radiopharmaceuticals; Fluorodeoxyglucose F18; Precision medicine.

A drenal masses are a frequent finding in clinical prac- tice. The greatest portion of adrenal masses are be- nign and non-functioning; most of them are incidentally discovered mainly due to the wide diffusion and accuracy of high-resolution imaging techniques and require a dif- ferential diagnosis with the less frequent malignant le- sions (both primary and metastatic) and hyperfunctioning conditions, such as pheochromocytoma (Pheo), Cushing’s Syndrome and hyperaldosteronism. The so-called “adre- nal incidentalomas” are masses greater than 1 cm that are incidentally detected by abdominal imaging techniques such as computed tomography (CT), magnetic resonance

imaging (MRI) and ultrasound (US) performed for other indications.1, 2 They are usually benign findings with a prevalence of about 4%, ranging from 2% to 10% depend- ing on age2,3 with lower values in children (<0.5%).4

When an adrenal mass is discovered, clinical evaluation and biochemical testing are the starting point, followed by imaging studies to distinguish a benign lesion such as non-secretory adenoma, adrenal cyst, hematoma or my- elolipoma, from a malignant one such as adrenocortical carcinoma, lymphoma, malignant Pheo, angiosarcoma or adrenal metastases in patients affected by cancer.3,5

Biochemical testing is essential to distinguish whether

LORUSSO

an adrenal nodule secretes hormones or not. To this aim dosage of mineralocorticoids, glucocorticoids, adrenal androgen hormones, and catecholamines must be per- formed. The adrenal gland is divided in two sites (cortex and medulla) composed by several cell types. The adrenal cortex, producing steroids, is divided into 3 zones: 1) the outer zona glomerulosa, producing the mineralocorticoid aldosterone; 2) the zona fasciculata, synthesizing corti- sol; 3) the zona reticularis, which produces the androgen precursor dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). Adrenal masses originating from adrenal cortex can produce aldosterone, cortisol, and rarely DHEAS caus- ing Cushing’s Syndrome, primary aldosteronism and ad- renal hyperandrogenism, respectively. The most common hormonal abnormality is MACS (mild autonomous corti- sol secretion) characterized by abnormal 1-mg overnight dexamethasone suppression test.6 A mixture of aldosterone and cortisol secretion is also possible.7 Adrenocortical car- cinoma (ACC), usually found in about 0.3% of adrenal tu- mors,6 is very malignant with high recurrence rates even in patients with microscopically complete resection8-10 and can produce multiple hormones.11 Adrenal androgen ex- cess typically is associated with ACC.6 The adrenal medul- la produces catecholamines. Tumors originating from this site are Pheos, which produce catecholamine excess (epi- nephrine or norepinephrine) that is typically proportionate to size7 and causes hypertension that may be paroxysmal, and other symptoms such as sweating, headache and palpi- tations. About 4% of Pheos are biochemically silent.12

Dedicated imaging modalities are required to differ- entiate benign from malignant adrenal lesions. The most used are CT and/or MRI. US can detect adrenal lesions too, but it is less sensitive and more operator-dependent in comparison with CT or MRI. CT is the first-level imag- ing tool once an adrenal mass is discovered; a dedicated acquisition protocol is usually performed.13 Some benign lesions such as hematomas, cysts and myelolipomas are clearly characterized by CT and MRI. Imaging patterns such as homogeneous density at CT or homogeneous sig- nal intensity at MRI, as well as unchanged lesion size at 6-12 months follow-up suggest a benign mass. Converse- ly, ACC are usually large and heterogeneous lesions with peripheral contrast-enhancement and central necrosis.14 At unenhanced CT, an attenuation value (that is the Houn- sfield Unit, HU) ≤10 is indicative of lipid rich lesions, showing high specificity for adenoma.15 This cutoff value is accurate also for large adrenal masses (>4 cm).6 Another typical radiological feature of adenomas is the high wash- out rate on contrast-enhanced CT (absolute washout >60%

or relative washout >40%).16, 17 The most useful MRI tech- nique to characterize adrenal masses is the Chemical Shift Imaging, which allows to detect the intracellular lipid typically contained in adenomas with loss of signal in the “out of phase” sequence.13, 18-20 However, about 30% of adrenocortical adenomas show an atypical pattern on CT/ MRI due to low cytoplasmatic fat.14 An important criterion at morphologic imaging is lesion size that is proportional to the risk of malignancy. The prevalence of malignancy is 9% for adrenal lesions of 2-4 cm and 34% for lesions >4 cm.21 In clinical practice, lesions ≤4 cm in size that are not clearly characterized by CT/MRI are followed up by imaging after at least 6 months; stable lesions are consid- ered benign. Lesions >4 cm need discussion at multidisci- plinary board to define individualized management.14

Patients with symptoms or biochemistry indicating a functioning lesion may benefit from functional imaging studies in selected cases to obtain an accurate diagnosis before adrenalectomy, which is the standard of care for unilateral hyper-functioning adrenal tumors.22 Currently, laparoscopic adrenalectomy is the gold standard treatment for small to medium-sized (≤6 cm) benign adrenal tumors, both functioning and non-functioning with a reduction of postoperative morbidity and postoperative pain.23

Nuclear medicine imaging allows the functional charac- terization of different conditions by using multiple radio- pharmaceuticals, which explore the metabolic pathways involved in hormonal production by cortical and medullary adrenal masses or other metabolic pathways such as glucose metabolism, overexpression of somatostatin receptors or chemokine receptors type 4.14 This review aims to overview the status of molecular imaging in the functional character- ization of adrenal masses and its potential role in providing useful indications to guide personalized therapeutic choices.

Functional imaging of adrenal cortex

In this section, single-photon emission computed tomog- raphy (SPECT) and positron emission tomography (PET) radiopharmaceuticals for adrenal cortex as well as the im- aging findings in adrenocortical diseases are described. Table I reports the principal radiopharmaceuticals and the metabolic pathways by which they are incorporated into adrenal cortex.

SPECT radiopharmaceuticals

Radiocholesterol analogs

The radiolabeled cholesterol analogs [131]]-iodocholesterol (the first adrenocortical-avid radiotracer introduced in clin-

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

LORUSSO

TABLE I .- Adrenal cortex radiopharmaceuticals: explored metabolism or function and principal clinical indications.
Radiopharmaceutical	Explored metabolism or function	Principal clinical indications
SPET radiotracers
[13]]]-60-iodomethyl-19-norcholesterol	Glucocorticoid synthesis	Cushing's Syndrome and primary aldosteronism
[123I]-iodometomidate ([123I] -IMTO)	Glucocorticoid synthesis	Primary aldosteronism; ACC staging
PET radiotracers
[11C]-Metomidate ([11C] -MTO)	Glucocorticoid synthesis	Primary aldosteronism
[68Ga]-pentixafor	C-X-C chemokine receptor 4 expression	Primary aldosteronism
[18F]-Fluorodeoxyglucose ([18F] -FDG)	Glucose metabolism	Benign lesions vs. adrenal malignant tumors; ACC staging and follow-up; benign lesions vs. adrenal metastasis.

ACC: adrenocortical carcinoma.

ical practice) and [131]]-60-iodomethyl-19-norcholesterol (a second-generation compound currently in use) are spe- cific radiotracers used for more than 40 years for adreno- cortical scintigraphy due to high specificity and accuracy in defining adrenal cortical masses.24, 25 These radiophar- maceuticals bound to low-density lipoproteins in the cir- culation and are taken up into adrenocortical cells where they are esterified and intracellularly trapped. Adrenocor- tical uptake of radiocholesterol analogs is under control of the hypothalamic-pituitary-adrenal axis and the renin-an- giotensin-aldosterone axis.26 Seven days before and during radiocholesterol scintigraphy, Lugol solution or saturated potassium iodide solution is administered to avoid thyroid uptake of “free” radioiodine.27 In case of hyperaldosteron- ism, the patient must take a 7-10-day course of dexametha- sone to suppress non-autonomous hormone synthesis.26 In clinical practice, adrenocortical scintigraphy has demon- strated to be useful in confirming and localizing hormone- secreting adrenal adenoma in the context of Cushing’s Syndrome and primary aldosteronism. Major limitations of adrenocortical scintigraphy are the relatively high ra- diation dose (the effective dose is 1.5 mSv/MBq);28 the need of time-consuming acquisition protocols (4-7 days from injection to obtain an adequate adrenal/background ratio); the poor spatial resolution; and the current limited availability of [131]]-60-iodomethyl-19-norcholesterol.29 Due to these several drawbacks this radiopharmaceutical is no longer widely used.

[123I]-iodometomidate

Metomidate is an imidazole-based methyl ester analogue of etomidate and is a potent inhibitor of the enzymes in- volved in corticosteroids synthesis: 11-ß-hydroxylase (CYP11B1), which is expressed across all adrenocortical zones and aldosterone synthase (CYP11B2), which is ex- pressed in aldosterone-producing cells.14, 30 Metomidate

binds with high affinity and specificity to the adrenocorti- cal CYP11B enzymes, which are exclusively expressed in adrenocortical cells.31 [123I]-iodometomidate for SPECT imaging has a potential advantage over the PET radiotrac- er [11C]-metomidate (see the paragraph “PET radiophar- maceuticals” below) due to its longer half-life (13.2-hours for 123I versus 20 minutes for 11C). [123I]-iodometomidate SPECT/CT and [11C]-metomidate PET/CT help to dif- ferentiate adrenocortical and non-adrenocortical lesions and can visualize metastases of adrenocortical carcino- ma.31-34 Both compounds show advantages over [13]]]-6ß- iodomethyl-19-norcholesterol, such as shorter imaging timing, low radiation exposure to the patient and higher image resolution. A limitation of [123I]-iodometomidate SPECT/CT is the lack of identifying adenomas smaller than 1 cm in diameter.35

PET radiopharmaceuticals

[1]C]-metomidate (11C-MTO)

As [123I]-iodometomidate, [11C]-metomidate can dis- tinguish between adrenal cortical and non-cortical le- sions.36 However, PET/CT with [11C]-metomidate showed lower sensitivity and specificity than [18F]-FDG-PET/ CT in discriminating between benign and malignant ad- renal lesions.37 [11C]-metomidate has shown to be par- ticularly useful for visualizing aldosterone-secreting ad- enoma.14, 38 Since aldosterone synthase (CYP11B2) and 11-ß-hydroxylase (CYP11B1) have a similar chemical structure, [11C]-metomidate has high affinity for both of them. Therefore, [11C]-metomidate sensitivity for CY- P11B2 expressing lesions may be subject to interference from nonspecific binding to CYP11B1. This situation may be solved by dexamethasone pretreatment to downregulate 11ß-hydroxylase, thus allowing imaging of aldosterone- producing adenoma.36, 39, 40 Beside the need of premedi-

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

cation with dexamethasone, other disadvantages of [11C]- metomidate are the short half-life of 11C (20 minutes) that limits its use to centers with on-site cyclotron34 and its high non-specific binding to the liver which may impact on assessing the right adrenal gland uptake.36

[68 Ga]-Pentixafor

The chemokine receptor 4 (CXCR4) is a transmembrane G protein-coupled receptor overexpressed in many types of hematopoietic and solid malignancies causing tumor growth, and metastasis development.41 Its expression in- creases in aldosterone-producing tissue of normal adrenals and in aldosterone-producing adenomas and is closely associated with the expression of CYP11B2, involved in aldosterone synthesis and highly expressed in hyperaldo- steronism.42-45 At in-vitro studies, non-functioning adrenal adenomas do not express CXCR4,42 whereas strong ex- pression of CXCR4 was detected by Chifu et al. in 50% of ACC samples.46 There is no need of dexamethasone sup- pression when using this radiopharmaceutical for visual- ization of aldosterone-producing adenoma.45

[18F]-Fluorodeoxyglucose ([18F]-FDG)

[18F]-FDG is a glucose analog extensively used for PET/ CT imaging in oncology. Most cancers, especially those with an aggressive pattern of growth, typically present an increased glucose consumption, which is in part related to overexpression of the glucose transporters and increased hexokinase activity.47 Even though [18F]-FDG is not spe- cific for the adrenal gland, it can identify malignant tumors such as ACC and metastatic lesions, which show high up- take; in particular, ACC is almost always [18F]-FDG posi- tive with a very high negative predictive value.48

Imaging findings in functioning adrenocortical diseases

Among functioning adrenocortical disease, the most im- portant conditions are adrenal hypercortisolism and hyper- aldosteronism. Functional diagnostic investigations can play a fundamental role in the diagnostic framework and, consequently, in guiding therapeutic choices.

Adrenal hypercortisolism

Adrenal hypercortisolism is the overproduction of corti- sol because of an adrenal adenoma or, less frequently an adrenal carcinoma or bilateral nodular adrenal hyperpla- sia. Historically, adrenocortical scintigraphy with [13]]]- 6ß-iodomethyl-19-norcholesterol has been considered a highly sensitive and accurate method depicting the various

forms of adrenal hypercortisolism with typical patterns. In particular:

· adenomas show unilateral activity. The contralateral normal adrenal cortex is not visualized due to suppression of ACTH by the high levels of circulating cortisol pro- duced by the adenoma;49-52

· hypersecreting adrenocortical carcinomas usually are not visualized because of inadequate tracer uptake by poorly differentiated tumor cells; the contralateral adrenal gland is not visualized too, due to suppression of ACTH. However, tracer uptake depends on the degree of cellular differentiation, and thus some well differentiated tumors can be visualized with radio-cholesterol;

· bilateral cortical nodular hyperplasia shows bilateral uptake that is usually asymmetric due to the presence of large nodules in one gland and small nodules in the con- tralateral one.

Despite these typical patterns, there is no need of adre- nocortical scintigraphy in patients with hypercortisolism and typical adenoma at CT/MRI. Adrenocortical scintig- raphy can be of some utility in selected cases to confirm a cortisol-secreting adenoma in patients with borderline hor- mone values (subclinical Cushing’s Syndrome) or to dis- tinguish unilateral adenoma from bilateral cortical nodular hyperplasia. 14, 26, 53 In patients with hypercortisolism and a large heterogeneous mass an ACC is suspected, which can be functionally characterized by 18F-FDG PET/CT showing high tracer uptake both in the primary tumor and distant metastases. Also [11C]-metomidate PET/CT, when available, can be useful for ACC staging.31

Adrenal hyperaldosteronism

Primary hyperaldosteronism is the most common cause of secondary hypertension due to an excess of mineralo- corticoid production in the zona glomerulosa accounting for 1-20% of hypertensive patients.7 Hypokalemia and alkalosis are typical manifestation of primary hyperaldo- steronism, but most of the patients show normokalemia, so screening for this condition is recommended in all hy- pertensive patients presenting with an adrenal nodule.54 In 75% of the cases, primary hyperaldosteronism is caused by an aldosterone secreting adenoma and in 25% of cases by bilateral hyperplasia. A differential diagnosis is impor- tant to choose the most suitable treatment as adenoma is surgically resected, while hyperplasia is treated with min- eralcorticoid receptors antagonists or potassium-sparing diuretics. However, it must be stressed that nonfunctioning adenoma can coexist with aldosterone-secreting adenoma or bilateral hyperplasia. 14 A diagnosis made exclusively by

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

morphologic imaging can lead to inappropriate therapeutic choices in up to 40% of cases.14 Adrenal venous sampling (AVS) is the gold standard for subtyping primary hyper- aldosteronism.54 It is an invasive procedure with possible complications (rupture of adrenal vein, gland hemorrhage, adrenal insufficiency, hypertensive crisis, or thrombosis) and is highly dependent on the expertise of intervention- al radiologist.55 Moreover, the SPARTACUS Trial could not demonstrate its beneficial effect on decrease of blood pressure after surgery, and showed that this procedure pro- duces extra health-care costs that cannot be justified by proportional improvements in patients’ quality of life.56 In this clinical scenario, functional imaging is usually re- quired after unsuccessful AVS localization, which is not uncommon.

In hyperaldosteronism, adrenocortical scintigraphy with [13]]]-6ß-iodomethyl-19-norcholesterol under dexa- methasone suppression has shown to be useful in case of inconclusive AVS, mainly when SPET/CT is performed.57 Typically, early adrenal visualization (before day 5) is representative of hyperfunction of the zona glomerulosa58 and two main pathological scintigraphic patterns can be observed: 1) an unilateral radiotracer uptake before the 5th day postinjection is indicative of aldosterone-secret- ing adenoma (Figure 1); 2) a bilateral radiotracer uptake before the 5th day postinjection is indicative of bilateral hyperplasia. However, the above-mentioned limitations of radio-cholesterol (high radiation dose, poor spatial resolu- tion, and limited availability) are responsible of the less and less wide use of this procedure.

Regarding the radiopharmaceuticals that target the CY- P11B enzyme family, [11C]-metomidate for PET/CT imag- ing has a new emerging role in visualizing aldosterone- secreting adenoma and consequently in guiding treatment. As this tracer can also visualize nonfunctioning adenoma,

Figure 1 .- [131]]-60-iodomethyl-19-norcholesterol scintigraphy (poste- rior view) performed under dexamethasone suppression in a patient with hyperaldosteronism showing early unilateral uptake in the right adrenal (arrow) at 3 days (A) and 5 days (B) postinjection indicating an aldoste- rone secreting adenoma.

dexamethasone suppression is necessary prior to PET/CT. Typically, adrenal adenoma shows higher SUV max values than the contralateral adrenal gland. The use of [123I]-io- dometomidate SPECT/CT in this clinical setting is limited by its low spatial resolution and the lack of identifying ad- enomas smaller than 1 cm in diameter.35

At present, 68Ga-pentixafor is probably the most prom- ising PET/CT radiopharmaceutical for primary hyperaldo- steronism. In their prospective study, Ding et al. showed that 68Ga-pentixafor SUV max was strongly related to the molecular expression of CXCR4 and CYP11B2 and that this radiotracer could distinguish unilateral aldosterone- producing adenoma from bilateral idiopathic adrenal hy- perplasia and nonfunctional adrenal adenoma.45 Thanks to the emerging role of these new tracers (CYP11B ligands and 68Ga-pentixafor) it is expected that nuclear medicine modalities will have an increasingly important role in the management of patients with primary hyperaldosteronism for guiding therapy.

Functional imaging of adrenal medulla

In this section, SPET and PET radiopharmaceuticals for studying the adrenal medulla as well as the imaging find- ings in benign and malignant Pheo are described. Table II reports the principal radiopharmaceuticals and the meta- bolic pathways by which they are incorporated into adre- nal medulla.

SPET radiopharmaceuticals

[123/131I]-metaiodobenzylguanidine ([123/131]]-MIBG)

Radioiodinated MIBG is an iodinated guanidine analogue structurally similar to the neurotransmitter norepineph- rine (NE) and like NE is accumulated in catecholamine- secreting tissues. A sodium-dependent cell membrane noradrenaline transporter (NET) is responsible of MIBG uptake in target tissues. Once in the cytoplasm, MIBG is stored in neurosecretory vesicles by another specific active uptake mechanism, which is mediated by vesicular mono- amine transporters.59-61 Unlike NE, MIBG does not bind to postsynaptic receptors. For scintigraphic imaging, the tracer of choice is MIBG radiolabeled with 123I allowing high quality SPECT and favorable dosimetry (the effective dose in adults is 0.013 mSv/MBq).62 For therapeutic pur- pose, MIBG radiolabeled with 131I at high specific activ- ity is used. Many drugs, such as non-selective alpha- and beta-receptors blockers (labetalol in particular), sympa- thomimetics, antipsychotics, tricyclic antidepressants and

LORUSSO

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

TABLE II .- Adrenal medullary radiopharmaceuticals: explored metabolism or function and principal clinical indications.
Radiopharmaceutical	Explored metabolism or function	Principal clinical indications
SPET radiopharmaceutical
[123I]-metaiodobenzylguanidine ([123I] -MIBG)	Catecholamine uptake and storage	Pheochromocytoma and paraganglioma
PET radiopharmaceutical
[124I]-metaiodobenzylguanidine ([124I] -MIBG)	Catecholamine uptake and storage	Pheochromocytoma and paraganglioma
[18F]-meta-fluorobenzylguanidine ([18F]-mFBG)	Catecholamine uptake and storage	Pheochromocytoma and paraganglioma
[18F]-Dihydroxyphenylalanine ([18F]-DOPA)	Amino acid uptake, decarboxylation, and storage	Pheochromocytoma and paraganglioma
[68Ga]-Somatostatin analogues	Somatostatin receptor status	Pheochromocytoma and paraganglioma
[C]-Hydroxyephedrine ([11C]-HED)	Catecholamine uptake and storage	Pheochromocytoma and paraganglioma
[18F]-Fluorodeoxyglucose ([18F]-FDG)	Glucose metabolism	Pheochromocytoma and paraganglioma (in selected cases)

tricyclic-related antidepressants, cocaine and opioids can potentially interfere with MIBG uptake and/or retention with various mechanisms. Therefore, these drugs should be withdrawn before imaging and therapy for at least one week (or longer for labetalol).63 To protect the thyroid from the uptake of “free” radioiodine, potassium iodide (Lugol’s 5% solution) is administered one hour before MIBG injection according to European Association of Nu- clear Medicine/Society of Nuclear Medicine and Molecu- lar Imaging (EANM/SNMMI) guidelines.63 With regard to [123I]-MIBG scintigraphic procedure, reference to EANM/ SNMMI procedure guidelines for radionuclide imaging of pheochromocytoma and paraganglioma is suggested.63

PET radiopharmaceuticals

[ 124 I]- metaiodobenzylguanidine ([124I]-MIBG)

[124I]-MIBG is a positron-emitting tracer with 4.2-days physical half-life, allowing delayed imaging and dosimet- ric evaluation, which is important for planning an appro- priate radiation dose before [13]]]-MIBG therapy. Thanks to higher-resolution images than those of [123I]-MIBG SPECT, it has been successfully used for imaging patients with pheochromocytoma as well as children with neuro- blastoma.64 Recently, Weber et al. demonstrated high de- tection rate of 124I-MIBG PET/CT for staging and re-stag- ing primary and metastatic Pheos, also allowing tailored treatments by identifying patients eligible for surgical re- section or 131I-MIBG therapy.65 When compared to [123]]- MIBG, major disadvantages of 124I-MIBG, especially in pediatric patients, are the higher effective dose due to the longer half-life and the emission of high energy photons;64 moreover, the use of this PET tracer is hampered by its limited availability.

[18F]-meta-fluorobenzylguanidine ([ 18F]-mFBG)

This is a fluorinated PET analog of MIBG. With respect to radioiodinated MIBG, [18F]-mFBG is more hydrophilic and, thus, has a more faster tissue uptake and renal clear- ance.61 With this tracer, there is no need of pharmacologi- cal thyroid protection. Only few data are available in the literature on the use of [18F]-mFBG for PET imaging of NET-expressing tumors (Pheo/paraganglioma and neuro- blastoma); therefore, this tracer must still be considered experimental.61, 66

[18F]-dihydroxyphenylalanine ([18F]-DOPA)

Among the various PET agents that share with MIBG the catecholamine transport and/or storage mechanisms (these include 18F-DOPA, 11C-hydroxyephedrine, and 18F-fluorodopamine), at present time 18F-DOPA repre- sents the best PET alternative to MIBG for evaluating neural-crest-derived tumors.67-70 [18F]-DOPA is a radio- labeled amino acid transported into target cells via the large neutral amino acid transporter-1 (LAT-1). Then, it is converted by aromatic amino acid decarboxylase (AADC) in [18F]-fluorodopamine, which is trapped into secretory vesicles via vesicular monoamine transporters or degraded by other enzymes.71 The major advantages of [18F]-DOPA over [123I]-MIBG are short imaging time, less radiation dose to the patient, and no need of thyroid blockade and of withdrawing medication. [18F]-DOPA is commercially available in many countries. Only faint uptake of [18F]-DOPA is seen in normal adrenals, and this is a clear advantage over [123I]-MIBG and [68Ga]- somatostatin analogues. Procedure guidelines for [18F]- FDOPA imaging of neuroendocrine tumors have been published.72

LORUSSO

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

[68Ga]-somatostatin analogues

[68Ga]-somatostatin analogues, DOTATATE (DOTA- Tyr3-octreotate), DOTATOC (DOTA-Tyr3-octreotide) or DOTANOC (DOTA-NaI3-octreotide) bind to somatostatin receptors (SSTR) with high affinity and are subsequently internalized in target cells. These PET tracers, which have replaced 111In-octreotide (extensively used in the past for conventional scintigraphy), are currently the elective ra- diopharmaceuticals for the functional imaging of neuro- endocrine tumors, mainly those of the gastro-entero-pan- creatic tract.73 In recent years, their use has extended to Pheos and paragangliomas, too. Procedure guidelines for imaging neuroendocrine tumors with [68Ga]-somatostatin analogues have been published.72

[18F]-Fluorodeoxyiglucose ([18F]-FDG)

Although [18F]-FDG lacks specificity, it plays a role in se- lected cases of Pheo (see “Imaging findings in Pheo” below).

Imaging findings in Pheo

According to the World Health Organization (WHO),71, 74 Pheos are tumors originating from chromaffin cells of ad- renal medulla, whereas paragangliomas are extra-adrenal tumors arising from chromaffin cells of the sympathetic or parasympathetic paraganglia.63 About 80% of chro- maffin cells tumors are Pheos,75 which are usually func- tioning and can produce epinephrine and norepinephrine, unlike extra-adrenal sympathetic paragangliomas, which usually produce norepinephrine only.76 Pheo is most fre- quently solitary and sporadic; small portions of patients have inherited germline mutations and present with mul- tiple lesions and at a younger age than those with sporadic Pheo. Patients with multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 and von-Hippel Lindau syndrome usually have Pheo and rarely paraganglioma. Mutations of the genes coding for the succinate dehydro- genase (SDH) subunits are usually associated with sympa- thetic paraganglioma and less frequently with Pheo.77 Ac- cording to the revised WHO classification 2017, Pheos (as paragangliomas) are referred to as “metastatic” or “non- metastatic” rather than “malignant” or “benign.”78 About 10% of Pheos are associated with metastases, which may be present at initial diagnosis or may develop during fol- low-up, even up to many years from initial Pheo.77 The reported prevalence of Pheo is 0.2-0.6% of patients with hypertension and typical symptoms (headaches, palpita- tions, pallor, sweating, and anxiety) and 4-7% of patients with adrenal incidentaloma.22,71 When there is a biochemi- cal diagnosis of Pheo by measurements of urinary frac-

tionated metanephrines or plasma free catecholamines, imaging studies are performed to localize the tumor. CT and MRI are highly sensitive (98-100% sensitivity) in spo- radic Pheos, whereas sensitivity decreases in recurrent or metastatic disease.79 The specificity of CT and MRI is low (about 70%), due to the high prevalence of adrenal inci- dentalomas.75

The recent EANM/SNMMI Guidelines63 define the clinical indications for functional imaging in patients with Pheo (and paraganglioma):

· confirmation of Pheo diagnosis. In case of typical symptoms and increased metanephrine levels, a Pheo is suspected, and anatomic imaging may be sufficient. Con- versely, in case of increased normetanephrine levels, both Pheo and sympathetic paraganglioma are suspected; there- fore, a whole-body functional imaging study is required to confirm the diagnosis;

· staging at initial presentation. Functional imaging is indicated when metastases are suspected, in particular in presence of large primary tumors (>5 cm) or SDHB mu- tations that carry a risk of malignancy of 31-71%.63, 80-82 Typical metastatic sites are lymph nodes (regional or dis- tant), lung, liver and bone;

· restaging and follow-up. Patients with tumor charac- teristics that favor aggressive behavior, require a lifetime follow-up including annual catecholamine measurements and whole-body imaging every 2-3 years.63 With respect to anatomic imaging, functional imaging is poorly influ- enced by post-therapeutic changes. Moreover, it is very useful for assessing treatment response in case of inoper- able or metastatic disease;63

· selection for targeted radionuclide therapy. Func- tional imaging plays an essential role for selecting patients with inoperable/metastatic disease suitable for targeted [13]]]-MIBG therapy or therapy with [177Lu]-DOTA-Tyr3- octreotate).83

When studying a patient with suspected Pheo with [123]]- MIBG scintigraphy, increased or asymmetrical adrenal uptake associated with adrenal enlargement indicates the presence of Pheo; tumor uptake is often inhomogeneous, due to necrotic or calcified areas into the mass (Figure 2). Areas of uptake outside the adrenal glands and sym- pathetic paraganglia indicate metastatic lesions. In these cases, performing [123I]-MIBG scintigraphy is an essen- tial step for selecting patients suitable for targeted [131]]- MIBG therapy.83 According to cumulative data reported in the literature, the sensitivity of [123I]-MIBG scintigraphy for Pheo is good (about 86%);84, 85 specificity is high (95- 100%).63 False negative results may be caused by technical

LORUSSO

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

Figure 2 .- [123I]-MIBG scintigraphy in a patient with a left adrenal Pheo (arrow) showing heterogeneous MIBG uptake and heterogeneous densi- ty at CT for central necrosis. A) Whole body imaging; B) fused SPECT/ ČT images; C) low-dose CT.

Posterior

Figure 3 .- [18F]-DOPA PET/CT showing intense tracer uptake in a left adrenal Pheo (arrow). A) maximum intensity projection image; B) axial coregistered low-dose CT; C) axial fused PET/CT images.

factors such as limitation in spatial resolution, or by intrin- sic tumor characteristics. Lower values of sensitivity (52- 75%) are observed for metastatic Pheos or familial, extra- adrenal, multifocal paragangliomas.63 In these cases, PET tracers such as [18F]-FDOPA, [68Ga]-DOTA-somatostatin analogues or [18F]-FDG can provide useful information for lesion detection and disease staging. [18F]-FDOPA shows a very high sensitivity (>90%) for sporadic and inherited Pheo (Figure 3) and metastatic SDHB-negative Pheo/para-

ganglioma, whereas sensitivity decreases to 20% in meta- static SDHB-positive Pheo/paraganglioma.63, 86 According to the recent Practice Guidelines from EANM/SNMMI, [18F]-FDOPA PET/CT is recommended in patients with sporadic and inherited pheochromocytomas (NF1, RET, VHL, MAX), except SDHx-positive patients.63 Accord- ing to literature data, [68Ga]-somatostatin analogues are the most sensitive functional imaging method for head and neck paragangliomas, whereas they have shown lower sensitivity than [18F]-FDOPA for sporadic Pheo.87 [18F]- FDG uptake in Pheos (and paragangliomas) depends on the differentiation degree of the tumor. Pheos usually show increased tracer uptake, even though variable. The usefulness of this method is limited by the low specific- ity.86, 88 For this reason, [18F]-FDG PET/CT is not recom- mended for initial diagnosis of Pheo. Nevertheless, it can identify those neural-crest-derived tumors that do not take up MIBG at presentation or lose MIBG uptake do to cell de-differentiation, such as metastatic Pheos (and paragan- gliomas) and those with underlying SDHx mutations.63 In these conditions, 85% sensitivity and 55% specificity are reported.89

Nonfunctioning adrenal masses

Many nonfunctioning adrenal incidentalomas show a typi- cal appearance at CT/MRI and can be easily characterized. This group includes several benign conditions such as ad- renocortical adenomas with low attenuation at unenhanced CT and chemical shift at MRI, as well as myelolipomas, cysts, and hematomas. Also, adrenal lesions <4 cm in size showing size stability on CT/MRI at least 6-12 month apart, are considered benign.14 In all these cases functional imaging is not recommended.22 These cases usually do not undergo surgical removal or biopsy of the adrenal lesion. Conversely, surgical resection may be required for some non-functioning adrenal lesions because of their large and rapid growth or indeterminate findings on CT/MRI. How- ever, these inconclusive findings may cause an extensive use of surgical procedures for benign nodules with poten- tial surgical morbidity.90 Among these lesions, two catego- ries should be considered, depending on their finding in oncologic or non-oncologic patients, respectively. In these conditions functional imaging may play an important role.

In non-oncologic patients, the differential diagnosis is between ACC and a benign nodule. In this group of pa- tients, [18F]-FDG PET/CT can be helpful in characterizing large or indeterminate masses based on tumor metabo- lism and plays an important role in the initial staging of

to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.

Figure 4 .- [18F]-FDG PET/CT showing no tracer uptake in a benign left adrenal adenoma (arrow). A) maximum intensity projection image; B) axial coregistered low-dose CT showing a left adrenal nodule of about 4 cm in diameter and atypical pattern with an attenuation value of 38 HU; C) axial fused PET/CT images (tumor-to-liver SUV max ratio =0.9). Figure 5 .- [18F]-FDG PET/CT in a 64-year-old woman with a history of small cell lung cancer treated with chemotherapy and radiotherapy showing intense tracer uptake in a right adrenal lesion (arrow) as well as two additional areas of abnormal uptake in the liver (arrowheads). A) maximum intensity projection image; B) axial coregistered low-dose CT; C) axial fused PET/CT images (tumor-to-liver SUV max ratio =3.4).

ACC and in the subsequent follow-up. Even though high FDG uptake is usually associated with malignant lesions and very low uptake with benign ones, according to Sun- din et al.14 there is a “grey zone” with unclear imaging findings. Some studies have tried to distinguish benign lesions from malignant ones through semiquantitative parameters such as SUVmax values that are more accurate than visual analysis. According to Metser et al., a SUV- max cutoff of 3.1 yielded a sensitivity, specificity, positive predictive value, and negative predictive value of 98.5%, 92%, 89.3%, 98.9%, respectively.91 However, threshold values highly vary across studies.14 The use of tumor-to- liver- uptake ratio seems to be more accurate than visual analysis in distinguishing benign from malignant lesions (Figure 4). According to Guerin et al., a ratio >1.5 is as- sociated with malignancy, showing sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 86.7%, 86.1%, 56.5, 96.9, and 86.2%, respec- tively. However, some adrenocortical cancers and large retroperitoneal sarcomas may show lower uptake values.92 [18F]-FDG is an important tool for assessing the extent of disease by revealing distant metastases in malignant ad- renal diseases.93 [11C]-metomidate, when available, can distinguish adrenocortical tumors (showing tracer uptake) from non-adrenocortical tumors (showing no uptake), due to its specific uptake in adrenal cortex.36

In oncologic patients it is important to distinguish be-

tween benign adrenal nodules and adrenal metastases from extra-adrenal malignancies (most frequently non-small cell lung carcinoma, lymphoma, colorectal cancer, and re- nal cell carcinoma). It must be stressed that <30% of adre- nal masses in patients with extra-adrenal malignancies are metastases.94 In this clinical setting [18F]-FDG PET/CT has an important role in differentiating between a benign nod- ule and adrenal metastasis, provided that the primary tu- mor is FDG avid.14 Moreover, in patients with adrenal me- tastases [18F]-FDG PET/CT is essential to assess the extent of metastatic involvement, thus guiding treatment decision (Figure 5). [18F]-FDG PET/CT may presents some pitfalls due to false negative results, which can be caused by small metastases (<5 mm), hemorrhagic or necrotic lesions or by low [18F]-FDG uptake after chemotherapy; and false posi- tive results, which can be caused by inflammatory lesions or Pheos but also by adrenal adenomas.14

Conclusions

Functional imaging plays an important role in providing additional diagnostic information in selected patients with functioning or nonfunctioning adrenal masses. Several ra- diotracers are available, which explore different metabolic pathways involved in adrenal cortex and medulla disfunc- tions, which are characterized with high accuracy. The as- sessment of glycolytic activity by [18F]-FDG PET/CT al-

LORUSSO

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES lows to identify malignancy with high sensitivity. Thanks to the emerging role of various PET tracers, it is expected that nuclear medicine modalities in combination with morphologic imaging will have an increasingly important role in the management of patients with adrenal masses by guiding personalized therapeutic strategies. References 1. Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007;356:601-10. 2. Terzolo M, Stigliano A, Chiodini I, Loli P, Furlani L, Arnaldi G, et al .; Italian Association of Clinical Endocrinologists. AME position statement on adrenal incidentaloma. Eur J Endocrinol 2011;164:851-70. 3. Dinnes J, Bancos I, Ferrante di Ruffano L, Chortis V, Davenport C, Bayliss S, et al. MANAGEMENT OF ENDOCRINE DISEASE: Im- aging for the diagnosis of malignancy in incidentally discovered adre- nal masses: a systematic review and meta-analysis. Eur J Endocrinol 2016;175:R51-64. 4. Ciftci AO, Senocak ME, Tanyel FC, Büyükpamukçu N. Adrenocortical tumors in children. J Pediatr Surg 2001;36:549-54. 5. Prado-Wohlwend S; Grupo de Trabajo de Endocrinología de la SEM- NIM. Functional imaging of adrenal cortex. Rev Esp Med Nucl Imagen Mol (Engl Ed) 2020;39:393-404. [English, Spanish]. 6. Bancos I, Prete A. Approach to the Patient With Adrenal Incidentalo- ma. J Clin Endocrinol Metab 2021;106:3331-53. 7. Approach to the Patient with an Incidental Adrenal Mass. Med Clin N Am 2021;105:1047-63. 8. Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 2002;20:941-50. 11. Arlt W, Biehl M, Taylor AE, Hahner S, Libé R, Hughes BA, et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocrinol Metab 2011;96:3775-84. 12. Gruber LM, Hartman RP, Thompson GB, Mckenzie TJ, Lyden ML, Dy BM, et al. Pheochromocytoma Characteristics and Behavior Differ Depending on Method of Discovery. J Clin Endocrinol Metab 2019;104:1386-93. 13. Reginelli A, Vacca G, Belfiore M, Sangiovanni A, Nardone V, Vanzulli A, et al. Pitfalls and differential diagnosis on adrenal lesions: current con- cepts in CT/MR imaging: a narrative review. Gland Surg 2020;9:2331-42. 14. Sundin A, Hindié E, Avram AM, Tabarin A, Pacak K, Taïeb D. A Clin- ical Challenge: Endocrine and Imaging Investigations of Adrenal Masses. J Nucl Med 2021;62(Suppl 2):26S-33S. 15. Viëtor CL, Creemers SG, van Kemenade FJ, van Ginhoven TM, Ho- fland LJ, Feelders RA. How to Differentiate Benign from Malignant Ad- renocortical Tumors? Cancers (Basel) 2021;13:4383. 16. Mody RN, Remer EM, Nikolaidis P, Khatri G, Dogra VS, Gane- shan D, et al .; Expert Panel on Urological Imaging. ACR Appropriate- ness Criteria® Adrenal Mass Evaluation: 2021 Update. J Am Coll Radiol 2021;18(11S):S251-67. 17. Schloetelburg W, Ebert I, Petritsch B, Weng AM, Dischinger U, Kircher S, et al. Adrenal wash-out CT: moderate diagnostic value in Vol. 66 - No. 2 This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically 9. Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A. Extent of dis- ease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg 2006;30:872-8. or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. 10. Libé R, Borget I, Ronchi CL, Zaggia B, Kroiss M, Kerkhofs T, et al .; ENSAT network. Prognostic factors in stage III-IV adrenocortical car- cinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol 2015;26:2119-25. to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,

distinguishing benign from malignant adrenal masses. Eur J Endocrinol 2021;186:183-93.

18. Korobkin M, Giordano TJ, Brodeur FJ, Francis IR, Siegelman ES, Quint LE, et al. Adrenal adenomas: relationship between histologic lipid and CT and MR findings. Radiology 1996;200:743-7.

19. Israel GM, Korobkin M, Wang C, Hecht EN, Krinsky GA. Compari- son of unenhanced CT and chemical shift MRI in evaluating lipid-rich adrenal adenomas. AJR Am J Roentgenol 2004;183:215-9.

20. Mayo-Smith WW, Lee MJ, McNicholas MM, Hahn PF, Boland GW, Saini S. Characterization of adrenal masses (< 5 cm) by use of chemical shift MR imaging: observer performance versus quantitative measures. AJR Am J Roentgenol 1995;165:91-5.

21. Ebbehoj A, Li D, Kaur RJ, Zhang C, Singh S, Li T, et al. Epidemiolo- gy of adrenal tumours in Olmsted County, Minnesota, USA: a population- based cohort study. Lancet Diabetes Endocrinol 2020;8:894-902.

22. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2016;175:G1-34.

23. Raffaelli M, De Crea C, Bellantone R. Laparoscopic adrenalectomy. Gland Surg 2019;8(Suppl 1):S41-52.

24. Sarkar SD, Beierwaltes H, Ice RD, Basmadjian GP, Hetzel KR, Ken- nedy WP, et al. A new and superior adrenal scanning agent, NP-59. J Nucl Med 1975;16:1038-42.

25. Bergström M, Bonasera TA, Lu L, Bergström E, Backlin C, Juhlin C, et al. In vitro and in vivo primate evaluation of carbon-11-etomidate and carbon-11-metomidate as potential tracers for PET imaging of the adrenal cortex and its tumors. J Nucl Med 1998;39:982-9.

26. Gross MD, Avram A, Fig LM, Rubello D. Contemporary adrenal scintigraphy. Eur J Nucl Med Mol Imaging 2007;34:547-57.

27. Wong KK, Miller BS, Viglianti BL, Dwamena BA, Gauger PG, Cook GJ, et al. Molecular Imaging in the Management of Adrenocortical Can- cer: A Systematic Review. Clin Nucl Med 2016;41:e368-82.

28. Radiopharmaceuticals (Addendum to ICRP Publication 53). ICRP Publication 80. Ann. ICRP 28 (3).

29. Mendichovszky IA, Powlson AS, Manavaki R, Aigbirhio FI, Ch- eow H, Buscombe JR, et al. Targeted Molecular Imaging in Adrenal Disease-An Emerging Role for Metomidate PET-CT. Diagnostics (Basel) 2016;6:42.

30. Nanba K, Rainey WE, Udager AM. Approaches to Gene Mutation Analysis Using Formalin-Fixed Paraffin-Embedded Adrenal Tumor Tis- sue From Patients With Primary Aldosteronism. Front Endocrinol (Laus- anne) 2021;12:683588.

31. Kreissl MC, Schirbel A, Fassnacht M, Haenscheid H, Verburg FA, Bock S, et al. [123I]Iodometomidate imaging in adrenocortical carcino- ma. J Clin Endocrinol Metab 2013;98:2755-64.

32. Mitterhauser M, Dobrozemsky G, Zettinig G, Wadsak W, Vierhapper H, Dudczak R, et al. Imaging of adrenocortical metastases with [11C] metomidate. Eur J Nucl Med Mol Imaging 2006;33:974.

33. Hahner S, Stuermer A, Kreissl M, Reiners C, Fassnacht M, Haenscheid H, et al. [123 I]Iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes. J Clin Endocrinol Metab 2008;93:2358-65.

34. Hahner S, Sundin A. Metomidate-based imaging of adrenal masses. Horm Cancer 2011;2:348-53.

35. Naruse M, Umakoshi H, Tsuiki M, Yokomoto M, Tagami T, Ta- nabe A, et al. The Latest Developments of Functional Molecular Im- aging in the Diagnosis of Primary Aldosteronism. Horm Metab Res 2017;49:929-35.

36. Silins I, Sundin A, Nordeman P, Jahan M, Estrada S, Monaz- zam A, et al. Para-chloro-2-[18F]fluoroethyl-etomidate: A promis- ing new PET radiotracer for adrenocortical imaging. Int J Med Sci 2021;18:2187-96.

or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically

LORUSSO

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

37. Zettinig G, Mitterhauser M, Wadsak W, Becherer A, Pirich C, Vier- happer H, et al. Positron emission tomography imaging of adrenal mass- es: (18)F-fluorodeoxyglucose and the 11beta-hydroxylase tracer (11)C- metomidate. Eur J Nucl Med Mol Imaging 2004;31:1224-30.

38. Bergström M, Juhlin C, Bonasera TA, Sundin A, Rastad J, Akerström G, et al. PET imaging of adrenal cortical tumors with the 11beta-hydroxy- lase tracer 11C-metomidate. J Nucl Med 2000;41:275-82.

39. O’Shea PM, O’Donoghue D, Bashari W, Senanayake R, Joyce MB, Powlson AS, et al. 11 C-Metomidate PET/CT is a useful adjunct for later- alization of primary aldosteronism in routine clinical practice. Clin Endo- crinol (Oxf) 2019;90:670-9.

40. Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, et al. Evaluation of the sensitivity and specificity of (11)C-metomidate posi- tron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn’s adenomas. J Clin Endocrinol Metab 2012;97:100-9.

41. Bluemel C, Hahner S, Heinze B, Fassnacht M, Kroiss M, Bley TA, et al. Investigating the Chemokine Receptor 4 as Potential Theranostic Target in Adrenocortical Cancer Patients. Clin Nucl Med 2017;42:e29-34.

42. Heinze B, Fuss CT, Mulatero P, Beuschlein F, Reincke M, Musta- fa M, et al. Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma. Hypertension 2018;71:317-25.

43. Demmer O, Dijkgraaf I, Schumacher U, Marinelli L, Coscona- ti S, Gourni E, et al. Design, synthesis, and functionalization of di- meric peptides targeting chemokine receptor CXCR4. J Med Chem 2011;54:7648-62.

44. Demmer O, Gourni E, Schumacher U, Kessler H, Wester HJ. PET imaging of CXCR4 receptors in cancer by a new optimized ligand. ChemMedChem 2011;6:1789-91.

45. Ding J, Zhang Y, Wen J, Zhang H, Wang H, Luo Y, et al. Imaging CXCR4 expression in patients with suspected primary hyperaldosteron- ism. Eur J Nucl Med Mol Imaging 2020;47:2656-65.

46. Chifu I, Heinze B, Fuss CT, Lang K, Kroiss M, Kircher S, et al. Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma. Front Endocrinol (Lausanne) 2020;11:597878.

47. Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al .; European Association of Nuclear Medicine (EANM). FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging 2015;42:328-54.

48. Kiseljak-Vassiliades K, Bancos I, Hamrahian A, Habra M, Vaidya A, Levine AC, et al. American Association of Clinical Endocrinology Dis- ease State Clinical Review on the Evaluation and Management of Ad- renocortical Carcinoma in an Adult: a Practical Approach. Endocr Pract 2020;26:1366-83.

49. Kubo A, Kinoshita F. Nuclear Medicine Notebook. Sixth edition. To- kyo: Kanehara & Co.Ltd .; 2020. pp. 150-156.7.

50. Schteingart DE, Seabold JE, Gross MD, Swanson DP. Iodocholester- ol adrenal tissue uptake and imaging adrenal neoplasms. J Clin Endocrinol Metab 1981;52:1156-61.

51. Avram AM, Fig LM, Gross MD. Adrenal gland scintigraphy. Semin Nucl Med 2006;36:212-27.

52. Riaz S, Syed R, Aziz TA, Alnaim A, Chung TT, Wan S, et al. The value of 18F-FDG PET-CT and 131I-norcholesterol scintigraphy in the characterization of high-risk adrenal masses. Nucl Med Commun 2020;41:189-95.

53. Ricciato MP, Di Donna V, Perotti G, Pontecorvi A, Bellantone R, Cor- sello SM. The role of adrenal scintigraphy in the diagnosis of subclinical Cushing’s syndrome and the prediction of post-surgical hypoadrenalism. World J Surg 2014;38:1328-35.

54. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guide- line. J Clin Endocrinol Metab 2016;101:1889-916.

55. Rossi GP, Barisa M, Allolio B, Auchus RJ, Amar L, Cohen D, et al. The Adrenal Vein Sampling International Study (AVIS) for identifying the major subtypes of primary aldosteronism. J Clin Endocrinol Metab 2012;97:1606-14.

56. Dekkers T, Prejbisz A, Kool LJ, Groenewoud HJ, Velema M, Spiering W, et al .; SPARTACUS Investigators. Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes Endocrinol 2016;4:739-46.

57. Wong KK, Fig LM, Youssef E, Ferretti A, Rubello D, Gross MD. Endocrine scintigraphy with hybrid SPECT/CT. Endocr Rev 2014;35:717-46.

58. Spyridonidis TJ, Apostolopoulos DJ. Is there a role for Nuclear Medi- cine in diagnosis and management of patients with primary aldosteron- ism? Hell J Nucl Med 2013;16:134-9.

59. Wafelman AR, Hoefnagel CA, Maes RA, Beijnen JH. Radioiodinated metaiodobenzylguanidine: a review of its biodistribution and pharmaco- kinetics, drug interactions, cytotoxicity and dosimetry. Eur J Nucl Med 1994;21:545-59.

60. Kölby L, Bernhardt P, Levin-Jakobsen AM, Johanson V, Wängberg B, Ahlman H, et al. Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters. Br J Cancer 2003;89:1383-8.

61. Pandit-Taskar N, Zanzonico P, Staton KD, Carrasquillo JA, Reidy-La- gunes D, Lyashchenko S, et al. Biodistribution and Dosimetry of 18F-Me- ta-Fluorobenzylguanidine: A First-in-Human PET/CT Imaging Study of Patients with Neuroendocrine Malignancies. J Nucl Med 2018;59:147-53.

62. Bombardieri E, Giammarile F, Aktolun C, Baum RP, Bischof Delaloye A, Maffioli L, et al .; European Association for Nuclear Medi- cine. 1311/123I-metaiodobenzylguanidine (mIBG) scintigraphy: pro- cedure guidelines for tumour imaging. Eur J Nucl Med Mol Imaging 2010;37:2436-46.

63. Taïeb D, Hicks RJ, Hindié E, Guillet BA, Avram A, Ghedini P, et al. European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2019;46:2112-37.

64. Aboian MS, Huang SY, Hernandez-Pampaloni M, Hawkins RA, VanBrocklin HF, Huh Y, et al. 124I-MIBG PET/CT to Monitor Meta- static Disease in Children with Relapsed Neuroblastoma. J Nucl Med 2021;62:43-7.

65. Weber M, Schmitz J, Maric I, Pabst KM, Umutlu L, Walz M, et al. Diagnostic performance of [124I]m-iodobenzylguanidine PET/CT in pa- tients with pheochromocytoma. J Nucl Med 2021;jnumed. 121.262797.

66. Samim A, Tytgat GA, Bleeker G, Wenker ST, Chatalic KL, Poot AJ, et al. Nuclear Medicine Imaging in Neuroblastoma: Current Status and New Developments. J Pers Med 2021;11:270.

67. Rufini V, Treglia G, Castaldi P, Perotti G, Calcagni ML, Corsello SM, et al. Comparison of 123I-MIBG SPECT-CT and 18F-DOPA PET-CT in the evaluation of patients with known or suspected recurrent paraganglio- ma. Nucl Med Commun 2011;32:575-82.

68. Timmers HJ, Taieb D, Pacak K. Current and future anatomical and functional imaging approaches to pheochromocytoma and paraganglio- ma. Horm Metab Res 2012;44:367-72.

69. Rufini V, Treglia G, Castaldi P, Perotti G, Giordano A. Comparison of metaiodobenzylguanidine scintigraphy with positron emission tomogra- phy in the diagnostic work-up of pheochromocytoma and paraganglioma: a systematic review. Q J Nucl Med Mol Imaging 2013;57:122-33.

70. Vyakaranam AR, Crona J, Norlén O, Hellman P, Sundin A. 11C- hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma. Cancers (Basel) 2019;11:847.

71. Carrasquillo JA, Chen CC, Jha A, Ling A, Lin FI, Pryma DA, et al. Imaging of Pheochromocytoma and Paraganglioma. J Nucl Med 2021;62:1033-42.

72. Bozkurt MF, Virgolini I, Balogova S, Beheshti M, Rubello D, Decristoforo C, et al. Guideline for PET/CT imaging of neuroendo-

cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically

MOLECULAR IMAGING IN PATIENTS WITH ADRENAL MASSES

LORUSSO

crine neoplasms with 68Ga-DOTA-conjugated somatostatin recep- tor targeting peptides and 18F-DOPA. Eur J Nucl Med Mol Imaging 2017;44:1588-601.

73. Andreasi V, Partelli S, Muffatti F, Manzoni MF, Capurso G, Falconi M. Update on gastroenteropancreatic neuroendocrine tumors. Dig Liver Dis 2021;53:171-82.

74. Lloyd RV, Osamura YR. Kloppel G, Rosa J. Who Classification of Tumours of Endocrine Organs. Fourth edition. Geneva: World Health Or- ganization; 2017.

75. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocy- toma. Lancet 2005;366:665-75.

76. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al .; Endocrine Society. Pheochromocytoma and para- ganglioma: an endocrine society clinical practice guideline. J Clin Endo- crinol Metab 2014;99:1915-42.

77. Jasim S, Jimenez C. Metastatic pheochromocytoma and paragan- glioma: management of endocrine manifestations, surgery and ablative procedures, and systemic therapies. Best Pract Res Clin Endocrinol Metab 2020;34:101354.

78. Lam AK. Update on Adrenal Tumours in 2017 World Health Orga- nization (WHO) of Endocrine Tumours. Endocr Pathol 2017;28:213-27.

79. Leung K, Stamm M, Raja A, Low G. Pheochromocytoma: the range of appearances on ultrasound, CT, MRI, and functional imaging. AJR Am J Roentgenol 2013;200:370-8.

80. Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tu- mor size and primary tumor location as prognostic indicators. J Clin En- docrinol Metab 2011;96:717-25.

81. Hamidi O, Young WF Jr, Gruber L, Smestad J, Yan Q, Ponce OJ, et al. Outcomes of patients with metastatic phaeochromocytoma and para- ganglioma: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 2017;87:440-50.

82. Dahia PL, Clifton-Bligh R, Gimenez-Roqueplo AP, Robledo M, Jimenez C. HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Metastatic pheochromocytomas and paragangliomas: proceedings of the MEN2019 workshop. Endocr Relat Cancer 2020;27:T41-52.

83. Taïeb D, Pacak K. Molecular imaging and theranostic approaches in pheochromocytoma and paraganglioma. Cell Tissue Res 2018;372:393-401.

84. Rufini V, Calcagni ML, Baum RP. Imaging of neuroendocrine tumors. Semin Nucl Med 2006;36:228-47.

85. Wiseman GA, Pacak K, O’Dorisio MS, Neumann DR, Waxman AD, Mankoff DA, et al. Usefulness of 123I-MIBG scintigraphy in the evalua- tion of patients with known or suspected primary or metastatic pheochro- mocytoma or paraganglioma: results from a prospective multicenter trial. J Nucl Med 2009;50:1448-54.

86. Granberg D, Juhlin CC, Falhammar H. Metastatic Pheochromo- cytomas and Abdominal Paragangliomas. J Clin Endocrinol Metab 2021;106:e1937-52.

87. Maurice JB, Troke R, Win Z, Ramachandran R, Al-Nahhas A, Naji M, et al. A comparison of the performance of 68Ga-DOTATATE PET/ CT and 123I-MIBG SPECT in the diagnosis and follow-up of pha- eochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2012;39:1266-70.

88. Čtvrtlík F, Koranda P, Schovánek J, Škarda J, Hartmann I, Tüdös Z. Current diagnostic imaging of pheochromocytomas and implications for therapeutic strategy. Exp Ther Med 2018;15:3151-60.

89. Kan Y, Zhang S, Wang W, Liu J, Yang J, Wang Z. 68Ga-somatostatin receptor analogs and 18F-FDG PET/CT in the localization of metastatic pheochromocytomas and paragangliomas with germline mutations: a me- ta-analysis. Acta Radiol 2018;59:1466-74.

90. Thompson LH, Ranstam J, Almquist M, Nordenström E, Bergenfelz A. Impact of Adrenalectomy on Morbidity in Patients with Non-Func- tioning Adrenal Cortical Tumours, Mild Hypercortisolism and Cushing’s Syndrome as Assessed by National and Quality Registries. World J Surg 2021;45:3099-107.

91. Metser U, Miller E, Lerman H, Lievshitz G, Avital S, Even-Sapir E. 18F-FDG PET/CT in the evaluation of adrenal masses. J Nucl Med 2006;47:32-7.

92. Guerin C, Pattou F, Brunaud L, Lifante JC, Mirallié E, Haissaguerre M, et al. Performance of 18F-FDG PET/CT in the Characterization of Adrenal Masses in Noncancer Patients: A Prospective Study. J Clin Endo- crinol Metab 2017;102:2465-72.

93. Deandreis D, Leboulleux S, Caramella C, Schlumberger M, Baudin E. FDG PET in the management of patients with adrenal masses and adre- nocortical carcinoma. Horm Cancer 2011;2:354-62.

94. Hammarstedt L, Muth A, Sigurjónsdóttir HÁ, Almqvist E, Wängberg B, Hellström M; Adrenal Study Group of Western Sweden. Adrenal le- sions in patients with extra-adrenal malignancy - benign or malignant? Acta Oncol 2012;51:215-21.

Conflicts of interest .- The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Authors’ contributions .- Margherita Lorusso and Vittoria Rufini Contributed equally to this work. Conceptualization: Margherita Lorusso, Vittoria Rufini, Francesco Pennestrì; methodology: Carmela De Crea, Rocco Bellantone, Marco Raffaelli; formal analysis and investigation: Margherita Lorusso, Vittoria Rufini, Carmela De Crea, Francesco Pennestrì, Rocco Bellantone, Marco Raffaelli; writing - original draft preparation: Margherita Lorusso, Vittoria Rufini, Francesco Pennestrì; writing - review and editing: Vittoria Rufini, Carmela De Crea, Rocco Bellantone; supervision: Carmela De Crea and Marco Raffaelli All authors read and approved the final version of the manuscript.

History .- Article first published online: March 28, 2022. - Manuscript accepted: March 15, 2022. - Manuscript received: February 17, 2022.

Quartz 4

Explorer

35343669

Integration of molecular imaging in the personalized approach of patients with adrenal masses

ABSTRACT

Functional imaging of adrenal cortex

SPECT radiopharmaceuticals

Radiocholesterol analogs

[123I]-iodometomidate

PET radiopharmaceuticals

[1]C]-metomidate (11C-MTO)

Imaging findings in functioning adrenocortical diseases

Adrenal hypercortisolism

Adrenal hyperaldosteronism

Functional imaging of adrenal medulla

SPET radiopharmaceuticals

PET radiopharmaceuticals

[18F]-dihydroxyphenylalanine ([18F]-DOPA)

Nonfunctioning adrenal masses

Conclusions

Graph View

Table of Contents

Backlinks