Nuclear Oncology, 1 Ed.

CHAPTER 19

TUMORS OF THE ADRENAL GLANDS

Shinji Yamamoto • Per Hellman • Anders Sundin

INTRODUCTION

The adrenal glands are small but because of the hormones they produce, they are essential for maintaining life. Located adjacent to the upper and medial aspects of both the right and left kidneys, they weigh about 4 g and are composed of an outer, lipid-rich adrenal cortex and an inner medulla. The cortex has three histologic layers: Zona glomerulosa (ZG), zona fasciculate (ZF), and zona reticularis (ZR). Hormone production in the adrenal cortex is regulated by the adrenocorticotropic hormone (ACTH) in the hypothalamic– pituitary–adrenal (HPA) axis, and the renin–angiotensin system (RAS) mainly through angiotensin II. The adrenal cortex produces the steroid hormones aldosterone (in ZG), cortisol (in ZF), and the androgens (in ZR).1 The adrenal medulla is derived from the neuroectoderm and contains chromaffin cells and is therefore part of the sympathetic nervous system. These cells produce catecholamines (epinephrine and norepinephrine) and secrete them into the blood. Adrenal tumors arise from both the cortex and medulla. In many cases these tumors are functional and produce hormones that, in excess amounts, give rise to various symptoms. Some patients seek medical attention for these symptoms, where hypertension is a common finding regardless of which hormone is in excess. With current high-resolution imaging techniques, mainly computed tomography (CT), incidental findings of adrenal tumors, so-called incidentalomas, are common and are found in up to 1.8% to 7.1% of all abdominal and thoracic CT examinations that include the adrenals in the field of view.2 Radionuclide evaluation was introduced in 1970s to analyze the functional status of these tumors, as well as anatomic location and eventual metastases of malignant tumors. The past decade has seen rapid developments in radionuclide imaging of adrenal tumors: Indeed, some of the tracers that have been previously described are now out of date and have been replaced by new, potent, and effective tracers (Table 19.1).3 Technical innovations include better spatial resolution. Radionuclide imaging has progressed from classic scintigraphic planar imaging to single-photon emission computed tomography (SPECT) and positron-emission tomography (PET), leading to better image clarity and more precise diagnosis. Moreover, the integration of anatomic and radionuclide imaging is currently achieved using combinations with CT in hybrid systems, SPECT/CT and PET/CT and recently, PET/magnetic resonance imaging (PET/MRI). Radionuclide therapeutic modalities have also advanced and are now used in many institutes worldwide.

TABLE 19.1

RADIONUCLIDE AGENTS FOR IMAGING OF ADRENAL TUMORS

CLINICAL PROBLEMS ASSOCIATED WITH ADRENAL IMAGING

Adrenal gland imaging is associated with several problems related to the clinical questions. The adrenal glands are small and when searching for functioning adrenal tumors, such as in the case of primary aldosteronisms (PAs) where a micronodular disease or a small adenoma may be present, there is a risk that these tumors may be below the detection limits of conventional imaging methods such as CT or MRI.

Nevertheless, the overall CT sensitivity to detect intra-adrenal tumors >0.5 cm is 93% to 100%.4 However, patients who present with the clinical symptoms of adrenal disease are rare compared to those who are diagnosed with an incidentaloma—an adrenal tumor diagnosed when the patient has undergone radiologic imaging, usually CT, for reasons other than the suspicion of adrenal disease. The incidence of incidentalomas increases with age. A multicenter study in south-western Sweden, comprising 3,801 randomly selected CT examinations, showed 4.5% mean frequency of adrenal incidentaloma (range: 1.8% to 7.1% between centers).2 These tumors are almost always benign when there is no cancer history and, conversely, malignant in up to about half of cancer patients,5,6 although this high proportion has recently been questioned.

CHARACTERIZATION OF ADRENAL INCIDENTALOMAS

The work up of the incidentaloma patient should aim at excluding hormonal overproduction and malignancy. The biochemical work-up is usually performed by an endocrinologist, whereas a radiologist needs to characterize the adrenal mass according to predefined criteria. Before starting to characterize an incidentaloma, the patient’s previous imaging studies should be requested and reviewed. Frequently, the incidentaloma may be found in a previous CT or MRI that includes the adrenal region, although it may not have been reported. According to the Swedish National Guidelines, incidentalomas that have remained unchanged in size and internal structure for a year may be disregarded. Seen during morphologic imaging, generally CT, a benign adrenal lesion is typically small with a rounded to oval shape. The internal structure in a benign incidentaloma is homogeneous, well defined and sharply delineated from the surrounding retroperitoneal fat. Malignant masses are often larger with a heterogeneous internal structure. They may be lobulated and diffusely delineated and are sometimes seen to invade adjacent organs and tissues. An area of macroscopic fat is typical of a benign myelolipoma (Fig. 19.1). In this instance, variations are large and this area of macroscopic fat may either be restricted to a very small region or comprise almost the whole of the tumor.

FIGURE 19.1. Transverse intravenously contrast-enhanced CT image showing a myelolipoma in the right adrenal gland. The tumor is predominately fat attenuating (–100 HU) and containing small higher attenuating areas and is somewhat dislocating–compressing the liver. The finding of macroscopic fat within the tumor is typical for a benign myelolipoma.

Attenuation measurement in nonenhanced (native) CT examinations is important in assisting the characterization of adrenal incidentalomas. A region of interest (ROI) positioned in the fatty part of the myelolipoma will typically show –100 Hounsfield units (HUs). On the other hand, the most frequent incidentaloma, the adrenocortical adenoma is composed of cytoplasmatic fat. This will decrease the attenuation, if the lesion measures ≤10 HU it can be considered to be a benign adrenocortical adenoma with 71% sensitivity and 98% specificity.7 The attenuation should be measured in a large ROI (diameter 2/3–3/4 of the tumor) but avoiding partial volume effects from the surrounding retroperitoneal fat. A recent study confirms this almost maximum specificity for attenuation measurements in the precontrast CT examination and reports 65% sensitivity and 99% specificity.8 The sensitivity to detect cytoplasmatic fat is comparably high with MRI using in- and out-of-phase sequences.9,10

Some of the adrenal incidentalomas measuring >10 HU may be confirmed as benign lesions by characterizing their wash-out of IV contrast media at CT performed before (precontrast) and after IV contrast enhancement in the venous phase and after 10 to 15 minutes.1116 Malignant tumors are generally hypovascular and, compared to normal tissues, they have a larger interstitial space in which high pressure impedes the contrast enhancement and delays the contrast medium wash-out. By contrast, benign lesions are generally well vascularized; they contrast enhance rapidly and have a fast contrast medium wash-out. To calculate the contrast medium wash-out, the attenuation of the incidentaloma is measured (ROI) in the precontrast (unenhanced, U), contrast-enhanced (enhanced, E) and delayed (D) phases 15 minutes after injection. The “absolute wash-out” is calculated according to the formula (E – D)/(E – U) where in daily clinical practice, the cut-off 0.6 is applied. A wash-out >0.6 indicates a benign lesion and <0.6 indicates that the tumor may be malignant.

The imaging work up and follow-up for most incidentalomas is adequately managed by CT and MRI. Further characterization is needed for a minority of these tumors and several molecular imaging techniques are available for these patients.

According to the Swedish National Guidelines, adrenal incidentalomas characterized as benign adrenocortical adenomas by their benign morphologic appearance and shown to contain cytoplasmic fat by a CT attenuation ≤10 HU or measuring less than 3 to 4 cm in transaxial diameter generally require no further imaging or radiologic follow-up. However, the relevant routines vary in different countries. In order not to misdiagnose a simple cyst (attenuation approximately 0–15 HU) as a benign adrenocortical adenoma, it should, however, be confirmed that the lesion is contrast enhancing. Similarly, there is generally no need for further imaging in some larger lesions >4 cm that are apparently benign, for example, in a myelolipoma or a cyst. The significance of contrast medium wash-out varies between centers. According to the current Swedish Guidelines, lesions with >10 HU precontrast attenuation with a benign appearance based on contrast medium wash-out (>0.6) are nevertheless subjected to follow-up imaging in 1 year.

DIAGNOSIS, STAGING, AND FOLLOW-UP OF ADRENOCORTICAL CARCINOMA

Patients with adrenocortical carcinoma (ACC) usually present when the tumor is large. They can already be at a locally advanced stage and may have metastasized.17 Approximately 50% of the tumors are functioning18 but hormonal symptoms and signs such as amenorrhea and virilization, or Cushingoid habitus and skin changes, may initially be overlooked by both the patient and the physician. By the time the CT is performed, the tumor is generally round to oval, frequently lobulated and fairly often calcifications are found. Loss of a fat plane between the tumor and surrounding tissues suggests invasion, most often to the kidney and liver. A tumor thrombus extending into the inferior vena cava is not an infrequent finding. Metastases are most often found in lymph nodes, liver, lungs, and bones.19 Staging of ACC is shown in the American Joint Committee on Cancer manual.20 The decision regarding surgical versus nonsurgical management of patients with a nonfunctioning incidentaloma was previously governed primarily by its size. All lesions larger than approximately 4 cm were removed because of the risk of a malignant tumor. Today, this decision is increasingly influenced by the imaging characterization of the incidentaloma as mentioned above.

Before a biopsy of an adrenal tumor is performed, pheochromocytoma needs to be ruled out biochemically. A localized ACC is generally not biopsied because of the risk of tumor cell seeding. Therefore imaging characterization is important and PET/CT with 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) or 11C-metomidate may be used for this characterization and to stage the disease. When an adrenal metastasis is suspected, core needle biopsy or fine needle aspiration cytology may be a more appropriate diagnostic procedure than further imaging. A patient with a single metastasis in the adrenal may be operated on but 18F-FDG PET/CT can help to confirm that there are no additional lesions.

If the ACC is hormonally active, the clinical and biochemical follow-up is significant for detecting recurrent disease after surgical intervention and to monitor medical therapy. Conventional radiologic imaging, mainly CT or MRI, is also performed periodically. Functional imaging by PET/CT with 18F-FDG or 11C-metomidate is valuable, especially when radiologic imaging is inconclusive. In the case of nonfunctioning ACC, no biochemical parameter can be used and CT and MRI are the primary methods for follow-up after treatment. In these patients, 18F-FDG PET/CT or 11C-metomidate PET/CT are probably even more helpful for the detection of recurrent disease.

DIAGNOSIS, STAGING, AND FOLLOW-UP OF PHEOCHROMOCYTOMA

The diagnosis of pheochromocytoma is usually biochemical (increased normetanephrine, metanephrine, epinephrine, or norepinephrine in plasma or urine) in patients with sympathomimetic symptoms such as palpitations, sweating, headache, and hypertension. In hereditary syndromes, mainly multiple endocrine neoplasia type 2 (MEN2) or von Hippel–Lindau (VHL), but also neurofibromatosis type 1 (NF1) or the syndromes associated with paragangliomas (with mutations in SDHD, SHDB, or SDHC), biochemical or functional imaging may indicate the development of pheochromocytoma. Morphologic imaging (CT and MRI) shows the tumor to be rounded, sometimes with calcifications and with varying internal structure (homogeneous to heterogeneous). Necrosis and cystic changes may be found centrally. Pheochromocytomas are generally hypervascular and therefore, well contrast-enhancing lesions.

Radionuclide imaging of these tumors consists of methyl-iodobenzylguanidine scintigraphy, somatostatin receptor (SR) imaging, and PET/CT using 18F-FDG and more specialized tracers such as 18F-dihydroxyphenylalanine (18F-DOPA), 11C-hydroxy-ephedrine, and 18F-6-[18F]-fluorodopamine (18F-FDA).

Malignant pheochromocytoma is diagnosed by the presence of metastasis (in liver, lungs, bones, brain, lymph nodes, etc.), signs of invasive primary tumor, or recurrence after surgical resection. Detection of recurrent tumor is performed by monitoring of symptoms, biochemical parameters, and follow-up with morphologic and radionuclide imaging.

INDICATION FOR RADIONUCLIDE IMAGING OF ADRENAL GLANDS

CT and MRI are the gold standards for morphologic imaging of adrenal tumors. Functional evaluation by radionuclide imaging is added in some cases. Indications for radionuclide imaging are as follows: (1) Biochemically and radiologically suspected adrenal tumors, where CT/MRI is inconclusive, (2) incidentalomas with/without biochemical parameters, not characterized as benign tumors by CT/MRI, (3) patients with hereditary diseases which are known to cause pheochromocytomas, (4) follow-up after surgery/medical therapy of adrenal malignant tumor.

INDICATION FOR RADIONUCLIDE THERAPY FOR ADRENAL GLAND DISEASES

The first option for the management of adrenal tumors is surgical intervention. The indications for radionuclide therapy in adrenal disease are as follows: (1) Nonresectable adrenal tumors, which include invasive tumors with or without metastases, (2) multiple recurrences or metastases of malignant adrenal tumors previously treated surgically, with chemotherapy or radiologically by locally ablative procedures (e.g., intra-arterial embolization/chemo-embolization, radiofrequency ablation). In all cases, the type of tumor should be confirmed, thus indicating which type of therapy is needed. No prophylactic or adjuvant radionuclide therapy is currently used in cases of R0 resections.

TABLE 19.2

ADRENAL NEOPLASMS

Tumors in the Adrenal Cortex

The tumors that may arise in the adrenal cortex are listed in Table 19.2. Benign adrenocortical adenomas are divided into functional adenomas (hormone-producing adenomas) and nonfunctional adenomas. Functional adenomas include aldosterone-producing adenomas (APAs), or adenomas secreting cortisol giving rise to Cushing syndrome. Very rarely, occasional androgen-producing adenomas have been described.

Primary Aldosteronism

PA is caused by (1) APA, (2) aldosterone-producing carcinoma (APC), (3) bilateral idiopathic hyperaldosteronism (IHA), and (4) unilateral adrenal hyperplasia (UAH), or familial aldosteronism types I to III. According to the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, iodocholesterol scintigraphy (NP-59) is not recommended for the diagnosis of PA. The method has low sensitivity and has generally been abandoned. Diagnosis and evaluation of adrenal hypersecretion of aldosterone is laborious and suffers from low sensitivity. Adrenal venous sampling and subsequent hormonal analysis is currently the standard procedure for lateralization, but this is a difficult procedure, especially sampling from the right adrenal gland. The results are very operator dependent. Additional methods to guide the clinician in this setting are needed but are currently unavailable. Other tests such as the posture stimulation test, NaCl infusion and the florinef test are all generally unsatisfactory. Recently, 11C-metomidate PET/CT has been used, after suppression of the ACTH axis by pretreatment with dexamethasone. This procedure has been found to visualize APAs with higher tracer uptake (standardized uptake values, SUV) than to 11C-metomidate PET/CT without cortisone pretreatment.21,22

Cushing Syndrome

Cushing syndrome is caused by excessive circulation of glucocorticoids, giving rise to a classical range of signs and symptoms. Diagnosis is easier than for PA and is made by 24-hour urinary cortisol measurements or by performing a dexamethasone suppression test. The most common etiology is Cushing disease, caused by pituitary hypersecretion of ACTH, generally by a pituitary micro-adenoma, which causes bilateral adrenocortical hyperplasia. Adrenal scintigraphy with 131I-norcholesterol (NP-59) was previously used to image hyperplasia. Functioning ACC causes the Cushing syndrome. The tumor, as well as eventual metastases, can be identified with 11C-metomidate PET/CT or with 18F-FDG with slightly lower sensitivity.

RADIONUCLIDE IMAGING OF ADRENOCORTICAL TUMORS

131I-norcholesterol (NP-59) and 6β-[75Se]-Selenomethyl-1 g-Norcholesterol (Scintadren Scintigraphy)

Iodocholesterol scintigraphy with 131I-19-iodocholesterol and an improved agent, NP-59, was introduced in 1970s. These tracers had been used for scintigraphy including SPECT mainly to preoperatively localize APAs (Conn adenomas) in PA.3,23 Drawbacks of the technique were the limited spatial resolution of planar imaging and SPECT, making small tumors difficult to visualize, and a high radiation dose to the patient (30 mSv or even more). NP-59 is no longer available either in the United States or in most European countries because the production of the tracer was terminated.

In the past, scintigraphy with 6β-[75Se]-selenomethyl-1 g-norcholesterol (Scintadren) was also utilized to image the adrenal cortex and adrenal cortex–derived tumors,3 but used less often for the diagnosis of APAs caused by slow accumulation in the adrenals requiring a long-lived radionuclide (t1/2 120 days). Scintadren is also no longer in use in the United States or most other countries.

The discovery of an adrenal tumor during morphologic imaging does not by itself suffice for preoperative localization because occasionally the patient’s radiologically evident tumor can be nonsecreting and a very small Conn adenoma may instead be harbored in the contralateral adrenal. Thus, currently, hypertensive patients with a biochemical diagnosis of PA undergo lateralization of the Conn adenoma by selective venous sampling instead.

11C-Metomidate-PET and PET/CT and 123I-Metomidate Scintigraphy

Metomidate is the methyl ester of etomidate that has been used as an anesthetic agent.24,25 Etomidate, the ethyl ester, and metomidate are both powerful inhibitors of the two CYP11B enzymes 11β-hydroxylase (CYP11B1, P45011β) and aldosterone synthase (CYP11B2, P450aldo) that are involved in cortisol and aldosterone synthesis, respectively. Metomidate and etomidate have been labeled with 11C and 18F as PET tracers26,27 and metomidate has been labeled with 123I for scintigraphy28 and 131I for purposes of therapy because of their specific adrenocortical binding properties. There are numerous studies published on the metomidate-based imaging of adrenocortical tumors. Generally, these have shown that the sensitivity and specificity to diagnose adrenocortical tumors is high but measurements of tracer uptake cannot be applied to differentiate benign from malignant lesions.

The binding of 11C-metomidate and 11C-etomidate was initially shown to be high and specific in adrenal cortical tissue from different species by using frozen section autoradiography.27 Because of its better radiochemical characteristics, 11C-metomidate was chosen for PET in vivo and the adrenals were successfully imaged in primates. In the initial clinical study,29 of 15 patients with unilateral adrenal tumors, 11C-metomidate PET correctly identified those of adrenocortical origin (six adenomas, one hyperplasia, two adrenocortical cancers) with a high tracer uptake, whereas the noncortical lesions (one myelolipoma, one pheochromocytoma, one metastasis, one mesenchymal tumor, and two cysts) showed low or no uptake.29 Physiologic accumulation of 11C-metomidate is generally seen in normal adrenals and in gastric juice into which the tracer and/or its metabolites were transported. From time to time, patients display high radioactivity concentrations in the gall bladder. The uptake in the liver is intermediate and may sometimes interfere with the depiction of adrenocortical tumors in the right adrenal. A comparative study on 11C-metomidate PET and CT of adrenocortical cancer, consisting of 13 examinations in 11 patients, visualized all viable tumors with a high tracer uptake. Two lesions that were missed by CT were adequate.30 It is interesting to note that three completely necrotic adrenocortical cancer lesions were false negative at 11C-metomidate PET; that the tracer uptake in the ACC lesions showed a high uptake with the peak SUV ranging from 5 to 32, and that treatment with adrenal steroid inhibitors and chemotherapy was found to decrease the tracer accumulation in the tumors. An example of 11C-metomidate PET/CT in ACC is shown in Figure 19.2.

In a comparison of 11C-metomidate and 18F-FDG, 21 patients underwent PET with both tracers. 11C-metomidate uptake was highest in the ACCs, followed by the functioning adenomas and nonfunctional adenomas, and was lowest in the noncortical tumors.31,32 18F-FDG PET detected two out of the three malignant adrenal lesions; the nonmalignant adrenal lesions were negative. Another comparative study based on 16 patients who had PET imaging with 11C-metomidate and 18F-FDG (1 adrenal metastasis, one adrenocortical cancer, one malignant pheochromocytoma, ten adenomas, one hyperplasia, two benign pheochromocytomas). As with previously published results, 11C-metomidate PET differentiated the adrenocortical from nonadrenocortical tumors and also 18F-FDG PET differentiated the malignant from the benign tumors. An interesting finding was that the 11C-metomidate uptake in the contralateral normal adrenal was not suppressed in patients with Conn tumors whereas this was the case in those with Cushing syndrome when a subgroup of nine patients with functioning adrenocortical tumors was considered.

A strict correlation of the histopathologic diagnosis and findings from 11C-metomidate PET was performed in 73 patients with 75 adrenal tumors (26 adenomas, 13 adrenocortical cancers, 8 hyperplasia, 6 pheochromocytomas, 3 metastases, and 19 tumors of nonadrenal origin).33 The study also included small adrenal tumors (size range: 1 to 20 cm). Because of this, the sensitivity to distinguish the adrenocortical from the nonadrenocortical lesions, compared with previous studies, decreased to 89% because of false-negative observations in three ≤1 cm tumors. Because of a false-positive finding in one patient, specificity was 96%. PET measurements of the tracer uptake (SUV) could not distinguish benign from malignant adrenocortical tumors.

The role of 11C-metomidate PET was investigated in a clinical setting to characterize 44 adrenal incidentalomas in 38 patients as compared to CT and MRI.22 11C-metomidate PET was found to be best used as a problem-solving tool for the few patients in whom CT and MRI failed to characterize the tumor.

In two studies on patients with PA, 11C-metomidate PET was performed before and after premedication with oral dexamethasone. The aim was to visualize small Conn adenomas.34,35 The hypothesis was that corticoid treatment decreases ACTH secretion and thereby the 11β-hydroxylase concentrations in normal adrenal parenchyma but not in Conn adenomas, and consequently increases the tumor to normal tissue contrast. In the first study on nine patients with Conn adenomas and, for purposes of comparison, two subjects with nonfunctioning lesions, the small (average: 1.7 cm; range: 1 to 2.5 cm) tumors were all visualized by 11C-metomidate PET in all examinations but with similar visibility and tumor to normal adrenal ratios in examinations performed before and after corticoid pretreatment.

[123I]-iodometomidate has recently been developed as a SPECT tracer29 and has the potential advantage of much better availability than 11C-metomidate-based PET imaging. Preclinical and clinical evaluation demonstrated high and specific uptake of [123I]-iodometomidate in normal adrenals, in adrenocortical tumors and in ACC metastases. Interestingly, the tracer uptake in the liver is relatively lower for [123I]-iodometomidate than for 11C-metomidate, potentially facilitating visualization of right-sided adrenal tumors. Clinical tumor imaging can be achieved 4 to 6 hours after [123I]-iodometomidate injection but the highest target-to-background ratios were reached after 24 hours and the effective dose is a mere 3 to 4 mSv. Like 11C-metomidate PET, [123I]-iodometomidate SPECT is unlikely to differentiate benign from malignant adrenocortical lesions. On the one hand, SPECT imaging has lower spatial resolution than PET, which may be a disadvantage for the visualization of small adrenal lesions. On the other hand, the longer half-life of 123I-iodine may result in a better lesion-to-background ratio than with 11C-metomidate PET. No comparative study on [123I]-iodometomidate SPECT and 11C-metomidate PET has been published to date.

FIGURE 19.2. 11C-metomidate-PET/CT examination (transverse images) of a patient with an adrenocortical carcinoma on the left side (A) and regional para-aortic lymph node metastases (B). In each panel (A and B) the noncontrast enhanced CT is displayed UPPER LEFT, the PET UPPER RIGHT, the PET/CT fusion LOWER LEFT and the maximum intensity projection (MIP) of the PET volume on the LOWER RIGHT. The primary tumor (A) displays a high tracer uptake except for the ventral–lateral part, which is probably necrotic. 11C-metomidate is also found in the gastric juice and the radioactivity in the stomach is clearly seen in the MIP (lower right). Two regional lymph node metastases (B) are found on the left side of the aorta and the physiologic radioactivity in the gastric juice is clearly seen.

18F-Fluorodeoxyglucose PET and PET/CT

PET/CT with 18F-FDG is routinely used in general oncologic imaging for tumor staging, diagnosis of recurrent disease, therapy monitoring, detection of occult tumors, and to differentiate malignant from benign lesions. It may also be used for ACC.

In a study of 28 patients with ACC, the results of 18F-FDG PET/CT were correlated to those of contrast-enhanced CT that was performed separately because the CT in conjunction with PET was carried out with a reduced radiation dose and used merely for attenuation correction.36 18F-FDG PET/CT showed a 90% and 93%, lesion-based sensitivity and specificity, respectively, and the corresponding figures for CT were 88% and 82%. The two methods were complementary and 12% of the lesions were diagnosed only by 18F-FDG PET/CT and 10% only by CT. In a patient-based analysis, the methods were concordant in 25/28 patients (89%) and showed 95% sensitivity, whereas the specificity was 83% for 18F-FDG PET/CT and 100% for CT. In a smaller study of 12 patients who underwent 18F-FDG PET to assess recurrent or metastatic adrenocortical cancer, the sensitivity was 83%.37

RADIONUCLIDE THERAPY OF ADRENOCORTICAL CARCINOMA

Advanced ACC has a poor prognosis. The median survival at the time of diagnosis of stage IV ACC is less than 12 months.38 Even with cytotoxic chemotherapy, objective regression occurs in up to 25% of patients.39 Beneficial effects of radiotherapy were observed in some reports; the consensus conference on the management of ACC treatment judged radiotherapy in ACC to be effective.18 The disease is very rare and thus the results of radionuclide treatment for ACC have only been reported by one center to date.

131I-Metomidate Therapy

Because some adrenocortical cancer lesions exhibit very high and specific uptake of [123I]-iodometomidate, the potential to treat ACC patients with [131I]-iodometomidate has been investigated.29,40,41 The tracer bound to adrenocortical cytochrome P450 family 11B enzymes and was rapidly metabolized within a few minutes, mainly by hepatic esterases. Whole-body elimination of [131I]-iodometomidate showed a half-life of 20 hours.29,40 The clinical experiences of 11 patients with advanced nonresectable ACC were reported.41 The patients received up to 20 GBq [131I]-iodometomidate. It was possible to achieve stable disease in five patients and even partial response in one patient, with ongoing disease stabilization and a median progression-free survival of 14 months (range: 5 to 33 months). The treatment was well tolerated in all patients and the main side effects were transient thrombocytopenia and leucopenia.

Tumors in the Adrenal Medulla

The tumors that may arise in the adrenal medulla are listed in Table 19.2. All of these tumors are rare but patients who have specific hereditary diseases are particularly at risk.

Pheochromocytoma/Paraganglioma

Pheochromocytoma is derived from adrenalin-producing chromaffin cells in the adrenal medulla. Paraganglioma is a rare tumor originally derived from extra-adrenal neural crest cells, the paraganglia, regardless of its location. Pheochromocytoma/paraganglioma is characterized by excess catecholamine secretion and sympathomimetic symptoms. Patients with hereditary syndromes such as MEN2 (genetic mutations of the RET gene), VHL, NF1, or mutations in either the succinyl dehydrogenase subunits B (SDHB), SDHC, and SDHD, or susceptibility genes such as SDHA, MAX, TMEM127, SDHAF2, EGLN1/PHD2, and KIF1Bβ are all at risk of developing pheochromocytoma or paraganglioma.4,4244 Twenty percent to 30% of pheochromocytomas and paragangliomas are associated with these hereditary syndromes.45 In MEN2, approximately 50% of patients develop pheochromocytoma following the occurrence of medullary thyroid cancer, which has higher penetration than pheochromocytomas.46 Pheochromocytomas with MEN2 are usually found in the adrenal glands. They tend to be benign; more than 50% of patients have bilateral adrenal tumors.47 Tumors derived from chromaffin cells express the membrane norepinephrine transporter (NET), which can be the target of specific radiolabeled ligands.48 These ligands have characteristics that allow them to enter sympathomedullary tissue through the NET system and to be marginally metabolized.

Another means of functionally imaging these tumors is through receptor-mediated pathways, for example, the SRs, using 111In-Pentetreotide (Octreoscan). However, metastatic pheochromocytomas can become dedifferentiated and lose both the NET system and/or SRs.4951 Excess glucose uptake, mainly via GLUT-1 receptor is seen in various hypermetabolic tumors including pheochromocytoma; hence the glucose analog 18F-FDG can be used for functional imaging of the tumor.52

Neuroblastic Tumors

The fetal adrenal cortex is penetrated by sympathogonia of neural crest origin that develop into the adrenal medulla. The sympathogonia differentiate into chromaffin cells and ganglion cells in the adrenal medulla. Neuroblastic tumors arise from primitive neural crest cells of the sympathetic nervous system from the neck, posterior mediastinum, adrenal gland, retroperitoneum, and pelvis.53 Neuroblastic tumors can be divided into three types that will be described below. Neuroblastoma is an aggressive and rare type of cancer of the sympathetic nervous system that mainly occurs in infants and very young children. The median age at diagnosis is 15 months.54 In most patients the tumor arises from neuroblasts in the adrenal glands but tumors may also develop in other nerve tissues ranging from the neck to the pelvis.53 The majority (98%) are sporadic, but familial neuroblastomas are reported.55 Prognosis depends on the age at diagnosis, and patients diagnosed before the age of 18 months are regarded as having a good prognosis.56 v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) gene amplification is associated with a worse prognosis.57 The revised versions of the International Neuroblastoma Staging System and International Neuroblastoma Risk Group Staging System are used for disease staging.5658Ganglioneuroblastoma is very rare, of intermediate aggressiveness, and arises from neural crest sympathogonia found commonly in the posterior mediastinum, retroperitoneum, adrenal medulla, and neck.53 Ganglioneuroblastoma occurs in older children but might also occur in adults.59 The revised version of the International Neuroblastoma Pathology Classification defines prognostic subsets of ­ganglioneuroblastoma.60 Ganglioneuroblastoma is composed of well-differentiated elements such as ganglion cells, Schwann cells, and nerve fibers, with primitive neuroblasts. This tumor is less aggressive than neuroblastoma.59 Ganglioneuroma in the adrenal glands is a very rare tumor and arises from ganglion cells, is well differentiated, and has a benign character.53 Ganglioneuromas occur in older children. Elevated urine homovanillic acid (HMA) and vanillylmandelic acid (VMA) are used for the diagnosis. For the diagnosis, imaging by CT, MRI, and MIBG scintigraphy are performed, as well as a biopsy. Functional imaging with radiolabeled ligands for pheochromocytomas/paragangliomas other than MIBG may also be utilized. However, functional imaging studies cannot differentiate these three types of neuroblastic tumors; pathologic evaluation is needed to establish the definitive diagnosis.

RADIONUCLIDE IMAGING OF ADRENAL MEDULLARY TUMORS

Table 19.3 shows the sensitivity and specificity of radionuclide imaging methods for the detection of adrenal medullary tumors.

Metaiodobenzylguanidine Imaging

Metaiodobenzylguanidine (MIBG) is a guanetidine derivative and structural and functional analogs of norepinephrine. It enters the cell by the uptake-1 NET and/or by passive diffusion and selectively accumulates in the noradrenergic neurosecretory granules of chromaffin tissue.61,84 Some pharmaceuticals, however, may interact with MIBG by blocking the uptake or depletion of storage vesicle contents.85 Such pharmaceuticals include antihypertensive drugs (Labetalol, Reserpine, Nifedipine), tricyclic antidepressants, sympathomimetics and cocaine. This interaction may produce false-negative results. These drugs should be discontinued prior to evaluation. Free iodine accumulates in the thyroid gland and may cause thyroiditis and thyroid dysfunction. The thyroid iodine uptake is saturated with potassium iodine used prior to performing MIBG scintigraphy. Scintigraphy with 123I-MIBG and 131I-MIBG is used to visualize pheochromocytomas and other sympathomedullary neoplasms such as neuroblastoma, and has long been regarded as the gold standard radionuclide imaging method to detect these tumors (Fig. 19.3).86For 131I-MIBG the sensitivity to detect pheochromocytomas is 77% to 90% and the specificity 95% to 100%.50,6167 123I-MIBG is better than 131I-MIBG with superior detection efficiency and a lower radiation exposure for the patient.87 It has a sensitivity of 83% to 100% and specificity of 95% to 100%.50,61,64,65,67,7277 123I-MIBG SPECT can be performed for the evaluation of these tumors. However, even with three-dimensional acquisitions using SPECT, the spatial resolution is low (∼1.5 cm) and the detection of small lesions may therefore be difficult. Recently, there have been reports on the additional value of fusion imaging by radiolabeled MIBG SPECT/CT and SPECT/MRI88 and to detect pheochromocytoma and neuroblastoma.8991 The particular strengths of radiolabeled MIBG SPECT/CT were the detection of local recurrences, small extra adrenal pheochromocytomas, multifocal tumors, or the presence of metastatic disease.

When MIBG is negative in patients in whom an adrenomedullary tumor is suspected, PET/CT with specific tracers such as 18F-6-[18F]-fluorodopamine (18F-FDA), 18F-fluorodihydroxyphenylalanine (18F-DOPA), or 11C-hydroxyephedrine can be utilized. When PET with one of these tracers is negative, the tumor may have lost the type I uptake transporter and have transferred to become malignant. In these cases, 18F-FDG PET/CT or somatostatin receptor scintigraphy (SRS) may be positive.92,93

Somatostatin Receptor Imaging

SRS with 111In-DTPA-Pentetreotid (Octreoscan) is the standard radionuclide imaging method for patients with neuroendocrine tumors.9496 Pheochromocytomas mainly express the somatostatin receptor (SR), subtypes 2, 3, and 5. SRS has shown 89% sensitivity by patient-based analysis and 69% by region-based analysis for localizing malignant tumors or metastatic pheochromocytomas/paragangliomas.67 However, only 25% to 38% of the primary benign pheochromocytomas are positive at SRS with lesion/region-based analysis.50,67 Currently 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTA-TOC), 68Ga-DOTA-Tyr3-octreotate (68Ga-DOTA-TATE), and 68Ga-DOTA-1-NaI3-octreotide (68Ga-DOTA-NOC) are becoming available for SR imaging by PET/CT and have provided high sensitivity and specificity in the detection of pheochromocytomas and paragangliomas.62,78,79,97

2-[18F] Fluoro-2-Deoxy-D-Glucose (18F-FDG) PET/CT Imaging

18F-FDG reflects excessive glucose uptake mainly via GLUT-1 in various hypermetabolic tumors.98 This uptake of 18F-FDG is nonspecific and 18F-FDG PET/CT is regarded as the second-line method for detecting pheochromocytoma/paraganglioma (Fig. 19.4), although the method has high sensitivity for metastatic tumors.99,100 In the past, the specificity for 18F-FDG PET in non–18F-FDG metastatic pheochromocytomas has been reported to be low.100 However, according to a recent study, the sensitivity of 18F-FDG PET is similar to that of 123I-MIBG SPECT/CT in benign pheochromocytoma/paraganglioma.71 For nonmetastatic tumors, the lesion-based sensitivity of 18F-FDG PET/CT and 123I-MIBG was 77% and 75%, respectively, and the corresponding specificity was 90% and 92%. For metastatic tumors, the region-based sensitivity of 18F-FDG PET/CT was 83%, and 50% for 123I-MIBG SPECT/CT.71 SDHB-related metastases were more accurately detected by 18F-FDG PET/CT than by 123I-MIBG SPECT.69 The authors emphasized that SDH- and VHL-related tumors were all detected by 18F-FDG PET whereas 60% of MEN2-related pheochromocytomas were 18F-FDG PET negative. The SUV was higher in SDH- and VHL-related tumors than in MEN2- and NF1-related tumors.71

TABLE 19.3

SENSITIVITY AND SPECIFICITY OF RADIONUCLIDE IMAGING METHODS FOR DETECTION OF ADRENAL MEDULLARY TUMORS

FIGURE 19.3. 123I-MIBG scintigraphy in a patient with pheochromocytoma on the right side seen in planar images (A) frontal view (left) and posterior view (right) and SPECT/CT (coronal reformatted images) (B).

18F-Flurorodihydroxyphenylalanine (18F-DOPA) PET/CT Imaging

Dihydroxyphenylalanine (DOPA) is the precursor of all endogenous catecholamines. 18F-dihydroxyphenylalanine (18F-DOPA) is transported via the amino acid transporter system. 18F-DOPA can be decarboxylated to dopamine by the enzyme l-amino acid decarboxylase to 18F-dopamine, which is stored in intracellular vesicles.101 18F-DOPA can be used for PET imaging of benign pheochromocytomas and glomus tumors.74,102 The advantage of 18F-DOPA is the lack of uptake in the normal adrenal glands and every uptake in the anatomical compartment of the adrenal gland could therefore be classified as pathologic.74 18F-DOPA had high sensitivity for both primary tumors and metastases.69,74,76,77,80 However, subgroup analysis showed that region-based sensitivity was high for non-SDHB (93%) metastases but low for SDHB-related metastases (20%) without clear explanation.69

11C-Hydroxyephedrine PET/CT Imaging

11C-Hydroxyephedrine is synthesized using 11C-methyliodine by direct N-methylation of metaraminol to create a synthetic false transmitter analog of norepinephrine.103 Its mode of transmembrane transport is similar to that of norepinephrine, which is selectively and rapidly transported into the sympathetic neuron by the NET. In contrast to norepinephrine, 11C-hydroxyephedrine is resistant to metabolism in the terminal endings of the sympathetic neuron, leading to accumulation. Moderate physiologic 11C-hydroxyephedrine accumulations are seen in organs with sympathetic innervation, such as the myocardium, liver, spleen, pancreas, salivary glands, and normal adrenal medulla.103With these characteristics, 11C-hydroxyephedrine was originally developed as a PET tracer to investigate the sympathetic innervations of the heart. 11C-hydroxyephedrine became the first available positron-emitting probe of the sympathetic nervous system suitable for administration in humans.104 With excellent imaging quality, PET studies demonstrated that 11C-hydroxyephedrine accumulated at high levels in pheochromocytomas and neuroblastomas.81,105 There have been a few studies evaluating the effectiveness of 11C-hydroxyephedrine PET for pheochromocytomas/paragangliomas.75,81,82,106,107 The Institute in Uppsala, Sweden, reported excellent sensitivity (92%) and specificity (100%) in 19 patients with pheochromocytomas (Fig. 19.5).106 Another group reported that 11C-hydroxyephedrine PET demonstrated all sites of confirmed disease in eight patients with pheochromocytoma without any false-negative results. However, there was one false-positive case with medullary hyperplasia.107 In this report, 11C-hydroxyephedrine PET detected the tumors more accurately than 131I-MIBG, especially in cases of bilateral and extra-adrenal lesions. Franzius’ group reported that in 14 patients (six neuroblastomas, five pheochromocytomas, one ganglioneuroblastoma, and two paragangliomas), 11C-hydroxyephedrine PET detected 80 of 81 tumor lesions, including bone and soft tissues, with 99% sensitivity and maximum specificity. 123I-MIBG SPECT/CT detected 75 of 81 lesions with 93% sensitivity and maximum specificity.75 Our institute recently reported our 11 years’ experience with 11C-hydroxyephedrine PET. 11C-Hydroxyephedrine PET (n = 69) and PET/CT (n = 101) examinations on 134 patients were analyzed, showing no false-positive and just six false-negative examinations (sensitivity 91%, specificity 100%).82 The question of hereditary disorders was further investigated. It was found that the sensitivity of 11C-hydroxyephedrine PET in MEN2 patients was lower (73%) but with 100% specificity. The mean SUVmax was significantly higher when sympathetic symptoms were present and in metastatic sites compared to primary tumors. The SUVmax correlated significantly with plasma normetanephrine and urinary norepinephrine. The mean SUVmax in 11C-hydroxyephedrine-positive primary tumors was significantly higher than in normal adrenal glands, which suggested that the degree of 11C-Hydroxyephedrine accumulation (SUVmax) in the tumors correlated with malignancy and biochemical data. Figure 19.6 is an example of a 11C-hydroxyephedrine-PET/CT examination in recurrent pheochromocytoma.

FIGURE 19.4. 18F-FDG PET/CT (transverse images) in a patient with pheochromocytoma on the right displaying a high tracer uptake. No metastases were diagnosed. The noncontrast-enhanced CT is displayed upper left, the PET upper right, the PET/CT fusion lower left and the maximum intensity projection (MIP) of the PET volume on the lower right.

These results suggested that 11C-hydroxyephedrine PET and PET/CT can be clinically used to localize these tumors. However, despite these promising reports, this tracer has not been widely used in clinical setting to detect adrenal tumors. This is because of the limited availability of 11C-hydroxyephedrine and the short physical half-life of 11C (20.4 minutes) thus requiring an in-house cyclotron and on-site production of this tracer.108 By contrast, 18F-FDG is commercially available and can be transported to PET centers lacking a cyclotron. Radio-iodinated MIBG scintigraphy is the established, standard radionuclide imaging method with comparably wide availability and with high sensitivity and specificity. In metastatic disease, when 131I-MIBG therapy is being considered, 123I-MIBG is regularly performed to evaluate the patients’ eligibility for this treatment. 11C-Hydroxyephedrine PET/CT may be most suitable as a problem-solving tool if 123I-MIBG fails to visualize the disease.

18F-6-[18F]-Fluorodopamine (18F-FDA) PET/CT Imaging

The dopamine analog 18F-6-[18F]-fluorodopamine (18F-FDA) is a catecholamine precursor and an excellent substrate for both the plasma NET and intracellular vesicular monoamine transporter in catecholamine-producing cells.61PET with 18F-FDA is reported to have excellent results in localizing both primary and metastatic pheochromocytomas/paragangliomas.67,69,70,83,109 In 99 consecutive studies including 26 patients with nonmetastatic pheochromocytomas and 34 patients with metastatic pheochromocytomas, the sensitivity and specificity for nonmetastatic pheochromocytomas were 78% and 77% in a lesion-based analysis, and sensitivity for metastatic pheochromocytomas was 97% in a patient-based analysis.70 Uptake in adrenal hyperplasia and metabolically active brown fat were sometimes experienced.67

FIGURE 19.5. 11C-hydroxy-ephedrine-PET/CT examination (transverse images) of a patient with biochemical evidence of a pheochromocytoma but equivocal CT finding. The 11C-hydroxy-ephedrine-PET/CT examination shows an intermediate tracer uptake in the right adrenal consistent with a pheochromocytoma that was later surgically resected. The noncontrast-enhanced CT is displayed upper left, the PET upper right, the PET/CT fusion lower left and the maximum intensity projection (MIP) of the PET volume on the lower right.

FIGURE 19.6. 11C-hydroxy-ephedrine-PET/CT examination (transverse images) of a patient previously having undergone surgical resection of a large pheochromocytoma on the right side. Biochemical evidence of recurrent tumor could not be confirmed by follow-up CT. 11C-hydroxy-ephedrine-PET/CT showed a retro-crural lymph node metastasis on the right side. Surgical clips are found in front of the right kidney after surgical resection of the primary tumor. The noncontrast-enhanced CT is displayed upper left, the PET upper right, the PET/CT fusion lower left, and the maximum intensity projection (MIP) of the PET volume on the lower right.

11C-Epinephrine PET/CT Imaging

11C-Epinephrine was tested as a PET tracer in patients with pheochromocytomas/paragangliomas but the diagnostic yield was less than that of 123/131I-MIBG.110

COMPARISON OF RADIOPHARMACEUTICALS FOR VISUALIZATION OF PHEOCHROMOCYTOMA/PARAGANGLIOMA

In a comparative study, detection of benign pheochromocytomas by MIBG scintigraphy showed a sensitivity of 83% but the corresponding figure for 18F-FDG PET was merely 58% by patient- and lesion-based analysis. By contrast, in malignant pheochromocytomas, 123I-MIBG scintigraphy showed 88% sensitivity and 18F-FDG PET 82% by patient-based analysis. The author thus concluded that uptake of 18F-FDG is found in a greater percentage of malignant than benign pheochromocytomas and that 18F-FDG PET is useful when tumors fail to concentrate 123I-MIBG.52 In the comparative study, it was demonstrated that 18F-FDA PET was better than 131I-MIBG scintigraphy for localization of metastatic pheochromocytomas with patient-based sensitivities of 100% and 56%, respectively.109 18F-FDA PET was also compared with 123I-MIBG scintigraphy and SRS with Octreoscan in nonmetastatic and metastatic pheochromocytomas in 53 patients.67 The overall patient-based sensitivity for 18F-FDA PET was 90%, 123I-MIBG scintigraphy 76%, and SRS 22%. In a region-based analysis, the overall sensitivity for 18F-FDA PET was 75%, 123I-MIBG scintigraphy 63%, and SRS 64%. The authors concluded that 18F-FDA PET should be used in the evaluation of pheochromocytoma because of its better sensitivity. In the evaluation of metastatic pheochromocytomas, 123I-MIBG was shown to be the least informative modality.67 18F-DOPA PET was shown to be superior to 123I-MIBG scintigraphy to localize catecholamine-producing tumors with lesion-based sensitivity/specificity of 98%/100%, and 53%/91%, respectively.77 In a comparative study, 18F-DOPA, 18F-FDG, 18F-FDA PET, and 123I-MIBG scintigraphy were tested in the same patient group.69 Lesion-based sensitivities for nonmetastatic tumors were 81% for 18F-DOPA PET, 88% for 18F-FDG PET/CT, 77% for 18F-FDA PET/C, and 77% for 123I-MIBG scintigraphy. For metastatic tumors, the region-based sensitivity was 45% for 18F-DOPA PET, 74% for 18F-FDG PET/CT, 76% for 18F-FDA PET/CT, and 57% for 123I-MIBG scintigraphy. In patients with SDHB metastatic tumors, 18F-FDA and 18F-FDG showed higher region-based sensitivities (82% and 83%) than 123I-MIBG (57%) and 18F-DOPA (20%). The author concluded that 18F-FDA PET/CT was the preferred method to localize primary tumors and to exclude metastases.

RADIONUCLIDE THERAPY FOR TUMORS OF THE ADRENAL MEDULLA

[131I] MIBG Therapy

Radionuclide therapy with [131I] MIBG is performed in patients with nonresectable pheochromocytoma/paraganglioma and neuroblastoma because of multiple metastases/recurrence or direct invasion into other organs.111 Patients should have pretreatment evaluation by [123I] or [131I] MIBG scintigraphy and should have 123/131I-MIBG-positive tumors if the treatment is to be efficacious. The treatment was introduced in 1983.112 but the effectiveness of [131I] MIBG therapy alone or combined with chemotherapy is still limited and the outcome for malignant pheochromocytoma with this treatment remains poor. Those patients who responded to the treatment were shown to have prolonged survival (9 months longer median survival) compared to those who did not respond.112 Nevertheless, given the lack of effective alternatives [131I] MIBG treatment is still used, at least to stabilize the disease and especially to treat metastatic disease.

Radiolabeled Peptide (Somatostatin Analog) Therapy

Metastatic pheochromocytoma can be treated by the radiolabeled somatostatin analog 90-Yttrium-DOTA-Tyr3-octreaotide (90Y-DOTA-TOC), 177-Lutetium-DOTA-Tyr3-octreotide (177Lu-DOTA-TOC), and 177-Lutetium-DOTA-Tyr3-octreotate (177Lu-DOTA-TATE).113115 In some tumors, especially in neuroblastomas, binding to the SRs per se induces apoptosis and thereby reduces tumor volume. Radionuclide therapy using 177Lu- and 90Y-labeled somatostatin analogs is often referred to as peptide receptor radiotherapy (PRRT) and has mainly been utilized in malignant and metastatic pheochromocytomas and paragangliomas. Twenty-eight patients with nonresectable, SR-positive pheochromocytomas and paragangliomas received 90Y-DOTA-TOC (25 patients) and 90Y-DOTA-TOC followed by 177Lu-DOTA-TOC (three patients), and at restaging 8 to 12 weeks after the last treatment cycle, two patients had partial remission, five patients had minor responses, thirteen had stable disease, two had mixed responses, and six remained progressive.115 The authors concluded that the therapy seemed less effective than in gastroentero-pancreatic NETs and had low toxicity, mainly leukopenia and thrombocytopenia. From a theoretical point of view, combined treatment with MIBG and PRRT could have synergistic effects and might thus be considered.116

CONCLUSION

With the escalating use of cross-sectional imaging, mainly CT, the increasing incidence of adrenal incidentalomas creates a clinical problem because they represent a wide range of both benign and malignant lesions which require radiologic and endocrinologic characterization. Most incidentalomas may be diagnosed as benign by means of morphologic imaging, generally CT or MRI, by establishing that the lesion contains cytoplasmic or macroscopic fat, or by calculating the intravenous contrast medium wash-out or through follow-up of tumor size. Radionuclide imaging represents a range of complementary tools to distinguish between the tumor lesions that need to be surgically removed and those that will neither require surgery nor long-term follow-up.

Imaging of tumor metabolism with 18F-FDG PET/CT can differentiate benign from malignant adrenal tumors with high accuracy, despite the nonspecific nature of the tracer117 and can also assist in the diagnosis and staging of pheochromocytoma. Targeting of tissue-specific enzyme expression by 11C-metomidate PET/CT and 18F-DOPA scintigraphy are ways of differentiating adrenocortical from nonadrenocortical tumors and are suitable for tumor characterization and detection of metastatic disease when ACC is suspected.

123/131I-MIBG scintigraphy remains the gold standard for radionuclide imaging of adrenal medullary tumors because of its wide availability and because it is a means to evaluate the patients’ eligibility for 131I-MIBG therapy. Because of its availability, 18F-FDG PET/CT also represents an alternative although it is nonspecific. PET/CT with a specific tracer such as 11C-hydroxyephedrine, 18F-DOPA, and 18F-FDA are problem-solving tools and are recommended when 123I-MIBG scintigraphy fails. Although radionuclide therapy of malignant adrenal medullary disease utilizing 131I-MIBG is currently the most commonly preferred method, over the past few years, PRRT using 177Lu-octreotate and 90Y-octreotide have emerged as an alternative.

FUTURE CONSIDERATIONS

The greatest progress in radionuclide imaging is in PET/CT with the development of new tracers. This is hampered, however, by problems related to the high cost and regulatory issues. In some countries, PET/CT is still limited to a few university centers.

123I-MIBG scintigraphy, because of its wide availability, will continue to have an important role in radionuclide imaging and will be useful to evaluate a patient’s eligibility for 131I-MIBG therapy. For localization of adrenal medullary tumors, PET and CT with specific tracers have shown high sensitivity and specificity, some of them perform better than 123I-MIBG scintigraphy. The use of PET/CT with these tracers will probably increase in the future.

Somatostatin scintigraphy remains the gold standard for SR imaging but PET/CT with 68Ga-labeled somatostatin analogs, because of their better spatial resolution, high image contrast, and logistic advantages, will most probably gradually replace single-photon somatostatin scintigraphy.

Imaging of adrenocortical tumors using specific PET tracers such as metomidate and etomidate is an interesting field for future development. In PA, adrenal venous sampling is a cumbersome procedure that frequently has to be repeated because of initial failure. Currently, this represents the only available means of lateralization of hypersecretion because NP-59 scintigraphy no longer is in use.

A potential future lateralization method that is of interest is PET/CT with the highly specific tracer 11C-metomidate. It has been shown that very small adrenocortical lesions can be distinguished by means of cortisol premedication before PET/CT examination. Early evaluation of 18F-metomidate and 18F-etomidate in primates has shown better imaging characteristics than 11C-metomidate. The 18F-labeled tracers are most probably the better choice for exploring lateralization in PA.

The high specific uptake of 11C-metomidate in ACC not only makes it a powerful diagnostic tool but also opens up the investigation of metomidate as a new treatment option for ACC by using [131I] IMTO for radionuclide therapy.

ACKNOWLEDGMENTS

We acknowledge our colleagues and staff at the Nuclear Medicine Department, Karolinska University Hospital, Stockholm, Sweden, and at the PET Center, Uppsala University Hospital, Uppsala, Sweden.

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