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Quarterly Medical Review - Medical Functional Imaging
Adrenal functional imaging
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Rudolf A. Wernerª, Andreas Schirbela, Andreas K. Bucka, Martin Fassnachtb, Stefanie Hahnerb,*
ª University Hospital, University of Würzburg, Department of Nuclear Medicine, Germany
b University Hospital, University of Würzburg, Division of Endocrinology and Diabetes, Department of Medicine I, Oberdürrbacher Str. 6, Würzburg 97080, Germany
ARTICLE INFO
Article History: Available online 4 February 2022
ABSTRACT
Given the more widespread use of conventional imaging techniques such as magnetic resonance imaging or computed tomography, recent years have witnessed an increased rate of incidental findings in the adrenal gland and those adrenal masses can be either of benign or malignant origin. In this regard, routinely con- ducted morphological imaging cannot always reliably distinguish between cancerous and noncancerous lesions. As such, those incidental adrenal masses trigger further diagnostic work-up, including molecular functional imaging providing a non-invasive read-out on a sub-cellular level. For instance, [18F]FDG positron emission tomography (PET) as a marker of glucose consumption has been widely utilized to distinguish between malignant vs benign adrenal lesions. In addition, more adrenal cortex-targeted radiotracers for PET or single photon emission computed tomography have entered the clinical arena, e.g., Iodometomidate or IMAZA, which are targeting CYP11B enzymes, or Pentixafor identifying CXCR4 in adrenal tissue. All these tracers are used for diagnosing tumors deriving from the adrenal cortex. Furthermore, radiolabeled MIBG, DOPA, and DOTATOC/-TATE are radiotracers that are quite helpful in detecting pheochromocytomas originat- ing from the adrenal medulla. Of note, after having quantified the retention capacities of the target in-vivo, such radiotracers have the potential to be used as anti-cancer therapeutics by using their therapeutic equiva- lents in a theranostic setting. The present review will summarize the current advent of established and recently introduced molecular image biomarkers for investigating adrenal masses and highlight its transfor- mation beyond providing functional status towards image-guided therapeutic approaches, in particular in patients afflicted with adrenocortical carcinoma.
@ 2022 Elsevier Masson SAS. All rights reserved.
1. Introduction
Given the increased use of conventional, cross-sectional imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT), recent years have witnessed an expanded rate of incidental findings in the adrenal gland [1,2] and such adrenal masses can be either of benign or malignant origin [2]. In patients who underwent CT or MRI, incidental adenomas are identified in up to 5% of the cases [1]. Equivocal findings on morphological imaging, how- ever, trigger further diagnostic work-up. In this regard, functional molecular imaging emerged as a powerful tool to further distinguish between adrenocortical tumors from non-adrenocortical lesions. Pro- viding a non-invasive read-out on a subcellular level targeting enzymes or membrane-bound receptors, positron emission tomogra- phy (PET) or single photon emission computed tomography (SPECT) radiotracers are widely used to interrogate the underlying patho- physiology of incidentally discovered adrenal masses [2]. Of note, the amount of intravenously administered radiopharmaceuticals is kept
small, so that interference with physiological processes can be avoided [3]. Moreover, molecular imaging of adrenal lesions has been advocated to have prognostic potential, thereby identifying high-risk patients under guideline-compatible treatment [4,5] or to change management [6]. Moreover, after having quantified the retention capacities of the therapeutic target in-vivo, specific radiotracers have the potential to be used as anti-cancer therapeutics by using their theranostic equivalents [7-10].
In the present review, we will summarize the current advent of established and recently introduced molecular image biomarkers for investigating adrenal masses and highlight its transformation beyond providing functional status towards image-guided therapeutic approaches, in particular in patients afflicted with pheochromocy- toma (PHEO) or adrenocortical carcinoma (ACC).
2. Adrenal incidentaloma
According to the National Institute of Health State-of-the-Science Statement on the management of the clinically inapparent adrenal mass in 2002, adrenal incidentalomas are characterized as inapparent adrenal mass which are discovered accidentally during diagnostic
* Corresponding author. E-mail address: hahner_s@ukw.de (S. Hahner).
work-up of a clinical condition not primarily related to an adrenal disease [11]. A significant proportion of those asymptomatic findings in the adrenal gland are nonfunctioning adrenocortical adenomas not requiring therapy, whereas other conditions require an immediate therapeutic intervention, such as adrenalectomy. Such diagnoses triggering treatment include, but are not limited to ACC, metastases of a primary outside the adrenal gland, or pheochromocytoma and account for about 10% of adrenal incidentalomas [2,12,13]. As the precise identification of the underlying entity is of utmost importance for further therapeutic management, current guidelines recommend risk stratification at the time of first discovery aiming to characterize an adrenal mass as either benign or malignant. Non-contrast enhanced CT is widely utilized and an adrenal mass demonstrating Hounsfield Units ≤10 is with very high certainty benign. However, lesions with Hounsfield Units above 10 or even above 20 can be both benign or malignant and further work-up is required [2]. It goes without saying that endocrine diagnostic is crucial for all adrenal incidentalomas independent whether they are benign or malignant [2], but this is not the focus of this review.
2.1. SPECT radiotracers for assessment of adrenal incidentalomas
Although PET has an increased spatiotemporal resolution relative to SPECT, PET is mainly used in large academic centers [14] and thus, scintigraphy radiotracers enable for a more widespread use of func- tional adrenal molecular imaging. The SPECT compound [123]]Iodo- metomidate (IMTO), binding to the adrenocortical enzymes 11B- hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), demon- strated successful inhibition of both CYP11B enzymes in cell culture experiments while murine imaging studies revealed excellent image quality [8,15,16]. In a translational approach, radiotracer accumula- tion was noted only in adrenocortical tissue [8]. These findings were further corroborated in 51 patients scheduled for [123I]IMTO planar scintigraphy and SPECT/CT, demonstrating sensitivity and specificity >0.85 for the characterization of adrenal masses ≥2 cm in diameter (Fig. 1) [17]. Despite its promising imaging properties, [123I]IMTO has a relatively rapid metabolic inactivation and therefore, the metaboli- cally stabilized compound (R)-1-[1-(4-[123[]iodophenyl)ethyl]-1H- imidazole-5-carboxylic acid azetidinylamide ([123I]IMAZA) has been
introduced. Extensive preclinical evaluation by in-vitro cell-uptake assays, binding experiments to cryosections of human adrenocortical and non-adrenocortical tissue and in-vivo studies in mice, revealed high and specific binding of [123I]IMAZA to the CYP11B enzymes along with excellent imaging qualities in mice. In autoradiographic studies using human specimens, the signal was distinctively stronger for [125I]IMAZA than for the reference compound [125I]IMTO, sup- porting the notion of an improved binding to adrenocortical tissue in patients (Fig. 2). These considerations were further fueled by head- to-head comparisons of both compounds in patients afflicted with ACC, demonstrating lower background activity for the novel com- pound (Fig. 3A-D) [10].
2.2. PET radiotracers for assessment of adrenal incidentalomas
As the most widely utilized positron-emitting radiotracer, [18F] Fluorodeoxyglucose ([18F]FDG) has also been applied in the context of subtype differentiation in patients with adrenal incidentaloma. Spearheaded by Boland and coworkers, a meta-analysis aiming to determine the diagnostic utility of [18F]FDG in the context of inciden- tally discovered adrenal masses included 21 studies comprising a total of 1391 lesions in 1217 patients [18]. The sensitivity, specificity and accuracy for accurately characterizing an adrenal incidentaloma was >0.91, rendering this PET radiotracer as a suitable agent for this purpose. The authors even deemed subsequent serial imaging includ- ing CT washout or lipid-sensitive MRI unnecessary, once [18F]FDG PET has been conducted [18]. These considerations are further fueled by results of a prospective study investigating the usefulness of [18F] FDG in patients with previous history of cancer, with surgical speci- men serving as reference standard. Enrolling 77 individuals, a quanti- tative analysis was performed using a maximum standardized uptake value (SUVmax) derived from adrenal glands and corrected to healthy liver, providing an adrenal-to-liver ratio (ALR). An ALR cutoff of 1.45 demonstrated a sensitivity of 1 and a specificity of 0.88 to dis- tinguish adrenocortical adenomas from ACC [19]. Nonetheless, a recent meta-analysis applying stricter study inclusion criteria con- cluded that the evidence for the diagnostic value of [18F]FDG is lim- ited to reliably distinguish benign from malignant adrenal masses [20]. For instance, verified by histopathology, black adrenal
[18F]FDG
[123 I]IMTO
0
O
[125]IMTO
[125|]IMAZA
A B
A
B
high
kidney
liver
ACC
low
APA
CPA
adrenal gland
9
P
adenomas also demonstrated accumulation of [18F]FDG, with an SUV- max of ≥3 [21]. In addition, extra-adrenal tumors, which also metasta- size to the adrenal glands, demonstrate an increased [18F]FDG accumulation, such as lung cancer, lymphoma or even orphan malig- nancies including angiosarcoma or leiomyosarcoma [22-26] and therefore, more specific radiotracers, preferably targeting the adrenal cortex are intensively sought.
Initially developed as non-barbiturate imidazole anesthetic agents, etomidate (ETO) and later metomidate (MTO) revealed as potent inhibitors of 11-hydroxylase and aldosterone synthase [8,16,27,28]. As such, 11C-labeled MTO and ETO (representing the cor- responding ethyl ester) were investigated in a translational approach in monkeys and humans, demonstrating its feasibility to discriminate lesions of adrenocortical origin from non-adrenocortical lesions [29,30]. In further studies with surgical or biopsy specimens serving as reference, sensitivity and specificity was >0.89 for [11C]MTO to demonstrate adrenocortical origin of the investigated lesions (with PHEO, metastases to the adrenal gland, and nonadrenal masses hav- ing no [11C]MTO uptake). However, carbon-11 comes with multiple drawbacks, including its short half-life-time (20 min), a costly on-site cyclotron for production and no flexibility in the study design [31]. 18F-labeled radiotracers, which preferably bind to the adrenal gland would overcome this issue and therefore, the 11 ß-hydroxylase inhib- itor 2-[18F]fluoroethyl-etomidate ([18F]FETO) has entered the clinical arena [32]. After a thorough in-vitro and in-vivo evaluation in rodents [33], first human scans revealed increased radiotracer accumulation in the adrenals of healthy volunteers, thereby rendering 11B-hydrox- ylase selective agents as a potential substitute for their 11C-labeled
equivalents [32]. A recent study also reported on a para-fluorinated aromatic (R)-MTO derivative ([18F]FAMTO), which demonstrates spe- cific binding to CYP11B-rich pig adrenal glands in ex-vivo autoradi- ography studies along with excellent in-vivo kinetics in rodents with rapid accumulation in the adrenal gland [34]. More recently, Par- a-chloro-2-[18F]fluoroethyl-etomidate ([18F]CETO) was also intro- duced, which demonstrated specific binding to the adrenal cortex in rodents and non-human primates along with negligible hepatic uptake, rendering this radiotracer as highly sensitive non-invasive image biomarker for the adrenal glands [35]. All of these 18F-labeled radiotracers have the significant advantage of a half-life of 110 min and therefore, allow for dispatch to remote PET centers with no access to an on-site cyclotron [31,36]. Nonetheless, human studies, preferably in a prospective clinical setting are warranted to further evaluate the diagnostic potential of these tracers.
3. Primary aldosteronism (PA)
Characterized by excessive production of aldosterone causing hypertension, primary aldosteronism (PA) is associated with an increased rate of cerebrocardiovascular events, on-set of diabetes or metabolic syndrome [37]. To establish diagnosis and to differentiate between unilateral APA vs idiopathic bilateral adrenal hyperplasia (BAH), adrenal venous sampling (AVS) and CT are routinely con- ducted. Such classification of the underlying cause is of importance, as APA guides towards adrenalectomy, whereas BAH requires treat- ment with mineralocorticoid receptor antagonists [38]. Despite its high accuracy [39], AVS has several limitations, such as difficulties to
A
C (IMTO)
D (IMAZA)
B
E
265 Gy
117 Gy
185 Gy
133 Gy
10 min
1 h
2 h
4 h
22 h
successfully cannulate the adrenal veins, increased risk of adrenal hemorrhage, lack of standardized procedures or interpretation, increased costs, and high radiation burden varying from center to center [38,40]. As such, molecular functional imaging for PA may pro- vide a sophisticated approach to adequately characterize adrenal lesions in the context of PA [38].
3.1. SPECT radiotracers for assessment of PA
19-[13]]]iodocholesterol and its improved equivalent 60-[1311] iodomethyl-19-norcholesterol (NP-59) were used in patients with PA [41,42], as the cholesterol analogue NP-59 accumulates in the adrenal cortex [43]. NP-59 SPECT revealed a sensitivity of 81.8% and specific- ity of 66.7% to correctly diagnose APA with histopathology serving as reference [44]. Nonetheless, NP-59 puts a high radiation burden on
the patient and for this scintigraphy approach, multiple acquisitions over days are needed. Moreover, it is no longer available in Europe [38].
3.2. PET radiotracers for assessment of PA
Beyond its use for assessment of ACC, [11C]MTO demonstrated increased uptake in APA (with histopathology serving as reference), which was substantially increased when compared to the contralat- eral adrenal gland [45]. Burton et al. further investigated [11C]MTO enrolling 39 patients with PA and 5 with nonfunctioning adenoma. Indicating BAH, patients without lateralization on AVS revealed com- parable uptake between both adrenal glands, whereas patients with PA and lateralization on AVS to the side of the adenoma demon- strated significant increased radiotracer accumulation on the affected
side relative to the normal adrenal gland [46]. Of note, dexametha- sone achieves down-regulation of CYP11B1 and thus, dexamethasone injection 3 days prior to [11C]MTO administration increased tumor to normal adrenal SUVmax ratio, supporting the notion that such elabo- rated image protocols may be helpful to increase interpretative cer- tainty due to decreased background activity [46]. However, a recent prospective study recruited 58 subjects with confirmed PA and the lateralization of [11C]MTO PET and adrenal CT were compared with AVS and with immunohistochemical staining for CYP11B2 in a subco- hort which underwent adrenalectomy. In receiver operating charac- teristics, [11C]MTO PET-derived SUVmax had a relatively low area under the curve to predict successful adrenalectomy [47]. 11C-labeled radiotracers suffer from major drawbacks, as the short half-life of 20 min does not allow for delivery to remote hospitals or the imple- mentation of delayed image protocols [31]. As such, an 18F-labeled image agent specifically targeting CYP11B2, which is exclusively expressed in the zona glomerulosa has been introduced for subtype detection of PA [48]. CYP11B2 is specifically expressed in aldoste- rone-producing tissue whereas CYP11B1 expression is also found in cortisol-poducing and non-functioning adenomas [49,50]. Such a CYP11B2-directed radiotracer leveraging all advantages of 18F-label- ing would be of clinical value. In this regard, the recently introduced radiotracer [18F]CDP2230 revealed favorable properties in an ex- and in-vivo setting [48]. First, autoradiography studies demonstrated more specific binding when compared to [123I]IMTO. Second, in-vivo rat studies demonstrated increased accumulation in the adrenals, with negligible background uptake. Of note, due to the selectivity of CDP2230 for CYP11B2 over CYP11B1, dexamethasone may not be needed to increase image contrast [48]. Human studies for [18F] CDP2230 are so far lacking. However, the CETO Phase 1 trial will pro- vide further insights into the usefulness of 18F-labeled radiotracers for investigating PA. In this mono-centric, currently recruiting trial, [18F]CETO will be injected into healthy volunteers and 6 patients with PA (3 unilateral vs. 3 bilateral) to evaluate the ability of this radiotracer to separate between unilateral and bilateral PA [51].
Moreover, the C-X-C motif chemokine receptor 4 (CXCR4) has also been advocated to serve as a potential target for PET-based assess- ment of patients with PA. Investigated by an extensive ex-vivo work- up, high CXCR4 expression was noted in APA, strongly correlating with CYP11B2 expression. Such findings triggered the first patient study with CXCR4-targeted PET radiotracer [68Ga]Pentixafor. In 9 patients with established diagnosis of APA, tracer uptake was higher on the side of increased adrenocortical aldosterone secretion [40]. Overall, a sensitivity of 88.9% and a specificity of 87.2% for detection of APA was noted using this CXCR4-directed PET approach. These findings were corroborated in a prospective analysis in 36 patients [52].
4. Pheochromocytoma (PHEO)
As a rare neuroendocrine tumor originating from chromaffin cells of the adrenal medulla, approximately 4% of the patients with an adrenal incidentaloma are diagnosed with PHEO [53]. More specific molecular imaging of PHEO either targets the somatostatin receptor (SSTR) or bases on catecholamine analogs and metabolites.
4.1. SPECT radiotracers for assessment of PHEO
Given their increased expression of vesicular transporter systems, the norepinephrine targeting SPECT radiotracer [1231]/[13] []metaiodo- benzylguanidine (MIBG) has been utilized in PHEO, with the first reports dating back to the 1980ies [54]. A prospective multicenter trial reported on a sensitivity of 87% and a specificity of 73% using pla- nar scintigraphy, with the addition of SPECT resulting in further improved sensitivity (88%) [55]. These results confirmed previous retrospective studies reporting on sensitivities of 88-98% [56,57]. In
a recently published multicenter phase 2 trial, Pryma et al. also reported on the use of high-specific activity [13]]]MIBG for treatment in 68 patients with advanced PHEO or paraganglioma receiving at least one therapeutic cycle. 25% of the patients had a sustainable reduction of antihypertensive medication and 92% had a partial response or stable disease within 12 months. Median overall survival was 36.7 months. Haematotoxicity occurred in 90% of the patients, with 25% of the subjects requiring further hematologic support, such as red blood cell transfusions. A separate subanalysis for PHEO, how- ever, was not provided [58]. Another option for SPECT assessment of PHEO is the somatostatin receptor (SSTR) targeting SPECT compound [111In]pentetreotide (Octreoscan), but in a head-to-head comparison, this compound was not superior relative to MIBG [59,60].
4.2. PET radiotracers for assessment of PHEO
Similar to MIBG also targeting the norepinephrine transporter, the PET compound [11C]hydroxyephredrine has been initially utilized to locate PHEO [61]. Relative to other positron-emitting agents, its half- life is limited (20 min), triggering the development and clinical use of 18F-labeled compounds such as [18F]fluorodopamine (DPA) and [18F] dihydroxyphenylalanine (DOPA). Given the higher spatiotemporal resolution of PET relative to SPECT, the latter compound was superior when compared to [123I]MIBG in the detection of PHEO with 100% sensitivity for [18F]DOPA (mIBG, 71%). Of note, when compared to [18F]DPA, [18F]DOPA has a lack of uptake in the normal adrenal glands [62]. Nonetheless, a theranostic approach cannot be conducted with these radiotracers. SSTR-targeting PET compounds, such as 68Ga- labeled 1,4,7,10-tetraazacyclododecane-N,N’, N”,N’“-tetraacetic acid- D-Phe(1)-Tyr(3)-octreotide/-octreotate ([68Ga]DOTATOC/-TATE) have further shown high diagnostic utility. PHEOs are assigned to three clusters based on their respective genetic background and the associ- ated biochemical and clinical features, (cluster 1A, 1B and cluster 2). This has also been shown to have impact on the diagnostic sensitivity of available radiotracers. Whereas SSTR directed PET imaging with [68Ga]DOTATOC/-TATE has shown a higher sensitivity for cluster 1A tumors, [18F]DOPA PET is more suitable for cluster 1B and cluster 2 tumors [63].
From a theranostic perspective, SSTR-targeting compounds include 90Y/177Lu-labeled equivalents for therapy. Chang et al. inves- tigated a mixed cohort of PHEO and paraganglioma which underwent both [68Ga]DOTATATE and [18F]FDG. Although the overall number of lesions was comparable between both PET radiotracers, target-to- background ratio was substantially improved for the SSTR-targeted image agent [64]. Moreover, a recent study also reported on a high safety profile in 22 PHEO/paraganglioma patients which underwent peptide receptor radionuclide therapy (PRRT) with [177 Lu]DOTATATE. Disease stabilization was achieved in 20 of the patients, with an OS of 49.6 months. Severe grade 3 or 4 hematological or renal adverse events were not reported. In two patients, however, catecholamine- related symptoms were aggravated under PRRT, resulting in hyper- tensive crisis and therefore, PHEO patients should be closely moni- tored under therapy [65].
5. Adrenocortical carcinoma (ACC)
SPECT Radiotracers for Assessment of ACC. Recently introduced SPECT radiotracers for the assessment of ACC can also be used in a theranostic setting for the treatment of ACC. After demonstrating increased and highly specific tracer retention on [123I]IMTO SPECT, the theranostic twin [13]]]IMTO was applied to 11 patients suffering from ACC. A total of 19 treatment cycles were conducted in this patient cohort and 1.6 - 20GBq was administered. The treatment was well tolerated with acute adverse events reported in six patients dur- ing hospital stay, including transient nausea, mild intraabdominal pain (in patients with extensive abdominal tumor burden), and
edema of the lower limb. Best response was observed in one subject with a reduction in target lesion size by >50% from baseline, stable disease in 5/11 and progressive disease in the remaining 4 subjects. In responders, median progression-free survival was 14 months (range, 5-33 months) with ongoing disease stabilization in three patients at last follow-up [9].
Despite favorable treatment results, IMTO is rapidly metabolically inactivated, which triggered the development of novel radiotracers with high avidity towards CYP11B1/2 but increased metabolic stabil- ity. In this regard, the theranostic analog [123/131 I]IMAZA was devel- oped. As alluded to earlier, biodistribution experiments using 125I- labeled IMAZA and -IMTO (serving as reference standard), revealed increased and more preserved radiotracer uptake in the adrenal gland for the novel agent. Of note, in three advanced patients, [123]] IMAZA also demonstrated increased target-to-background ratio when compared to [123I]IMTO. Moreover, patients were also sched- uled for [13] ]]IMAZA treatment and post-therapeutic dosimetry dem- onstrated high doses of up to 256 Gray after the first and 210 Gray after the second cycle. Accordingly, a continuous decrease of meta- bolic activity and size of target lesions during follow-up was noted, with a progression-free survival of 21 and overall survival of 30 months. Such results render labeled IMAZA not only as a promising imaging agent, but also as an effective treatment approach in advanced disease (Fig. 3E) [10].
5.1. PET radiotracers for assessment of ACC
As cancer cells preferably convert glucose to lactate independent of oxygen level (Warburg effect), increased metabolic rate of tumors can be measured using [18F]FDG. As the most commonly used radio- tracer in nuclear oncology, initial reports on [18F]FDG in the context of ACC demonstrated an increased uptake in a small number of patients [66,67]. These initial results were further corroborated in a prospective setting enrolling 22 patients afflicted with ACC investi- gating 269 lesions. In a head-to-head comparison with thoracoabdo- minopelvic CT, complementary information was recorded in the vast majority of cases. 12% of lesions, however, were only seen on PET/CT, whereas 10% of the lesions were depicted on stand-alone CT. More- over, increased glucose consumption assessed by PET (SUVmax>10 or metabolic tumor volume >150 ml) was a predictor for survival, ren- dering [18F]FDG as a potential tool to identify high-risk individuals. However, only 15% of the lesions with ≤5 mm had increased radio- tracer accumulation, which increased to 58% for lesions with a size of 5-10 mm [5]. As such, limited spatial resolution along with potential partial volume effect hampered diagnostic accuracy on [18F]FDG PET [68]. Evaluating 12 patients with recurrent or metastatic disease, Mackie and coworkers reported on 10 subjects with correctly identi- fied recurrence by PET and concluded that most ACC accumulate and retain FDG. Again, small lesions in the liver and lung were false-nega- tive [69]. Ardito et al. also reported on the value of [18F]FDG PET/CT in the post-operative surveillance phase. In 57 patients after surgery, the increased specificity of PET was helpful to rule out ACC recur- rence if depicted on CT [70]. Taken together, [18F]FDG PET along with cross-sectional imaging has emerged as a valuable and widely avail- able tool for staging and restaging of ACC patients. Nonetheless, very small lesions have to be interpreted with caution, to avoid misinter- pretation and an increased rate of false-negatives.
Beyond [18F]FDG, more tissue endocrine function-targeting radio- tracers have been developed. For instance, [11C]MTO has been inves- tigated in a small cohort of 11 subjects afflicted with ACC which underwent 13 PET/CTs. While increased radiotracer accumulation was visualized in putative sites of disease, additional two lesions were exclusively recorded on PET when compared to stand-alone CT. Nonetheless, false-negative findings in 3 lesions were explained by necrotic tissue with histopathology serving as reference. Of note, a subanalysis revealed that patients under 11beta-hydroxylase
activity-interfering medication at time of scan had reduced uptake of [11C]MTO when compared to treatment-naïve patients. Therefore, as a potential pitfall suggesting a potential bias on scan interpretation, intake of such drugs at time of scan should be closely monitored. Nonetheless, such findings render [11C]MTO as a potential radiotracer for future serial monitoring of treatment efficacy [71]. Hennings et al. investigated 212 [11C]MTO PET examinations in 173 patients, with 13 subjects diagnosed with ACC. In a more sophisticated approach of semiquantification, SUV ratio between the tumor and the contralat- eral, non-affected gland was established and could separate between ACC and all hormonally hypersecreting adenomas when compared to normal adrenal glands [45].
Recently, the CXCR4 targeting PET radiotracer [68Ga]Pentixafor has entered the clinical arena [72]. Overexpressed in more than 20 tumor types, CXCR4 is of importance in tumor growth, invasiveness and metastasis [73,74]. Of note, CXCR4 has also been reported to be upregu- lated in ACC. Chifu et al. recently reported on an established chemokine receptor profiling investigating CXCR4 and CXCR7 in 187 and 84 sam- ples, respectively. Immunostaining was detected for CXCR4 in 98% and for CXCR7 in 100% of cases investigated with particularly high expres- sion levels found in 50% of these specimens. In 50% of these cases, expression of these chemokine receptors was recorded, with strong cytoplasmatic CXCR4 expression primarily shown in metastases (when compared to primaries and local recurrence). CXCR4 membrane stain- ing also correlated with the proliferation index Ki67 and therefore, some patients may benefit from CXCR4-directed imaging and therapy [75]. Given these encouraging ex-vivo findings established by Chifu and coworkers [75], Bluemel et al. investigated the CXCR4-targeted PET probe [68Ga]Pentixafor in patients afflicted with ACC and performed a head-to-head comparison with [18F]FDG (Fig. 4). Although CXCR4 PET revealed more lesions in two patients, [18F]FDG was superior in 13 patients identifying more lesions. Given the increased radiotracer accu- mulation in brain and liver of the latter radiotracer, [68Ga]Pentixafor is more suitable to detect brain or hepatic lesions, as the target-to-back- ground ratio is substantially improved in those organs when Pentixafor has been applied. Noteworthy, after having quantified the retention capacities of CXCR4 in-vivo using molecular imaging, such radiotracers have also the potential to be used in a theranostic setting for CXCR4- directed endoradiotherapy (ERT). In the cohort investigated by Bluemel et al. 70% of the subjects were rated suitable for such a CXCR4-targeted therapeutic approach. CXCR4-directed ERT has not been conducted in ACC, but in advanced stage multiple myeloma, reporting on a heteroge- neous, but remarkable therapeutic effect in some patients [76,77]. Nonetheless, CXCR4-based ERT causes bone marrow ablation, making autologous stem cell support mandatory in all potential treatment can- didates and therefore, is only an option if stem cells could be harvested prior to treatment on-set [72].
Of note, SSTR targeting PRRT has already been conducted in ACC. Of 19 ACC patients which underwent [68Ga]DOTATOC PET/CT, two patients were identified as suitable candidates for SSTR-based radio- nuclide therapy using the theranostic equivalent [90Y]/[177 Lu ]DOTA- TOC. After multiple treatment cycles, both patients demonstrated an overall disease control of 4 and 12 months, respectively [78].
Fig. 5 provides an overview of relevant SPECT and PET radiotracers in adrenal functional molecular imaging.
6. Future perspectives
6.1. Image-guided strategies for CXCR4 inhibition in ACC
To date, no CXCR4-inhibition approach in ACC is available, but Kitawaki et al. reported on inhibitory effect of the CXCR4 antagonist AMD3100 on the proliferation in human ACC cell lines [79]. Once such CXCR4-directed treatments have entered the clinical arena, a molecular-image guided strategy may be feasible. In this regard, CXCR4-inhibition could be initiated at the maximum of target
[18F]FDG
[68Ga]Pentixafor
”
2
.
expression revealed by [68Ga]Pentixafor PET, thereby increasing ther- apeutic efficacy. Moreover, off-target adverse effects outside the adre- nal gland could also be monitored by such a whole-body PET approach. These considerations are further fueled by a recent transla- tional study, reporting on improved cardiac outcome in myocardial infarction. In animals after myocardial infarction, AMD3100 treat- ment at the maximum of the PET signal led to substantial better car- diac function during follow-up when compared to animals that had been treated when the radiotracer signal has been dissipated [80].
Such studies highlight the potential of PET-guided CXCR4 inhibition, e.g., in patients afflicted with ACC.
6.2. Novel targets for potential theranostic approaches in ACC
The theranostic principle is based on the use of radiolabeled com- pounds which can be applied for both imaging and therapy [31]. In this regard, prostate-specific membrane antigen (PSMA)-directed PET/CT and subsequent PSMA-targeted endoradiotherapy is widely
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O
NH2
HO
NH
NH
HN
H
0
R = COOH: [68Ga]DOTATOC R = CH2OH: [68 Ga]DOTATATE
HO
0
NH2
[68Ga]Pentixafor
[111In]pentetreotide
used for the diagnosis and treatment of prostate cancer [81]. Ex-vivo analyzes of tumor specimens of patients with ACC, however, sug- gested that increased neovasculature is also tightly linked to PSMA overexpression on the tumor cell surface in highly aggressive disease [82]. As such, one may speculate that PSMA-directed in-vivo imaging can be also applied to ACC patients, as recently demonstrated in a case report [83]. In this regard, such findings may lay the foundation for PSMA-directed endoradiotherapy in advanced cases.
7. Conclusion
Initially established in the 70ies, functional molecular imaging has seen an unprecedented success for the assessment of adrenal masses. For the work-up of adrenal incidentalomas, molecular imaging may have clinical value to differentiate between malignant vs benign adrenal lesions, e.g., by using the most widely available PET radio- tracer [18F]FDG or 11 -hydroxylase selective imaging agents, such as [11C]MTO or 18F-labeled equivalents. Moreover, the highly selective SPECT compounds [123I]IMTO or [123I]IMAZA have also demonstrated excellent image quality with high affinity to adrenal tissue in patients with ACC. Those radiotracers can also be used in a theranostic setting. After having examined the retention capacities in-vivo using [123]] IMTO or -IMAZA, 131I-labeled counterparts have been successfully administered in a therapeutic setting and such an approach led to prolonged progression-free survival in heavily pretreated ACC patients. Moreover, the concept of SSTR-targeted imaging and treat- ment with [68Ga]/[177Lu]DOTATATE/-TOC has been also applied to ACC and PHEO. Novel theranostic agents are currently emerging and thus, one may hypothesize on an increased use of theranostic approaches in adrenal gland tumors in the future.
Disclosure of interest
AS and SH filed a patent application WO/2014/048,568 for IMAZA. All other authors declare no potential conflicts of interest.
Sources of funding
This review work was supported by the Deutsche Forschungsge meinschaft (DFG) (project number 314061271 - TRR 205; AL 203/11- 1) and IZKF Würzburg (Grant No. F-365, A.S., S.H.).
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