Imaging in Adrenocortical Carcinoma and Malignant Pheochromocytoma

Abstract

Incidental adrenal nodules are often found in diagnostic imaging, and differential diagnosis can be challenging. Patient history, biochemical tests, radiology, and nuclear medicine imaging are crucial to discriminate between benign and malignant lesions and accurately define the need for surgical treatment, avoiding unnecessary adrenalectomies. Non-contrast CT may detect intracellular fat (less than 10 HU), indicative of adenoma, but lesions with more than 10 HU fall into a “grey zone” where lesion size, washout CT, or chemical-shift MRI may be helpful for the definition of lipid-poor adenoma, pheochromocytoma, adrenocortical carcinoma or other malignant lesions. Moreover, nuclear medicine methods (such as ¹⁸F-FDG PET/CT and ¹¹C-METO for adrenocortical carcinoma; ¹²³I-MIBG, ¹²⁴I-MIBG PET/CT and ⁶⁸Ga-DOTANOC, ⁶⁸Ga-DOTATOC, and ⁶⁸Ga-DOTATATE PET/CT for pheochromocytoma) have the capabilities to assess important details, useful both for detection, differential diagnosis and therapy response assessment. Multidisciplinary evaluation is essential to create a more accurate diagnostic pathway for each lesion for the best patient management.

5.1 Introduction

The possibility of identifying primitive adrenal neoplasms at an early stage contrasts with the difficulty differentiating the nature of subclinical lesions, the so-called adrenal incidentalomas, i.e., lesions with a short axis ≥1 cm incidentally detected in non-oncological patients being examined for various reasons unrelated to the adrenal gland. These lesions, whose prevalence increases with age (up to 10% in patients aged 70 years), are mostly adenomas (70%) and, in 20% of cases, benign lesions of other nature (myelolipomas, benign pheochromocytomas, schwannomas, vascular lesions). Incidental malignant lesions account for approximately 10% and are most commonly represented by secondary lesions, adrenocortical carcinoma (ACC), pheochromocytoma (PHEO), and primary B lymphoma [1, 2]. It is therefore crucial to make a correct differential diagnosis between benign lesions, PHEOs with signs of malignancy, adrenocortical carcinomas and other primary/secondary lesions.

Approximately 70% of adrenal adenomas (AA) are represented by lipid-rich adenomas, which are characterized by high amounts of microscopic cytoplasmic fat, with attenuation values ≤10 HU (Hounsfield units) on unenhanced computed tomography (CT); moreover, they are often <4 cm in size and have a homogeneous structure. The very low attenuation value is considered very suggestive for AA (with sensitivity values of 55–71% and specificity of 98–100%) since attenuation ≤10 HU is rarely found in other adrenal neoplasms. Even the most recent guidelines of the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) state that homogeneous lesions with HU <10 can exclude ACC with sufficient certainty. The remaining AA show attenuation ≥10 HU and are described as “lipid-poor”. They are indistinguishable from other neoplasms on unenhanced CT, although they are less likely to be functioning [3].

If an adrenal nodule shows attenuation values >10 HU on unenhanced CT, a washout CT scan or magnetic resonance imaging (MRI) should be performed to confirm the possible adenomatous nature of the nodule. In nodules with attenuation values up to 20 HU, MRI with chemical-shift imaging (CSI) accurately assesses intracytoplasmic fat. At the same time, its use is considered inappropriate for lesions with 20–30 HU, since washout CT has shown 100% sensitivity in predicting lipid-poor adenomas, compared to 64% for CSI MRI. In addition, when a lesion has attenuation values ≥43 HU, an ¹⁸F-FDG PET/CT may be more valuable, given the higher risk of malignancy [4]. Intralesional macroscopic fat (due to intratumoral adipocytes) has so far been considered a benign feature diagnostic of myelolipoma in accordance with the recommendations of the American College of Radiology [5]. However, because of the reported cases of adrenal neoplasms (including ACC) with macroscopic fat [6, 7], especially in lesions <4 cm, some authors suggest a cautious diagnostic approach, with a quantitative threshold of ≥50% macroscopic fat for this type of diagnosis.

In the case of adrenal incidentalomas, ¹⁸F-FDG PET/CT has the advantage of distinguishing between benign and malignant tumors, although it does not provide robust information on the origin of the adrenal masses. With a sensitivity ranging between 86–100% and a specificity between 80–100% for the assessment of malignancy of adrenal lesions, depending on visual or semiquantitative assessment used, this imaging modality is helpful to rule out any diagnosis of ACC or metastatic disease [8]. Positive predictive value (PPV), negative predictive value (NPV) and accuracy have been reported as 81%, 100% and 95%, respectively [8,9,10]. Currently, the American College of Radiology recommends the use of ¹⁸F-FDG PET/CT to define an indeterminate adrenal mass in patients with a history of cancer [5]. Radiolabeled metomidate has also a role for the assessment of adrenal incidentalomas, with sensitivity and specificity of 89% and 96%, respectively, in distinguishing adrenocortical from non-adrenocortical tumor masses [8,9,10].

5.2 Washout CT of Adrenal Lesions

The washout CT study is considered an essential test in the differential diagnosis between AA and primary or secondary adrenal neoplasms, with the possibility of calculating absolute and relative washout of contrast. The protocol includes the acquisition of unenhanced CT scans, followed by acquisitions in the portal-venous phase and late phase, respectively at 60–70 s and 15 min from contrast injection, with measurement of the lesion attenuation values and determination of the absolute (APW) and relative percentage washout (RPW) values using the following formulae:

$$ APW=\frac{HU\; portal\ venous- HU\; delayed}{HU\; portal\ venous- HU\; unenhanced}\times 100 $$

$$ RPW=\frac{HU\; portal\ venous- HU\; delayed}{HU\; portal\ venous}\times 100 $$

APW values ≥60% showed a sensitivity of 86–94% and a specificity of 92–96% in diagnosing AA, and RPW ≥40% showed a sensitivity of 96% and a specificity of 100% in diagnosing AA [11]. However, a recent multicenter study [12] analyzing a large and selected case series showed that the prevalence of malignant lesions in homogeneous nodules <4 cm did not differ significantly between the category with washout >60% and <60% (Fig. 5.1). This experience also showed that about 1/3 of PHEOs may show washout >60%; moreover, these enhancement features may also be observed in adrenal metastases from hepatocellular and renal cell carcinomas, which may show little fat component.

Fig. 5.1

Unenhanced CT in a 48-year-old patient with incidental detection of a 2 × 2 cm left adrenal lesion with attenuation values of 34 HU (a). The hormonal work-up was negative for hypersecretion and a washout CT (b, c) was performed to characterize the lesion, which showed an absolute and relative washout of 84% and 51%, respectively, suggesting a lipid-poor adrenal adenoma. After multidisciplinary discussion and in view of the high baseline attenuation of the lesion, a second imaging modality was suggested. On CSI MRI (d, e, f) the lesion showed no out-of-phase signal loss, with an adrenal/spleen CSI ratio of 1.06 (indeterminate if ≥0.71) and an ASII of 1.1% (indeterminate if ≤16.5%). PET-CT with FDG showed no pathological uptake by the lesion, and after a multidisciplinary case review with the patient, he preferred to wait for a follow-up unenhanced CT scan in 6 months rather than undergoing immediate surgery to rule out significant lesion growth (>20% maximum diameter in addition to at least 5 mm increase in maximum diameter), which has remained indeterminate to date

5.3 MRI of Adrenal Lesions

MRI of the adrenal glands relies on its intrinsic high contrast resolution and tissue characterization, particularly in detecting intracytoplasmic and macroscopic fat. The standard MRI protocol includes dual-echo T1-weighted (T1w) for CSI, T2-weighted (T2w) sequences, and T1w/T2w sequences with fat suppression.

In CSI, specific sequences can indicate a decrease in signal for the entire lesion or certain parts of it, which can reveal the amount of intracellular fat present. Microscopic fat content on MRI can be evaluated through two methods: qualitative visual assessment or quantitative measurements that involve placing regions of interest on in-phase and out-of-phase images. These measurements can be done with or without reference to the spleen signal, and allow for the calculation of signal intensity indices that reflect signal loss. These indices are represented by the adrenal-to-spleen CSI ratio (ASR) and the adrenal-signal-intensity index (ASII). In addition, T1w and T2w sequences with fat suppression are used in the MRI study protocol to assess macroscopic fat content (adipocyte aggregates or myelolipomatous portions). The addition of dynamic examination with paramagnetic contrast agents can further improve the diagnostic accuracy of MRI in diagnosing AA, with a sensitivity of 94% and specificity of 98% compared with 87% and 95% for imaging with CSI sequences alone. It is important to note that diffusion-weighted imaging (DWI) sequences alone cannot accurately determine the classification of adrenal lesions as benign or malignant. This is due to the fact that adenomas, which are typically benign, may still exhibit diffusion restriction on DWI [2, 3].

For incidental adrenal lesions <4 cm in size, without evidence of associated fat, without hormonal changes and not detected on PET scan, management is decided on a multidisciplinary basis, including the patient’s preference. In this case, the lesion should be reassessed after 6–12 months with unenhanced imaging (CT or MRI) to assess any enlargement, in accordance with the ESE clinical practice guidelines [13] (Figs. 5.2 and 5.3).

Fig. 5.2

(a) Coronal venous phase CT in a 38-year-old male shows a heterogeneous ACC in the left adrenal loggia, displacing the left kidney inferiorly. Amorphous calcifications are also visible (black arrow). (b) 28-year-old woman who underwent a CT scan due to abdominal pain. The axial CT venous phase shows an inhomogeneous mass in the left adrenal fossa with peripheral hypervascularity due to the presence of solid tissue and a central hypodense area secondary to necrosis (asterisk). The lesion displaces the spleen and the pancreatic tail anteriorly

Fig. 5.3

Summary of diagnostic work-up for the management of incidental adrenal lesions or lesions with evidence of hormonal hypersecretion and/or pressure symptoms, according to European Society of Endocrinology and European Network for the Study of Adrenal Tumors guidelines

5.4 Adrenocortical Carcinoma

ACC are often quite large at diagnosis (>6 cm in about 70%) and at advanced stages (18–26% stage III and 21–46% stage IV). Moreover, it is frequent to observe compression and dislocation caused by the mass on the adjacent organs and, occasionally, neoplastic thrombosis of the adrenal and renal veins, with possible extension to the inferior vena cava (IVC) or right atrium [8]. In about 15% of cases ACC can be found as a smaller, incidental lesion that requires further characterization. The few reports in the literature on early-stage ACC suggest that, regardless of size, the following radiological features may serve as criteria for an early diagnosis: lesions with high attenuation values (≥30 HU), calcifications (30% of cases), irregular shape, inhomogeneous structure and poorly defined contours, although there are no imaging-specific features [2].

According to the ENSAT guidelines, contrast-enhanced CT (CECT) of the chest, abdomen and pelvis is the imaging modality of choice for initial staging and follow-up during and after treatment. At the same time, MRI and PET/CT may provide additional information in selected cases [14]. CECT is performed not only to assess adrenal lesion vascularity, but also (especially in large tumors) to define local relationships, infiltration of adjacent organs, endovascular extension, peritoneal spread, lymphadenopathies or distant metastases.

ACC typically appears inhomogeneous on unenhanced CT, with hypoattenuating areas of necrosis or cystic degeneration and slightly hyperattenuating components from hemorrhagic events or calcifications. In CECT the tumor is equally inhomogeneous, with thicker peripheral solid tissue (“rim enhancement”) and central necrotic portions (Fig. 5.4). Calculation of APW and RPW in large lesions is not relevant, but in a smaller lesion with a homogeneous structure these would be <60% and <40%, respectively. Similarly, on MRI, the signal is typically inhomogeneous, iso/hypointense to the liver parenchyma on T1w sequences, except in hemorrhagic areas where the signal is slightly hyperintense. T2w sequences are the best ones to emphasize cystic degeneration or necrotic areas. Prominent and inhomogeneous enhancement with slow washout follows the injection of gadolinium-chelate contrast agents.

Fig. 5.4

(a) Coronal venous phase CT scan in a 72-year-old man shows a large inhomogeneous mass (ACC) invading the inferior vena cava and inseparable from the liver. Axial 3D GRE fat-suppressed T1w after contrast administration (b) and coronal T2w (c) MRI sequence in a 52-year-old woman show enlarged left renal vein and inferior vena cava (asterisk) due to the presence of heterogeneous intraluminal neoplastic tissue originating from the voluminous mass located in the left adrenal fossa (ACC). Note the intrinsically better resolution of contrast-enhanced MRI compared to CT

Beyond the depiction of pathologic lymph nodes and metastases, preoperative imaging is essential to define the presurgical assessment of the patient. Indeed, it is essential to evaluate the infiltration of renal and hepatic parenchyma and the possible presence of neoplastic thrombosis of the adrenal and renal vessels and involvement of the IVC. Both CT and MRI have a high sensitivity and specificity in the assessment of these diagnostic details, even though MRI has been shown to be superior to CT in detecting IVC invasion and assessing its extension (with respect to the hepatic veins’ confluence and right atrium) due to its intrinsic multiplanarity and contrast resolution. Hepatic parenchymal infiltration by the mass must be suspected in the presence of neoplastic involvement of periadrenal fat, disappearance or reduction <1 mm of the fat line between the liver and the neoplasm, compression and mass effect on the IVC or right hepatic lobe, disruption of the adrenal capsule, enhancement of the periadrenal liver parenchyma, focal bulging of the ACC towards the liver or inclusion of the mass by the liver parenchyma >180° [15].

Metastatic diffusion is often already present at the time of diagnosis, resulting in enlarged para-aortic lymph nodes (25–46%), pulmonary lesions (45–97%) and liver metastases (48–96%). Hepatic metastases (especially when small) tend to be hypervascular with subsequent washout, and are best appreciated in the arterial phase following contrast injection, which is why this phase is considered necessary for follow-up imaging. The use of contrast-enhanced MRI using hepatospecific gadolinium-chelates (such as Gd-BOPTA or Gd-EOB-DTPA) may be useful for a more accurate staging of secondary hepatic involvement, allowing an accurate differential diagnosis between metastases and benign hypervascular lesions (in particular, focal nodular hyperplasia-like regenerative nodules associated with long-term chemotherapy or other benign lesions).

The assessment of response to therapy in locally advanced or metastatic disease still relies on the RECIST 1.1 criteria, which are based on dimensional changes in “target” lesions. However, tumors (and metastases) do not always have standard volumes, and different areas of the same tumor may respond differently to therapy, with changes in size resulting from therapy-induced necrosis. For this reason, in recent years it has been proposed to consider not only the size criterion, but also changes in vascularity, assessed as variations in enhancement in HU (based on the Choi criteria), as well as volumetric changes of target lesions. In our experience, we have also shown that concordance of all three criteria is associated with better outcomes and overall survival [16]. In ACC, ¹⁸F-FDG PET/CT has the ability to evaluate the overall extent of disease and the presence of metastases, thus guiding the management of the patient, even though false negative results have been reported in 11% of cases [17]. Reported sensitivity, specificity, PPV, NPV and accuracy values are 100%, 40–95%, 71%, 100% and 76%, respectively, for the diagnosis of ACC [18, 19]. Moreover ¹⁸F-FDG PET/CT can be helpful to predict the metabolic response of ACC, and some insights on its prognostic role have emerged. In this setting, patients with higher tracer uptake seem to be characterized by a poorer prognosis, although the reported findings are conflicting [17]. Metomidate (METO) is the methyl ester of etomidate inhibitors of the CYP11β enzymes (11β-hydroxylase and aldosterone synthase) and can be labeled with different isotopes (¹²³I, ¹²⁴I or ¹¹C) and used therefore to image the adrenal cortex with scintigraphy or PET/CT. In this setting, ¹¹C-METO has a sensitivity of 72% for the assessment of ACC [19].

5.5 Malignant Pheochromocytoma

The main imaging criteria suggestive of malignant PHEOs include large size, evidence of infiltration of adjacent organs, and lymphadenopathy. All PHEOs may have malignant potential, which is not detectable on imaging, especially in lesions ≤4 cm that do not show local invasion or metastasis at diagnosis. For this purpose, several scoring systems have been proposed to predict the malignant potential of the lesion. The two most widely accepted are PASS (Pheochromocytoma of the Adrenal Gland Scaled Score) and GAPP (Grading System for Adrenal Pheochromocytoma and Paraganglioma). These grading systems consider as possible features of malignancy: attenuation >10 HU, even in heterogeneous lesions with cystic (approximately 7% of adrenal cysts are PHEOs) or necrotic/hemorrhagic portions and calcifications (in 20% of cases) [20]. It is important to note that on washout CT, at least 35% of PHEOs may present with APW and RPW similar to those of lipid-poor AA. The abundant and disordered blood supply determines the pronounced enhancement in the arterial and venous phase, which is greater than that observed in lipid-poor AA. A recent paper published by the Society of Abdominal Radiology [21] has proposed the use of a venous-phase attenuation threshold of 130 HU, which has a high specificity for the diagnosis of PHEO (100%), although with sensitivity values of only 38%.

On MRI, PHEOs may show very high signal on T2w sequences (known as the “light bulb sign”), which is present in only 50% of PHEOs; in other cases they show generally higher T2w signal compared to the contralateral adrenal gland and lipid-poor adenomas. These lesions do not have intracytoplasmic fat and therefore appear slightly hypointense on T1w sequences and do not show a signal loss on CSI (Fig. 5.5). DWI has a role only in the detection of PHEOs <1 cm [20].

Fig. 5.5

36-year-old man with an incidental adrenal mass discovered on ultrasound at an outside center. Unenhanced axial CT (a) shows a well-circumscribed oval mass with a maximum size of 5.3 cm involving the right adrenal gland with pre-contrast attenuation of 34 HU. Axial contrast-enhanced arterial phase CT (b) shows early enhancement with high lesion attenuation (122 HU) in the portal venous phase (c). On 15-min delayed CT scans (d), the lesion shows an attenuation value of 65 HU, resulting in absolute and relative washout values of 65% and 47%, respectively. In view of these washout values and after multidisciplinary case discussion, MRI was performed to better define the lesion characteristics and to try to rule out a lipid-poor adenoma in a patient with elevated catecholamines on hormonal work-up. Axial out-of-phase and in-phase T1w CSI GRE images (e, f) show that the mass has no decrease in signal intensity, with high signal on axial T2w images, also known as the “light bulb sign” (g). Also on contrast-enhanced MRI, the lesions showed bright and early contrast enhancement (h). The mass was surgically resected and pathologically proven to be a pheochromocytoma

5.6 Nuclear Medicine and Pheochromocytoma

Molecular imaging can be useful in PHEO to assess the presence of disease when borderline metanephrine levels and indeterminate adrenal masses are present, for the assessment of locoregional and distant extension of disease, for the assessment of its aggressiveness, the detection of therapeutic molecular targets and to evaluate the response to therapy [22]. The European Association of Nuclear Medicine (EANM) guidelines recommend to perform nuclear imaging for PHEO in the case of large tumors (>5 cm), succinate dehydrogenase subunit B (SDHB) mutated status, noradrenergic biochemical phenotype, and/or high methoxytyramine levels [22, 23]. Interestingly, most published studies considered nuclear medicine modalities for the evaluation of both PHEO and paraganglioma (PGL)—together referred to as PPGL. Moreover, pregnancy and breastfeeding are general contraindications for molecular imaging procedures. ¹¹¹In-DTPA-pentetreotide specifically binds to somatostatin receptors (SSTR) and can be therefore used to visualize PHEO with scintigraphy or single photon-emission CT (SPECT), although with low overall sensitivity (30%). Moreover, considering the high radiation exposure, cost and long waiting periods for imaging, its use has fallen out of favor [24].

Metaiodobenzylguanidine (MIBG) is an analog of norepinephrine taken up by norepinephrine transporters and then stored in neurosecretory vesicles of sympathetic presynaptic neurons [23]. ¹²³I-MIBG scintigraphy or SPECT/CT is useful for the assessment of PHEO in terms of disease burden, with sensitivities and specificities ranging between 83–100% and 70–100%, respectively [24]. ¹³¹I-MIBG can also be used to image PHEO, but it has some dosimetric and resolution issues that discourage its use. In this setting, ¹²³I-MIBG scintigraphy is therefore useful for the selection of potential candidates for ¹³¹I-MIBG radiometabolic therapy [22]. Thyroid blockade with administration of 130 mg of potassium iodide should be performed 1 h before tracer injection in the case of ¹²³I-MIBG or 24 h before and continued daily for at least 5 days for ¹³¹I-MIBG. Many drugs modify the uptake of MIBG and have to be suspended before scintigraphy. Rare adverse events such as tachycardia, pallor or vomiting can be experienced by the patients during administration of the tracer and can be prevented by slow injection [23]. ¹²³I-MIBG scintigraphy should not be used in patients with SDHB mutation, hereditary, extra adrenal and metastatic PPGL, which exhibit only a low rate of positivity [22]. In contrast, this imaging modality is useful in patients with negative genetic screens, those with bilateral adrenal lesions, suspicious conventional imaging scans and subjects with biochemical suspicion of PHEO [25]. The general sensitivity of SPECT/CT is hampered by a low spatial resolution and therefore ¹²⁴I-MIBG PET/CT is emerging as a new imaging modality for the assessment of PHEO, although with reported similar accuracy to ^123/131I-MIBG scintigraphy [25].

⁶⁸Ga-DOTANOC, ⁶⁸Ga-DOTATOC and ⁶⁸Ga-DOTATATE are labeled SSTR analogues (SSA) used in PET/CT that can contribute to PPGL detection, in particular when metastatic or extra-adrenal diseases are present, with an overall sensitivity ranging between 80–100% and a detection rate between 93–98% [22]. Notably, DOTATATE binds most avidly to SSTR2, the most common somatostatin receptor expressed in PPGLs, and is therefore the most widely used in particular for cluster 1A PHEO (especially SDHx), and metastatic and pediatric PPGL [23]. The sensitivity of ⁶⁸Ga-SSA PET/CT has been reported to be 94% for pediatric SDHx-related diseases, 99% for metastatic SDHB-related and SDHD-related PPGLs, and 100% for SDHA-related neoplasm. Moreover, it can also be used to determine whether a patient is likely to benefit from peptide receptor radionuclide therapy and, in the case of restaging, it can change the management in most of the patients [22].

¹⁸F-FDG has high sensitivity in the detection of metastatic PPGL, in particular for SDHB patients, with reported values ranging between 77–100% [25]. However, PHEO usually has increased but variable tracer uptake and reported specificity, PPV and NPV for PET/CT near 96% [22, 23]. Interestingly, MEN-2-associated PHEOs are ¹⁸F-FDG-avid in only 40% of the cases, and cluster 1 patients have higher uptake compared to cluster 2 subjects. As a consequence, ¹⁸F-FDG PET/CT should be considered in the preoperative workup of PPGL, in particular in SDHB metastatic neoplasms [22, 23].

¹⁸F-L-dihydroxyphenylalanine (¹⁸F-DOPA) is taken up by L-type amino-acid transporter (LAT) and is stored in neurosecretory granules of catecholamine-producing cells. Therefore, high sensitivity and specificity in the detection of non-metastatic PHEO have been reported, with sensitivity of 94% in patients of known genetic background and 100% in apparently sporadic non-metastatic PHEO [23, 25]. In the case of metastatic disease, ¹⁸F-DOPA PET/CT was found to perform better for SDHB-negative PPGLs (93% sensitivity) than for SDHB-positive cases (20% sensitivity), where ¹⁸F-FDG uptake may be higher. Furthermore, high sensitivity for the detection of VHL-, EPAS1 (HIF2A)-, and FH-associated PPGLs were reported [22]. Interestingly, some authors suggest the administration of 200 mg of carbidopa 1 h before the examination to block decarboxylation of DOPA to dopamine and improve the uptake in target tissues [23].

5.7 Comparison Between Nuclear Medicine Modalities

Generally speaking, PET/CT technology has been shown to be superior to SPECT/CT and scintigraphy, with higher spatial resolution, greater sensitivity and fewer indeterminate or equivocal findings. Furthermore, in PHEO patients ¹²³I-MIBG has significantly outperformed ¹¹¹In-pentetreotide in the detection of disease. Due to its nonspecific and variable accumulation, ¹⁸F-FDG is not considered the tracer of choice for PPGLs imaging, although with superior sensitivity compared to ¹²³I-MIBG imaging in SDHx-related and metastatic tumors [22].

According to the latest EANM guidelines, in the case of sporadic PHEO, the first-choice imaging modality should be ¹⁸F-DOPA PET/CT or ¹²³I-MIBG SPECT/CT, the second one should be ⁶⁸Ga-SSA PET/CT and the third should be ¹⁸F-FDG PET/CT. As for inherited PHEO (NF1, RET, VHL and MAX) with the exception of SDHx, the first choice should be ¹⁸F-DOPA PET/CT, the second ¹²³I-MIBG SPECT/CT or ⁶⁸Ga-SSA PET/CT while the third should be ¹⁸F-FDG PET/CT. In the case of extra-adrenal sympathetic and/or multifocal and/or metastatic SDHx mutation, the first choice should be ⁶⁸Ga-SSA PET/CT, the second choice ¹⁸F-FDG PET/CT or ¹⁸F-DOPA PET/CT and the third one should be ¹⁸F-FDG PET/CT and ¹²³I-MIBG SPECT/CT or ¹⁸F-FDG PET/CT and ¹¹¹In-DTPA-pentetreotide SPECT/CT. Moreover, all the third choices should be considered only if ¹⁸F-DOPA and ⁶⁸Ga-SSA PET/CT are not available. Interestingly, in cluster 3 subjects, the most sensitive functional imaging modality is unknown (Fig. 5.6) [22, 23, 25].

Fig. 5.6

Maximum intensity projection (a) and axial fused PET/CT images (c, e) of a ⁶⁸Ga-DOTATOC scan performed for staging in a patient with pheochromocytoma, showing intense uptake by the primary lesion and multiple skeletal and pulmonary metastases. The same findings were confirmed on anterior view (b) and axial fused SPECT/CT images (d, f) of a 123I-MIBG scan of the same patients, but without demonstration of pulmonary uptake

5.8 Conclusions

The radiological and nuclear medicine imaging of adrenal lesions still represents a diagnostic challenge, where the role of the different methods is seen as a “link” in the wider multidisciplinary chain. The integration of unenhanced CT, washout study and MRI features, similarly to the findings of molecular imaging methods, must therefore be considered in the clinical-functional context of the individual patient. Many radiomics studies are investigating the potential of more in-depth texture analysis at CT and MRI, which could increase accuracy in the differential diagnosis between benign and malignant lesions. In addition, the application and standardization of radiogenomic analyses may, in the near future, allow more precise and personalized management of oncological and surgical treatments for better patient outcomes.