Research in molecular genetics has resulted in the identification of more than 20 susceptibility genes for tumors of the entire paraganglia system [7, 25]. Most PHEOs occur sporadically, whereas the majority of symp-PGLs are associated with germline driver mutations. Depending on their location, the most commonly found gene mutations are (1) unilateral PHEO: succinate dehydrogenase complex subunit B or D (SDHB or SDHD) and VHL; (2) bilateral PHEO: SDHB, RET, VHL, NF1, MYC-associated factor X (MAX), and TMEM127; and (3) symp-PGLs with or without PHEO: SDHB, SDHD, VHL, and HIF2A. Other genes account for a small minority of cases. Recent tumor sequencing has also led to the identification of somatic events in a large number of PHEOs/PGLs (The Cancer Genome Atlas, unpublished observations) (Table 14.1). Patients presenting with metastatic disease mainly include those with SDHB and perhaps SDHD (excluding HNPGLs), FH, and MAX-related PHEOs/PGLs, although, at present, about 50 % of metastatic PHEOs/PGLs are non-hereditary [5].

There are several potential causes to consider for the differential diagnosis in the presence of an adrenal or extra-adrenal mass (Table 14.2). However, the masses that belong to either PHEO or PGL are usually detected by imaging-specific characteristics that include the value of Hounsfield units (HU), T2-weighted bright images, and positivity on PHEO-/PGL-specific functional imaging, as described below.

On non-contrast computed tomography (CT), PHEO/PGL can demonstrate a variety of appearances. Two thirds of PHEO/PGLs are solid, while the remainder are complex or have undergone cystic or necrotic changes [26]. Typically, the CT attenuation of PHEO/PGL is about soft tissue attenuation and thus greater than 10 HU, with most PHEOs/PGLs 20–30 HU or higher. PHEO/PGL can present with a high attenuation due to the presence of hemorrhage or calcifications. In contrast, necrotic tissue presents with a low attenuation. Typically, a PHEO/PGL demonstrates avid enhancement (often greater than 30 HU) [27]. In addition, enhancement can be heterogeneous, or there may be no enhancement due to cystic, necrotic, or degenerated regions within the lesion [28]. On magnetic resonance imaging (MRI), the classic imaging appearance of PHEO/PGL is “light bulb” bright on T2-weighted imaging. In reality, 30 % of PHEOs/PGLs demonstrate moderate or low T2-weighted signal intensity [27, 29]. PHEOs/PGLs typically demonstrate avid contrast enhancement following the administration of intravenous gadolinium-based contrast material [30, 31].

Nowadays, positron emission tomography (PET) is a cornerstone in the evaluation of hereditary as well as non-hereditary PHEOs/PGLs. The broad diversity of PET biomarkers enables assessment of different metabolic pathways and receptors. Beyond its localization value, this imaging modality provides unique opportunities for better characterizing these tumors at molecular levels (e.g., the presence of catecholamines and their metabolites, specific cell membrane receptors and transporters), mirroring ex vivo histological classification but on a whole-body, in vivo, scale (Table 14.4).

Thus, successful PHEO-/PGL-specific localization depends on the presence of molecules (imaging targets) for which PET radiopharmaceuticals are currently available. Based on several recent studies, it has been uncovered that PHEO-/PGL-specific imaging targets have various expressions based on whether these tumors belong to pseudohypoxic or kinase signaling clusters, present as metastatic, are located in or outside the adrenal gland, or are derived from the sympathetic or parasympathetic nervous system. Currently, ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) is the most accessible PET radiopharmaceutical, but lacks specificity for these tumors. ¹⁸F-fluorodopamine (¹⁸F-FDA) and ¹¹C-hydroxyephedrine (¹¹C-HED) are the most specific tracers for chromaffin tumors, but are available in very few centers and fail in metastatic and hereditary PHEOs/PGLs [32–34].¹⁸F-fluorodyhidroxyphenylalanine (¹⁸F-FDOPA) is available from different pharmaceutical suppliers, but its sensitivity widely depends on the genetic background and whether the PHEO/PGL is sympathetic or parasympathetic [35–37]. Metastatic behavior of these tumors can also affect the expression of amino acid transporters [38]. Newly developed ⁶⁸Ga-labeled peptides, as in other neuroendocrine tumors, have shown very interesting results and, in our opinion, should be positioned first for many indications due to their exceptional affinity to somatostatin receptor type 2 found on these tumors [39–44].

PHEOs and PGLs usually have highly elevated uptake values with specific radiopharmaceuticals based on their genetic background. For example, ¹⁸F-FDOPA PET/CT was replaced by ⁶⁸Ga-DOTATATE PET/CT as the best available imaging modality for metastatic PHEO/PGL, especially in those with SDHB mutations and head and neck PGLs [40–42]. The Octreoscan has been suggested not to be used anymore due to its suboptimal performance in the detection of these tumors and the growing availability of ⁶⁸Ga-DOTATATE PET/CT. However, the use of other ⁶⁸Ga-labeled DOTA analogues (⁶⁸Ga-DOTATOC and ⁶⁸Ga-DOTANOC) needs to be confirmed in a large population of patients. A variety of new radiopharmaceuticals have been developed as potential competitors of ⁶⁸Ga-DOTATATE (⁶⁸Ga-labeled somatostatin antagonists, ⁶⁴Cu-labeled SSA [45], or ¹⁸F-SiFAlin (silicon-fluoride acceptor)-modified TATE), but they need to be evaluated [46].

Proper evaluation of PHEO/PGL is a key point for choosing the necessary treatment plan for follow-up and outcome for these patients. The presence of SDHx mutations markedly influences sensitivity of ¹⁸F-FDG, ¹⁸F-FDOPA, and ⁶⁸Ga-DOTA-SSAs PET/CT. ¹⁸F-DOPA PET/CT has a sensitivity approaching 100 % for sporadic PHEO and a very high specificity (95 %), but can miss tumors in SDHx-mutated patients. ¹⁸F-FDOPA PET/CT still remains a very good modality for the detection of some metastatic PHEO/PGLs – it ranks as the second best for the detection of HNPGLs, and it can also be used for patients with non-hereditary metastatic PHEO/PGL [18, 35, 36, 38, 47, 48]. By contrast, SDHx tumors usually exhibit highly elevated ¹⁸F-FDG uptake values. However, ¹⁸F-FDG PET/CT positivity is present in about 80 % of primary PHEOs. Thus, ¹⁸F-FDG PET/CT remains a good alternative for the detection of metastatic PHEO/PGL, especially those related to SDHx mutations [49]. Several potential diagnoses should be considered in cases of ¹⁸F-FDG-avid adrenal masses (Table 14.3).

The use of ⁶⁸Ga-DOTA-SSAs in the context of PHEOs/PGLs has been studied less, but has shown excellent preliminary results in localizing these tumors, especially metastatic and head and neck ones, as discussed above. A head-to-head comparison between ⁶⁸Ga-DOTA-SSA and ¹⁸F-FDOPA PET has been performed in only five studies: one retrospective study from Innsbruck Medical University (⁶⁸Ga-DOTATOC in 20 patients with unknown genetic background) [50], three prospective studies from the NIH (SDHB, HNPGL, and sporadic metastatic PHEOs/PGLs) (⁶⁸Ga-DOTATATE in 17 and 20 patients), and one prospective study from La Timone University Hospital (⁶⁸Ga-DOTATATE in 30 patients) [40–42]. In these studies, ⁶⁸Ga-DOTA-SSA PET/CT detected more primary head and neck PGLs as well as SDHx-associated PGLs than ¹⁸F-FDOPA PET/CT [51]. By contrast, in the context of sporadic PHEO, ¹⁸F-FDOPA PET/CT may detect more lesions than ⁶⁸Ga-DOTATATE, although larger studies are needed to confirm those results [51]. One of the main drawbacks of ⁶⁸Ga-DOTA-SSA is the very high physiological uptake by healthy adrenal glands [52]. Furthermore, there are also different affinities of various DOTA-SSAs to somatostatin receptors. DOTATATE has the best affinity to somatostatin receptor type 2, mostly expressed on PHEO/PGLs, followed by DOTATOC. DOTANOC has the lowest affinity to somatostatin receptor type 2 and has some affinity to somatostatin receptor type 5, which is least abundant on PHEOs/PGLs. Therefore, the use of DOTANOC may result in suboptimal detection of PHEO/PGL, especially their metastatic lesions. Studies comparing ⁶⁸Ga-DOTATATE and ⁶⁸Ga-DOTATOC are currently unavailable. Excellent results with DOTA analogues in both sporadic as well as SDHx-related metastatic PHEOs/PGLs resulted in the use of ¹⁷⁷Lu-DOTATATE (Lutathera) in radiotherapy of these tumors [53–57]. This is followed by the preparation of clinical protocols in order to properly assess the efficacy of this treatment on a large population of well-characterized patients with metastatic or inoperable PHEO/PGL (Lin, Pacak et al. NIH protocol in preparation, 2016).

Successful PHEO/PGL management requires an interdisciplinary team approach. Precise identification of clinical context and the genetic status of a patient enables a personalized use of functional imaging modalities. Currently, it is recommended to adopt a tailored approach using a diagnostic algorithm based on tumor location, biochemical phenotype, and any known genetic background (Table 14.5) [48, 58].