Anatomical imaging methods usually follow clinical suspicion and positive biochemical tests. Their role is to detect and locate pheochromocytomas.

The valuable general morphological features that help identify pheochromocytomas include size, consistency, and shape. The size may vary from 1 to 15 cm (27), or, rarely, even more. At the time of the diagnosis, the average size is approximately 4–6 cm (27–32). Smaller tumours usually consist of solid, relatively homogeneous tissue (Fig. 1). For larger tumours, the presence of greater or lesser central necrosis with a peripheral rim of tumour tissue is typical (Fig. 2). There is also a pure cystic form of pheochromocytoma.

The shape of a pheochromocytoma is usually spherical and the edges are relatively smooth.

The diverse morphological appearance of pheochromocytomas may well mimic other adrenal masses on CT and MRI scans (33). Differential diagnosis should aim to distinguish a pheochromocytoma from an adenoma, metastasis, or adrenal carcinoma.

Abdominal sonography may incidentally detect an adrenal mass, especially on the right side because of the acoustic window of the liver. Otherwise, the role of ultrasound in the management of pheochromocytomas is limited.

CT is the most common imaging method used in the diagnosis of pheochromocytomas. Compared to MRI, it is more widely available, less expensive, and offers better spatial resolution. The main disadvantage of CT is ionizing radiation. CT scans can reveal adrenal pheochromocytomas larger than 5–10 mm with sensitivity >95% (34).

The differentiation of a pheochromocytoma from a lipid-rich adenoma by means of the unenhanced attenuation value in Hounsfield units (HU) is straightforward, since the attenuation in pheochromocytomas is always higher than 10 HU (Fig. 1a) (29). This fact results from an absence of intra-cytoplasmic lipids within pheochromocytoma tumours, which also applies to metastases and adrenocortical carcinomas (35). If the average unenhanced attenuation value of a lesion exceeds 10 HU, it is possible to perform histogram analysis of the unenhanced CT image; if there are 10% or more negative pixels in the histogram, an adenoma can be confirmed as it is thus distinguished from other adrenal lesions, including pheochromocytomas (36). Currently, more advanced methods of histogram evaluation (also called ‘CT texture analysis’) have been introduced (37); according to a recent paper, pheochromocytomas had a significantly higher mean grey-level intensity, entropy, and mean of positive pixels, but lower skewness and kurtosis in unenhanced images compared to lipid-poor adenomas (32).

After the administration of an iodine contrast medium, pheochromocytomas usually display pronounced enhancement, often more than 130 HU. In smaller solid lesions, the enhancement is relatively homogeneous (Fig. 1b), while in larger lesions the character of the enhancement is more or less heterogeneous; something that is very typical of pheochromocytomas with central necrosis is the pronounced enhancement of the peripheral rim of the viable tumour tissue (Fig. 2). Although strong enhancement occurs in most pheochromocytomas, it cannot be considered specific, since there is significant overlap of contrast enhancement with other types of adrenal lesions (29); only a single article has reported significant differences in the enhancement of adenomas and pheochromocytomas (38).

The targeted adrenal CT protocol usually includes late-enhancement scans (i.e., 7–15 min after the application of a contrast medium), which allows the measurement of the absolute and relative decreases in post-contrast attenuation, which reflect the rate of contrast medium washout. Adenomas are believed to express rapid washout compared to the slower washout of pheochromocytomas (39–42). However, according to some papers, up to one third of pheochromocytomas overlap with adenomas in terms of their relative or absolute washout rate (Fig. 1a-c) (30,31). Furthermore, washout rates are unable to distinguish pheochromocytomas from adrenal carcinomas or metastases (41).

Studies with a non-ionic contrast medium (Iohexol) failed to confirm the widespread opinion that the intravenous administration of an iodinated contrast medium can lead to increased secretion of catecholamines from pheochromocytomas or may even lead to a hypertensive crisis (43). This result was replicated by another study providing evidence that the administration of iodinated non-ionic contrast media in patients with a suspected or known pheochromocytoma is safe, and the administration of α-adrenergic receptor blockers before the administration of the contrast medium is not necessary (44).

MRI is not a first-choice imaging tool because of its lower spatial resolution, lower logistical availability, higher price, and stricter safety regulations. But it benefits from being free of ionizing radiation and therefore suitable e.g., in cases of pregnant women or children or in patients with adverse reactions to an iodinated contrast medium.

The appearance of pheochromocytomas in T₁- and T₂-weighted images depends on whether the tumour is solid, cystic, or haemorrhagic/necrotic. Cystic tumours display high signal intensity in T₂-weighted images. A similar picture is seen in pheochromocytomas with central necrosis (Fig. 3), but the classical pattern of a T2 hyperintense pheochromocytoma is relatively uncommon (27). The signal intensity of the haemorrhage in T₁- and T₂-weighted images could vary considerably, because the signal changes over the time since it depends on the age of the haematoma. However, generally speaking, the signal intensity of blood is predominantly high in T₁-weighted images. Smaller solid pheochromocytomas could be distinguished from adrenal adenomas by means of chemical shift imaging, because unlike adenomas, pheochromocytomas contain no intracellular lipids, and thus they show no signal changes in out-of-phase and in-phase images (Fig. 4a and b) (45).

Another option of MRI is diffusion-weighted imaging (DWI) and calculation of apparent diffusion coefficient (ADC) maps (Fig. 4c and d). Significantly higher ACD values were observed in pheochromocytomas compared to adenomas and metastases (46). ADC histogram analysis was also applied and revealed significant differences between pheochromocytomas and adenomas (47). ADC values might also help to distinguish benign from malignant pheochromocytomas (48).

MR spectroscopy of pheochromocytomas has been studied but is not routinely used (49,50).

Although the use of paramagnetic contrast agents is rarely necessary, strong post-contrast enhancement of pheochromocytomas is similar to contrast-enhanced CT (51).

Paramagnetic contrast agents used in MRI do not lead to the hypersecretion of catecholamines (52).

After the morphological imaging studies have been obtained, the functional imaging modality could be utilized to confirm the source of the increased production of catecholamines. For most of the cases one of the following methods is employed-¹²³I-MIBG scintigraphy, ¹⁸F-FDG, or ¹⁸F-DOPA PET/CT and somatostatin receptor imaging. The selection of the functional modality could be based on knowledge of the patient's genetic background, as recommended by the European Association of Nuclear Medicine (53).

For a long time, radioactive iodine-labelled ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) has been used to reveal pheochromocytomas. MIBG is a guanethidine precursor and its structure resembles that of norepinephrine. Following intravenous application, it is transported by the reuptake mechanism into presynaptic adrenergic neuron cells, where it accumulates in catecholamine secretory granules through the adenosine triphosphate system (ATPase-dependent proton pump). The scintigraphic examination uses the intravenous application of ¹²³I-MIBG tracer. The sensitivity of ¹²³I-MIBG ranges between 85 and 88% for pheochromocytomas and between 56 and 75% for paragangliomas, whereas its specificity ranges from 70 to 100% and 84 to 100%, respectively. Its sensitivity for metastatic pheochromocytomas is between 56 and 83%, whereas for recurrent disease it is ~75% (7).

Physiological MIBG uptake occurs in the salivary glands, the heart, the liver, and the spleen. Slightly elevated accumulation is also seen in the thyroid gland. Because of the renal excretion of the tracers, radioactivity is observed in the kidneys and the urinary bladder. The varying level of accumulation can also be observed in the nasal mucosa, neck muscles, lungs, and intestine. Medication which can prevent MIBG from accumulating in tumours (e.g., insulin, reserpine, amphetamine, calcium channel blockers, sympathomimetics) should be discontinued before the examination (54).

Pheochromocytomas appear on scintigrams as focal increased concentrations of radioactivity in the adrenal medulla but also in ectopic adrenergic tissue or metastases (Fig. 5). Paragangliomas can easily be missed on CT and MRI scans.

The advantages of ¹²³I-MIBG are high-quality examination with less exposure to radiation and, compared to the later methods, its wide availability and relatively low cost.

Nowadays the ¹²³I-MIBG examination is mostly recommended for patients with metastatic paragangliomas detected by other imaging modalities, when radiotherapy using ¹³¹I-MIBG is planned. Occasionally, it is used in some patients with an increased risk of metastatic disease because of the large size of the primary tumour or extra-adrenal, multifocal (except paragangliomas of the skull base and neck), or recurrent disease (7).

Another option in the visualization of pheochromocytomas is the detection of somatostatin receptors, whose concentration is increased in neuroendocrine tumours, including pheochromocytomas (Fig. 6). This imaging method uses radionuclide-labelled peptides, specifically somatostatin analogues (¹¹¹In-pentetreotide, ^99mTc-HYNIC-TOC). Somatostatin receptor imaging is mainly used in paragangliomas because of the relatively high physiological uptake of the radiopharmaceutical in the kidneys. This method is not recommended for hereditary tumours.

In most published examination schemes PET/CT with corresponding tracers is the preferred method for the detection of pheochromocytomas and paragangliomas and further wide use of this method can be expected. The most commonly used radiopharmaceuticals in this PET scanning are ¹⁸F-3, 4-dihydroxyphenylalanine (¹⁸F-DOPA) and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG); the selection of the tracer is based on localization of the tumour and its genetic background (7,53).

The advantage of ¹⁸F-DOPA imaging is the lack of significant uptake in the normal adrenal medulla. The efficiency of ¹⁸F-DOPA imaging of paragangliomas depends on the localization of the tumour and genetic status. ¹⁸F-DOPA PET/CT is an excellent diagnostic tool for head and neck paragangliomas, but its sensitivity can be lower in retroperitoneal paragangliomas (55). In metastatic disease the ¹⁸F-DOPA PET detection rate of the lesions is higher in SDHB-negative patients than in SDHB-positive ones (56).

The visualization of paragangliomas using ¹⁸F-FDG PET/CT is influenced by the degree of tissue differentiation, localization of the tumour, and genetic status (53). Increased ¹⁸F-FDG uptake is a usual finding in pheochromocytomas, but the intensity of this uptake is variable. The sensitivity of ¹⁸FDG PET/CT in the detection of pheochromocytomas is high, but unfortunately, its specificity is lower. In metastatic disease the ¹⁸F-FDG PET/CT detection rate of the lesions is higher in SDHB-positive patients (Fig. 7) (contrary to ¹⁸F-DOPA PET) (57). In patients with known metastatic pheochromocytomas, ¹⁸FDG PET/CT is preferred over ¹²³I-MIBG. ¹²³I-MIBG is performed in this group of patients when treatment with ¹³¹I-MIBG is being considered (7).

¹⁸F-fluorodopamine (¹⁸F-FDA) and ⁶⁸Ga-DOTA-peptides that specifically bind to somatostatin receptors are experimental PET tracers that have been successfully used in clinical studies (39). ⁶⁸Ga-DOTA-peptides seem to represent the near future of the molecular imaging of pheochromocytomas. Their superiority in the localization of sporadic metastatic pheochromocytomas compared to all other functional and anatomical imaging modalities has been demonstrated (58–60).

Sporadic pheochromocytomas-the sensitivity of ¹²³I-MIBG is similar to the case of PET imaging and superior to somatostatin imaging.

Head and neck paragangliomas-the most sensitive method is ¹⁸F-DOPA PET/CT, but according to new studies imaging using ⁶⁸Ga labelled somatostatin analogues achieves similar results. The usage of ¹⁸FDG PET/CT is beneficial in SDHx-related head and neck paragangliomas.

Retroperitoneal paragangliomas-the sensitivity of ¹⁸F-DOPA PET/CT is higher than ¹²³I-MIBG scintigraphy, and ¹⁸F-FDOPA PET/CT is more specific than ¹⁸FDG PET/CT. High sensitivity is exhibited by ¹⁸FDG PET/CT in SDHx- and VHL-related sympathetic paragangliomas.

Metastatic pheochromocytomas and paragangliomas-¹⁸F-FDG PET/CT is the preferred method in SDHB-related patients and the usage of ¹⁸F-FDOPA PET/CT can be advantageous in the absence of SDHB mutations; in patients with unknown genetic status ¹⁸F-FDG PET/CT should be used, optionally in combination with ¹⁸F-FDOPA PET/CT or somatostatin receptor imaging. ¹²³I-MIBG allows the appropriateness of radiotherapy to be assessed using ¹³¹I-MIBG.

The risk of catecholamine hypersecretion is significantly increased by biopsy. Therefore, needle biopsy should be avoided in clinically suspected pheochromocytomaπs and surgery should be performed directly (68,69).

Preoperative pharmacological management of the pheochromocytoma is always needed to reduce the risk of perioperative complications. Pharmacological preparation of the patient significantly reduces the risk of perioperative mortality (70,71). Crucially, the patient should have an alpha-blocker administered for at least 14 days prior to surgery to reduce the risk of vasoconstriction. A beta-blocker can be administered prior to surgery as well to prevent tachycardia, if necessary. The administration of beta-blockers must not begin prior to alpha-blockade because of the risk of severe hypertension. An experienced anaesthesiologist should be present during the surgery to reduce the risk of possible circulatory complications.

The surgical method of choice in the treatment of pheochromocytomas is laparoscopic adrenalectomy, performed via the trans- or retroperitoneal approach. The retroperitoneal approach is particularly suitable for the right adrenalectomy.

The rule of thumb for preventing complications during the resection of pheochromocytomas is to perform an early occlusion of the vein draining the adrenal medulla (known as the vena centralis), flowing into the renal vein on the left side (Fig. 8) and into the inferior vena cava on the right side. This is to minimize the secretion of catecholamines into the circulation during manipulation of the gland. Some well-established advantages of the laparoscopic approach include lower blood loss, less need for narcotics, a shorter hospital stay, and a more favourable cosmetic effect. The previous assumption that the intra-abdominal insufflation of carbon dioxide may induce hypertension has been refuted.

Open adrenalectomy is currently indicated only in tumours with signs of invasion into the surrounding structures or in the presence of a thrombus. The open approach is also preferred in tumours larger than 8–12 cm (72) and in the event of paraganglioma (7). In cases of a bilateral pheochromocytoma, e.g., in patients with VHL syndrome or MEN2A, partial adrenalectomy can be performed at least on one side to preserve the secretion of adrenal hormones.

In the long-term prognosis of patients after surgery is excellent; however, hypertension persists in almost 50% of cases (9).