Current Approaches and Recommended Algorithm for the Diagnostic Localization of Pheochromocytoma

Abstract

PHEOCHROMOCYTOMAS (PHEO) (1–3) are catecholamine-producing tumors that arise from chromaffin cells. PHEO are mostly situated within the adrenal medulla, although in about 9–23% of cases, tumors develop from extraadrenal chromaffin tissue (adjacent to sympathetic ganglia of the neck, mediastinum, abdomen, and pelvis) and are often referred to as paragangliomas (4–6). PHEO situated in the adrenal gland are identified more commonly than those in extraadrenal tissues, because clinicians usually focus on the adrenal gland as a main source of catecholamine production. Although they usually choose a proper imaging technique to attempt the localization of PHEO in the adrenal gland, they are often confused as to which algorithm to follow and what technique to choose for the detection of extraadrenal PHEO. Furthermore, physicians often neglect the facts that up to approximately 25% of patients with apparent sporadic PHEO may, in fact, be carriers of germline mutations, indicating hereditary disease with a predisposition for extraadrenal, often multifocal, PHEO (7); that in children, multifocal and extraadrenal PHEO are found in up to 30–43% of cases (6, 8–12); that malignant PHEO account for up to 26–35% of cases (13–18); that the prevalence of malignancy in sporadic adrenal PHEO is 9% (5); and that about 10% of patients with PHEO present with metastatic disease at the time of their initial work-up (19). After initial failed surgery, patients with metastatic PHEO are commonly reevaluated using metaiodobenzylguanidine (MIBG) scintigraphy, a modality that should actually be performed before surgery to confirm that a tumor was indeed a PHEO (5–9% of the population harbor an adrenal tumor, most commonly a benign adenoma) (20–22) or to rule out metastatic disease. These patients are then reoperated upon, suffering additional surgery-related complications and substantial financial expenses. Some clinicians consider the presence of sporadic unilateral small PHEO as indicative of benign disease. This was concluded in older studies of series of patients with PHEO (23–25). However, more recent works from large series of patients with benign and malignant disease in the United States and Europe do not support this view; rather, they support the opinion that there are no absolute clinical, imaging, or laboratory criteria to predict malignancy and clinical course of PHEO (5, 16, 19, 26–32). Nevertheless, PHEO tumors with a diameter larger than 5 cm have a higher potential to metastasize, and such patients should be followed more frequently (33). Consequently, it seems that ruling out metastatic PHEO before initial surgery would be useful, because the detection of other lesions may dramatically affect treatment and follow-up. Localization of PHEO should be attempted using at least two imaging modalities. Anatomical imaging studies [computed tomography (CT) and magnetic resonance imaging (MRI)] should be combined with functional (nuclear medicine) imaging studies for optimal results to locate primary, recurrent, or metastatic PHEO. Functional imaging studies (enabled by the presence of the noradrenergic transporter system on PHEO cells) include [123I]- or [131I]MIBG scintigraphy, 6-[18F]fluorodopamine ([18F]DA), [18F]dihydroxyphenylalanine ([18F]DOPA), [11C]hydroxyephedrine, and [11C]epinephrine positron emission tomography (PET) (34–38). Chromaffin cells in various neuroendocrine tissues [such as PHEO, but also medullary thyroid carcinoma (MTC)] express the plasma membrane norepinephrine transporter and the intracellular vesicular monoamine transporter. The norepinephrine transporter is responsible for the cellular uptake of both MIBG (39) and [18F]DA (36). We have recently shown that [18F]DA PET scanning could theoretically represent yet another imaging modality for the detection of MTCs (40) because MTC cells often express the norepinephrine transporter and concentrate MIBG (41). In most cases, functional imaging modalities are either able to confirm that a tumor is a PHEO or can lead to further diagnostic work-up. For example, in a patient with positive plasma metanephrines and MIBG imaging studies showing uptake in extraadrenal locations, the possible presence of multiple endocrine neoplasia type 2 (MEN 2)-related tumors (including MTC) should be considered and assessed with measurement of serum calcitonin and/or RET mutations. Functional imaging studies are also very helpful to rule out metastatic disease in most cases. However, as malignant PHEO may undergo tumor dedifferentiation with loss of specific neurotransmitter transporters (Refs. 42 and 43 , and Pacak, K., unpublished observation), leading to the inability to accumulate these isotopes and consequent lack of localization, [18F]fluorodeoxyglucose ([18F]FDG) PET scanning or somatostatin receptor scintigraphy (Octreoscan) may be required as the next step of the imaging algorithm. [18F]FDG is a nonspecific imaging agent whose accumulation is based on the higher metabolic