Current Approaches and Recommended Algorithm for the Diagnostic Localization of Pheochromocytoma

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 rate of tumors compared with surrounding normal tissue. Another characteristic of dedifferentiated tumors is either the loss or the gain of specific receptors. More particularly, malignant PHEO often expresses somatostatin receptors (44–47), thus enabling scintigraphy with the somatostatin analog octreotide. In this review we provide readers with current views of the roles of various imaging modalities for biochemically proven PHEO based on elevated plasma metanephrines (36, 48–50) with emphasis on new functional PET imaging agents. Furthermore, we recommend an algorithm implementing anatomical and functional imaging modalities to assure proper localization of benign and malignant PHEO. The proposed algorithm serves not only to localize PHEO, but also to confirm that a tumor is indeed a PHEO and to differentiate adrenal tumors, including incidentalomas from PHEO. Whenever possible, in treating benign or malignant PHEO, surgical excision of any accessible mass should be considered (13, 51–54), because it may alleviate symptoms from catecholamine excess, improve quality of life, and possibly in some patients with only osseous metastatic lesions help to increase their survival. However, in the presence of extensive organ metastatic lesions, the removal of primary lesions and incomplete removal of metastatic lesions in organs are not considered to have an effect on the patients’ survival (55), although further studies are needed. The proposed algorithm serves to guide and optimize surgery in patients with adrenal and extraadrenal PHEOs. Finally, although no cost-effectiveness analyses of PHEO localization have yet been performed, we believe that our approach deals with some “cost” issues, including less radiation exposure to patients. CT and MRI are common initial imaging modalities used for the localization of PHEO. These studies localize PHEO with high sensitivity, but less than optimal specificity. As these imaging modalities are currently less expensive and time consuming as well as more readily available than functional imaging studies, they should be used as first line imaging modalities. In addition, they should always be carried out over the abdomen first, because PHEO are mostly situated within the adrenal medulla. In some specific situations (see below), anatomical imaging for PHEO can be performed with ultrasound (U/S). PHEO that secrete only epinephrine are uncommon, although they are frequently found in patients with MEN 2 (56). Patients with PHEO that secrete only epinephrine have high plasma or urinary epinephrine or metanephrine levels, and almost always have an adrenal tumor. In these patients, CT or MRI of the abdomen are a first choice examination for the diagnostic localization of PHEO. On the other hand, norepinephine and normetanephrine can be secreted by PHEO localized both within and outside the adrenal gland (48). If no adrenal masses are seen, attention should be focused initially to the paraspinous area (57). The majority of paragangliomas occur in the paraaortic region or around the renal hilum and may be visible on CT/MRI (57). Adrenal PHEO of 0.5–1.0 cm or larger or metastatic PHEO at least 1.0–2.0 cm in size can be detected by CT (36, 58), preferably with 2- to 5-mm-thick scanning sections (59). As most adrenal PHEO tumors have a diameter of at least 3 cm, they can be readily visualized with CT (Fig. 1A). Adrenal adenomas can be differentiated from metastases with CT densitometry (60–62). More particularly, a homogenous mass with a density measurement of less than 10 Hounsfield units (HU) on an unenhanced CT is most probably an adenoma (62), whereas if the mass is inhomogeneous and/or has a density measurement of 10 HU or more, the diagnosis is uncertain. Although nonfunctioning adenoma is the most common possibility, a metastasis or functioning tumor should also be considered. For cases with inconclusive clinical and biochemical results, further imaging assessment should be sought using washout after administration of contrast medium (61, 63). Small 1- to 2-cm PHEO tumors are usually homogeneous in appearance, with soft tissue density (∼40–50 HU) and show uniform enhancement with contrast (64). Larger PHEO tumors may undergo hemorrhage and can be inhomogeneous, and areas of low density can be seen after tumor necrosis (57, 64–66). A, Abdominal CT of a 44-yr-old man with MEN 2A. Bilateral adrenal PHEOs (5–6 cm in maximum diameter) are evident (arrows); the lesion in the left adrenal appears to be bilobed. B, Abdominal T2-weighted MRI of the The adrenal PHEOs show a high tumors and the left PHEO was which their of PHEO are to the and the and the sympathetic ganglia and organ the and the in the or the urinary CT of the abdomen and should be performed first, followed by and imaging if this CT is CT is for small The of CT in the localization of PHEO are the and high sensitivity, which if a PHEO is in the adrenal gland for extraadrenal, or PHEO is about before surgery The of CT may to about to the of CT in PHEO has been shown to be in some studies, from for lesions to the adrenal unenhanced CT followed by and CT imaging a of and a of CT the surrounding a PHEO and localization of the tumor, although such as surgical may imaging In some patients with PHEO, CT may be or have whereas MRI are positive but these cases are in patients with no of and possibly also receptor administration is for patients with biochemically proven PHEO to contrast for CT examination However, no in plasma was in 10 patients with PHEO a contrast CT not a of a If a high unenhanced and are performed and the PHEO tumor is there is no to to but functional imaging is required to confirm that a tumor is indeed PHEO and to rule out metastatic disease. If the CT is in a patient with biochemically proven PHEO, MRI should be MRI should be for CT in children, and situations radiation exposure be situations MRI is in of CT are Another imaging modality that is used in the diagnostic work-up of adrenal PHEO or detection of metastatic disease is with or enhancement (36, On MRI PHEO have a those of the and and can be differentiated with from tissue. MRI adrenal masses based on the presence of in benign adenomas and the of in PHEO, or malignant tumors The of PHEO with a high on (Fig. and no loss on (Fig. More particularly, almost PHEO have a more than that of the or and often more than on T2-weighted (57, However, such can be by or and an with PHEO be considered and specific additional imaging is to confirm that the tumor is PHEO. PHEO may show medium quality on T2-weighted and an inhomogeneous appearance, if they are the of MRI imaging of PHEO are high in adrenal disease and the lack of exposure to MRI is a imaging modality for the detection of and PHEO, because it and whereas the of from surrounding tissues MRI can be carried out with or using contrast are very and do not the of and thus no with is MRI the of imaging and assessment of the a tumor and surrounding in compared with this modality of in the of patients with PHEO in these to rule out However, for detection of extraadrenal, or PHEO is compared with that of adrenal disease Although some have high of MRI in PHEO in most the of this modality has been shown to be to about MRI is a more expensive imaging modality than MRI should be used as the initial imaging for imaging PHEO in or (36, because it not any radiation or in the of to CT contrast agents. On imaging, PHEO are usually seen as well or masses that low and homogenous PHEO tumors frequently undergo hemorrhage or and in this is (64). The of in PHEO has been assessed in small of patients and has been to be the of our extensive studies on the of in the diagnosis of PHEO have not been performed, but it is to be as in older studies the for adrenal tumors was about As is a modality with no radiation it can be a choice in the diagnostic work-up of PHEO in patients, such as and but it is not to The low and of using this imaging modality a choice in the initial of patients of PHEO in the However, 10% of PHEO are and although they are readily seen with those in the adrenal gland be differentiated from renal and of PHEO as MEN 2 or type and in may account for the high prevalence of multifocal and or only extraadrenal PHEO in studies of in up to 30–43% of (6, As views of the abdomen it is for imaging extraadrenal PHEO and rule out multifocal disease. to the presence of surgical or of the patient may also the of In this modality is not for patients, and we do not recommend it specific and in cases CT and MRI are not Adrenal masses are present in about of the population Although most adrenal masses are about of adrenal masses are indeed PHEO most adrenal are not PHEO, the for specific diagnostic imaging after anatomical studies are performed in patients with of PHEO. as there is no on the of absolute clinical, imaging, or laboratory criteria to predict malignancy and of PHEO in patients with PHEO, the to metastatic disease or multiple tumors is This be with functional imaging modalities using various that provide physicians with imaging is also in PHEO in patients in imaging is and in the detection of metastatic However, functional imaging are by the of in thus their to localize PHEO to the the of the or the urinary PHEO cells usually express specific catecholamine plasma membrane and vesicular transporter enabling imaging with and as well as with PET In we present a of available for localization of PHEO. Some are in clinical whereas are currently for of PHEO in and in from with or potential for PET for of PHEO in and in from with or potential for PET MIBG is an that is performed with the and at the of the MIBG is tissues by a noradrenergic transporter system and a vesicular transporter MIBG is thus within However, MIBG not show any to receptors and is The plasma membrane and vesicular uptake is and can be by such as and as well as by have to be for on the with the of of for which the is before this in has been shown to and uptake has a and high For imaging, [131I]MIBG is at from 0.5–1.0 or in an at the of has a and than is at from 3 in to 10 in The radiation from 10 that of [131I]MIBG in the United States is The of in [131I]MIBG is less than and after MIBG a further small of thyroid accumulation of the which may paragangliomas and thyroid patients should a of a or in the of to a of should be or of a before the patient for or after administration of [123I]- or the of a of thyroid as seen in with and in have larger of [131I]MIBG for of neuroendocrine tumors is performed after if at for For imaging is performed at and if at the urinary and in sympathetic show MIBG uptake after On some the large and the may also show MIBG the normal adrenal may show uptake as as of patients after The of uptake may be the left and and should be in the to or More [131I]MIBG uptake is seen in normal adrenal of after Some of the MIBG is up by and may occur of the MIBG is the with in and and scintigraphy has been used in the work-up of patients with PHEO PHEOs as areas of MIBG uptake (Fig. emission CT is usually carried out is in or metastatic PHEO, tumors with or tumors in or in areas with A, of a patient with a adrenal PHEO. focus of uptake is seen B, the patient was with [18F]DA two of uptake seen [131I]MIBG scintigraphy has a from and a high for PHEO scintigraphy has a from and a high for PHEO In the clinical for but not patients, a on or scintigraphy a diagnosis of PHEO, whereas uptake on or scintigraphy usually the presence of PHEO. positive [131I]MIBG have been in cases of adrenal carcinoma and in lesions such as MIBG may be in cases of with to that with MIBG uptake and with PHEO tumors that have necrosis or dedifferentiated PHEO Adrenal adenomas have positive uptake and anatomical of the renal may also lead to positive imaging results The higher and the of using lead to recommend over [131I]MIBG scintigraphy imaging of with although not yet in diagnostic potential in the of patients with PHEO PET imaging is performed within or after the of agents. radiation exposure and are the of whereas the and of the and PET (including the more In the of patients with PHEO, PET with [11C]hydroxyephedrine, or [11C]epinephrine have been used most often is also and at the [18F]DA has been used with various malignant the uptake of with in be in the imaging of these tumors (Fig. In of patients, [18F]FDG PET was used with some for imaging metastatic PHEO and more metastases than or [131I]MIBG PHEO may accumulate [18F]FDG more compared with benign of uptake of with could not malignant from benign disease with may be for dedifferentiated and/or PHEO cells up imaging with [18F]FDG PET nonspecific for PHEO and should be used as an initial [18F]FDG of a patient with a PHEO. uptake is evident over the adrenal with and In of diagnostic localization of PHEO, and [11C]epinephrine PET have also detected PHEO tumors In the most recent with uptake was seen in of patients appears to from chromaffin possibly because of less vesicular of this compared with epinephrine is a for the norepinephrine transporter compared with the other of and [11C]epinephrine is the of which the of and high are also to their more as an is then for production. The that uptake of MIBG may also uptake of and [11C]epinephrine is a of and has also been used in patients with PHEO. do not show was used in a of patients with benign adrenal PHEO and a small of patients with extraadrenal, but not PHEO In the tumors localized with whereas in the PET imaging was with MRI results in of patients and a tumor that was not seen with [131I]MIBG scintigraphy In a recent of 10 patients with tumors are to PHEO, as they arise from the tissue of the and of the tumors by PET by MRI is a more specific for the norepinephrine transporter compared with most other including norepinephrine or Consequently, an analog of should be a imaging agent than norepinephrine or In of a new imaging was at the [18F]DA is a analog of and a for both the plasma membrane and intracellular vesicular transporters in cells. of [18F]DA results in a of more than and of these cells has shown that [18F]DA is an agent to localize adrenal and extraadrenal PHEO, including metastatic lesions and We recently a of a series of patients with PHEO in [18F]DA PET positive and localized PHEO tumors in We have also seen patients with [131I]MIBG but positive [18F]DA in the of metastatic PHEO K., unpublished Furthermore, in patients with biochemically proven PHEO plasma [18F]DA PET studies positive in metastatic disease and more about the and of metastatic lesions compared with [131I]MIBG [18F]DA of a patient with a primary PHEO tumor and multiple metastatic lesions in the abdomen, mediastinum, and The renal and the are We believe that [18F]DA PET in as a functional imaging agent in PHEO. [18F]DA PET results in a radiation than [131I]MIBG the also thyroid with administration of PET scanning is carried out after the administration of as to the to for [131I]MIBG and as to the [18F]DA is also more specific for PHEO than other such as because the are up as by cells and are to of [18F]DA PET is that this agent is currently available in only a clinical studies are to with receptors have and are of somatostatin receptors are and 5 are in neuroendocrine tumors, whereas type and type 3 low in these tumors to of PHEO cells express somatostatin receptors 2 and other neuroendocrine tumors, as shown by studies using such as in and is an analog of somatostatin that is and has for type 2 somatostatin high for type 5 for type 3 and no for and receptors of somatostatin with a of and of and is usually used for octreotide. is a and with is a the and other is in of and views are at and as needed. imaging should be is by the within of uptake include and and recent surgery positive results in patients with also show uptake receptor scintigraphy either or has been used in patients with PHEO However, the of the is by the normal presence of somatostatin receptors in a of tissues as well as in Another to imaging of PHEO with is the of uptake seen in the which the of for small tumors in the region and although the of such as and can renal this technique is not yet PHEO may also show tumor in the loss of somatostatin receptors and studies can also be in these patients. a have compared with by in the patients with PHEO have not found somatostatin receptor scintigraphy to be helpful in the localization of primary PHEO tumors with studies in most patients with benign PHEO positive or [131I]MIBG PHEO are detected with compared with of because MIBG as well as [18F]DA are in patients with malignant PHEO, possibly because of of the membrane norepinephrine transporter by less well differentiated cells K., unpublished In such cases, should be performed to localize PHEO, because this modality has detected lesions in patients with neuroendocrine tumors (Fig. This is more as more metastases of neuroendocrine tumors positive on compared with metastases of well differentiated neuroendocrine tumors metastatic disease with lesions in the abdomen, and seen on an of a patient with PHEO. of in the is In this studies not show of We currently do not recommend MIBG scintigraphy, or as the first imaging modalities in the diagnostic localization of PHEO, because of compared with CT/MRI and the time to for imaging although these modalities are of in further diagnostic work-up of PHEO and approach for the diagnostic localization of PHEO has yet to be of the disease is (36, and is by plasma metanephrine and from that with these and lead to positive results, such as and biochemical can be using the with measurement of plasma metanephrine and normetanephrine to localize PHEOs in the of biochemical is only there is of at a before these tumors secrete of In we the of anatomical imaging CT or for initial imaging of the in patients with biochemically proven PHEO. In some cases, such as in or MRI is but ultrasound may also be considered. for diagnostic localization of PHEO. and T2-weighted MRI positive and T2-weighted MRI examination positive for examination for scintigraphy over [131I]MIBG scintigraphy, of PHEOs may not express the norepinephrine transporter system or may have a low of catecholamine As as CT is lesions on unenhanced CT with than 10 HU the presence of PHEO, whereas those with higher than 10 HU may be followed by and CT (61, 63). If MRI is as the initial anatomical imaging and should be CT or MRI imaging of the abdomen, and should be followed by additional CT this modality in such as in and MRI is If CT are is to be by in patients with surgery that may in The presence of PHEO should always be out or with functional imaging if CT and MRI are but PHEO is biochemically The functional imaging of choice is if this is not then [131I]MIBG should be If the MIBG is PET studies should be performed with specific preferably [18F]DA or If these are also the patient probably has an type of PHEO which tumor cells do not express the norepinephrine transporter system or may have a low of catecholamine or malignant PHEO, and scintigraphy with nonspecific such as somatostatin receptor scintigraphy with or should be carried with measurement of metanephrines to localize the tumor the of a is an modality to be used with in cases imaging have This is and is at (6, If to such is not then a localization work-up after is a more and We for review of the and for with this and and for on Hounsfield multiple endocrine neoplasia type magnetic resonance medullary thyroid somatostatin receptor scintigraphy with or positron emission emission