Functional scintigraphy of the adrenal gland - PDF Document

Presentation Transcript

  1. European Journal of Endocrinology (2002) 147 13–28 ISSN 0804-4643 REVIEW Functional scintigraphy of the adrenal gland Domenico Rubello1,2, Chuong Bui2, Dario Casara1, Milton D Gross3, Lorraine M Fig3and Brahm Shapiro2 1Nuclear Medicine Service, Department of Radiotherapy, Regional Hospital of Padova, Padova, Italy,2Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA and3Nuclear Medicine Service, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan, USA (Correspondence should be addressed to D Rubello, Servizio di Medicina Nucleare 2^, Unita ` Operativa di Radioterapia, via Giustiniani 2, Azienda Ospedaliera di Padova, 35100 Padova, Italy) Abstract Over the last 30 years nuclear medicine imaging of the adrenal gland and its lesions has been achieved by the exploitation of a number of physiological characteristics of this organ. By seeking and utilising features which are quantitatively or qualitatively different from those of the adjacent tis- sues, functional depiction of the adrenal gland and its diseases, which in most cases retain the basic physiology of their tissue of origin, including both the cortex and the medulla, are now a useful clini- cal reality. Agents widely used in clinical practice include: (a) uptake and storage of radiolabelled cholesterol analogues via the low density lipoprotein (LDL) receptor and cholesterol ester storage pool in the adrenal cortex (131I-6-b-iodomethyl-norcholesterol,75Se-selenomethyl-norcholesterol); (b) catecholamine type I, presynaptic, uptake mechanism and intracellular granule uptake and storage mechanism in the adrenal medulla and extra-adrenal paraganglia (131I-, meta-iodo-benzyl-guanidine (MIBG),18F-metafluoro-benzyl-guanidine); (c) cell surface receptor bind- ing of peptides/neurotransmitters/modulators such as for the family of five subtypes of somatostatin receptors (123I-tyr-octreotide,111In-DTPA-octreotide,111In-DOTA-octreotide and many others); (d) although not specific for the adrenal gland, increased glycolysis by tumours, particularly the most malignant varieties,18F-2-fluoro-D-deoxyglucose can thus be expected to depict certain malignant lesions such as malignant pheochromocytomas (particularly the minority which are not detected by MIBG) and adrenal incidentalomas (particularly when they occur in patients with known extra- adrenal malignancies). There are a variety of adrenal tissue characteristics with potential for exploitation but which are not currently in clinical use, and which may, nevertheless, have potential as imaging agents. These include: (a) inhibitors of adrenal cortical steroid hormone synthesis enzymes (e.g. radiolabelled ana- logues of metyrapone); (b) radiolabelled lipoproteins which bind to adrenocortical LDL receptors; (c) inhibitors of catecholamine biosynthesis enzymes (e.g. radiolabelled analogues of tyrosine and related amino acids); (d) cell surface receptors for various peptides and hormones which may be over- expressed on adrenal cortical or adrenal medullary tumours (e.g. radiolabelled analogues of ACTH on adrenocortical cells of zona fasciculata or zona glomerulosa origin, neurotransmitter/hormone message peptides binding to cell surface receptors such as bombesin, vasoactive intestinal polypeptide, cholecystokinin and opiate peptides); (e) the adrenal cortex can also synthesise cholesterol ab initio from acetate, and preliminary studies with11C-acetate positron emission tomography have shown interesting results. 123I- and 124I- European Journal of Endocrinology 147 13–28 Adrenal cortex Radiotracers for adrenal cortex imaging The adrenal cortex is constituted of three layers. The outer layer, the glomerulosa zone, produces mineralo- corticoids (mainly aldosterone) under the control of the renin–angiotensin–aldosterone axis. Conversely, both the middle layer, the fasciculata zone, which pro- duces glucocorticoids (mainly cortisol) and the inner layer, the reticulata zone, which produces sex hor- mones, are regulated by the hypothalamic–pituitary– adrenal axis. Many radiotracers have been developed to image the adrenal cortex by exploiting different physiological mechanisms of steroid hormone uptake and metabol- ism. Many efforts have been made to label cholesterol, initially with (131I-19-iodocholesterol; CL-19-I) (2, 3).131I-6-b-iodo- methyl-norcholesterol (NCL-6-I) was initially recog- nised as a contaminant derived from the synthesis of CL-19-I and was shown to have at least a fivefold 14C-cholesterol (1) and then with 131I q 2002 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  2. 14 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 fatty meal or another cholecystagogue to reduce gall- bladder activity (15). NCL-6-I is administered by slow intravenous injection at the dosage of 1mCi/1.7m2 body surface area (13, 14). Baseline imaging (without hormonal manipulation) is usually obtained by planar scans of the abdomen 5 days after tracer adminis- tration; further imaging on days 6–7 (until day 14 with Scintadren) can be obtained, especially in cases with relatively high interfering bowel background activity (15). Single photon emission computed tomo- graphy (SPECT) acquisition has been suggested to be useful in some cases (16). In some pathologies, such as primary hyperaldosteronism and masculinising or feminising adrenal tumours, baseline NCL-6-I imaging has poor sensitivity due to the overlapping uptake of the adrenocorticotrophin (ACTH)-dependent normal adrenal tissue of the inner zones which can mask the uptake of a relatively small tumour (generally the size of Conn’s tumour is less than 2cm) (17). To improve the sensitivity of NCL-6-I scintigraphy in these patients, suppression of the normal adrenal cortex is achieved by pretreating the patient with dexamethasone. In normal subjects, during dexamethasone suppression (DS), the normal adrenal cortex is not visualised until day 5 post-injection when faint uptake can be seen due to a physiological breakthrough mechanism (17). Using DS NCL-6-I scintigraphy, imaging is usually obtained on days 3, 4 and 5 after tracer injection; longer delayed imaging (e.g. days 7 and 14) can be useful, especially when Scintadren is administered. greater avidity for adrenal cortex in rats and dogs and a greater in vivo stability than CL-19-I (4). Moreover, NCL-6-I showed a more rapid decrease of background activity in humans, making scintigraphic visualisation of the adrenal glands easier (3, 4). Another group of radiotracers comprises the inhibitors of adrenal cortical steroid hormone synthesis such as metyrapone and related compounds labelled with123I,131I,111In and 99mTechnetium (99mTc), but at present no successful clinical agent is available (5). Among the inhibitors of adrenal steroid synthesis there are also some posi- tron-emission tracers such as11C-etiomidate and11C- metomidate that have been investigated (6). Another promising approach consists of labelling the low density lipoproteins (LDLs) with111In or99mTc. LDLs are the principal carrier of cholesterol in the blood and for these there are specific receptors in the surface of the adrenocortical cells (7). Some other positron-emission tracers have been synthesised and among them11C- acetate was shown to accumulate in adrenal adenomas (8). Currently, NCL-6-I is the radiotracer most widely used in clinical practice for adrenal cortical imaging (9). A compound similar to NCL-6-I but labelled with 75Se (75Se-6-b-selenomethyl-norcholesterol; dren, Nyocomed-Amersham) is available in Europe (10). The results obtained with Scintadren are compar- able with those of NCL-6-I (10). The only marginal advantages of Scintadren over NCL-6-I is that the shelf life is up to 6 weeks and delayed imaging as late as 2 weeks can be obtained, when the background activity is negligible (10). NCL-6-I is carried in the cir- culation by LDL and is trapped into the adrenal cortex cells by specific LDL receptors (11). Once within the cytoplasm, NCL-6-I is esterified but does not appear to befurthermetabolised(11).However,thereisanentero- hepatic circulation which can cause an increase in the background colonic activity (12). Scinta- Normal NCL-6-I distribution Following the injection, NCL-6-I concentration in the adrenal cortex is rapid, but to obtain an adrenal-to- background ratio favourable for imaging, the acqui- sition has to be delayed to days 4–5 (18). In normal subjects, faint NCL-6-I uptake is seen in the adrenals. The right adrenal is more cephalad and located deeper than the left adrenal and shows a slightly greater uptake as a common, physiologic finding; the left to right uptake ratio ranges from 0.9 to 1.2 (9, 11, 13, 14). Also, the overlapping liver uptake can contribute to the slightly greater uptake of the right adrenal. Uptakes differing by more than 50% exceed the normal asymmetry and should be considered abnormal (9, 11, 13, 14). The adrenal NCL-6-I uptake can be quantified by a region of interest (ROI) method and background and depth correction. The adrenal uptake in normal subjects ranges from 0.075 to 0.26% (mean 0.16%) of the administered dose (19). Gallbladder activity can interfere with the accu- rate visualisation of the right adrenal gland especially in DS scintigraphy. The lateral and anterior projections are useful to interpret the scan correctly (13, 14). Colo- nic activity can also be seen due to biliary excretion and subsequent enterohepatic circulation of NCL-6-I Patient preparation and NCL-6-I scintigraphic technique It is an absolute requirement that drugs which may interfere with the hypothalamic–pituitary–adrenal axis (e.g. glucocorticoids) or on the renin–angiotensin– aldosterone axis (e.g. spironolactone, most diuretics, sympathetic inhibitors, oestrogens) be discontinued to avoid distortion of the biodistribution and misinterpre- tation of the scintigraphic imaging (11, 13). Moreover, attention should be paid to patients with high serum lipoprotein levels because decreased or even absent NCL-6-I uptake by the adrenal cortex has been observed, probably due to the expanded extra- and intracellular cholesterol pool and to the down-regu- lation of the specific adrenocortical LDL receptors (13). Saturated potassium iodine solution (SSKI) or Lugol’s solution are given to the patient to block thy- roidal uptake of free131I (14). Laxatives can be given to reduce the bowel background activity as well as a www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  3. 15 Adrenal scintigraphy EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 (15). Activity in the thyroid and stomach can be observed in the presence of free131I. non-visualisation pattern suggests the presence of an adrenocortical carcinoma (11, 13, 14, 21). Usually, the NCL-6-I concentration per gram of tissue is insuffi- cient to allow the scintigraphic depiction of the malig- nant tumour. This, however, generally maintains the capability to secrete an excess of glucocorticoids which causes the suppression of ACTH and, conse- quently, the non-visualisation of the contralateral normal adrenal (21). In a small minority of patients, the adrenocortical carcinoma is depicted by NCL-6-I scintigraphy and in even fewer cases can its metastases also be visualised (21). Clinical applications of NCL-6-I scintigraphy Cushing’s syndrome Bilateral symmetric visualisation. Bilateral symmetric visualisation is the typical finding of the ACTH-depend- ent corticoadrenal hyperplasia (11, 13, 14). This is the most frequent cause of Cushing’s syndrome and can be due to a pituitary tumour or to ectopic ACTH pro- duction. Very high adrenal uptakes, exceeding 1% of the administered dose, strongly suggest the presence of an ectopic source of ACTH (14). Adrenal remnant localisation. In Cushing’s patients pre- viously treated by bilateral adrenalectomy but who have persistent hypercortisolism, NCL-6-I scintigraphy has been proven to be a highly sensitive procedure for the detection of functioning remnants (11, 13, 14). Moreover, it should be emphasised that when an adre- nal gland is destroyed or removed, the contralateral gland shows a compensatory hyperplasia (even nodular hyperplasia) and an increase in NCL-6-I uptake (22). Asymmetric adrenal visualisation. Asymmetric adrenal visualisation, greater than 50%, suggests the presence of an ACTH-independent adrenocortical hyperplasia (11, 13, 14). It is worth noting that, in marked asym- metric nodular hyperplasia, computed tomography (CT) or magnetic resonance imaging (MRI) can under- estimate the bilateral nature of the disease because it may reveal only a unilateral nodular involvement; this misdiagnosis can lead to inappropriate unilateral surgery (14, 17, 20). In contrast, NCL-6-I scintigraphy has been proven to accurately detect the asymmetric but bilateral nodular hyperplasia with high sensitivity (Fig. 1) (20). Primary hyperaldosteronism In patients with pri- mary hyperaldosteronism, DS NCL-6-I scintigraphy is the procedure of choice in cases where CT scanning does not reveal an obvious Conn’s adenoma, most fre- quently occurring in the presence of small bilateral hyperplasia. Early unilateral adrenal visualisation (,5 days) suggests the presence of a solitary adrenal adenoma (Fig. 3), whereas early bilateral visualisation (,5 days) suggests the presence of bilateral hyperplasia (Fig. 4) (11, 13, 14, 17, 23). However, the early images (before day 5) are not necessarily an absolute gold standard, especially using Scintadren which has a slower decrease in background activity in comparison with NCL-6-I; thus delayed imaging (until day 14) may be required. CT has been shown to be sensitive in detecting most adenomas but can fail in diagnosing Unilateral adrenal visualisation.Unilateral adrenal visual- isation is the typical finding of the solitary adrenocorti- cal adenoma (11, 13, 14). Because of the suppression of ACTH, the contralateral normal adrenal is not usually visualised (Fig. 2). Bilateral non-visualisation. tration of glucocorticoids or the presence of high serum lipoprotein levels has been excluded, the bilateral Once exogenous adminis- Figure 1 Bilateral, asymmetrical ACTH- dependent nodular hyperplasia causing Cushing’s syndrome depicted by NCL-6-I. A 73-year-old female with biochemistry consist- ent with long-standing ACTH-dependent Cushing’s syndrome who, at CT scan, showed a bilateral nodular enlargement of the adrenal glands, 4.6cm on right, 1.3cm on left. (A) Transverse CT abdomen showing bilateral asymmetrical adrenal enlargement, right larger than left, indicated by white arrows. (B) NCL-6-I posterior abdominal scan (without DS) with bilateral, asymmetrical tracer uptake, right adrenal much greater than left. Adrenal glands are indicated by white arrows. www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  4. 16 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 Figure 2 Adrenocortical adenoma causing Cushing’s syndrome, depicted by NCL-6-I. A 48-year-old female with ACTH-independent Cushing’s syndrome and a 3cm left adrenal mass on CT scan which proved to be an adrenocortical adenoma when resected. (A) Anterior (Ant) and (B) posterior (Post) abdominal NCL-6-I scans without DS. The black arrow indicates left-sided, intense adrenal uptake. Note that the right adrenal is suppressed (not visualised) because of low ACTH; there is normal tracer uptake in the liver (L); faint colonic uptake is seen in the anterior view (A). bilateral hyperplasia (11, 13). In contrast, NCL-6-I scintigraphy accurately depicts patients with bilateral hyperplasia (11, 13). It must be pointed out that early bilateral visualisation can also be observed in sec- ondary hyperaldosteronism (24) and, thus, an accurate pre-scintigraphic differential diagnosis is of paramount importance. A late (.5 days) adrenal visualisation is a typical finding in normal adrenals (17); however, this pattern can also be observed in some unusual cases of dexamethasone-suppressible (24). investigate patients with abdominal pain or to stage an extra-adrenal neoplasm (28–30). The reported prevalence of incidentalomas in clinical series, includ- ing both cancer and non-cancer patients, ranges from 0.35 to 4.36% (26, 27) but in an autopsy series a fourfold greater prevalence was found (31). The dis- covery of an adrenal incidentaloma represents a serious diagnostic and therapeutic dilemma in clinical practice (e.g. benign versus malignant lesion; prompt surgical removal versus ‘wait and see’ policy). It has been clearly documented that the majority of inciden- talomas are benign masses that do not require an aggressive approach (29). However, if a solitary meta- static lesion is present without evidence of other meta- static spread, the patient could benefit from the surgical extirpation of such a lesion. In a large meta- analysis on adrenal incidentalomas performed by Kloos et al. (27), the prevalence of adrenal cortex ade- noma was estimated to be 36–94% in non-oncologic patients and 7–68% in oncologic patients, while ad- renal metastases were found in 0–21% of the non- oncologic patients and in 32–73% of the oncologic patients. Moreover, cysts were found in 4–22% of cases, myelolipoma in 7–15%, pheochromocytoma in hyperaldosteronism Adrenalhyperandrogenismandhyperoestrogenism These conditions are rare. The DS NCL-6-I scintigraphy may be useful in a manner similar to that for primary hyperaldosteronism and the interpretative criteria are the same (25). Incidentalomas Due to the widespread use of high- resolution morphological imaging techniques such as CT, MRI and ultrasound, an exponentially growing number of unexpected adrenal masses, so-called inci- dentalomas, are being disclosed (26, 27). In most cases, these morphologic procedures are performed to Figure 3 Left adrenal aldosteronoma demon- strated with NCL-6-I under DS. A 57-year-old female with biochemical evidence of hyper- aldosteronism and a 2cm left adrenal mass on CT scan. (A) Transverse abdominal CT scan demonstrating 2cm left adrenal mass (black arrow). (B and C) Anterior (Ant) and posterior (Post) abdominal NCL-6-I scans on day 3 post-injection. (D and E) Anterior and posterior abdominal NCL-6-I scans on day 5 post-injection. Left-sided abnormally increased adrenal tracer uptake is indicated by black arrows. Note that adrenal imaging occurs early, before day 5 (B and C). There is normal uptake in liver (L), bowel (B) and gallbladder (GB). Note also that great care should be taken not to confuse GB with the right adrenal gland (B). www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  5. 17 Adrenal scintigraphy EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 mass (34). However, the published data are controver- sial. In several series, the prevalence of benignity has been reported as high as 76–100% in large masses greater than 5cm (35, 36). Conversely, malignant tumours have been documented in relatively small adrenal masses, sized less than 2.5cm (33, 37). Serial CT imaging has been used, in that those masses showing a progressive growth are more likely to be malignant (28, 30). However, those patients with malignant masses diagnosed only after demon- strable growth on serial CT studies may suffer from a delay in the diagnosis and appropriate therapy (27). One of the most useful CT criteria is the unenhanced CT attenuation coefficient (38). An attenuation coeffi- cient of 0 or less Hounsfield Units (HU) was found to be 100% specific in distinguishing benign adenomas from metastases (27, 38); however, a rather low sensi- tivity was reported, ranging from 33 to 47% (27, 39). Increasing the threshold of the HU attenuation coeffi- cient, a better sensitivity was achieved but with a con- comitant loss in specificity (39). Among the MRI criteria, the chemical shift technique, based on the difference of resonance frequency between protons in water and lipids, has shown promising results. The loss of signal intensity using the opposed-phase imag- ing technique is a typical finding of lipid-rich masses such as benign cortical adenomas (40). However, some lipid-depleted cortical adenomas as well as occasional cases of lipid-rich metastases and pheo- chromocytomas have been described (41, 42). Fine needle aspiration (FNA) biopsy has been proven to be highly accurate (80–100%) in distinguishing benign adrenal masses from metastatic disease (30, 43). How- ever, the distinction of benign cortical adenomas from well-differentiated adrenocortical carcinomas is often difficult (43). Moreover, in patients with pheochromo- cytomas, FNA biopsy can cause a severe, even fatal, hypertensive crisis (27). Adrenocortical radiocholes- terol scintigraphy has been proven to be the most accu- rate non-invasive imaging technique in differentiating benign cortical adenoma from space-occupying or destructive adrenal lesions (26, 27, 44). Three scinti- graphic patterns can be observed in patients with inci- dentaloma: (a) the concordant pattern reveals increased tracer uptake in the adrenal mass depicted at morpho- logic imaging; this pattern is consistent with the pres- ence of a benign cortical adenoma or nodular hyperplasia (Fig. 5); (b) the discordant pattern reveals an absent, decreased or distorted uptake by the adrenal mass depicted at morphologic imaging; this pattern is consistent with the presence of a space-occupying or destructive lesion (e.g. metastasis, adrenocortical carci- noma, adrenomedullary tumour, haemorrhage, cyst, granulomatous disease) (Figs. 6 and 7) ; (c) the non- lateralising pattern reveals normal symmetrical adrenal uptake. In masses greater than 2cm the non-lateralising pattern is consistent with the presence of a pseudoad- renal mass, while in masses smaller than 2cm, due to Figure 4 Bilateral adrenal hyperplasia causing primary hyper- aldosteronism demonstrated by NCL-6-I under DS. A 35-year-old female with hypertension, biochemical evidence for hyperaldo- steronism and a report of bilateral adrenal thickening on CT scan performed elsewhere. (A and B) Anterior (Ant) and posterior (Post) abdominal NCL-6-I scans on day 4 post-injection. (C and D) Anterior and posterior abdominal NCL-6-I scans on day 5 post- injection. Bilateral abnormally premature adrenal visualisation on day 4 is indicated by black arrows in (B), and again at day 5 in (D). Note the faint normal liver uptake and intense, extensive activity in the large bowel, this may be especially intense in primary hyperaldosteronism due to hypokalaemia reducing colonic motility. 0–11%, and other adrenal lesions with smaller percen- tages. Interestingly, the prevalence of pseudo-adrenal masses, e.g. lesions arising from organs located near to the adrenals such as the stomach, pancreas and kid- neys is by no means negligible, accounting for 0–10% of all incidentalomas (27). The diagnostic algorithm to be adopted in patients with incidentalomas is an object of debate in the literature. However, once those lesions with an obvious radiological diagnosis (e.g. simple cyst, myelolipoma) are excluded, a rational diagnostic approach to incidentalomas should comprise the fol- lowing steps: (a) obtain an accurate clinical and bio- chemical profile to identify present with a hypersecretory mass; these masses usually require surgical removal, and (b) in non-hyper- secretory masses, which represent the majority of cases, it is required that a differential diagnosis of benign versus malignant be made, bearing in mind that the probability of malignancy is rather low (27, 29). CT and MRI are widely used for this purpose but none of the parameters investigated with both these procedures has been proven to be sensitive and specific enough (32). A size criterion of, typically, 5cm has been empirically established to select those patients who are candidates for surgery (33). There is some evi- dence in the literature that the relative risk of malig- nancy increases with the increasing of the size of the those patients who www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  6. 18 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 Figure 5 Left-sided incidentally discovered adrenal mass showing a concordant pattern. The patient underwent an abdominal CT scan for investigation of abdominal pain and at low attenuation a left adrenal mass was discovered. Screening biochemical tests of adreno- cortical and adrenomedullary hormones were all within the normal range. The adrenal mass was subsequently studied by MRI and NCL-6-I scintigraphy. (A) Transverse abdominal CT scan. Left adrenal mass indicated by the white arrow. (B) Coronal MRI image of the lower thorax and upper abdomen. Left adrenal mass indicated by the white arrow. (C) Posterior abdominal NCL-6-I scan revealing an intense tracer uptake in the left adrenal (black arrow). Note the faint normal liver uptake (L). All the above findings together indicate that the left adrenal mass is a benign, non-hypersecretory adenoma. Note the contralateral adrenal gland shows no uptake due to suppression by the adenoma even though all parameters of cortisol secretion were within the normal wide range. the limitations of the spatial resolution of scintigraphy, this pattern is non-specific (27). A concordant pattern has 100% accuracy in predict- ing the presence of a benign adrenal mass, and a discordant pattern or a non-lateralising pattern in masses greater than 2cm have 100% accuracy in predicting the absence of a non-hypersecretory adrenal adenoma and, thus, leads to suspicion of malignancy (27). Per- haps emission tomography (PET) might play a role in further investigation of the possibility of malignancy in inciden- talomas with a discordant pattern or in those with a non-lateralising pattern in masses smaller than 2cm. This topic is discussed below. the nervous ganglia that are widely and variably dis- tributed through the body from the base of the skull to the floor of the pelvis (45). Epinephrine, norepinephrine and dopamine are the most frequently produced cat- echolamines: they are synthesised from tyrosine and then stored within intracytoplasmic granules linked to chromogranin and other proteins. Catecholamines can serve as hormones that are released into the circu- lation (e.g. adrenal medulla) or neurotransmitters that are secreted into the synaptic cleft. A substantial frac- tion of the secreted catecholamines re-enters sym- pathomedullary cells by two re-uptake mechanisms: the type I re-uptake mechanism is energy, sodium and temperature dependent, saturable and specific, while type II re-uptake mechanism is based on passive diffusion and is relatively non-specific. Once it re-enters the cytoplasm, catecholamines are once again concen- trated in the storage granules. Tumours can arise both from the adrenal medulla and sympathetic nervous ganglia (45, 46). The most 18F-2-fluoro-D-deoxyglucose (18F-FDG) positron Sympathomedulla The adrenal medulla represents the largest component of the sympathetic nervous system that also comprises Figure 6 Left-sided incidentally discovered adrenal mass showing a discordant pattern. A 61-year-old male 5 years post-cistectomy and neo-bladder construction. Serial staging and surveillance CT scans showed an enlarg- ing left adrenal mass. Screening hormonal measurements showed no hypersecretion. Laparoscopic adrenalectomy revealed a pheochromocytoma. (A) Detail of a tranverse CT of the abdomen showing left adrenal mass (white arrow). (B) NCL-6-I posterior (Pos) abdominal scan showing faint normal liver tracer uptake (L), normal right adrenal tracer uptake (arrow head) and faint and splayed out left adrenal tracer uptake (discordant pattern) (black arrow). www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  7. 19 Adrenal scintigraphy EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 Figure 7 Low grade right adrenocortical carcinoma showing faint NCL-6-I visualisation. A 41-year-old female with incidental discovery of a 5cm right adrenal mass which was stable on serial CT imaging. Biochemical investigations revealed no evidence for any hormonal hypersecretion. At surgical excision, the tumour was encapsulated and there was no evidence of local extension or vascular invasion. (A) Tranverse abdominal CT scan. The black arrow indicates a 5cm right adrenal mass. (B and C) Anterior and posterior abdominal NCL-6-I scans, without DS. The black arrows indicate faint, patchy, irregular uptake in right-sided corticoadrenal carcinoma. L ¼ normal liver uptake. The arrow heads indicate normal adrenocortical tracer uptake in the left adrenal gland. Note that at variance with the case described here, the vast majority of adrenocortical carcinomas are not depicted by NCL-6-I and in the case of adrenal cancer hyper- secreting cortisol, uptake in the contralateral normal adrenal gland is suppressed. and124I-MIBG have been investigated with promising results (47). At the moment, the most widely used tracer in clinical practice is MIBG labelled with or123I. frequent type of tumour is the pheochromocytoma which generally arises from the adrenal medulla and in most cases is a solitary, benign lesion. However, in about 10% of cases, pheochromocytomas arise from nervous ganglia, so-called paraganglioma. Paragangli- omas are more likely to be multicentric and/or malig- nant than pheochromocytomas and these conditions occur in about 10% of cases (46). Bilateral pheo- chromocytomas or hyperplasia are usually observed in patients with multiple endocrine neoplasia (MEN) both type IIA and type IIB, and in patients with von Hippel–Lindau or von Recklinghausen syndrome (46). 131I Patient preparation and MIBG scintigraphic technique Some drugs are known or may be expected to interfere with type I re-uptake and/or intracytoplasmic granular storage, mainly labetalol (which in addition to a- and b-adrenergic blocking has tricyclic properties), re- serpine, sympathomimetics, calcium antagonists, tri- cyclic antidepressants and cocaine (47–51). Patients should be taken off these drugs for an appropriate time prior to scintigraphy. To control hypertension, a-blockers (such as phenoxybenzamine) or b-blockers (such as propranolol) can be administered (50). To minimise free radioiodine thyroidal uptake, pretreat- ment with SSKI or Lugol’s solution is given (47–49). Laxatives can be given to decrease gastrointestinal activity.131I-MIBG at a dosage of 0.5-1.0mCi or123I- MIBG at a dosage of 2-10mCi are administered by slow intravenous injection obtained at 24, 48 and 72h with authors suggest additional imaging on day 7 (52)), and at 4–6 and 24h and sometimes 48h with123I- MIBG. Whole body scans and spot planar images are obtained. Using 123I, SPECT imaging can also be acquired (53). In patients with malignant disease that are candidates for radioisotope therapy, MIBG is used for dosimetric purposes (47). Radiotracers specific for sympathomedullary imaging Many radiotracers have been developed for the localis- ation in tumours arising from the adrenal medulla and nervous ganglia, such as radiolabelled catecholamines (14C-dopamine,11C-epinephrine), radiolabelled enzyme inhibitors of catecholamine biosynthesis (various tyro- sinederivates)andneuronalblockingagents(bretylium, guanethidine analogues) (47). Among guanethidine analogues, meta-iodo-benzyl-guanidine (MIBG) labelled with various iodine isotopes has been proven to be the most reliable tracer for human studies (48). The MIBG molecular structure is similar to that of norepi- nephrine: it is trapped by the sympathetic cells by means of the type I re-uptake mechanism and is then concentrated within the storage granules, but it does not undergo further metabolism (49). Recently, some positron-emitting tracers such as drine,11C-epinephrine,18F-metafluoro-benzyl-guanidine (47–50). Imaging is 131I-MIBG (some 11C-hydroxyephe- 131I- www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  8. 20 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 Figure 8 Normal, physiological123I-MIBG biodistribution. (A) Anterior head, neck and upper chest. (B) Anterior chest and abdomen. (C) Anterior lower abdomen and pelvis. (D) Posterior head, neck and upper chest. (E) Posterior chest and abdomen. (F) Posterior lower abdomen and pelvis. N ¼ nasopharynx, S ¼ salivary glands, L ¼ liver, H ¼ heart, U ¼ urinary bladder. Normal MIBG biodistribution catecholamines, the unaffected adrenal medullary tissue retains the capacity of trapping MIBG with uptake values similar to normal subjects (56). More- over, a positive correlation was found between MIBG uptake and the number of storage granules in the tumoural tissue, but not with plasma or urinary catecholamines, suggesting that the uptake and storage of MIBG by the normal adrenal tissue is not regulated by a catecholamine feedback mechanism (57). In normal subjects, salivary glands, liver, spleen and bladder are commonly depicted. Kidney uptake is early and may be transient. A variable degree of uptake in the myocardium and lungs can be observed. Thyroid and stomach can be visualised if free radio- iodine is present and, in delayed images, colonic activity can also be seen (Fig. 8) (54). Normal adrenals are uncommonly and faintly visualised with (,20% of cases at 48h) (54) whereas a faint uptake is frequently seen using123I-MIBG (Fig. 9) (47). In con- trast, most adrenal pheochromocytomas show intense focal uptake (Figs 10 and 11). The MIBG uptake by the adrenomedulla can be calculated using an ROI method with background and depth correction (55– 57): in normal subjects it ranges from 0.01% to 0.22% of the injected dose 22h post-injection (55). Interestingly, Bomanji et al. (56, 57) observed that in the presence of pheochromocytoma, paraganglioma or neuroblastoma with elevated plasma and urinary 131I-MIBG Principal clinical applications of MIBG scintigraphy MIBG has been proven to be highly accurate in locating tumours arising from sympathomimetic system cells. Evaluating a group of 600 patients with pheochromocytoma, Shapiro & Gross (58) found an 88% sensitivity and a 99% specificity. Slightly greater sensitivity has been reported with SPECT imaging than with be emphasised that MIBG scintigraphy is particularly useful for the identification of multicentric or meta- static pheochromocytomas due to the ability to evalu- ate the entire body (59) (Fig. 12). It may be difficult to distinguish benign multicentric from multiple meta- static pheochromocytomas unless metastatic foci are depicted in areas other than those in which sympath- etic tissue is normally found (e.g. bone, bone marrow, lymph nodes, liver) (53, 59). In patients with neuro- fibromatosis, MIBG has been reported to be useful in the differential diagnosis of pheochromocytoma from retroperitoneal neurofibromata (60). The accuracy of MIBG is also very high in patients with neuroblastoma, with reported sensitivity of 90% and specificity of 99% (61). Both in malignant pheochromocytoma and neuroblastoma, MIBG has been proven to be of use nervous 123I-MIBG and 131I-MIBG (53). It should Figure 9 Normal, physiological adrenal medullary123I-MIBG uptake. (A) Anterior (Ant) lower chest and abdomen and (B) posterior (Post) lower chest and abdomen. H ¼ heart, L ¼ liver. Black arrows indicate bilateral physiological adrenal medulla uptake. www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  9. 21 Adrenal scintigraphy EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 Figure 11 Right adrenal pheochromocytoma demonstrated by 123I-MIBG and CT scans. A 31-year-old male with a family history of von Hippel–Lindau disease and demonstrated to carry the gene, having intermittent palpitations, and undergoing systematic screening. (A and B) Anterior (Ant) and posterior (Post) chest and abdomen scans. L ¼ liver, H ¼ heart. The black arrow in (B) indi- cates abnormal focus of123I-MIBG uptake in the region of the right adrenal gland. (C) Transverse abdominal CT sections. The black arrow indicates right adrenal pheochromocytoma lying between the inferior vena cava and the right kidney. Figure 10 Left adrenal pheochromocytoma demonstrated by123I- MIBG and MRI. A 50-year-old female with hypertension, a history of neurofibromatosis, elevated plasma catecholamines and a 3cm left adrenal mass on MRI. (A) Anterior abdomen scan. L ¼ normal liver uptake. The black arrow indicates intense, abnormal focal tracer uptake in the region of the left adrenal gland. (B) Posterior abdomen scan. L ¼ liver. The black arrow indicates left adrenal pheochromocytoma. (C) Abdominal MRI, transverse section with left adrenal pheochromocytoma indicated by the white arrow. forms, pheochromocytoma or adrenal medulla hyper- plasia can be present together with the MTC (62). In these patients, MIBG scintigraphy is of great use for the early detection of pheochromocytoma, even in the absence of a clinically evident hypersecretory syn- drome. In this condition, given our inability to non- invasively determine the presence of malignancy and to predict the risk of spontaneous hypertensive crisis that can be severe and even fatal, a surgical curative approach is advisable (27). The second indication con- cerns the use of MIBG scintigraphy in the post-surgical follow-up of MTC patients with increased calcitonin and/or carcino-embryonic antigen (CEA) levels to visu- alise metastatic foci of MTC; unfortunately, a rather low sensitivity, ranging from 33 to 45% has been reported in these patients, particularly for detection of liver tumour deposits (61). For the same clinical purpose, other radiotracers such not only in the staging of the disease but also during follow-up to distinguish scar from persistent or recur- rent disease, to permit early diagnosis of relapses, to monitor the response to treatment, and to select those patients who are candidates for treatment with131I- MIBG (58). Other clinical applications of MIBG scintigraphy There are a number of series on the use of MIBG scinti- graphy in other neuroendocrine tumours, especially medullary thyroid carcinoma (MTC) and carcinoid (50, 61). With regard to MTC, there are two different indications for MIBG scintigraphy. The first hinges on the fact that familial MTC is often associated with a MEN syndrome and that, both in the IIA and IIB 201thallium chloride, as www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  10. 22 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 Figure 12 Malignant metastatic pheochromo- cytoma demonstrated by123I-MIBG and CT scans. A 31-year-old female after bilateral adrenalectomy with hypertension, end-stage renal failure and recent superior vena cava (SVC) obstruction. (A) Anterior chest and abdomen scan. L ¼ normal liver uptake. Arrows indicate multiple abnormal foci of 123I-MIBG uptake depicting multiple meta- static pheochromocytoma deposits in superior mediastinum, lower posterior mediastinum and para-aortic region. (B) Thoracic transverse CT section. The white arrow indicates the superior mediastinal mass responsible for SVC obstruction. 99mTc-(V)-DMSA (olimercaptosuccinic acid), anti-CEA monoclonal antibodies, 99mTc-methoxy-isobutyl-iso- nitrile and rates superior to MIBG, ranging from 65 to 85% (50, 61, 63, 64). As with MTC, the sensitivity of MIBG scintigraphy in carcinoid patients is less than ideal, with reported values ranging from 30 to 60% (50, 61). spleen, liver, kidneys and bladder. Faint uptake can also be observed in the pituitary, thyroid and salivary glands. Bowel activity is usually seen and generally increases in delayed images (66). Cardiovascular blood-pool activity is commonly seen in the early images and, thus, delayed images are more useful to depict mediastinal lesions. 111In-octreotide have shown sensitivity 111In-octreotide scinti- Other radiotracers for symphatomedullary imaging Clinical applications of graphy111In-octreotidescintigraphyhasdemonstrated high sensitivity for detection of pheocromocytoma (86%), paraganglioma (100%) and neuroblastoma (89%) (66). However, an adrenal mass can be obscured by the presence of an intense kidney activity. Moreover, 111In-octreotide is not a specific tracer for symphato- medullary tumours as it also shows significant uptake in most other neuroendocrine tumours, both benign and malignant, as well as in some non-endo- crine tumours (e.g. breast cancer, Hodgkin’s disease and non-Hodgkin’s lymphoma, meningioma, etc) and also in several non-tumoural granulomatous diseases (e.g. sarcoidosis, tuberculosis, etc) and auto-immune disorders (e.g. Graves’ disease, rheumatoid arthritis, etc) (50). This uptake is related to the widespread dis- tribution throughout the body of cells expressing somatostatin receptors on their surface, including acti- vated lymphocytes (50). Thus, it seems reasonable to consider choice technique for sympathomedullary imaging after MIBG scintigraphy, especially when the MIBG is completely or partly false negative (Fig. 13). Conversely, due to its high sensitivity,111In-octreotide scintigraphy can be considered as the scintigraphic imaging tech- nique of first choice in neuroendocrine tumours such as carcinoids (50, 67), pituitary tumours (68) and pan- creatic and gastro-intestinal amine precursor uptake and decarboxylation (APUD)-omas (50, 69, 70). With par- ticularregardtocarcinoids,inanextensivemeta-analysis, Hoefnagel(50)calculatedan86%sensitivityinagroupof 451 patients evaluated with111In-octreotide, while in a group of 275 patients evaluated with sensitivity of 70% was found. Furthermore, in MTC patients, Somatostatin analogues such as (111In-octreotide; where DTPA is diethylene-triamine- penta-acetate) and DOTA is tetra-aza-cyclododecane-N,N0N00,N00-tetra-acet- ate), have been extensively investigated for imaging of sympathomedullary and tumours, as well as of other non-tumoural diseases in which an over-expression of somatostatin receptors is present on the cell surface (65).111In-octreotide is cur- rently widely utilised in clinical practice. Octreotide is an 8 amino acid peptide that binds specifically to the family of somatostatin receptors, with greater affinity for subtypes II and V (66). Some promising b-emitting radiotracers such as been synthesised for PET imaging and are under inves- tigation (65). Somatostatin analogues, 111In-DTPA-octreotide 123I-tyr3-octreotide, 111In-DOTA-octreotide (where other neuroendocrine 86Y-DOTA-tyr3-octreotide have 111In-octreotide scintigraphy as a second- 111In-octreotide scinti- 111In-octreotide scintigraphy Patient preparation and graphic techniques does not require specific patient preparation. The dis- continuation of somatostatin analogues 1 week prior toscintigraphy isgenerally recommended (50). Imaging is usually obtained 4–6 and 24h after the intravenous injection of 3–6mCi spot planar and SPECT images should be obtained. SPECT has higher sensitivity than planar imaging in some series (67). Laxatives can be given to reduce activity in the bowel. 111In-octreotide. Whole body, 131I-MIBG a Normal111In-octreotide biodistribution In normal subjects, relatively high uptake is observed in the 111In-octreotide scintigraphy has revealed a www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  11. 23 Adrenal scintigraphy EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 Figure 13 Widespread metastatic pheochromocytoma poorly depicted by123I-MIBG and better depicted by111In-octreotide. (A) Three overlapping posterior123I-MIBG scans which demonstrate only one pheochromocytoma deposit in the abdomen (arrow). Note the normal uptake in salivary glands (S), in heart (H), in spleen (SP), in liver (L) and urinary bladder (U). (B and C) Whole body, anterior and posterior111I-octreotide scans demonstrating multiple pheochromocytoma deposits in the neck, thorax and abdomen (arrows). Note the normal tracer uptake in liver (L), spleen (S), right kidney (K) (the left kidney is absent due to prior surgery) and colon (G). *indi- cates the only tumoural deposit depicted by both123I-MIBG and111In-octreotide. 90Y-DOTA-octreotide sensitivity of approximately 65% in detecting meta- static disease especially when spread to the neck and chest (71).111In-octreotide can be useful in combi- nation with radiocholesterol scintigraphy in patients with corticoadrenal nodular hyperplasia due to an ectopic ACTH hypersecretion. In these cases, radio- cholesterol may be used to depict the adrenal disease while ACTH-producing tumour (14). Lastly, some radiolabelled somatostatin analogues such as are used for radioisotope therapy of malignant meta- static neuroendocrine tumours (66). Adrenal malignancies 111In-octreotride can be useful to locate the A large variety of positron-emitter tracers have been synthesised and are currently under investigation for www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  12. 24 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 FDG administration. In addition to injection in a con- trolled environment, some investigators administer muscle relaxants and benzodiazepines. adrenal imaging. Some of them are specific for the adrenal cortex (11C-acetate,11C-etiomidate,11C-meti- omidate) (6) or medulla (11C-hydroxyephedrine, epinephrine) (47) while others are not tissue specific but are used to detect malignant lesions at all sites includingtheadrenal,suchas11C-tyrosine,11C-methio- nine,11C-thymidine and18F-FDG (72).18F-FDG (FDG) is the most widely used positron-emitter tracer in clinical oncology (72). Deoxy-glucose (DG) is a glucose analogue that enters the cell using specific transmem- brane carrier proteins (72). Once within the cytoplasm, DG is phosphorylated to DG-6-phosphate but does not appear to be further metabolised (51). In most malig- nant tumours there is an increase of glycolytic metabol- ism which accounts for elevated DG uptake (72). For the purpose of imaging, DG can be radiolabelled with 18F to yield FDG, an efficient PET imaging agent for many tumours. However, an elevated FDG uptake has also been described in acute/ septic and chronic/granu- lomatous diseases due to the increased glycolytic metabolism of activated leukocytes (73–75). 11C- Clinical applications of FDG-PET FDG is the positron-emitter radiotracer most widely used in clinical practice during the last decade (72). It is currently utilised as a tumour-seeking agent to image both the primary tumour and metastatic disease (e.g. skeletal and visceral metastases) in many types of cancers (72). FDG-PET has been proven to be highly sensitive not only in cancer staging but also during follow-up, to distinguish scar or fibrosis from persistent viable tumours after treatment, for early detection of local relapse or metastases (especially in patients with- out any clinical evidence of disease but with increased serum tumoural markers), and to monitor the response to therapy (72). The FDG uptake is often related to the degree of malignancy, and tumours that are character- ised by rapid growth and aggressive histological grad- ing usually show high FDG uptake (79). In contrast, slow-growing tumours such as many endocrine lesions can show various degrees of FDG uptake (80–82); in particular, some well-differentiated endocrine tumours may not be visualised by FDG-PET (80–82). Some authors have argued that FDG uptake by endocrine tumours is related to the aggressiveness of the neo- plasm and that high uptake has to be considered as a poor prognostic factor (81, 82). Unfortunately, FDG is not a tumour-specific tracer, because an abnormally increased FDG uptake has also been documented in some benign diseases such as acute and chronic infec- tions and granulomatous diseases (e.g. mycosis, sarcoi- dosis, osteomyelitis and others) (72, 74). The elevated FDG uptake in these diseases has been related to increased glycolytic metabolism leukocytes. As far as the adrenal is concerned, most of the studies reported have dealt with the potential role of FDG-PET in the staging of patients with known extra-adrenal can- cers (8, 83, 84). It has been well documented that FDG- PET provides a greater sensitivity than traditional radio- logic imaging (8, 72, 80, 82–85). Inthis regard,patients with lung cancer (the tumour which most frequently spreads to the adrenal) have been extensively studied, and FDG-PET has been proven to reveal additional, unknown metastatic foci in 19–34% of cases (8, 72, 83, 84).Specifically, the prevalenceofadrenal metastases discoveredby FDG-PET has beenreported tobeashighas 9.9% in several studies (8, 83, 84). The upstaging result- ingfromFDG-PETcan playanimportantroleintheplan- ning of therapeutic strategies in oncologic patients (e.g. solitarymetastasistotheadrenalmayberesectedtogether withtheprimarywithcurativeintent)(Fig.14)(8,72,83, 84). In some patients, the adrenal metastasis can be the first manifestation of a cancer, and FDG-PET has been proven to be useful in locating the primary tumour (86). Patient preparation and FDG-PET technique An overnight or a 4–6h fast is required to reduce the circulating pool of glucose (76). In diabetic patients, careful monitoring of blood glucose levels is recom- mended. If the FDG-PET is performed during, or close to, radio- and/or chemotherapy, there exists a possi- bility of obtaining false positive or false negative results (77). FDG is injected intravenously at a dosage of 8– 20mCi. Before injection, the patient should be recum- bent, relaxed and in a low light and noise environment to prevent physiological increase of FDG uptake in skeletal muscles and some areas of the brain. For ima- ging, a PET scanner is used to acquire whole body and/or regional images, typically commencing 40– 60min after FDG administration. Attenuation correc- tion is usually applied and quantitative analysis can be performed by calculating the standardised uptake value. Some attempts have been made to obtain FDG imaging using a dual-head gamma camera and the coincidence acquisition method; however, currently, this method shows lower sensitivity and spatial resol- ution than FDG-PET (78). by activated Normal FDG biodistribution FDG normally concentrates in the brain and relatively high tracer uptake is also observed in the kidneys and bladder. Various degrees of uptake can be seen in the heart. Mild uptake is commonly seen in the liver and spleen (72, 76, 77). In some cases, relatively high bowel uptake can interfere with interpretation in the abdomen (72, 77). Finally, a wide range of localisation and intensity can occur in skeletal muscles. This is related to contraction at the time of, or shortly before, www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  13. 25 Adrenal scintigraphy EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 modality to visualise the small minorityof pheochromo- cytomas that do not accumulate MIBG (88). Regarding the potential role of FDG-PET in dis- tinguishing benign from malignant adrenal masses, particularly those disclosed by CT, MRI and ultrasound performed for the investigation of non-adrenal diseases (e.g. abdominal pain, staging of various cancers such as lung) so called ‘incidentalomas’, FDG-PET may have an increasing importance. In a study by Boland et al. (8), a series of 24 adrenal masses initially revealed by CTscan in 20 cancer patients were investigated and FDG-PET was able to discriminate adrenal metastases (14/14) from benign adrenal masses (10/10) in all cases with 100% accuracy. Erasmus et al. (84) performed FDG- PET in a group of 27 patients with bronchogenic carcin- oma and concomitant adrenal mass(es). FDG-PET depicted all the adrenal metastatic lesions ðn ¼ 25Þ and was correctly negative in 8/10 benign adrenal masses. However, significant FDG concentration was observed in 2/10 benign adrenal masses (8% false posi- tive rate). Thus, in this study, the FDG-PET showed 100% sensitivity and 80% specificity in detecting ad- renal malignancy. Despite the favourable results, it has to be emphasised that these studies were performed in selected groups of oncologic patients, i.e. in patients with an expected prevalence of adrenal metastases con- siderably greater than in the general population (26, 27). Furthermore, it has been well established that the majority of cases of ‘incidentaloma’ are discovered in non-oncologic patients in whom the probability of malignancy (either primary or metastatic) is rather low (26, 27). In a recent study by Maurea et al. (89), an unselected group of 27 patients with unilateral adrenal incidentaloma depicted at CT or MRI were investigated. Interestingly, 82% of the enrolled patients were studied for reasons other than clinical staging of a known extra-adrenal cancer and 81% of them had a non-hypersecretory adrenal mass. They found that 13/14 (93%) of the benign adrenal masses, including five adrenal adenomas, did not show FDG uptake; the only exception was a case of benign pheochromo- cytoma which was FDG avid. At the same time, 13/13 (100%) malignant adrenal lesions, including a surprisingly high number of adrenocortical carcinomas (n ¼ 7; 53% of all malignant lesions in this series), showed abnormally increased FDG uptake. Further studies performed on larger numbers of unselected patients with non-hypersecretory adrenal masses are needed to clarify the full potential utility of FDG-PET in distinguishing benign versus malignant adrenal incidentalomas. Figure 14 Recurrent non-small cell carcinoma of the right lung depicted by FDG-PET and CT scan with concomitant solitary metastasis to left adrenal gland. A 40-year-old male with a sus- pected recurrence of a non-small cell carcinoma of the right lung, after right lower lobe resection. (A) Detail of transverse abdominal CT showing enlargement of the left adrenal gland (black arrow). (B) Coronal FDG-PET scan of chest and abdomen demonstrates abnormal focal tracer uptake in recurrent thoracic primary tumour (black arrow) and left adrenal metastasis (black arrow). (C) Tranverse abdominal FDG-PET scan demonstrates intense abnormal focal uptake in left adrenal metastasis (arrow). Note the faint normal liver tracer uptake. R, right (in B) and (C)). Primary malignancies arising from the adrenal cortex represent a rare condition; in these cases FDG-PET is useful in the localisation of distant meta- stases (87). Two other major topics have to be discussed: (a) the utility of FDG-PET in depicting pheochromocytomas and related lesions, and (b) the role of FDG-PET in dis- tinguishing benign from malignant adrenal masses, particularly those discovered incidentally. Regarding the first topic, Shulkin et al. (88) have studied a large group of patients with pheochromo- cytoma, both benign and malignant, and compared results of MIBG scintigraphy with FDG-PET. The authors found that most malignant pheochromo- cytomas (14/17; 82%) and, in addition, a considerable percentage of benign pheochromocytomas (7/12 cases; 58%) were depicted by FDG-PET. Moreover, in patients with malignant pheochromocytomas, the FDG-PET was highly sensitive for revealing metastatic spread. However, it has to be emphasised that the sensitivity of MIBG was greater than that of FDG, both in benign (83% versus 58%) and malignant pheochromo- cytomas (88% versus 82%). Furthermore, in cases posi- tive with both MIBG and FDG, the tumour and its metastases were better depicted with MIBG than with FDG. All pheochromocytomas which failed to concen- trate FDG were well depicted by MIBG. Nevertheless, it is interesting to note that in four patients in whom MIBG was negative, the FDG-PET was able to locate the tumour. Thus, there is a complementary role for both MIBG and FDG in pheochromocytoma and, in particular, FDG can be useful as a second-line imaging Conclusions By thoughtful exploration of the metabolic character- istics which render the adrenal cortex and medulla and lesions derived from these tissues different from www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  14. 26 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 adrenal cortical scintigraphy. Seminars in Nuclear Medicine 1981 9 128–148. 18 Thrall JH, Freitas JE & Beierwaltes WH. Adrenal scintigraphy. Seminars in Nuclear Medicine 1978 8 23–41. 19 Gross MD, Shapiro B & Beierwaltes WH. The functional character- ization of the adrenal gland by quantitative scintigraphy. Recent Advances in Nuclear Medicine 1983 6 83–115. 20 Fig L, Ehrman D, Gross MD, Shapiro B, Schteingart D & Glazer G. The localization of abnormal adrenal function in ACTH-independ- ent Cushing’s syndrome. Annals of Internal Medicine 1988 109 547–553. 21 Pasieka JL, Requeda E, Reach JE, Plouin PF & Savoie JC. Adrenal scintigraphyofwell-differentiated(functioning)adrenocorticalcar- cinomas: potential surgical pitfalls. Surgery 1992 112 884–890. 22 Gross MD, Shapiro B, Freitas JE, Meyers L, Francis IR, Thompson NWet al. Clinical significance of the solitary functioning adrenal gland. Journal of Nuclear Medicine 1991 32 1882–1887. 23 Nomura K, Kusakabe K, Maki M, Ito Y, Aiba M & Demura H. Iodomethylnorcholesterol uptake in an aldosteronoma shown by dexamethasone-suppression scintigraphy: relationship to ade- noma size and functional activity. Journal of Clinical Endocrinology and Metabolism 1990 71 825–830. 24 Gross MD & Shapiro B. Adrenocortical scintigraphy. In Nuclear Medicine in Clinical Diagnosis and Treatment, edn 2, pp 805–812. Eds IPC Murray & PJ Ell. London: Churchill & Livingstone, 1998. 25 Gross MD, Shapiro B, Swanson DP, Woodbury M, Schteingart DE & Beierwaltes WH. The relationship of 131I-6b-iodomethyl-19- norcholesterol (NP-59) adrenal cortical uptake to indices of androgen secretion in women with hyperandrogenism. Clinical Nuclear Medicine 1984 9 264–270. 26 Gross MD & Shapiro B. Clinical review 50: clinically silent adrenal masses. Journal of Clinical Endocrinology and Metabolism 1993 77 885–888. 27 KloosRT,GrossMD,FrancisIR,KorobkinM&ShapiroB.Incidentally discovered adrenal masses. Endocrine Reviews 1995 16 460–484. 28 Herrera MF, Grant CS, van Heerden JA, Sheedy PF & Ilstrup DM. Incidentally discovered adrenal tumors: an institutional perspec- tive. Surgery 1991 110 1014–1021. 29 Glazer HS, Weyman PJ, Sagel SS, Levitt RG & McClennan BL. Non- functioning adrenal masses: incidental discovery on computed tomography. American Journal of Roentgenology 1982 139 81–85. 30 Hussain S, Belldegrun A, Seltzer SE, Richie JP, Gittes RF & Abrams HL. Differentiation of malignant from benign adrenal masses: pre- dictive indices on computed tomography. American Journal of Roentgenology 1985 144 61–65. 31 Russell RP, Masi AT & Richter ED. Adrenal cortical adenomas and hypertension. A clinical pathologic analysis of 690 cases with matched control and a review of the literature. Medicine 1972 51 211–225. 32 Allard P, Yankaskas BC, Fletcher RH, Parker LA & Halvorsen RA Jr. Sensitivity and specificity of computed tomography for the detection of adrenal metastatic lesions among 91 autopsied lung cancer patients. Cancer 1990 66 457–462. 33 Abecassis M, McLoughlin MJ, Langer B & Kudlow JE. Adrenal masses: prevalence, significance, and management. American Journal of Surgery 1985 149 783–788. 34 Siekavizza JL, Bernardino ME & Samaan NA. Suprarenal mass and its differential diagnosis. Urology 1981 18 625–632. 35 Siren JE, Haapiainen RK, Huikuri KT & Sivula AH. Incidentalo- mas of the adrenal gland: 36 operated patients and review of literature. World Journal of Surgery 1993 17 634–639. 36 KhafagiFA,GrossMD,ShapiroB,GlazerGM,FrancisI&Thompson NW.Clinicalsignificanceofthelargeadrenalmass.BritishJournalof Surgery 1991 78 828–833. 37 Dominguez-Gadea L, Diez L, Bas C & Crespo A. Differential diag- nosis of solid adrenal masses using adrenocortical scintigraphy. Clinical Radiology 1994 49 796–799. 38 Lee MJ, Hahn PF & Papanicolau N. Benign and malignant adrenal masses: CT distinction with attenuation coefficients, size, and observer analysis. Radiology 1991 179 415–418. adjacent structures it has been possible to develop a series of clinically useful radiopharmaceuticals for both diagnosis (including planar scintigraphy, SPECT and PET) and therapy. These principles which are broadly applicable may be considered when designing radiopharmaceuticals for use with many other tissues and disease processes. There remain a wide variety of other adrenal tissue characteristics which might yet be explored to produce other clinically useful radiopharmaceuticals. References 1 Beierwaltes WH, Wieland DM, Yu T, Swanson D & Mosley S. Adrenal imaging agents: rationale, synthesis, formulation and metabolism. Seminars in Nuclear Medicine 1978 8 5–21. 2 Counsell RE, Renade VV, Blair RJ, Beierwaltes WH & Weinhold PA. Tumor localizing agents. IX. Radioiodinated cholesterol. Steroids 1970 16 317–328. 3 Kojima M, Maeda M, Ogawa H, Nitta K & Ito T. New adrenal-scan- ning agent. Journal of Nuclear Medicine 1975 16 666–668. 4 Sarkar SD, Beierwaltes WH, Ice RD, Basmadjian GP, Hertzel KR, Kennedy WP et al. A new and superior adrenal scanning agent, NP-59. Journal of Nuclear Medicine 1975 16 1038–1042. 5 Beierwaltes WH, Wieland DM, Mosley ST, Swason DP, Sarkar SD, Freitas JE et al. Imaging the adrenal glands with radiolabeled inhibitors of enzymes: concise communication. Journal of Nuclear Medicine 1978 19 200–203. 6 Bergstrom M, Juhlin C, Bonasera TA, Sunding A, Rastad J, Akerstrom G et al. PET imaging of adrenal cortical tumors with the 11beta-hydroxylase tracer 11C-metomidate. Journal of Nuclear Medicine 2000 41 275–282. 7 Hay RV, Flemming RM, Ryan JW, Williams KA, Strak VJ, Lathrop KA et al. Nuclear imaging analysis of human low density lipopro- tein biodistribution in rabbits and monkeys. Journal of Nuclear Medicine 1991 32 1239–1245. 8 Boland G, Goldember MA, Lee MJ, Mayo-Smith WW, Dixon J, McNicholas MM et al. Indeterminate adrenal mass in patients with cancer: evaluation at PET with 2-F-18-fluoro-2-deoxy-D- glucose. Radiology 1995 194 131–136. 9 Gross MD, Shapiro B, Thrall JH, Freitas JE & Beierwaltes WH. The scintigraphic imaging of endocrine organs. Endocrine Reviews 1984 5 221–281. 10 Shapiro B, Britton KE, Hawkins LA & Edwards CE. Clinical experi- ence with 75-Se-selenomethylcholesterol adrenalimaging. Clinical Endocrinology 1981 15 19–27. 11 Gross MD, Falke THM & Shapiro B. Adrenal glands. In Endocrine Imaging, pp 271–349. Eds MD Sandler, JA Patton, MD Gross, B Shapiro & THM Falke. Connecticut: Appleton & Lange, 1992. 12 Lynn MD, Gross MD & Shapiro B. Enterohepatic circulation and distribution of I-131-iodomethyl-19-norcholesterol Nuclear Medicine Communications 1986 7 625–630. 13 Shapiro B, Fig L, Gross MD & Khafagi F. Radiocholesterol diag- nosis of adrenal disease. Critical Reviews in Clinical Laboratory Sciences 1989 27 265–298. 14 Gross MD & Shapiro B. Radionuclide imaging of the adrenal cortex. Quarterly Journal of Nuclear Medicine 1999 43 224–232. 15 Shapiro B, Nakajo M, Gross MD, Freitas JE, Copp JE & Beierwaltes WH. Value of bowel preparation in adrenocortical scintigraphy with NP-59. Journal of Nuclear Medicine 1983 24 732–734. 16 Ishimura J, Kawanaka M & Fukuchi M. Clinical application of SPECT in adrenal imaging with I-131-6b-iodomethyl-19-norcho- lesterol. Clinical Nuclear Medicine 1989 14 278–281. 17 Gross MD, Valk TW, Swanson DP, Thrall JH, Grekin RJ & Beierwaltes WH. The role of pharmacologic manipulation in (NP-59). www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  15. 27 Adrenal scintigraphy EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 39 SingerAA,ObuchowshiNA,EinsteinDM&PaushterDM.Metastasis oradenoma?Computedtomographyevaluationintheadrenalmass. Cleveland Clinical Journal of Medicine 1994 61 200–205. 40 Mitchell DG, Crovello M, Matteucci T, Petersen RO & Miettinen MM. Benign adrenocortical masses: diagnosis with chemical shift MR images. Radiology 1992 185 345–351. 41 Greene KM, Brantly PN & Thompson WR. Adenocarcinoma meta- static to the adrenalgland simulating myelolipoma:CTevaluation. Journal of Computed Assisted Tomography 1985 9 820–821. 42 Heaston DK, Handel DB, Ashton PR & Korobkin M. Narrow gauge needle aspiration of solid adrenal masses. American Journal of Roentgenology 1982 138 1143–1148. 43 Gross MD, Shapiro B, Bouffard JA, Glazer GM, Francis IR, Wilton GP et al. Distinguishing benign from malignant adrenal masses. Annals of Internal Medicine 1988 109 613–618. 44 Gross MD, Wilton GP, Shapiro B, Cho K, Samuels BI, Bouffard JA et al. Functional and scintigraphic evaluation of the silent adrenal mass. Journal of Nuclear Medicine 1987 28 1401–1407. 45 Bravo EL. Evolving concepts in the pathophysiology, diagnosis, localization and treatment of pheochromocytoma. Endocrine Reviews 1994 15 356–368. 46 Troncone L, Rufini V, Montemaggi P, Danza FM, Lasorella A & Mastrangelo R. The diagnosis and therapeutic utility of the radioiodinated metaiodobenzylguanidine (MIBG). Five years’ experience. European Journal of Nuclear Medicine 1990 16 325– 335. 47 Shapiro B, Gross MD & Shulkin B. Radioisotope diagnosis of malignant pheochromocytoma. Trends in Endocrinology and Metabolism 2001 12 469–475. 48 Shapiro B, Copp JE, Sisson JC, Eyre PL, Wallis J & Beierwaltes WH. 131-iodine-metaiodobenzylguanidine for the location of sus- pected pheochromocytoma: experience in 400 cases. Journal of Nuclear Medicine 1985 26 576–585. 49 Gross MD & Shapiro B. Adrenal hypertension. Seminars in Nuclear Medicine 1989 19 122–143. 50 Hoefnagel CA. Metaiodobenzylguanidine and somatostatin in oncology: role in the management of neural crest tumours. European Journal of Nuclear Medicine 1994 21 561–581. 51 Khafagi FA, Shapiro B, Fig LM, Mellette S & Sisson JC. Labetalol reduces iodine-131 MIBG uptake by pheochromocytoma and normal tissue. Journal of Nuclear Medicine 1989 30 481–489. 52 Lindberg S, Fjalling M, Jacobsson L, Jansson S & Tisell LE. Method- ology and dosimetry in adrenal medullary imaging with iodine- 131 MIBG. Journal of Nuclear Medicine 1988 29 1638–1643. 53 Chatal JF & Charbonnel B. Comparison of iodobenzylguanidine imaging with computed tomography in locating pheochromo- cytoma. Journal of Clinical Endocrinology and Metabolism 1985 61 769–772. 54 Nakajo M, Shapiro B, Copp J, Kalff V, Gross MD, Sisson JN et al. The normal and abnormal distribution of the adrenomedullary imaging agent I-131-metaiodobenzylguanidine man: evaluation by scintigraphy. Journal of Nuclear Medicine 1983 24 672–682. 55 Bomanji J, Flatman WD, Horne T, Fettich J, Britton KE, Ross G et al. Quantitation of iodine-123 MIBG uptake by normal adrenal medulla in hypertensive patients. Journal of Nuclear Medicine 1987 28 319–324. 56 Bomanji J, Bouloux PMG, Levison DA, Flatman WD, Horne T, Britton KE et al. Observations on the function of normal adreno- medullary tissue in patients with phaeochromocytomas and other paragangliomas. European Journal of Nuclear Medicine 1987 13 86–89. 57 Bomanji J, Levison DA, Flatman WD, Horne T, Bouloux PMG, Ross G et al. Uptake of iodine-123 MIBG by pheochromocytomas, paragangliomas, and neuroblastomas: a histopathological com- parison. Journal of Nuclear Medicine 1987 28 973–978. 58 Shapiro B & Gross MD. Radioiodinated MIBG for the diagnostic scintigraphy and internal radiotherapy of neuroendocrine tumors. In I Tumori della Cresta Endocrina, pp 65–94. Ed. L Troncone. Modena: Arcadia, 1991. 59 Shapiro B, Sisson JC, Lloyd R, Nakajo M, Satterlee W & Beierwaltes WH. Malignant pheochromocytoma: clinical, bio- chemical and scintigraphic characterization. Clinical Endocrin- ology 1984 20 189–203. 60 Kalff V, Shapiro B, Lloyd R, Sisson JE, Holland K, Nakajo M et al. The spectrum of pheochromocytoma in hypertensive patients with neurofibromatosis. Archives in Internal Medicine 1982 142 2092–2098. 61 Troncone L & Rufini V. MIBG in the diagnosis of neural crest tumours. In Nuclear Medicine in Clinical Diagnosis and Treatment, edn 2, pp 843–858. Eds IPC Murray & PJ Ell. London: Churchill & Livingstone, 1998. 62 GoodfellowPJ&WellsSAJr.RETgeneanditsimplicationsforcancer. Journal of the National Cancer Institute 1995 87 1515–1523. 63 Guerra UP, Pizzocaro L, Terzi A, Giubbini R, Maira G, Pagliaini R et al. New tracers for the imaging of the medullary thyroid car- cinoma. Nuclear Medicine Communications 1989 5 285–295. 64 Casara D, Rubello D, Tamagnini P, Bernante P & Pelizzo MR. 99mTc-MIBI scintigraphy: an effective imaging technique in detecting loco-regional metastases of medullary thyroid carcin- oma. Journal of Nuclear Medicine 2001 42 323 (Abstract). 65 Krenning EP, Kwekkeboom DJ, Reubi JC & Lamberts SWJ. Somato- statin receptor scintigraphy with 111In-DTPA-D-Phe1-octreotide. In Nuclear Medicine in Clinical Diagnosis and Treatment, edn 1, pp 757–764. Eds IPC Murray & PJ Ell. London: Churchill & Living- stone, 1994. 66 Krenning EP, Bakker WH, Kooij PPM, Breeman WA, Oei HY, de Joug M et al. Somatostatin receptor scintigraphy with 111In- DTPA-D-PHE1-octreotide in man: metabolism, dosimetry and comparison with 123-Try-3-octreotide. Journal of Nuclear Medicine 1992 33 652–658. 67 Gibril F, Reynolds JC, Doppman JL, Chen CC, Venzond J, Termanini B et al. Somatostatin receptor scintigraphy: its sensitivity com- pared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Annals of Internal Medicine 1996 125 26–34. 68 Van Royen EA, Verhoeff NP, Meylaerts SA & Miedema AR. Indium-111-DTPA-octreotide uptake measured in normal and abnormal pituitary glands. Journal of Nuclear Medicine 1996 37 1449–1451. 69 Kwekkeboom DJ, Krenning EP, Bakker WH, Oei HY, Kooij PP & Lamberts SW. Somatostatin analogue scintigraphy in carcinoid tumors. European Journal of Nuclear Medicine 1993 20 283–292. 70 Cadiot G, Lebtahi R, Sarda L, Bonnaud G, Marmuse JN, Kissuzaine C et al. Preoperative detection of duodenal gastrinomas and peri- pancreatic lymph node by somatostatin receptor scintigraphy. Gastroenterology 1996 111 845–854. 71 Kwekkeboom DJ, Reubi JC, Lamberts SW, Bruining HA, Muldler AH, Oei HYet al. In vivo somatostatin receptor imaging in medul- lary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 1993 76 1413–1417. 72 Strauss LG & Conti PS. The applications of PET in clinical oncol- ogy. Journal of Nuclear Medicine 1991 32 623–648. 73 Wahl RL. Targeting glucose transporters for tumor imaging: sweet idea, sour result. Journal of Nuclear Medicine 1996 37 1038–1041. 74 Joe A, Hoegerle S & Moser E. Cervical lymph node sarcoidosis as a pitfall in F18 FDG positron emission tomography. Clinical Nuclear Medicine 2001 26 542–543. 75 Kalicke T, Schmite A, Risse JH, Arens S, Kelelr E, Hausis M et al. Fluorine-18 fluorodeoxyglucose PET in infections bone diseases: results of histologically confirmed cases. European Journal of Nuclear Medicine 2000 27 524–528. 76 Lindholm P, Minn H, Leskinen-Kallio S, Bergman J, Ruotsalainen U & Joensu H. Influence of the blood glucose concentration of FDG uptake in cancer – a PET study. Journal of Nuclear Medicine 1993 34 1–6. 77 Strauss LG. Fluorine-18 deoxyglucose and false-positive results: a major problem in the diagnosis of oncological patients. European Journal of Nuclear Medicine 1996 23 1409–1415. (I-MIBG) in www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access

  16. 28 D Rubello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 78 Martin WH, Delbeke D, Patton JA & Sandler MP. Detection of malignancies with SPECT versus PET, with 2-fluorine-18-2- deoxy-D-glucose. Radiology 1996 198 225–231. 79 Lapela M, Leskinen S, Minn HR, Lindholm P, Kleim PJ, Soderstrom KOetal.Increasedglucosemetabolisminuntreatednon-Hodgkin’s lymphoma: a study with positron emission tomography and fluorine-18-fluorodeoxyglucose. Blood 1995 86 3522–3527. 80 Gasparoni P, Rubello D & Ferlin G. Potential role of fluorine-18- deoxyglucose (FDG) positron emission tomography (PET) in the staging of primitive and recurrent medullary thyroid carcinoma. Journal of Endocrinological Investigation 1996 20 527–530. 81 Adams S, Baum R, Rink T, Ashunam-Drager PM, Usadel KH & Hor G. Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for the tumours. European Journal of Nuclear Medicine 1998 25 79–83. 82 Pasquali C, Rubello D, Sperti C, Gasparoni P, Lessi G, Ferlin G et al. Neuroendocrine tumor imaging: can 18F-fluorodeoxyglucose positron emission tomography detect tumors with poor prognosis and aggressive behavior? World Journal of Surgery 1998 22 588–592. 83 MacManus MP, Hicks RJ, Matthews JP, Hogg A, McKenzie AF, Wirth A et al. High rate of unsuspected distant metastases by PET in apparent stage III non-small-cell cancer: implication for radical radiation therapy. International Journal of Radiation Oncology and Biological Physiology 2001 50 287–293. 84 Erasmus JJ, Patz EF Jr, McAdams HP, Murray JG, Herndon J, Coleman RE et al. Evaluation of adrenal masses in patients with bronchogenic carcinoma using 18F-fluorodeoxyglucose positron emission tomography. American Journal of Roentgenology 1997 168 1357–1360. 85 Casara D & Rubello D. Diagnostic scintigraphy in postoperative staging and follow-up of differentiated thyroid carcinoma. Rays 2000 25 207–219. 86 Trampal C, Sorensen J, Engler H & Langstrom B. 18F-FDG whole body positron emission tomography (PET) in the detection of unknown primary tumors. Clinical Positron Imaging 2000 3 160–164. 87 Schumacher T, Brink I, Morer E & Nietzsche EU. Imaging of an adrenal cortex carcinoma and its metastasis with FDG-PET. Nuklearmedizin 1999 38 124–126. 88 Shulkin BL, Thompson NW, Shapiro B, Francis IR & Sisson JC. Pheochromocytomas: imaging deoxy-D-glucose PET. Radiology 1999 212 35–41. 89 Maurea S, Mainolfi C, Bazzicalupo L, Panico MR, Imparato C, Alfano B et al. Imaging of adrenal tumors using FDG PET: com- parison of benign and malignant lesions. American Journal of Roentgenology 1999 173 25–29. imaging of neuroendocrine with 2-fluorine-18-fluoro-2- Received 17 October 2001 Accepted 20 March 2002 www.eje.org Downloaded from Bioscientifica.com at 05/04/2020 02:03:19PM via free access