Genitourinary > Adrenal imaging

Adrenal Imaging

Meta-iodobenzylguanidine (MIBG)

Pharmacology & Physiology

Structurally, MIBG resembles norepinephrine and guanethidine (a neurosecretory granule depleting agent). MIBG images the adrenal medulla (NOT the adrenal cortex) and sympathetic nervous tissue. It can be labeled to either ¹²³I or ¹³¹I. If using ¹²³I, a 7 fold larger dose is permitted and this allows for SPECT imaging. The higher dose provides a 10 fold higher photon flux at 24 hours, and is still 3 times higher at 48 hours. The 159 keV photon of ¹²³I is also more easily collimated and the images obtained are of higher quality. ¹²³I images also have improved spatial resolution.

MIBG localizes to storage granules in adrenergic tissue of neural crest origin and will concentrate in catecholamine producing adrenal medullary tumors [24]. Its uptake appears to occur through the energy requiring, sodium dependent (active transport) Type I amine uptake mechanism and there is some non-energy dependent diffuse (Type II) [12]. Once inside the cell, MIBG is concentrated in the intracellular hormone storage vesicles by an energy dependent, tetrebenazine (reserpine)-sensitive mechanism [1]. Uptake is proportional to the number of neurosecretory granules within the tumor. In neuroblastoma, the agent remains within the cellular cytoplasm, free of granular storage. It's retention in neuroblastoma is related to the rapid re-uptake of agent that has escaped the cell [12].

In childhood, extra-adrenal chromaffin tissue is abundant. The largest mass of such tissue is the Organ of Z?ckerkandl which is located anteriorly below the origin of the IMA. After the age of 3 years, these extra-adrenal sites regress except in sympathetic ganglia and the carotid bodies.

Normal distribution of MIBG:

• Adrenal medulla

¹³¹I: The adrenals are usually not seen, but may be faintly visualized in 10-20% on delayed images. The larger the dose of tracer used, the more likely the normal adrenal gland will be visualized. Also, due to the improved specific activity of MIBG used for imaging, increased visualization of the normal adrenal gland has been noted (up to 73% of patients on delayed imaging) [1]. The intensity of uptake in the normal adrenal should be less than the liver.
¹²³I: Adrenals are seen in 30% of patients. Although the activity is generally mild (less than liver intensity) and symmetric, it can be unilateral or asymmetric in up to 50% of cases. Confusion can then occur in differentiating this uptake from a pheochromocytoma. Unilateral uptake less than or equal to the liver can represent pheochromocytoma in 10% and 33% of cases, respectively. Unfortunately, 31% of normal adrenals are also visualized with uptakes less than or equal to the liver. The absence of an anatomic lesion on the abnormal side can be helpful in excluding a tumor. In general, most pheochromocytomas demonstrate uptake more intense than the liver (80%). [2]

• Liver: The liver is a major site of catecholamine degradation [13]. Liver uptake is inversely related to catecholamine levels.
• Spleen: Probably a manifestation of sympathetic innervation [13]
• Urinary bladder: Due to renal excretion of the tracer
• Colon/Bowel: Activity is seen in up to 15-20% of patients
• Salivary glands: Due to rich sympathetic innervation (occasionally lacrimal gland activity may be observed [41])
  
• Nasal mucosa [41]
  
• Heart/myocardium: Uptake is inversely related to catecholamine levels
• Lung
• Thyroid: May be seen in a small number of patients, even if it is being blocked.
• Uterine and neck muscle uptake [3]
• Upper thorax in children [4] due to the presence of sympathetically innervated brown fat [19]

Excretion

Most MIBG (about 85-90%) is excreted unchanged in the urine by 96 hours post injection. There is variable excretion into the gut (1 to 4%). The whole body half-life is about 24 hours, but the agent is retained in sympathetic nervous tissue for a prolonged period of time.

Indications

MIBG is used primarily to image Pheochromocytomas (Paragangliomas) and Neuroblastoma. Other APUD cell line tumors-- e.g. carcinoid, and medullary thyroid carcinoma-- demonstrate uptake of the tracer less frequently. Adrenal medullary hyperplasia may also be imaged.

Technique

Dose: 500 uCi ¹³¹I or 3 to 10 mCi ¹²³I. Imaging is performed at 1 and 3 days following ¹³¹I administration, and 6 and 24 hours after ¹²³I administration. Thyroid uptake of the tracer and free I-131 is blocked using Lugol's solution or Super-saturated potassium iodide (SSKI) for one day prior to and for 6 days following administration of the tracer [13]. The critical organ is the adrenal medulla (100 rad/ mCi ¹³¹I).

With the use of ¹²³I-mIBG manufactured with low free iodine (1-3%) and considering the 13.2 hour half-life of ¹²³I, extended thyroid blockade is probably unnecessary [37]. For ¹²³I-mIBG imaging, a single dose of SSKI (or the equivalent) is effective in reducing the thyroid dose by more than 50% (best given 1 hour prior to tracer administration) [37]. However, even with blockade, some thyroid uptake does occur due to symathetic nerve terminals in the thyroid gland [37]. The use of thyroid blockade for ¹²³I-mIBG can be individualized and may not be required in elderly patients as the radiation burden to the thyroid gland from the administration of 10 mCi of high-purity ¹²³I-mIBG has been estimated to be 70 mGy in nonblocked patients (siilar to the dose received from an I-123 thyroid scan) [37]. Prior to I-123 MIBG imaging, thyroid blockade can be performed with a saturated solution of potassium iodide 100mg/day starting 1 day before tracer injection and continuing for 2 days [39].

For I-123 imaging, planar continuous whole body images are acquired using a scan speed of 6.77 cm/min and SPECT images can be obtained if indicated [24]. For I-131 MIBG imaging, planar static images are obtained over the chest, abdomen, and pelvis for 20 minutes each using a dual headed camera, a high energy collimator, and a 20% window centered at the 364 keV photopeak [24]. Spot images are prefered to a continuous acquisition due to the low count rate [24].

Drugs which interfere with MIBG uptake

• Cocaine: Inhibits catecholamine uptake [12]
• Tricyclic antidepressants (Desipramine, Amitriptyline [Elavil]): Inhibit catecholamine uptake [12] and should be discontinued for 3-4 days prior to the procedure [24].
• Phenylpropanolamine/Pseudephredine/Phenylephrine- found in over the counter cold preparations and decongestants these agents deplete storage vesicle contents
• Catecholamine agonists: Sympathomimetics, Amphetamines, and Amphetamine-like compounds. Deplete storage vesicle contents [12]
• Reserpine: Depletes the catecholamine stores in the neurosecretory storage granules and inhibits vesicle active transport [12]. It should be discontinued for 3-4 days prior to the procedure [24].
• Antipsychotics: Phenothiazines (Thorazine) and thiothixines inhibit catecholamine uptake [12]
• Calcium channel blockers: Should be discontinued for 3-4 days prior to the procedure [24].
• Adrenergic blockers: Long acting beta-blockers: Labetalol and possibly metoprolol. Labetalol inhibits catecholamine uptake and depletes storage vesicle contents [12]. It should be discontinued for at least 3 weeks prior to scanning. The absence of salivary and parotid activity can serve as a clue that patients may be on this medication.
• Possibly some foods: Those which contain vanillin and catecholamine-like compounds such as chocolate and blue-veined cheeses

Disease Processes and Neoplasms Imaged with MIBG:

Pheochromocytoma

Clinical Presentation

Pheochromocytomas are a rare tumor (incidence of 0.05% in the general population in an autopsy series [36]) that arise from chromaffin cells (neural crest ectoderm involved with catecholamine synthesis) which is found in the adrenal medulla (85-90% of tumors arise in the adrenal medulla), sympathetic ganglia, Organ of Z?ckerkandl, and the aortic and carotid chemoreceptors. Patients with sporadic pheos are older at presentation with a mean age of 44 years [36]. Patients can present with paroxysmal HTN (50%) or sustained HTN (40-90%) associated with headache, sweating, palpitations, weight loss, and hyperglycemia (Note: Only 0.1% to 0.6% of patients with hypertension are found to have pheochromocytomas [18,36]). Symptoms may be precipitated by abdominal exertion such as heavy lifting or performing the Valsalva maneuver [17]. The clinical triad of headache, palpatations, and sweating are 90% specific for pheochromocytoma, the triad is uncommon- occurring in 10-36.5% of patients [36]. Other symptoms include nausea, flushing, weight loss, fatigue, and hyperglycemia [36]. Men and women are affected equally [18]. Pheos are exceptionally rare in the pediatric population, however, pediatric pheos have a higher incidence of malignancy (47% versus 10% in adults) [36]. Glucagon is contraindicated in these patients as they may cause catecholamine release from the tumor and precipitate a hypertensive crisis.  Biopsy is also generally not indicated for patients suspected of having pheochromocytoma- due to the risk of precipitating a hypertensive crisis [26]. The prognosis is very favorable for patients with benign lesions [36]. Classic indicators of poor prognosis include tumor size greater than 5 cm, extraadrenal tumor location, age younger than 30 years at first presentation, and metastatic disease [40]. The prognosis is poor for patients with malignant pheochromocytoma with a 5 year survival rate of 54% [36].

Laboratory abnormalities include elevated urinary and resting plasma catecholamine levels (97% and 99% sensitivity, respectively [21]), and elevated 24-hour urine vanillylmandelic acid (VMA) (50-90%) and metanepinephrine levels. These tests have sensitivities ranging from 89-100% [15]. Serum chromogranin A (CgA- a chromogranin protein which is cosecreted with neurotransmitters) is also an effective marker for pheochromocytoma [14].

Pheochromocytomas follow a rule of "ten": 10% are malignant (tend to be larger lesions), 10% are bilateral, 10% occur in pediatric patients, and 10% are extra-adrenal. However, due to advances in molecular diagnostics, it is likely that about 25% of pheochromocytomas have a genetic association [36]. Clinical features that may be associated with an increased risk for a malignant tumor include high preoperative 24 hour urinary dopamine levels, extraadrenal location, tumor weight > 80 gm, and persistent post operative hypertension [36].

Pheochromocytomas are associated with certain genetic disorders and affected patients typically present at a younger age (mean 25 years) [36]. Associated disorders include: Neurofibromatosis Type I (develop in approximately 1% of patients [36]), von Hippel-Lindau (develop in 10-26% of patients [36]), MEN syndromes IIa (50% prevalence [21]) & MEN IIb (90% prevalence [21]), and Carney's syndrome (which consists of smooth muscle tumors of the stomach, chondromatous pulmonary hamartomas, and extra-adrenal paragangliomas) [17]. Pheochromocytomas associated with MEN syndrome tend to be bilateral  (bilateral pheochromocytomas are found in up to 75% of these cases) and are almost always intraadrenal- they also tend to be benign [18]. Pheochromocytoma-paraganglioma syndromes are also associated with succinate dehydrogenase mutations (SDHB and SDHD) [36]. These gene mutations are found in about 10% of patients with pheochromocytoma [36]. Patients with SDHB mutation are more likely to have extra-adrenal tumors and head and neck paragangliomas [36]. Additonally, patients with SDHB mutations have up to a 50% risk for malignant pheo [36].

Extra-adrenal lesions occur in 10% of adults, and 30% of children. Extra-adrenal lesions are generally located in the retroperitoneal sympathetic ganglia in the paracaval/aortic region or near the organ of Z?ckerkandl. Other sites include the renal hilum (may have associated ipsilateral renal atrophy), the mediastinum (1%), and the urinary bladder (1%- associated with micturitional syncope). In adults, extra-adrenal lesions are malignant in 30-40% cases, while despite their higher prevalence, only about 2% of extra-adrenal lesions are malignant in children. The sensitivity of ¹³¹I-MIBG imaging is significantly lower in the diagnosis of exrtra-adrenal pheochromocytoma than in the diagnosis of adrenal pheochromocytoma [27].

Paragangliomatosis refers to the presence of "too numerous to count" pheochromocytomas. This condition is noted in about 5% of patients with extra-adrenal lesions. In this condition, the majority of the lesions are benign, but they may still be functionally active.

Radiographic Findings

CT:  CT can be performed safely with low osmolar, non-ionic I.V. contrast [18,23,36]. On CT most pheochromocytomas are greater than 3 cm in size. They are usually soft tissue density and the center of the lesion may be necrotic. Approximately two-thrids of the lesions are solid and the rest are complex or cystic [36]. The lesion may appear completely cystic. Calcification is noted infrequently- although, other authors indicate that calcificaiton can be seen in 10% of tumors and up to 21% of symptomatic lesions [36]. The tumor is hypervascular and will exhibit marked enhancement of the solid components [36].

MR: On MRI, pheochromocytomas have a signal intensity similar to or slightly lower than the liver on T1 images, but are extremely hyperintense on T2 images (up to 70% of lesions show very bright T2 signal [26]). This classic appearance is variable in prevalence- ranging from 11-65% of lesions [36]. Occasionally, lesions may be inhomogeneous, iso-, or hypointense to the liver. Up to 1/3 of lesions may have low signal on T2 images [36]. Unfortunately, due to the presence of necrosis within the lesion, over 20% of lesions will have an atypical appearance on T2 images [5]. On rare occasions, pheos may contain microscopic fat resulting in signal loss on chemical shift imaging (mimicking an adrenal adenoma) [36].

Angiography is contraindicated unless absolutely necessary as it may provoke a hypertensive crisis. In such cases, premedication is required. The lesion is typically hypervascular.

Scintigraphic Findings

In patients with biochemical abnormalities indicative of a pheochromocytoma, CT or MRI are more accurate in detecting primary tumors of the adrenal gland, but they are inferior to MIBG in the detection of extra-adrenal tumors which account for about 10% of lesions [6]. I-131 MIBG scan sensitivity for pheochromocytoma is 56-90% and specificity is 95-100% [5,15,17,34]. The sensitivity of I-123 MIBG (sensitivity 76-100%; specificity 84-100% [25,29,39]) has been reported to be higher than I-131 due to its superior imaging characteristics [24]. It has been reported that the exam sensitivity is lower for SDHB and VHL-related pheochromocytomas and paragangliomas [39].

The sensitivity of ¹²³I-MIBG is higher for the identification of adrenal lesions than for extraadrenal paragangliomas [29]. The sensitivity of I123-MIBG for paragangliomas is between 56-76% and the specificity between 84-100% [39].

I-123 MIBG also offers the option of performing SPECT imaging to aid in lesion loicalization and improved contrast resolution [25]. However, in one study, SPECT imaging only produced a slight improvement in exam sensitivity, while causing a slight drop in specificity [29]. The normal adrenal medulla is visualized with I131 MIBG in about 10% of cases, and in 50-80% of cases with I123 MIBG- and this physiologic uptake may obscure small lesions [34]. Pathologic adrenal uptake on MIBG imaging is usually more intense than the liver or non-homogeneous [39]. MIBG imaging is more sensitive for the detection of adrenal pheochromocytoma compared to Octreotide imaging (while MIBG imaging has a lower sensitivity for extra-adrenal paragangliomas) [34].

I-123 MIBG has been suggested to be less sensitivity for the evaluation of metastatic pheo when compared to Octreotide or 6-¹⁸F-Fluorodopamine PET imaging [25]. Approximately 10% of pheochromocytomas are cystic, but these lesions are still endocrinologically active and will concentrate MIBG. Unlike neuroblastoma, bone scan is superior to MIBG for detecting the presence of bone metastases in patients with pheochromocytoma.

Click here for discussion of PET imaging in pheochromocytoma

 

⁶⁸Ga-DOTATE

⁶⁸Ga-DOTATE can accumulate in pheochomocytomas and paragangliomas [45]. Lesion detection appears to be very high in patients with SDHB-related metastatic lesions [45].

Neuroblastoma

Clinical Presentation

Neuroblastoma arises from neural crest derivatives in the adrenal medulla or the sympathetic nervous system [20]. It is the most common extracranial solid malignant tumor of infants and children [19] and the 3rd most common childhood malignancy overall (after leukemia and primary CNS brain tumors [31]). It accounts for 10-15% of childhood malignancies [31] and for nearly 15% of all pediatric cancer fatalities [44]. About 50% of cases occur in children less than 2 years of age [20] (the median age at diagnosis is 19 months [44]), and 90% are seen by ages 5-8 years. Males are affected slightly more than females. Although there is no racial variation in incidence, African-Americans are more likely to have high-risk disease and fatal outcomes [41,44]. The majority of neuroblastomas are sporadic, but about 1% are familial and are associated with mutatuions in the ALK, PHOX2B, and KIF1B genes [44].

Neuroblastoma is also the most common malignancy in the first month of life and fetal/cogenital neuroblastoma (almost always adrenal in origin- 90% of cases) can also occur [16,44]. A unique perinatal variant is called cystic neuroblastoma which is characterized by one or more macroscopic cysts in the tumor that are felt to be related to prior hemorrhage/necrosis [43]. Associations with a familial predisposition (0.2%), bowel agangliosis, and congenital heart disease have been described, but none are very strong.

Symptoms of neuroblastoma include an abdominal mass, limp, nystagmus, or inability to walk. Hypertension is found in 30% of patients. Elevated urinary catecholamine levels (VMA & HVA) are seen in 75-90% of patients.

Metastases are present in 60-70% of patients at the time of diagnosis [19,31]. The skeleton or bone marrow is the most common site of metastatic disease (60%) (70% bone marrow and 55% bone [33])- when associated with irritability and limping this is known as Hutchinson syndrome [16]. Metastatic involvement of the skull can occur in up to 25% of cases [31]. Metastases can also go to lymph nodes (35-40% at the time of diagnosis), the liver, and intracranial (parenchymal or leptomeningeal metastases are found in 2-16% of cases [31]). Skin metastases are relatively common, especially in children younger than 1 year of age [16]. Skin lesions may appear as dark blue or purple masses- resembling blueberries- this appearance has been given the eponym "blueberry muffin syndrome" [16]. Ecchymotic orbital proptosis ("raccoon eyes") results from metastases to the perioribital bones and soft tissues causing obstruction of ophthalmic and facial veins [19,44].

Paraneoplastic syndromes are also seen and include:

• Infantile myoclonic encephalopathy (opsoclonus myoclonus ataxia syndrome): The condition occurs in 2-3% of neuroblastoma patients [44], but it is associated with occult neuroblastoma in 20-50% of cases. The syndrome consists of opsoclonus (random irregular eye movements or "dancing eyes"), myoclonus (rhythmic jerking movements of the extremitis), and cerebellar ataxia. The condition is generally associated with favorable well-differentiated neuroblastomas [41] and is believe to be immune mediated through antibodies that react with central nervous system antigens [44]. Tumor removal does not always improve neurologic symptoms, but immunotherapy with IV immunoglobulin can improve neurologic symptoms in up to 83% of patients during intial treatment, however, relapse is common [44].
• Verner-Morrison syndrome: Watery diarrhea, hypokalemia, and achlorhydria. Seen in 5% of cases, it is secondary to VIP (vasoactive intestinal peptide) production by the tumor (elevated VIP levels are noted in 25% of patients with neuroblastoma). The symptoms will improve following tumor resection [44]

Sites of Primary Neuroblastoma: 65% to 75% of cases are intraabdominal [41].

Approximately 80% of tumors occur in the abdomen [48]. Primary tumor location is associated with outcome with a higher risk for relapse with adrenal tumors and a lower risk for thoracic tumors [41].

Adrenals: Most frequent (35% to 66% of cases) intra-abdominal site. About 10% of cases are bilateral. Primary adrenal lesions are actually associated with a worse prognosis than extra-adrenal lesions.

Extra-adrenal abdominal sympathetic ganglia: Includes the Organ of Z?ckerkandl (a cluster of paraganglia near the aortic bifurcation, seen predominantly in children).

Intrathoracic: The mediastinum is the second most common location for primary neuroblastoma after the abdomen, most commonly the posterior mediastinum [42]. Approximately 15% to 20% of cases are intrathoracic and intrathoracic tumors are more common in infants [41]. The lesion generally arises posteriorly in the paravertebral sympathetic chain. Between 5-25% of patients will have an associated intraspinal component. Thoracic and cervical primaries are associated with a better prognosis.

Neck: Accounts for 1% to 5% of cases

Intracranial: Rare (approximately 2% of cases). Most commonly arises in the olfactory nerve (esthesioneuroblastoma), or cerebellum.

Staging [19], Treatment, and Prognosis of Neuroblastoma

INSS staging

• Stage I: Confined to the organ of origin with complete gross surgical excision
• Stage IIA: Localized tumor with incomplete gross excision
• Stage IIB: Localized tumor with complete of incomplete gross excision. Tumor extends into adjacent structures, but does not cross midline. Ipsilateral regional lymph nodes positive for tumor, but contralateral nodes are negative.
• Stage III: Unresectable tumor which crosses midline; or unilateral tumor with contralateral regional lymph node involvement
• Stage IV: Distant metastases
• Stage IVS: Localized primary lesion that does not cross midline, with metastases to liver, skin, and/or bone marrow (but NOT cortical bone) in infants younger than 1 year of age. Stage IVS disease is associated with very good survival following chemotherapy and radiation.

INRGSS staging [41]

L1- Localized tumor not involving vital structures and confined to one body compartment
L2- Local-regional tumor with one or more image-defined risk factors
M- Distant metastatic dissemination
MS- Metastatic dissemination limited to skin, liver, and/or bone marrow in patients younger than 18 months

Prognosis: The most important predictors of prognosis are age at presentation and stage [16]. Children who are less than one year of age have a significantly higher 5 year survival rate compared to patients diagnosed after the age of one [44]. Similarly, a lower stage or stage IVS disease are associated with a better prognosis [19]. Children with stage 1, 2, and 4S disease have a 3 year event-free survival of 75-90% [16]. Children under the age of 1 year with stage 3 and 4 tumors have a one-year event free survival rate of 80-90% and 60-75% respectively [16]. Children older than 1 year with stage 3 and 4 tumors have a 3 year event-free survival rate of 50% and 15%, respectively [16].

Unfavorable prognostic features include age ≥ 18 months, the presence of distant metastatic disease in patients older than 12-18 months (lymph nodes, bone or bone marrow, and liver), MYCN oncogene amplification on molecular pathology in patients of any age, and unfavorable histopathologic features  (high-risk neuroblastoma has a long term survival rate of about 40%) [32,47]. A complete response to induction chemotherapy is one of the main early prognostic factors in patients with high risk neuroblastoma [47]. A Curie score of greater than or equal to 2 at the end of induction therapy is associated with an inferior outcome [44]. Following induction, the event free survival has been reported to be 15% for anything more than minimal residual disease, compared to 46% for patients with a Curie score of less than 2 [44]. Another semiquantitative scoring system (SIOPEN) with a post induction skeletal score greater than 3 also identifies patients with a very poor prognosis who require different treatment strategies [47].

Tumor genetics: MYCN gene amplification occurs in about 20% of primary tumors and is associated with advanced tumor stage, rapid tumor progression, and poor outcome [44]. Chromosomal deletions ar found in up to 50% of neuroblastomas and those associated with a worse prognosis include deletion of 1p36, unbalanced gain of 17q, and deletion of 11q [44]. Neuroblstomas with a higher DNA content (DNA index > 1, hyperdiploid) are associated with a lower tumor stage and improved outcomes in children younger than 18 months [44].

Occasionally, the lesions may revert to a benign ganglioneuroma (0.2% to 1% of cases). Regression most often occurs in stage IVS and takes 6 to 12 months [16]. A persistently positive MIBG scan during and after induction therapy is associated with a poor outcome [19].

Therapy:

Surgery is the mainstay of treatment for low-risk tumors [44]. Chemotherapy is added for tumors that cannot be resected, as well as for intermediate risk patients [44]. For high risk patients, an aggressive multimodality treatment regimen is used combining chemotherapy, surgical resection, adjuvant high-dose chemotherapy with hematopoietic stem cell rescue, and radiation therapy [44]. Maintenance therapy entails the use of anti-GD2-immunotherapy with dinutuximab [44].

I-131 MIBG has been used in therapeutic doses as part of a multimodality approach for the treatment of neuroblastoma- predominatly in refractory and relapsed patients [30,41]. Up to 14% of patients receiving conventional I-131 MIBG therapy can have severe acute hypertension during the infusion likely due to unlabeled MIBG [46]. The outcome of the treatment has been variable with reported partial responses raning from 15-92% [30,46]. Myelosuppression is the main toxic effect and autologous peripheral blood stem cell rescue is often necessary after higher administered doses [41]. Thyroid disorders (hypothyroidism and nodules) are common after I131-MIBG therapy and continuous thyroid screening should be performed in these patients [41].

Scintigraphy in the Evaluation of Neuroblastoma

Agents: Either I-131 MIBG or I-123 MIBG can be used for imaging [20]. I-123 MIBG has a more favorable dosimetry (whole body radiation dose in about 5% of that of I-131 MIBG) and better imaging characteristics- including higher quality images, greater sensitivity for disease detection, lower risk to the thyroid gland, and the ability to perform SPECT imaging [20,28].  As a result, I-123 MIBG has essentially replaced I-131 MIBG for imaging. 

Patient preparation/imaging: A solution of potassium iodide is administered to reduce thyroid uptake of free radioiodine, beginning the day before injection and continued for 5 to 6 days. The recommended doses are 32 mg potassium iodide daily for children aged 1 month to 3 years, 65 mg for those 3 to 13 years, and 130 mg for those older than 13 years [20]. The additional use of a single dose of thyroxine (100 mcg/m²) and two doses of methimazole (0.25mg/kg/m²) can also be administered [20]. I-131MIBG (0.5-1.0 mCi/1.7 m² body surface area [7 to 15 uCi/kg])  is administered by slow IV injection over 90 seconds. Spot images of the entire body (chest, abdomen, and pelvis) should be obtained at 24-48 hours following tracer administration [20]. Images are acquired for 100,000 counts or 20 minutes, whichever comes first. A low-speed, whole body gamma camera can also be used to obtain the images. [12]

 For I-123 MIBG, a saturated solution of potassium iodide should be given the day before administration of the tracer and continued for 1 to 3 days [41]. A single dose of saturated solution of potassium iodide at the time of tracer injection has also been shown to adequately block thyroid uptake [41]. The dose of I-123 MIBG is 0.14 mCi/kg (5.2 MBq/kg) with a minimum administered activity of 1 mCi (370 MBq) [41]. I-123 MIBG imaging is performed 24 hours after tracer administration and at 48 hours if needed [41].

Image interpretation:

The modified Curie score is used for semiquantitative image interpretation [44]. The body is divided into nine skeletal segments with an additional segment for soft-tissue invovlement [44]. Each segment is assigned a score of 0-3 depending on the extent of disease involvement [44]. No involvement receives a score of 0; single site disease in the segment a score of 1; two or more sites of disease involving less than 50% of a segment receives a score of 2; and more than 50% involvement of a segment is given a score of 3 [44]. The maximum score is 30 and the score on post therapy imaging has prognostic significance [44].

Findings:

The overall sensitivity of MIBG in the detection of neuroblastoma is approximately 90% (about 10% of neuroblastomas do not show MIBG uptake, although other authors suggest that up to 30% may not show MIBG uptake [42]) [7,12,38,41]. The overall specificity of MIBG in the detection of neuroblastoma is 94% [12]. The extent of metastatic bone and bone marrow disease is most accurately defined by MIBG scintigraphy (sensitivity 90%, specificity 100%) [33]. Bone scanning often grossly underestimates the extent of osseous metastases and MIBG is superior to MDP for detecting the presence of skeletal metastases (likely because of the propensity for neuroblastoma metastases to originate within the bone marrow cavity and high physiologic physeal activity in children that can mask metastatic lesions) [8,12,33]. Bone scan has a reported sensitivity of 70-78% and a specificity of 51% for the detection of bone metastases [33].

Normalization of MIBG exams in patients with documented bone marrow metastases is a better predictor of successful treatment than MRI exams which can demonstrate persistent abnormal marrow signal despite the absence of metastases for up to 2 years [9].

Liver metastases may escape detection with MIBG imaging. This finding is not surprising as MIBG is physiologically concentrated in the liver, and therefore small lesions may be obscured [10]. SPECT increases diagnostic certainty, but does not increase lesion detection with I123-MIBG [11]. Recurrent neuroblastoma may not demonstrate MIBG accumulation in up to 50% of patients, suggesting that the role of MIBG may be more limited in this setting [16].

False positive MIBG exams have been described in association with atelectasis, pneumonia, focal nodular hyperplasia in the liver, radiation induced liver injury, accessory spleen, focal pyelonephritis, and vascular malformations [41].

Other agents:

TcMDP is concentrated in about two-thirds of primary lesions (and is felt to be related to presence of calcification). Bone scan detects the presence of skeletal metastases in 40-60% of patients, but localization of metaphyseal metastases (a common site of metastatic disease) can be difficult due to the adjacent physeal activity. A common finding on bone scan in patients with metaphyseal metastases is ill-defined increased activity in this area with loss of the sharp boundary between the growth plate and the metaphysis.

In-111 Octreotide can also be used to image neuroblastoma as MIBG negative paragangliomas will sometimes concenrtrate In-111 pentreotide [24]. Overall the agent has inferior sensitivity (55-70% [20]) compared to MIBG [19], and specificity also suffers as non-neuroendocrine tumors such as lymphoma and inflammatory infiltrates may also demonstrate tracer uptake [12].

PET:

FDG imaging:

Neuroblastomas are metabolically active tumors [22] that demonstrate moderate FDG uptake (higher stage lesions tend to show higher uptake than early stage disease [38]). PET scan findings correlate well with disease extent as determined by MIBG scans and the scans can be performed 60 minutes following tracer administration [19,22]. FDG PET has been found to be most beneficial in tumors that fail to accumulate or only weakly accumulate MIBG [28]. PET may also be better at identifying small lesions and localizing anatomic sites of disease due to its superior spatial resolution [19]. PET appears to be less useful in the detection of stage IV neuroblastoma because of suboptimal detection of marrow disease compared to MIBG scintigraphy due to normal FDG activity in hematopoietic bone marrow [22,28,32,38]. In one study, the sensitivity of FDG was 86% [32].

¹⁸F-FDOPA PET imaging in neuroblastoma:

FDOPA resembles natural L-DOPA [35]. The short-term accumulation of FDOPA is determined mainly by the reaction rate of amino acid decacrboxylase (AADC) which converts FDOPA into fluorodopamine, which is then stored in vesicles [35]. FDOPA imaging is very sensitive for the detection of neuroblasic tumors including neuroblastomas, ganglioneuromas, and ganglioneuromas [35]. Higher FDOPA upatake is associated with higher levels of AADC expression and urinary VMA levels [35]. Neuroblastic tumors have AADC activity and can be imaged by FDOPA PET [35]. Pre-treatment with carbidopa, an AADC inhibitor, one hour before injection of FDOPA improves availability of FDOPA for imaging [35]. FDOPA imaging can be performed 90 minutes following tracer administration, as opposed to I-123 imaging which requires a 24 hour period after injection prior to imaging [35].

Normal FDOPA uptake can be seen in the basal ganglia, gallbladder, kidneys, urinary tract, liver, and epiphyseal plates of the long bones [35]. Low level GI tract activity can also be seen [35]. Genitourinary and gallbladder activity are seen due to excretion of catecholamine metabolites [35].

FDOPA is the most sensitive and accurate method of identifying neuroblastoma localizations [47]. FDOPA has been shown to be more sensitive than ¹²³I-MIBG in staging neuroblastoma patients and in evaluating disease persistence after chemotherapy [47].

⁶⁸Ga-DOTATE:

⁶⁸Ga-DOTATE can accumulate in neuroblastoma lesions [45]. SSTR expression (specificically SSTR type 2) can be seen in 77-89% of neuroblastomas [45].

¹²⁴I-MIBG:

¹²⁴I is a positron emitting radionuclide with a half-life of 4.2 days (compared to 13.2 hours for ¹²³I) [48]. This results in higher patient radiation exposure with an effective dose twice that of an ¹²³I-MIBG scan when a very low activity is used for the exam [48] (the effective dose has been calculated to be 0.161-0.795 mSv/MBq which is approximately 10-20 times the effective dose of ¹⁸F-FDG in the pediatric population [48]).

¹²⁴I-MIBG has been shown to have superior lesion detection compared to ¹²³I-MIBG imaging [48]. Increased lesion detection using ¹²⁴I-MIBG has been correlated with higher Curie scores [48].

Correlative Radiographic Imaging in Neuroblastoma

Plain film findings in neuroblastoma include multicentric lytic skeletal lesions, metaphyseal lucent bands, and vertebral body collapse. Calcification is evident in at least 30% of cases [16]. On IVP there is typically inferior renal displacement rather than collecting system distortion (seen in Wilm's)

On CT neuroblastoma typically appears as a large complex mass which is often locally invasive into adjacent tissue and typically encases the great vessels, although a pseudocapsule maybe seen. Neuroblastomas often contain areas of necrosis, hemorrhage, and calcification (seen in between 50% to 80-85%). Calcification is usually coarse, amorphous, and mottled, but can be curvilinear or nodular. The mass may appear cystic and can mimic an adrenal hemorrhage in neonates. Neuroblastomas appear bright on T2-weighted MRI images.

 

Adrenal Medullary Hyperplasia

In patients with adrenal medullary hyperplasia, the level of accumulation of the radiotracer is related to the degree of medullary dysfunction. The exam typically reveals symmetric or nearly symmetric increased tracer uptake within the glands, with relative preservation of the glandular shape. Since the right adrenal gland is more superficial on posterior images, it may appear more intense than the left side.
 

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