UNSOLICITED REVIEW
Diagnosis and preoperative imaging of multiple endocrine neoplasia type 2: current status and future directions
David Taïeb*, Electron Kebebewt, Fréderic Castinetti+, Clara C. Chen§, Jean-François Henryîl and Karel Pacak **
*Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France, ¡Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, ¿Department of Endocrinology, La Timone University Hospital, Aix-Marseille University, Marseille, France, §Department of Radiology and Imaging Sciences Department, Warren Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA, [Department of Endocrine Surgery, La Timone University Hospital, Aix-Marseille University, Marseille, France and ** Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD, USA
Summary
Multiple endocrine neoplasia type 2 (MEN2) is a rare autoso- mal dominant syndrome caused by mutations in the RET protooncogene and is characterized by a strong penetrance of medullary thyroid carcinoma (all subtypes) and is often accompanied by pheochromocytoma (MEN2A/2B) and pri- mary hyperparathyroidism (MEN2A). The evaluation and management of MEN2-related tumours is often different from that of sporadic counterparts. This review article provides an overview of clinical manifestations, diagnosis and surgical management of MEN2 patients. This review also presents applications of the most up-to-date imaging modalities to MEN2 patients that are tightly linked to the clinical manage- ment and aims to guide physicians towards a rationale for the use of imaging prior to prophylactic thyroidectomy, initial surgery and reoperations for persistent/recurrent disease. This review also concludes that, in the near future, it is expected that these patients will indeed benefit from newly developed positron emission tomography approaches which will target peptide receptors and protein kinases. Identification of MEN2-specific radiopharmaceuticals will also soon arise from molecular profiling studies. Furthermore, subtotal (cortical- sparing) adrenalectomy, which is a valid option in MEN2 for avoiding long-term steroid replacement, will benefit from an accurate estimation through imaging of differential adrenocor- tical function.
Correspondence: David Taïeb, Department of Nuclear Medicine, La Timone University Hospital, European Center for Research in Medical Imaging, Aix-Marseille University, 264, rue Saint-Pierre, 13385 Marseille, France. Tel .: +33 (0) 4 91 38 44 06; E-mail: david.taieb@ap-hm.fr; Karel Pacak, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver NICHD, NIH, Building 10, CRC, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, Maryland 20892-1109, USA. Tel .: (301) 402 4594; Fax: (301) 402 4712; E-mail: karel@mail.nih.gov
(Received 11 March 2014; returned for revision 15 April 2014; finally revised 23 April 2014; accepted 21 May 2014)
Introduction
Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant syndrome (prevalence 2.5 per 100 000) caused by gain-of-function mutations in the Rearranged during Transfection (RET) protooncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinoma (MTC) and can be associated with pheochromocytoma (PHEO) and primary hyperparathyroidism (pHPT). MEN2-related tumours are preceded by a stage of cell hyperplasia.
MEN2 is divided into three groups, depending on their clini- cal features: MEN2A (55% of MEN2), MEN2B (5%) and famil- ial MTC (FMTC, 35-60%).1
To date, more than 70 different pathogenic germline RET mutations have been reported. Greater than 95% of families with MEN2A have a RET mutation in exon 10 or 11 (codon 634 in >85% of cases). In FMTC, mutations typically occur in exon 10, 13 or 14. Finally, individuals with MEN2B phenotype have mutation in exon 16 at codon 918 in 95% of cases. There are some families and individuals harbouring germline RET mutations in exon 10 that co-segregate with MEN2A/FMTC and Hirschsprung disease.
The MEN2 RET database (http://www.arup.utah.edu/database/ MEN2/MEN2_display.php) and the guidelines of the American Thyroid Association (ATA)2 serve as a repository for MEN2- associated RET sequence variation and reference for RET geno- type/MEN2 phenotype correlations.
Diagnosis
MEN2 can be revealed by the presence of one or more MEN- related tumours (MTC, PHEO and pHPT) or by clinical
features, especially in patients with MEN2B. MTC is usually the first manifestation of the disease and is often accompanied by a thyroid nodule in index cases. A thorough family history is important and should include questions regarding thyroid can- cer, PHEO, pHPT or unexplained sudden death in family mem- bers (secondary to an undiagnosed PHEO). However, MEN2 can be found in individuals without a family history, known as de novo mutations (e.g. 15% of MEN2A, >50% of MEN2B and 10% of FMTC). Symptoms and signs of catecholamine overse- cretion should be considered (e.g. sustained or paroxysmal ele- vations in blood pressure, headache, episodic profuse sweating, palpitations, pallor and apprehension or anxiety). On examina- tion, for a patient presenting with a thyroid mass, the extent of the mass should be carefully determined as well as the presence of neck lymphadenopathy or any phenotypic feature of MEN2. There are a few true single pathognomonic findings that will allow for definitive diagnosis of MEN2 by clinical inspection including the presence of nostalgia paraesthetica (posterior pig- mented pruritic patch and nostalgia) in MEN2A with codon 634 mutation or marfanoid body habitus (excessively long arms and legs) and thickened protruding lips due to multiple mucosal neuromas (also present on the distal portion of the tongue and gingiva) in MEN2B.
Medullary thyroid carcinoma typically arises from the pos- terosuperior parts of the thyroid lobes where the largest concen- tration of C cells is found. MEN2-related MTC presents at a younger age compared with sporadic cases. In all cases of MTC, preoperative assessment of urinary and/or plasma-fractionated metanephrines and serum calcium is recommended. If PHEO is diagnosed, it should be treated first. When the diagnosis of MEN2-related MTC is not made preoperatively, some pathologi- cal features may be indicative of MEN2 such as tumour multifo- cality, bilateral C-cell hyperplasia (CCH) or extensive lymph node (LN) metastasis. Regardless, all patients with presumed sporadic MTC should undergo genetic testing for RET muta- tions and have a pheochromocytoma excluded preoperatively.
Pheochromocytomas occur most often during young adult to mid-adult life. They are almost always confined to the adrenal medullas and unlikely to be metastatic. MEN2-related PHEOs are characterized by increased plasma concentrations of meta- nephrine (indicating that they consistently produce epinephrine, with or without norepinephrine).3 In PHEOs that exclusively produce norepinephrine, MEN2 can be excluded.4 The presence of bilateral PHEO is highly suggestive of hereditary PHEO but is not restricted to the MEN2 phenotype. In all cases of PHEO, assessment of serum calcitonin, calcium and PTH is recom- mended as PHEO could be the first clinical manifestation of MEN2. Elevated levels of serum calcitonin (usually greater than 100 pg/ml) enable diagnosis of MTC and therefore MEN2- related PHEO.
Primary hyperparathyroidism is rarely the first manifestation. Diagnosis is established by detecting mild hypercalcaemia with either mild elevations in PTH or (inappropriately) normal PTH levels. Assessment of serum calcitonin should be recommended in patients younger than 40 years of age. Nowadays, pHPT is diagnosed at an early stage and is often due to a single
parathyroid adenoma. pHPT in MEN2 is usually associated with RET mutations in codon 634.
A definitive diagnosis of MEN2 is made by RET sequencing (positive in 98% of cases). Genetic testing should be recom- mended in patients with phenotypic abnormalities and in all cases of MTC.
Key steps in the diagnosis and evaluation of MEN2
The following diagnostic algorithm outlines our approach for assessing a patient with a tumour belonging to the MEN2 tumour spectrum (i.e. MTC, PHEO, pHPT).
· Screen for a family history of thyroid cancer, PHEO, pHPT or unexplained sudden death.
· Screen for pathognomonic clinical findings: nostalgia paraes- thetica for MEN2A (codon 634 mutation), marfanoid body hab- itus and mucosal neuromas for MEN2B.
· Measurement of serum calcitonin in the evaluation of thyroid cancer, PHEO and pPHT diagnosed before the 4th decade. The routine measurement of serum calcitonin in all thyroid nodules remains controversial but should be encouraged, especially before surgery.
· Measurement of plasma or urine metanephrines, serum cal- cium and PTH in MTC patients.
· Refer MEN2 patients to a multidisciplinary referral centre for an appropriate evaluation and treatment.
· Perform RET sequencing in all cases of MTC (alone or in association with PHEO and/or pHPT). MTC with multifocal and bilateral tumours, CCH or extensive LN involvement are at higher risk of RET mutation.
Current radiopharmaceuticals
Preoperative localization of MEN2-related tumours involves various anatomical and functional imaging techniques. There are two major molecular imaging modalities used in nuclear medicine, namely positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Current SPECT/CT and PET/CT technologies enable attenua- tion correction of SPECT and PET studies and accurate locali- zation of positive foci. Radiopharmaceuticals for PET and SPECT potentially used in the imaging of MEN2 are detailed in Table 1.
Current status of preoperative imaging
Prior to prophylactic thyroidectomy
MEN2 provides a unique model for the early prevention and treatment of cancer based on genetic testing. In families known to have MEN2, genetic screening enables diagnosis of RET mutation carriers in childhood before C cells undergo malignant transformation. It has been demonstrated that when the disease is limited to CCH, children can be cured by total thyroidectomy alone. Recommendations for the timing of prophylactic thyroid- ectomy are stratified based on the type of RET mutations.2,5 No
| Acronym | Name | Imaging modality | Mechanism of cellular uptake | Indication |
|---|---|---|---|---|
| 131/123 I-MIBG | 131I/123I-Metaiodobenzylguanidine | SPECT | Norepinephrine transporter (NET) | PHEO |
| 18F-DOPA | 18F-dihydroxyphenylalanine | PET | L-type amino acid transporter 1 (LAT1/4F2hc) | PHEO/MTC |
| 68Ga-DOTATOC | 68Ga-DOTA-Tyr3-octreotide | PET | Somatostatin receptors | PHEO |
| 68Ga-DOTATATE | 68Ga-DOTA-Tyr3-octreotate | (sst2 for 68Ga-DOTATOC/TATE, | ||
| 68Ga-DOTANOC | 68Ga- Nal3- octreotide | sst2,3,5 for 68Ga-DOTANOC) | ||
| 18F-FDA | 18F-dopamine | PET | Norepinephrine transporter (NET) | PHEO |
| 11C-HED | 11C-hydroxyephedrine | PET | Norepinephrine transporter (NET) | PHEO |
| 99mTc-MIBI (sestamibi) | 99mTc-methoxy-isobutyl-isonitrile | SPECT | Passive diffusion across plasma membrane | pHPT |
PET, positron emission tomography; PHEO, pheochromocytoma; pHPT, primary hyperparathyroidism; MTC, medullary thyroid carcinoma; SPECT, single-photon emission computed tomography.
imaging study is needed prior to prophylactic thyroidectomy since the thyroid gland is normal6 and the likelihood of pHPT or PHEO at this stage is almost always zero, but both should be excluded by biochemical testing.
Prior to initial therapeutic surgery
Medullary thyroid carcinoma. At later stages, MTC becomes multicentric and bilateral with possible metastatic spread to both the central and lateral cervical lymph nodes.
Neck ultrasonography (US) is the method of choice for stag- ing nodal metastases and imaging the primary tumour(s). US is less accurate for detecting central compartment disease than the lateral compartments. However, a central compartment dissec- tion should be routinely performed in all patients undergoing a total thyroidectomy for clinically evident MTC as up to 80% of patients will have metastases to the central neck nodes. In cases when the primary tumour is less than 1 centimetre, the risk of lateral neck lymph node metastasis is lower and the need for lat- eral neck node dissection is based on the results of the preopera- tive US. In cases when the primary tumour is 1 cm or larger, the risk of lateral neck metastasis is higher and at least an ipsi- lateral lateral neck node dissection should be performed. Hypo- parathyroidism is the main complication of the initial surgery of MTC. The main reason is related to the difficulty of preserving inferior parathyroid glands during central lymph node dissection (LND), which aims to achieve an en bloc removal of both thy- roid and central compartment lymph nodes. The rate of hypo- parathyroidism is even more frequent when initial surgery was indicated for MTC and pHPT.
In large MTCs with possible local invasion, CT or MRI pro- vides a good characterization of the extent of tumour invasion into vital structures in the neck and mediastinal or surrounding structures. In patients with elevated calcitonin levels (>1000 pg/ ml), additional imaging studies should be considered to rule out distant (often hepatic) metastases. This should include whole- body CT, bone MRI (whole-body MRI or MRI of spinal and pelvic bone marrow), and bone scintigraphy. 18F-FDOPA and 18F-FDG PET/CT may be useful in patients suspected to have metastatic disease (Fig. 1). Many patients without detectable
MTC metastasis on imaging studies but elevated calcitonin levels are often found to have hepatic metastases upon laparoscopic liver evaluation. Even though identification of distant metastases makes curability by the primary surgery almost impossible, the primary tumour should still be removed to prevent local airway or oesophageal invasion.
Primary hyperparathyroidism. Primary hyperparathyroidism is often related to one or more abnormal parathyroid glands (Fig. 2). Parathyroidectomy should be limited to all abnormal glands and carefully assessed during surgery.
When pHPT is diagnosed in the preoperative work-up of MTC, minimally invasive (focused) surgical approach is not a treatment option of pHPT as bilateral cervicotomy is required for total thyroidectomy. In this context, US initially used for thyroid gland evaluation is often the first most frequently used modality for parathyroid gland imaging. The role of parathyroid scintigraphy (PS) is more limited. Nevertheless, PS can be pro- posed to detect ectopic or supernumerary glands. The precise localization of abnormal glands may also potentially reduce the area of surgical exploration and therefore reduce operating time and complications.
When pHPT is diagnosed after thyroidectomy in the follow-up of MEN2 patients, preoperative localizing studies are definitely needed and only a focused approach (FA) would be used based on two studies showing the same enlarged parathyroid gland(s). Parathyroid US and PS are the commonest imaging modalities used for selecting candidates for FA. Over the last decades, sev- eral protocols of parathyroid scintigraphy have been evaluated for parathyroid imaging including both single-tracer and dual- tracer methods and several acquisition techniques (i.e. planar acquisitions with parallel-hole or pinhole collimators and SPECT or SPECT/CT). Head-to-head comparison between different pro- tocols has rarely been addressed, but dual-tracer methods provide the highest sensitivity in the detection of small lesions and multi- glandular disease.7-12 In our opinion, for MEN2 patients, the optimal protocol should use 99mTc-MIBI/123I pinhole acquisition centred over the neck followed by cervicomediastinal SPECT/CT acquisition. Pinhole images offer the highest sensitivity while SPECT/CT images provide 3D images, which enable for precise
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localization of tumours located very deeply within the neck or in the posterosuperior mediastinum. False-negative results are attributed to small parathyroid lesions and cystic functioning parathyroid lesions (after necrosis or cystic degeneration). Neck, and especially chest, CTs or MRIs provide useful anatomical localization of ectopic parathyroid glands. The use of 4-dimen- sional computed tomography (4D-CT) for parathyroid imaging
has been reported13 but increases radiation exposure to the patient.
Pheochromocytoma. As the penetrance and the occurrence of unilateral as well as bilateral PHEO in MEN2 patients is at least 50%, there are specific approaches to MEN2-related PHEO. First, all known MEN2 patients need to be biochemically
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screened, usually once yearly for the presence of any newly developed unilateral or bilateral PHEOs. In screening at risk patients (with known RET mutation), false-negative results of biochemical testing can be common in tumours that are less than 6-7 mm in size.14,15 Once the biochemical diagnosis is confirmed (always by elevated plasma or urine epinephrine/ metanephrine levels), the imaging follows. Thus, it is not recommended to perform any adrenal imaging before the biochemical phenotype (always adrenergic) of a tumour is established. The exception to this rule could be in patients with characteristic spells of catecholamine excess despite negative biochemistry - a situation that commonly occurs in PHEOs smaller than 1 cm.
The most common and recommended approach to search for adrenal PHEO is to use MRI or adrenal CT (usually with 1-2 mm thin cuts). CT is preferable over MRI due to its excel- lent resolution that provides a very detailed anatomical location of a tumour and its surrounding structures. Furthermore, a high Hounsfield unit (HU) value (usually over 30) is very supportive of the presence of PHEO. Most PHEOs are heterogeneous. On CT, the typical imaging phenotype of a PHEO is a dense and hypervascular mass with slow contrast washout. On the other hand, the advantage of using MRI over CT is the lack of expo- sure to ionizing radiation, which is an important factor in hereditary cases undergoing continuous clinical follow-up,
children, pregnant women or those patients with recent expo- sure to any excessive radiation. On MRI, PHEOs have been described as enhancing masses having characteristically high sig- nal intensity on T2-weighted imaging (found in approximately one-third of solid tumours).16,17 A wide spectrum of imaging appearances may be seen (i.e. intracellular lipid, haemorrhage, intense enhancement, cystic change, calcifications, rapid contrast material washout).
Once the biochemical diagnosis is established and the PHEO is localized, the question is whether to use any functional imag- ing modality for these tumours. Currently, we do not recom- mend the use of any functional imaging if a tumour is less than 5 cm since the likelihood of metastasis is very small. However, in tumours larger than 5 cm, the likelihood of metastatic disease is high and whole-body functional imaging is advised. Currently, different functional imaging studies (123I-MIBG or 18F-FDA and 18F-FDOPA PET) could be performed as all are very specific to PHEO, including metastatic disease.
Limited data are available from current literature with respect to functional imaging studies in MEN2-related PHEOs. MIBG scan remains a gold standard in the evaluation of these tumours. MIBG is commercially available and labelled with 123I or 131I. 123 BI-MIBG scintigraphy is preferable to 131I-MIBG scintigraphy because (a) it provides higher-quality images (the 159 keV emis- sion of I-123 is better adapted to detection with conventional
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gamma cameras); (b) the lower radiation burden of I-123 allows a higher permissible administered activity, resulting in a higher count rate; (c) SPECT can more feasibly be performed with I-123; (d) less time elapses between injection and imaging with 123I-MIBG scintigraphy (24 h) than with 131I-MIBG scintigraphy (48-72 h).
MEN2-related PHEOs also increasingly concentrate the other radiopharmaceuticals that target the norepinephrine transporter (NET) system (111C-HED, 11C-ephedrine, 11C-phenylephrine, 18F-FDA). MEN2-related PHEOs are also highly avid for the 68 Ga-SSTa (DOTATOC/TATE/NOC).18 However, the main drawback of these different PET imaging modalities is related to high uptake by normal/hyperplastic adrenal medulla which limit their use prior to initial surgery. 111In-pentetreotide scintigraphy (OctreoScan® Mallinckrodt, Petten, the Netherlands) is subopti- mal for localizing MEN2-related PHEOs.
A special advantage of 18F-FDOPA PET over these tracers stems from its lack of high uptake in normal adrenal glands. Based on the recent European Association of Nuclear Medicine (EANM) guidelines, 18F-FDOPA uptake should be considered as pathological only in cases of asymmetrical adrenal uptake with concordant enlarged gland or adrenal uptake more intense than the liver with concordant enlarged gland.19 A combination of
18F-FDOPA PET/CT and CT/MRI was found to be the optimal imaging strategy.20,21 By contrast to PHEOs related to mutations in one of the genes encoding for succinate dehyrogenase subun- its (SDHx-related PHEOs), 18F-FDG PET is considered as sub- optimal in the diagnosis of MEN2-related PHEOs even if some tumours may exhibit high tracer uptake (Figs 3 and 4).22
In summary, information provided by anatomical imaging guides surgeons towards the most appropriate surgical route (laparoscopic, retroperitoneoscopic and laparotomy) and strat- egy (total vs subtotal). However, the final decision concerning the possibility of subtotal adrenalectomy is usually made intra- operatively, especially in tumours larger than 2 cm. A ‘watchful waiting’ strategy could also be acceptable in asymptomatic patients with negative biochemistry (these tumours are usually found during screening for RET carriers) since malignancy rarely occurs in MEN2 patients and negative biochemistry does not put a patient at higher risk of hypertensive crisis, arrhythmia or other cardiovascular complications. This is particularly applica- ble for tumours smaller than 2 cm. If possible, subtotal adrenal- ectomy (cortical-sparing surgery) is the treatment of choice in MEN2-related PHEO.23-25 Therefore, follow-up should not be delayed beyond the scheduled time for cortical-sparing surgery. In cases of bilateral PHEO, this strategy offers the advantage of
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potentially avoiding steroid supplementation and is usually achieved by performing cortical-sparing surgery on one gland, while the one with a larger tumour is fully removed.26 However, this strategy should be balanced by evaluating the risk of developing recurrent disease and/or metastases. The 10-year cumulative risk for developing recurrences is estimated to be 39-52%.27,28
Prior to reoperations for persistent/recurrent disease
Medullary thyroid carcinoma. A combination of radiological and functional studies with head-to-head comparison is needed to fully delineate the extent of the disease and define a personalized treatment strategy. Sensitivities of imaging studies are widely dependent on calcitonin levels. CT and functional imaging studies have low sensitivities when calcitonin levels are <150 pg/ ml.29
18F-fluoro-dihydroxyphenylalanine (18F-FDOPA PET) is the most useful PET tracer in detecting MTC. In the past decades, several studies have evaluated the role of 18F-fluoro-dihydroxy- phenylalanine (18F-FDOPA) PET(/CT) in the localization of per- sistent/recurrent MTC.30-35 18F-FDOPA, which was initially
developed to investigate dopaminergic neurotransmission, is taken up through a non-specific neutral amino acid transporter (LAT1/4F2hc complex). Overall, the lesion-based detection rate is about 70%.36 However, a head-to-head comparison between 18F-FDOPA PET and histological findings, the gold standard, have rarely been addressed. Based on our long-standing clinical experience, the number of metastatic lesions is often underesti- mated by 18F-FDOPA PET/CT (unpublished observations). More recently, it has been shown that 18F-FDOPA PET/CT pro- tocols need to be adapted to patients with MTC since tumour uptake of 18F-FDOPA decreases by 40% between early and delayed images (Fig. 1).37 It should be recommended to perform an early acquisition (during the first 15 min) centred over the neck and upper mediastinum followed by a standard 3D whole- body acquisition (Fig. 5). The potential interest of using carbid- opa (a selective extracerebral aromatic amino acid decarboxylase inhibitor) premedication for improving the bioavailability of the tracer is still unknown.
18F-FDG is taken up by tumour cells via glucose membrane transporters and phosphorylated by hexokinase into 18F-FDG- 6P. 18F-FDG-6P does not follow further enzymatic pathways, and it is assumed that 18F-FDG accumulates proportionally to
the glycolytic cellular rate. 18F-FDG PET/CT appears to be sub- optimal in MTCs. MTCs often exhibit high 18F-FDG uptake in later stages of disease and should be used as a biomarker of aggressiveness, as well as short calcitonin or CEA doubling times (less than 1 year).35 However, this technique may be useful in restaging MTC and when considering treatment intervention or experimental treatment options.
Although most NETs express somatostatin receptor type 2 (sst2), the distribution and density of sst2 are often variable and sometimes too low for effective somatostatin receptor targeting. The low expression of sst2 in MTC38,39 may explain the low sen- sitivity of the newly introduced 68Ga-SSTa for PET imaging in this setting. 40
Identification of distant metastases may indicate the need for specific treatments and may also be contraindicated for reopera- tive removal of cervical and/or mediastinal nodes unless they are symptomatic. In the absence of distant metastases, resection of locoregional disease (thyroid bed, LN) can be performed to avoid subsequent locoregional invasion or painful complications and reduce serum calcitonin. Remission status is rarely achieved after reoperations, but persistence of moderately high levels of calcitonin usually does not cause any symptoms.41 Only a small percentage of patients who have liver metastases and highly
elevated calcitonin may have diarrhoea and flushing. With the increasing use of radiosurgery in its various modalities, ablative approaches have become possible for tumours localized in chal- lenging anatomical areas. To this aim, functional imaging may help in the delineation of target biological volumes.
Primary hyperparathyroidism. In cases of persistent/recurrent pHPT, imaging is required to avoid extensive surgical exploration and limit surgical morbidity (recurrent laryngeal nerve injury, hypoparathyroidism).
Neck US and sestamibi scanning are commonly performed in recurrent pHPT. The subtraction method is also useful in thy- roidectomized patients who have thyroid tissue remnants.
In cases with negative imaging studies, additional imaging with MRI and CT scans as well as invasive imaging studies with venous sampling for PTH and hypocalcaemia infusion arterio- gram are indicated to help localize the enlarged parathyroid gland(s).
Pheochromocytoma. After subtotal adrenalectomy, patients need to first be biochemically screened for persistent/recurrent disease. Imaging is useful for early detection of recurrences from adrenal remnants. As stated below, radiopharmaceuticals that
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| first-line | second-line | third-line | |
|---|---|---|---|
| MTC | |||
| Prophylactic thyroidectomy | Neck US (optional) | MRI of bone marrow, bone scintigraphy, 18F-FDOPA PET/CT, 18F-FDG PET/CT* 18F-FDG PET/CT# | |
| Initial surgery | Neck US | Cervicothoracic CT and/or MRI 18F-FDOPA PET/CT, MRI of bone marrow, bone scintigraphy]} | |
| Reoperations pHPT | Neck US+cervicothoracic CT | ||
| Initial surgery | Neck US+/- Parathyroid scintigraphy (PS)§ | Parathyroid CT | |
| Reoperations | Neck US+PS | Parathyroid CT | |
| PHEO | |||
| Initial surgery | Abdominal CT or MRI+/-123I-MIBG or 18F-FDOPA PET/CT | 118F-FDG PET/CT or 18F-FDA PET/CT | 68 Ga-SSTa |
| Reoperations | Abdominal CT or MRI+123I-MIBG or 18F-FDOPA PET/CT | 118F-FDG PET/CT or 18F-FDA PET/CT |
PET, positron emission tomography; PHEO, pheochromocytoma; pHPT, primary hyperparathyroidism; MTC, medullary thyroid carcinoma; SPECT, single-photon emission computed tomography.
These recommendations should be adapted to the practical situation in each institution and should evolve with time. 18F-FDA PET is currently used at the NIH only. 68Ga-SSTa are nowadays accessible in many clinical and research centres in the world.
*In patients with highly elevated calcitonin and low uptake values on 18F-FDOPA PET/CT. 18F-FDG avidity is used as a biomarker of aggressiveness. ¡In patients with serum calcitonin>150 pg/ml.
¿First-line imaging choice in patients with short calcitonin and/or carcinoembryonic antigen (CEA) doubling time. §Routinely used in patients with previous history of thyroidectomy.
target the NET and vesicular monoamine transporters (VMATs) (123I-MIBG, 18F-FDA) are hampered by insufficient specificity. 18F-FDOPA PET/CT, characterized by lower normal/hyperplastic adrenal medulla uptake, may provide further information in the distinction between compensatory adrenal remnant hyperplasia and recurrent PHEO, when compared with CT. It is not uncommon to detect recurrent PHEO, developed from remnant retrocaval adrenal tissue, after a presumed total adrenalectomy (Fig. 6). 18F-FDG PET is considered as suboptimal even if some tumours may exhibit a high tracer uptake.22 Positron emission tomography/MR using an integrated system with simultaneous acquisition of both techniques also holds promise for PHEO, most likely for anatomical sites after a previous operation (e.g. recurrence). 42
The use of imaging is also recommended after resection of a PHEO at higher risk of malignancy even if fractionated meta- nephrines remain in the normal range (large tumour size and unfavourable histological features).
Future directions
Successful treatment of MEN2 heavily depends on accurate preop- erative staging and the medical team’s experience. The imaging modalities should be tailored to the clinical situation (Table 2).
For MTC, a highly sensitive diagnostic modality is still unavail- able. Presently, 18F-FDOPA PET is the most useful PET tracer in detecting persistent/recurrent disease. It is therefore possible that 18F-FDOPA PET may also be useful prior to initial surgery, although properly designed studies have not been carried out.
Specific overexpression of cholecystokinin 2 (CCK2)/gastrin receptors has been demonstrated in MTC and may represent new therapeutic and imaging targets. Development of CCK2/gastrin receptor ligands is still ongoing in different laboratories.43 Molec- ular imaging using engineered antibodies and fragments also pro- vides a general approach for targeting cell surface proteins with high affinity, such as CEA. Pretargeting techniques have also been developed for increasing selective tumour uptake.43
Excellent results from molecular profiling studies now provide important and promising information in the identification of new therapeutic and imaging targets. Functional imaging should benefit from the development of targeted therapies such as PET imaging with small-molecule tyrosine kinase inhibitors (TKI- PET). TKI-PET has been actively pursued to monitor the clinical potential of targeted therapeutics and treatments as well as to determine kinase receptor density changes related to disease pro- gression.44 The use of radiolabelled anticancer TKIs that target RET oncogene should also be of particular interest in the locali- zation and characterization of MTC.
In patients with pHPT, the use of parathyroid-specific PET tracers could improve detection of hyperplastic parathyroid glands. To this end, radiolabelled calcimimetics that bind to the calcium sensing receptor (CaR) as agonists could be a promising approach.
MEN2-PHEOs exihibit a high degree of cell differentiation and could therefore be accurately visualized by currently available
specific radiopharmaceuticals. Adrenal cortex-sparing surgery is a valid option for MEN2 disease. Preoperative mapping of different functional adrenal cortical areas and assessment of their degree of functionality could guide surgeons towards the most appropri- ate management and predict residual cortical function after corti- cal-sparing surgery. To this end, high-affinity PET ligands for the LDL-C and steroidogenic enzymes can play an important role.
Disclosure statement
The authors have nothing to disclose.
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