European Journal of Nuclear Medicine and Molecular Imaging (2021) 48:2801–2822 https://doi.org/10.1007/s00259-021-05334-y GUIDELINES The EANM practice guidelines for parathyroid imaging Petra Petranović Ovčariček 1,2 & Luca Giovanella 1,3,4 & Ignasi Carrió Gasset 5 & Elif Hindié 6 & Martin W. Huellner 7 & Markus Luster 1,8 & Arnoldo Piccardo 9 & Theresia Weber 10 & Jean-Noël Talbot 11 & Frederik Anton Verburg 1,12 Received: 25 January 2021 / Accepted: 23 March 2021 / Published online: 10 April 2021 # The Author(s) 2021 Abstract Introduction Nuclear medicine parathyroid imaging is important in the identification of hyperfunctioning parathyroid glands in primary hyperparathyroidism (pHPT), but it may be also valuable before surgical treatment in secondary hyperparathyroidism (sHPT). Parathyroid radionuclide imaging with scintigraphy or positron emission tomography (PET) is a highly sensitive procedure for the assessment of the presence and number of hyperfunctioning parathyroid glands, located either at typical sites or ectopically. The treatment of pHPT is mostly directed toward minimally invasive parathyroidectomy, especially in cases with a single adenoma. In experienced hands, successful surgery depends mainly on the exact preoperative localization of one or more hyperfunctioning parathyroid adenomas. Failure to preoperatively identify the hyperfunctioning parathyroid gland challenges minimally invasive parathyroidectomy and might require bilateral open neck exploration. Methods Over a decade has now passed since the European Association of Nuclear Medicine (EANM) issued the first edition of the guideline on parathyroid imaging, and a number of new insights and techniques have been developed since. The aim of the present document is to provide state-of-the-art guidelines for nuclear medicine physicians performing parathyroid scintigraphy, single-photon emission computed tomography/computed tomography (SPECT/CT), positron emission tomography/computed tomography (PET/CT), and positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with pHPT, as well as in those with sHPT. Conclusion These guidelines are written and authorized by the EANM to promote optimal parathyroid imaging. They will assist nuclear medicine physicians in the detection and correct localization of hyperfunctioning parathyroid lesions. Keywords Parathyroid scintigraphy . Hyperparathyroidism . [ 99m Tc]Tc-MIBI . [ 99m Tc]Tc-tetrofosmin . SPECT/CT . Dual-phase scintigraphy . Dual-tracer scintigraphy . 18F-labeled choline analogues . [11C]CH . [11C]MET . PET/CT . Cervical ultrasonography . 4D-CT . MRI This article is part of the Topical Collection on Endocrinology * Frederik Anton Verburg 7 Department of Nuclear Medicine, University Hospital and University f.verburg@erasmusmc.nl of Zurich, Zurich, Switzerland 1 8 EANM Thyroid Committee, Vienna, Austria Department of Nuclear Medicine, University Hospital Marburg, 2 Marburg, Germany Department of Oncology and Nuclear medicine, University Hospital Center “Sestre milosrdnice”, Zagreb, Croatia 9 Department of Nuclear Medicine, E.O. Ospedali Galliera, 3 Clinic for Nuclear Medicine and Competence Centre for Thyroid Genoa, Italy Diseases, Imaging Institute of Southern Switzerland, Bellinzona, Switzerland 10 Department of Endocrine Surgery, Katholisches Klinikum Mainz, 4 Clinic for Nuclear Medicine and Interdisciplinary Thyroid Centre, Mainz, Germany University Hospital and University of Zurich, Zurich, Switzerland 11 5 Nuclear Medicine, Hospital Tenon APHP and Sorbonne University, Department of Nuclear Medicine, Hospital Sant Pau and Paris, France Autonomous University of Barcelona, Barcelona, Spain 6 12 Department of Nuclear Medicine, Bordeaux Hospital and University, Department of Radiology and Nuclear Medicine, Erasmus MC, Bordeaux, France Rotterdam, The Netherlands 2802 Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 Preamble than men [3]. It is caused by the hyperfunction of one or more parathyroid glands, which are overproducing PTH. The European Association of Nuclear Medicine (EANM) is a Hyperfunctioning parathyroid glands are solitary adenomas professional non-profit medical association that facilitates in the majority of cases. Approximately 15–20% of cases are communication worldwide among individuals pursuing clini- caused by multiglandular disease (MGD) [4], i.e., multiple cal and research excellence in nuclear medicine. The EANM adenomas or hyperplasia, while parathyroid carcinoma ac- was founded in 1985. counts for less than 1% of cases. The majority of pHPT cases These guidelines are intended to assist practitioners in pro- (95%) occur sporadically, but approximately 5% are part of viding appropriate nuclear medicine care for patients. They hereditary syndromes, such as multiple endocrine neoplasia are not inflexible rules or requirements of practice and are types 1, 2, and 4 (MEN-1, MEN-2, and MEN-4) and not intended, nor should they be used, to establish a legal hyperparathyroidism-jaw tumor syndrome, or as part of non- standard of care. syndromic familial pHPT [5]. The ultimate judgment regarding the propriety of any spe- Familial hypocalciuric hypercalcemia, a potential differen- cific procedure or course of action must be made by medical tial diagnosis to pHPT, has to be recognized as it usually does professionals taking into account the unique circumstances of not require surgery. each case. Thus, there is no implication that an approach dif- Secondary hyperparathyroidism is a disorder characterized fering from the guidelines, standing alone, is below the stan- by increased serum PTH levels due to parathyroid gland hy- dard of care. To the contrary, a conscientious practitioner may perplasia, triggered by hypocalcemia, hyperphosphatemia, or responsibly adopt a course of action different from that set out decreased serum vitamin D concentration. The most common in the guidelines when, in the reasonable judgment of the causes of sHPT are vitamin D deficiency and chronic renal practitioner, such course of action is indicated by the condition disease. Sometimes pHPT and vitamin D deficiency occur of the patient, limitations of available resources, or advances simultaneously, which results in decreased or normal serum in knowledge or technology subsequent to publication of the calcium levels. Rarer causes are long-term treatment with lith- guidelines. The practice of medicine involves not only the ium or magnesium, intestinal malabsorption or malnutrition, science but also the art of dealing with the prevention, diag- or sunitinib treatment. nosis, alleviation, and treatment of disease. The therapy of sHPT depends on the primary cause. In the The variety and complexity of human conditions make it case of renal HPT, therapy mainly consists of a restriction of impossible to always reach the most appropriate diagnosis or dietary intake together with medical treatment with to predict with certainty a particular response to treatment. calcimimetics, vitamin D analogues, and phosphorus binders Therefore, it should be recognized that adherence to these [6]. Still, parathyroidectomy is required in patients with renal guidelines will not ensure an accurate diagnosis or a success- sHPT refractory to medical treatment, i.e., in approximately ful outcome. 15% of patients after 10 years and 38% of patients after All that should be expected is that the practitioner will 20 years of renal dialysis therapy [7]. follow a reasonable course of action based on current knowl- Paraneoplastic hyperparathyroidism is rare. In most cases it edge, available resources, and the needs of the patient to de- is due to parathyroid hormone-related peptide (PTH-rp) pro- liver effective and safe medical care. The sole purpose of these duction and the serum level of PTH is low in relation to hy- guidelines is to assist practitioners in achieving this objective. percalcemia. In rare cases, the culprit cancer produces PTH or both PTH and PTH-rp, while no hyperfunctioning parathyroid gland is present [8]. Most commonly, the PTH-rp secreting Introduction malignancies include squamous cell carcinoma (lung, head and neck, cervix) and some other solid tumors. Primary hyperparathyroidism is an endocrine disorder caused Parathyroid glands are typically located along both thyroid by one or more hyperfunctioning parathyroid glands. The sus- lobes. The superior parathyroid glands develop from the 4th picion of pHPT is typically raised by the detection of hyper- pharyngeal pouch and descend with the thyroid. They are calcemia and/or its associated symptoms. Parathyroid hor- located dorsal to the middle and upper poles of the thyroid, mone (PTH) serum concentration is elevated, or within nor- and above the inferior thyroid artery. The inferior parathyroid mal limits but inappropriate considering the presence of hy- glands develop from the 3rd pouch and descend with the thy- percalcemia. A rare type of pHPT is normocalcemic hyper- mus to ultimately remain close to the lower thyroid pole, and parathyroidism presenting with normal serum calcium levels more laterally [9]. Superior and inferior parathyroid glands but an elevated PTH concentration [1]. have a different relationship to the recurrent laryngeal nerve, Primary hyperparathyroidism is the third most common with the superior ones lying posterior to it, and the inferior endocrine disease [2], affecting women 2–3 times more often ones anterior to it. Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 2803 The incidence of ectopic parathyroid glands is approxi- (cUS), yielding a sensitivity of 81–95% [21, 22], which is mately 16% [10]. An ectopically located gland may be one mainly contributed by [ 99m Tc]Tc-MIBI scintigraphy. of the four standard parathyroid glands or a supernumerary Cervical ultrasonography can be combined with targeted gland. Most individuals (84%) have four parathyroid glands, fine-needle aspiration (FNA) cytology and detection of PTH two superior and two inferior glands, while supernumerary in the aspirate (FNA-PTH) in order to increase specificity and glands exist in 3 to 13% of individuals [11]. The total number confirm the diagnosis of hyperfunctioning parathyroid lesions of parathyroid glands in an individual with supernumerary in sonographically accessible locations [23]. Fine-needle as- glands may vary from 5 to 8 in number [12]. Rarely, in less piration cytology is recommended in highly selected cases, than 3% of cases, individuals may have only 3 glands [11]. e.g., atypical cUS presentation and uninformative Acquired ectopy of upper parathyroid glands is frequently [99mTc]Tc-MIBI. In case of negative standard imaging, encountered along the tracheoesophageal groove or more rare- second-line imaging may be performed, such as ly retroesophageally. They are usually in a lower position than N-[(18F)fluoromethyl]-2-hydroxy-N,N- expected (prolapsed glands) [13]. Moreover, ectopic glands dimethylethanaminium ([18F]FCH or [18F]fluorocholine) can be located anywhere along the migratory path [14], from PET/CT, L-[methyl-11C]methionine ([11C]MET) PET/CT, the carotid bifurcation to the pericardium. Ectopic sites, there- [ 11C]2-hydroxy-N,N,N-trimethylethanamium ([11C]CH) fore, include but are not limited to, a high cervical position, the PET/CT, so-called four-dimensional computed tomography carotid sheath, an intrathyroidal location, intrathymic location, (4D-CT), MRI, [ 1 8 F]fluorocholine PET/4D-CT or mediastinal location, or the paraesophageal region [15]. Very [18F]fluorocholine PET/MRI. [18F]fluorocholine PET/CT is rarely, they can also be located in the pericardium [16, 17]. also considered a potential “alternative” first-line method However, the most common location for ectopic upper para- whenever possible, as it appears to be an effective technique thyroid glands is along the esophagus, while ectopic lower even in patients with negative or equivocal standard imaging parathyroid glands most often have an intrathymic location findings. It is particularly useful in patients with sHPT [9]. [24–26]. Before revision surgery and/or in the case of negative Histologically, parathyroid glands consist of a chief, imaging techniques, invasive techniques, such as selective oxyphil, transitional oxyphil, and water-clear cells. Chief cells venous sampling or selective arteriography, may be are the most abundant cells [18]. They have a secretory func- performed. tion and are responsible for synthesizing and secreting PTH. Oxyphil cells are rich in mitochondria and their function is still unclear [19]. The function of water-clear cells is not clear- Goals ly understood as well. Owing to the abundance of mitochondria within the The EANM practice guidelines for parathyroid imaging are oxyphil cells, there is a high accumulation of [99mTc]Tc- written for nuclear medicine practitioners to promote the use MIBI and [99mTc]Tc-tetrofosmin in hyperfunctioning para- of optimal parathyroid imaging based on current knowledge. thyroid glands. The purpose of these recommendations is to assist in the per- Radionuclide parathyroid imaging reveals hyperfunction- formance, the correct interpretation, and reporting of the re- ing parathyroid glands located at typical sites as well as ectop- sults of the parathyroid imaging. ically. Using planar scintigraphy or SPECT, sensitivity is greater for adenomas compared with hyperplasia. Hyperplastic parathyroid glands are usually smaller than ade- Background nomas, which is associated with decreased sensitivity of ra- dionuclide imaging [20]. Other factors may also contribute to Primary hyperparathyroidism is defined as high serum PTH reduced sensitivity for MGD (e.g., tracer washout from some levels due to the presence of enlarged hyperfunctioning para- lesions in dual-phase imaging, the inhibitory effect of hyper- thyroid gland(s). It is the most common cause of elevated calcemia, etc.). However, it is important to recognize MGD, as calcium levels in the ambulatory setting [3], although it holds implications for a successful surgery. Each subsequent calcemia in some cases may be normal. Rarely, PTH levels surgery in a postoperative neck is technically challenging and are normal with concomitant hypercalcemia. Primary hyper- carries an additional risk of complications, including failure to parathyroidism represents a considerable public health prob- remove the culprit gland(s). lem due to its high incidence and repercussions to patients’ For the reasons stated above, it is necessary to identify the health. Therapy primarily consists of the surgical removal of most sensitive and specific diagnostic procedure to detect hy- the hyperfunctioning parathyroid gland(s) [27]. Symptomatic perfunctioning parathyroid glands. The currently most wide- patients require treatment and generally undergo parathyroid- spread preoperative imaging procedure is the combination of ectomy, which is the only definitive therapy. Surgery is also [99mTc]Tc-MIBI scintigraphy and cervical ultrasonography an important option in asymptomatic patients who can 2804 Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 develop hypercalcemia and target organ involvement later in before primary surgery for renal hyperparathyroidism, and life [28]. If surgery is indicated, preoperative localization of bilateral open neck exploration is considered in these patients. the hyperfunctioning gland(s) allows for selective parathy- Still, radionuclide imaging may be helpful in cases of revision roidectomy, reducing operation time, complications and hos- surgery. In such circumstances, a combination of imaging pitalization, improving postoperative recovery, and resulting modalities is often required [37]. in a better cosmetic outcome, and greater patient satisfaction Radionuclide imaging is useful preoperatively to guide the [29, 30]. Nuclear medicine techniques and cUS are crucial in surgeon toward the exact location of one or more hyperfunc- identifying and localizing hyperfunctioning parathyroid tioning parathyroid glands, especially in the case of ectopic glands. Both methods have advantages, as well as limitations. glands that cannot be visualized with cUS. Correct preopera- The advantage of radionuclide parathyroid imaging over cUS tive localization may shorten the duration of surgery, which lies in the identification of ectopic glands [31], as well as in nowadays mostly consists of minimally invasive parathyroid- easier recognition of posteriorly located upper glands [32]. ectomy combined with intraoperative PTH determination, Arguably it also enables an easier recognition of typically particularly in single-gland disease. In the past, bilateral open located hyperfunctioning parathyroid glands in the back- neck exploration was the standard surgical approach. ground of thyroiditis. It is known that thyroiditis is usually However, both techniques are appropriate and accomplish followed by enlarged lymph nodes that are sometimes imitat- high cure rates [39]. Excision of all hyperfunctioning parathy- ing hyperfunctioning parathyroid glands on cUS [33]. On the roid glands is pivotal for successful parathyroidectomy. other hand, suspected hyperfunctioning parathyroid glands in Radionuclide parathyroid imaging is especially useful in the neck on radionuclide imaging can be further examined patients with recurrent disease because the second operation with cUS in order to avoid false-positive results. In patients is technically more challenging than the first one, and hence a with multinodular goiter, [99mTc]Tc-MIBI scintigraphy might precise preoperative localization of hyperfunctioning parathy- be false negative, and cUS is mandatory [34]. In these cases, roid gland(s) is important. dual-tracer methods and [18F]fluorocholine PET/CT are use- Radionuclide parathyroid imaging is also useful in con- ful as well [35]. Additionally, cUS is a valuable method for junction with cUS, foremost in patients with hereditary disor- excluding coexisting thyroid pathology in most cases, al- ders, such as MEN-1, MEN-2, and MEN-4, although sensi- though in toxic multinodular goiter or thyroid remnants after tivity for hyperplasia is lower compared with sporadic adeno- hemithyroidectomy dual-tracer methods are helpful as well. If ma. In this context, PET/CT might be preferred, owing to its a hyperfunctioning parathyroid gland is identified during cUS, higher spatial resolution [40]. The identification of hyperfunc- radionuclide imaging may still prove to be useful because of tioning glands can be supported by a γ-probe during surgery, possible undetected MGD, as well as ectopic glands. For the especially in patients who underwent previous surgical treat- reasons stated above, in addition to radionuclide parathyroid ment [41]. gland imaging, using SPECT and/or PET tracers, these guide- lines will also discuss ultrasound of the parathyroid glands as the main complementary diagnostic imaging modality. Precautions Additionally, the use of 4D CT, MRI, and invasive techniques in identifying abnormal parathyroid glands will be addressed It is necessary to exclude pregnancy in women of childbearing in brief. age. In pregnant patients, radionuclide imaging should only be performed if deemed absolutely necessary, as decided by a Indications multidisciplinary team. Otherwise, it should be postponed af- ter pregnancy. Instead, cUS and MRI may be preferred in this Radionuclide parathyroid imaging is used for the localization case. of one or more hyperfunctioning parathyroid glands in pa- For more information, we advise to consult the American tients with pHPT, and not for the diagnosis of hyperparathy- College of Radiology (ACR) Practice Guideline for imaging roidism (HPT). It might be also valuable before surgical treat- pregnant or potentially pregnant adolescents and women with ment in sHPT due to possible detection of ectopic and super- ionizing radiation [42]. numerary glands, as well as a parathyroid gland with the low- In breastfeeding women, it is recommended to consult the est [ 99m Tc]Tc-MIBI uptake which may be partially International Commission on Radiological Protection (ICRP) autografted or preserved [36, 37]. Périé et al. recommend a Publication 128: Radiation Dose to Patients from combination of cUS and dual-tracer scintigraphy for routine Radiopharmaceuticals: A Compendium of Current use to localize hyperfunctioning parathyroid glands in patients Information Related to Frequently Used Substances [43]. with renal HPT undergoing surgical treatment [38]. However, When using 99mTc-labeled radiopharmaceuticals, interruption surgeons usually do not order [99mTc]Tc-MIBI scintigraphy of breastfeeding is not essential if free pertechnetate is absent Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 2805 in the radiopharmaceutical. However, a pause of 24 h during 3. Results of cervical US, including the thyroid and parathy- which expressed feeds are discarded is recommended in some roid glands summaries of product characteristics (SmPC) of 99mTc labeled 4. Results of other imaging modalities, such as 4D-CT, and radiopharmaceuticals with marketing authorization. In the MRI, if any case of Na[99mTc]TcO4, which is used for subtraction imag- 5. History of any prior neck and/or thoracic surgery ing, a 12 h pause is recommended. For Na[ 1 2 3 I]I, 6. History of malignancy, because of possible tracer accu- breastfeeding interruption for > 3 weeks is advised due to mulation in neoplastic tissue the risk of other iodine isotope contamination. However, if 7. History of recent nuclear medicine procedures the product has high purity (> 99.65%), the pause may be 8. Recent iodine intake (e.g., intravenous contrast medium, shorter. In the SmPC of some Na[123I]I preparations, 1– iodine-containing medication …) or thyroid hormone re- 3 days pause is recommended, and breastfeeding can be placement therapy in case of subtraction study with restarted when the activity level in the milk has reduced so Na[99mTc]TcO4 or Na[123I]I, or therapy with cinacalcet that it will not result in a radiation dose to the child greater and other calcimimetics in case of [99mTc]Tc-MIBI than 1 mSv. To be on the safe side we recommend a 3-day imaging pause. It is not known whether [11C]CH, 18F-labeled choline 9. Use of calcium channel blockers if scintigraphy is per- analogues, and [11C]MET are excreted in breast milk. Still, for formed with [99mTc]Tc-MIBI 11 C-labeled radiopharmaceuticals, interruption is not essential due to their short physical half-life. No recommendation Patients should be provided with information on how the concerning the pause in lactation for 18F-labeled choline ana- examination is performed and the estimated duration. The logues is available in ICRP publication 128, but it may be patient should be advised to stay calm during image acquisi- found in the SmPC of the 18F-labeled choline analogues prep- tion. In rare cases, e.g., in patients with severe claustrophobia, aration with a marketing authorization. A 12 h pause is rec- sedation may be helpful. ommended in some SmPCs. Patients may eat, drink, and take most of the necessary medications. However, active D vitamin analogues and calcimimetics may decrease [99mTc]Tc-MIBI uptake [44]. If Qualifications and responsibilities possible, these should be paused for 2 weeks before scintig- of personnel raphy [36]. Calcium channel blockers may reduce uptake of Nuclear medicine physicians, technicians and all other staff [99mTc]Tc-MIBI as well [45]. Friedman et al. in a retrospec- involved in performing and reporting parathyroid radionu- tive study found that the odds ratio for a negative scan is 2.88 clide imaging should be qualified according to applicable laws in patients taking calcium channel blockers compared with and regulations, and individual responsibilities should be those without such medication (OR 2.88, 95% CI, 1.03– clearly documented. 8.10; p = 0.045). Still, further studies are necessary to confirm the reversibility of this finding, and to determine the appropri- ate withdrawal period. Useful clinical information for optimal In a dual-tracer study, the thyroid scan should be performed imaging and interpretation without iodine saturation. Many factors can influence thyroid uptake of subtraction radiopharmaceuticals [46]. Dual-phase A request for parathyroid radionuclide imaging must be sub- [99mTc]Tc-MIBI scintigraphy, instead of dual-tracer scintigra- mitted to a nuclear medicine physician. It should provide suf- phy, is recommended for patients on thyroid hormone replace- ficient data to allow the responsible nuclear medicine physi- ment therapy to avoid therapy withdrawal and subsequent cian to assess the indication for the scan adequately, as well as development of hypothyroidism. to interpret the images. Currently, no standardized patient preparation or image The patient is also questioned (if possible) for relevant acquisition guidelines exist for parathyroid imaging with information that may help interpret the findings. PET tracers. In the case of radiolabelled choline, vigorous In pre-imaging reporting it is useful to document: exercise may increase muscle uptake of the radiopharmaceu- tical, so it is advisable to avoid such before scanning [47]. 1. Serum intact PTH level and either albumin corrected or If a diagnostic CT scan with iodinated contrast medium is ionized calcium and serum 25-hydroxy vitamin D level required, it is important to ask the patient about possible aller- (mandatory) gies to iodinated contrast medium as well as to ascertain an 2. Serum phosphorus, 24-h urinary calcium levels, creati- adequate kidney and thyroid function; for more information, nine, markers of bone turnover, e.g., bone-specific alka- we advise to consult the European Society of Urogenital line phosphatase (optional) Radiology (ESUR) guidelines on contrast media: Post- 2806 Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 contrast acute kidney injury—Part 1: Definition, clinical fea- usually washes out faster from the thyroid than from the hy- tures, incidence, role of contrast medium and risk factors; perfunctioning parathyroid, making it convenient for the Post-contrast acute kidney injury—Part 2: risk stratification, single-tracer dual-phase method. role of hydration and other prophylactic measures, patients However, not all hyperfunctioning parathyroid glands re- taking metformin and chronic dialysis patients [48, 49]. tain [99mTc]Tc-MIBI and thyroid tissue sometimes does not rapidly washout [56]. Therefore, in some cases, other proto- cols might be helpful. In the case of a rapid parathyroid wash- Scintigraphy and SPECT out, it would be reasonable to perform additional images be- tween the standard early and late phase ones. Alternatively, Parathyroid gland scintigraphy has involved many different dynamic imaging may be used. On the other hand, in the case radiotracers used with different protocols over the past of a slow thyroidal washout, subtraction imaging may be decades. helpful. In the 1980s, parathyroid gland scintigraphy was per- [99mTc]Tc-MIBI SPECT/CT scintigraphy is the current formed with [201Tl]thallous-chloride ([201Tl]TlCl) in combi- standard method for detecting hyperfunctioning parathyroid nation with [99mTc]Pertechnetate ([99mTc]NaTcO4) as a dual- glands, with a reported patient-based and lesion-based pooled tracer method. The success rate in operated patients was com- detection rate (DR) of 88% in a meta-analysis of twenty-three parably good, reaching 92% [50]. However, [201Tl]TlCl has papers including 1236 patients with pHPT [57]. Furthermore, poor physical characteristics as an imaging agent, due to sub- it was shown to be a cost-effective technique [58]. optimal photon energy (69–81 keV). Additionally, it has a However, its sensitivity is significantly lower in the case of long physical half-life (73 h) and thus results in a nowadays MGD compared with single-gland disease [59, 60], which is a unacceptably high whole-body radiation exposure. known issue also with other imaging modalities. Nichols et al. [201Tl]TlCl should no longer be used for parathyroid imaging. in a study of 651 patients with HPT (20% with MGD, and Furthermore, it is a cyclotron-produced radionuclide, and as 80% with single-gland disease) who underwent preoperative such relatively expensive. In 1989, Coakley et al. reported the dual-tracer [99mTc]Tc-MIBI/Na[99mTc]TcO4 scintigraphy use of [99mTc]Tc-MIBI for parathyroid localization, revealing found the sensitivity of this method to be 61% for MGD, vs. better imaging characteristics of this tracer compared with 97% for single-gland disease [60]. Medas et al. in a study that [201Tl]TlCl [51]. Eventually, [201Tl]TlCl was replaced with included 212 patients with HPT (8% with MGD, 91.5% with 99m Tc-labeled tracers of better physical characteristics: more single-gland disease, and 0.5% unknown) reported a sensitiv- favorable energy (140 keV) and shorter physical half-life ity of [99mTc]Tc-MIBI for MGD of 26.7% vs. 92.6% for (6 h), resulting in lower radiation exposure. Besides, 99mTc single-gland disease [59]. is ubiquitously available and comparatively inexpensive. The administered intravenous radioactivity in adults ranges More widespread use of [99mTc]Tc-MIBI and [99mTc]Tc- from 400 to 900 MBq, depending on the patient’s body mass, tetrofosmin began in the 1990s. The former was used in the whether or not SPECT is scheduled, and local regulations single-tracer and dual-tracer methods, while the latter was (Table 1). Whenever SPECT imaging is combined with CT, used mainly in a dual-tracer method in combination with care should be taken to use the lowest CT dose that is com- Na[99mTc]TcO4 or Na[123I]I. patible with the purpose. Radiopharmaceuticals targeting parathyroid glands [99mTc]Tc-1,2-bis[bis (2-ethoxyethyl) phosphino] ethane) ([99mTc]Tc-tetrofosmin) [99mTc]Tc-hexakis-(2-methoxy-2-isobutyl isonitrile) ([99mTc] Tc-MIBI) [99mTc]Tc-tetrofosmin is a lipophilic cation that localizes in thyroid and parathyroid tissue. Because there is no differential [99mTc]Tc-MIBI is the most widely used radiopharmaceutical washout between these tissues, it is suitable only for a dual- for parathyroid scintigraphy. It is a lipophilic cationic complex tracer subtraction method. The mechanism of uptake is similar that accumulates in hyperfunctioning parathyroid glands due to [99mTc]Tc-MIBI. It diffuses passively through the cell to their increased number of mitochondria [52], which is membrane and accumulates in mitochondria of parathyroid mainly related to the number of oxyphil cells [53]. Its uptake lesions [61]. The intravenously administered activity in adults and retention depend also on the cell cycle phase, parathyroid ranges from 400 to 900 MBq, depending on the patient’s body blood supply, capillary permeability, serum calcium level, ex- mass, whether or not SPECT is scheduled, and local pression of P-glycoprotein, and multidrug resistance (MDR) regulations. associated protein [54]. However, its use in parathyroid imaging is limited, despite [99mTc]Tc-MIBI has a greater uptake per gram of parathy- an overall good performance similar to that of [99mTc]Tc- roid tissue than per gram of thyroid tissue [55]. Additionally, it MIBI [56, 62, 63], owing, e.g., to the need for the dual- Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 2807 Table 1 Radiopharmaceuticals for parathyroid imaging. Characteristics, recommended activity range, and effective doses Radiopharmaceutical Administration Administered activity Photopeak Physical Effective dose per Effective dose for the upper route in adults (MBq) energy (keV) half-life activity unit (mSv/MBq) administered activity (mSv) Na[99mTc]TcO4 i.v. 74–150 140 6.04 h 0.0159* 2.4 [99mTc]Tc-MIBI i.v. 400–900 140 6.04 h 0.00703* 6.3 [99mTc]Tc-tetrofosmin i.v. 400–900 140 6.04 h 0.00629* 5.7 Na[123I]I o.a. (or i.v.) 7.4–14.8 159 13.2 h 0.108* (thyroid uptake 1.6 (thyroid uptake 15%) 15%) [18F]FCH i.v. 100–300 511 110 min 0.020** 6.0 [11C]MET i.v. 370–1100 511 20.3 min 0.00549* 6.0 [11C]CH i.v. 200–650 511 20.3 min 0.0044*** 2.9 i.v., intravenous; o.a.,oral administration,* [163],** [164],*** [165] tracer acquisition as well as local licensing and reimbursement to the EANM practice guideline/SNMMI procedure standard issues. for RAIU and thyroid scintigraphy [46]. Acquisition Subtraction radiopharmaceuticals Dual-phase parathyroid scan [99mTc]pertechnetate (Na[99mTc]TcO4) 99m [99mTc]Tc-MIBI scintigraphy is performed at two time points, Tc has a physical half-life of 6 h and emits gamma rays of i.e., at 10–15 min and 90–150 min after intravenous adminis- 140 keV. Na[99mTc]TcO4 is used in the dual-tracer method as tration of the radiopharmaceutical. The administered activity it is taken up by functioning thyroid cells. The ranges from approximately 400 to 900 MBq, depending on Na[99mTc]TcO4 image is subtracted from the [99mTc]Tc- the patient’s body mass, whether or not SPECT is scheduled, MIBI / [99mTc]Tc-tetrofosmin image, thus revealing hyper- and local regulations. Imaging is performed using large field- functioning parathyroid glands. of-view gamma cameras with low-energy, high resolution For further details on administered activity and image ac- (LEHR) collimators. The energy window should be in the quisition, please refer also to the EANM practice guideline/ range of 140 ± 10 keV and a matrix size of 128 × 128 or better SNMMI procedure standard for RAIU and thyroid scintigra- 256 × 256 should be employed. The entire neck and the chest phy [46]. The administered activity depends mainly on which down to the base of the heart should be included in the field of tracer is applied first, i.e., if the thyroid study is performed view. It is possible to use planar images in anterior and right before or after the [99mTc]Tc-MIBI / [99mTc]Tc-tetrofosmin and left anterolateral positions, but SPECT images, especially scan. If imaging starts with Na[99mTc]TcO4 scintigraphy, low- when fused with a simultaneously acquired CT, are superior er activities are required, i.e., 74–111 MBq compared with for anatomical localization of parathyroid tissue [64], espe- 150 MBq if the thyroid scan is performed after the cially in case of ectopic glands and altered neck anatomy [65]. [99mTc]Tc-MIBI scan. SPECT/CT with [99mTc]Tc-MIBI is superior to planar or stand-alone SPECT studies and dual-phase acquisition is more [123I]sodium-iodide (Na[123I]I) accurate than single-phase acquisition [66]. Therefore, it is recommended to perform at least one SPECT(/CT) study cov- 123 I has a half-life of 13 h and emits gamma radiation of ering the area between the skull base and the heart base. 159 keV. Na[123I]I is trapped but also organified by function- ing thyroid tissue. Na[123I]I is used in the dual-tracer method Dual-tracer parathyroid scan for subtraction purposes and provides good quality images. The Na[123I]I image is subtracted from a [99mTc]Tc-MIBI / [99mTc]Tc-MIBI usually has a differential washout between [99mTc]Tc-tetrofosmin image for easier visualization of re- the thyroid and parathyroid, so it is used as the single tracer of maining hyperfunctioning parathyroid gland tissue. dual-phase parathyroid scintigraphy in many nuclear medi- Disadvantages are its higher price compared with cine departments. However, sometimes the tracer washes out Na[99mTc]TcO4 and the 2 h waiting time between administra- rapidly from the parathyroid or is retained in the thyroid, es- tion of the radiopharmaceutical and acquisition of the scan. pecially in thyroid nodules. In such cases, the use of the dual- For further information on this radiopharmaceutical, we refer tracer method may be helpful. 2808 Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 Dual-tracer [99mTc]Tc-MIBI /Na[99mTc]TcO4 protocol Either recent study reported high sensitivity and specificity for sub- tracer, [99mTc]Tc-MIBI or Na[99mTc]TcO4 can be injected traction SPECT/CT (95% and 89%, respectively) [72]. The first. The administered activity of Na[99mTc]TcO4 is 74– positive predictive value (PPV) and negative predictive value 111 MBq if the protocol starts with thyroid imaging. For fur- were 97% and 83%, respectively. The accuracy in detecting ther details, please refer to the EANM practice guideline/ and localizing parathyroid adenomas were 94% and 92%, SNMMI procedure standard for RAIU and thyroid scintigra- respectively. However, this technique adds additional radia- phy [46]. 150 MBq of activity is used if thyroid imaging is tion exposure to the thyroid; it might take additional time and performed after the [99mTc]Tc-MIBI scan. is more expensive compared with a single-tracer method, al- Na[99mTc]TcO4 images are obtained 20–30 min after ad- though some institutions are trying to reduce administered ministration of the radiopharmaceutical, while [99mTc]Tc- activity and procedure length. MIBI images are obtained 10–15 min after injection. Images are inspected visually, normalized, and Na[99mTc]TcO4 im- Image analysis ages are either digitally or cognitively subtracted from the [99mTc]Tc-MIBI images. The following images are obtained: In dual-phase scintigraphy, early and delayed images are - a large field of view of the neck and mediastinum (from the inspected visually. Increased or sustained uptake on the de- skull base to the heart base); − a pinhole view of the thyroid layed [99mTc]Tc-MIBI image, compared with the early image, bed region; and a SPECT(/CT) acquisition whenever is considered a positive finding for a hyperfunctioning para- available. thyroid gland. However, some glands show a fast washout and In order to reduce administered activities and radiation ex- might not be identified clearly on delayed images. A fast posure, a waiting time of 2–3 days between tracers may be clearance is more common in hyperplastic glands. SPECT recommended. images may reveal parathyroid glands that are not seen on Imaging is performed using a large field-of-view gamma planar images. Additionally, SPECT/CT imaging provides a camera with LEHR collimators, a matrix size of 128 × 128 or superior anatomic localization of lesions. 256 × 256, and a 15% or 20% energy window centered at the In subtraction scanning, images need to be inspected visu- 140 keV (99mTc) photon peak. ally before and after subtraction. Focal accumulation of radio- pharmaceutical adjacent to the thyroid persisting after subtrac- Dual-tracer [99mTc]Tc-MIBI / Na[123I]I protocol Na[123I]I is first tion is suspicious for a hyperfunctioning parathyroid gland in administered orally or intravenously, and [99mTc]Tc-MIBI is loco typico; ectopic focal uptake is suspicious for an ectopic injected 2 h later. Na[123I]I and [99mTc]Tc-MIBI images are parathyroid lesion. As stated above, SPECT and SPECT/CT acquired simultaneously, starting 5 min after injection of yield an increased sensitivity, specificity, and more precise [99mTc]Tc-MIBI. Images are inspected visually, normalized anatomic localization compared with planar images. to thyroid counts, and Na[123I]I images are subtracted from The CT part of the study should be also analyzed for im- the [99mTc]Tc-MIBI images. The following images are obtain- portant findings, even without corresponding tracer uptake. ed: - a large field of view of the neck and mediastinum (from False-positive and false-negative results are occasionally the skull base to the heart base); − a pinhole view of the encountered. The most common causes of false-positive re- thyroid bed region; − a SPECT(/CT) acquisition when avail- sults are inflammatory thyroiditis, cervical lymphadenopathy, able [67–69]. and thyroid nodules (benign and malignant) behaving like Imaging is performed with a large field-of-view gamma parathyroid adenomas (in a single-tracer protocol) [73]. camera equipped with LEHR collimators. A matrix size of False-negative results usually occur due to small-sized hyper- 128 × 128 or 256 × 256 is recommended. For simultaneous functioning glands [73], a lack of oxyphil cells [74], parathy- acquisition, a 10% energy window centered on the 159 keV roid hyperplasia, multiglandular disease, and high expression is recommended for Na[123I]I and a 15–20% window centered of P-glycoprotein [75]. around 140 keV for [99mTc]Tc-MIBI. Alternatively, symmet- ric and asymmetric windows can be used (140 keV ± 7% for [99mTc]Tc-MIBI and 159 keV −4%; +10% for Na[123I]I) [70]. Positron emission tomography For Na[123I]I thyroid imaging, it is also possible to use a dedicated thyroid camera with a small field-of-view. The higher resolution of PET/CT imaging could improve the In both dual-tracer protocols images are subtracted at the detection of the smallest pathological glands, not visualized point of similar activity of [99mTc]Tc-MIBI in the thyroid by SPECT(/CT). It is recommended to use the scanner with gland and surrounding soft tissue. the highest system sensitivity and reconstruction protocols Dual-tracer scintigraphy with subtraction imaging has an optimized for small lesion detection (BSREM instead of excellent performance in the detection and localization of hy- OSEM). Whenever PET imaging is combined with CT, care perfunctioning parathyroid glands [71]. Woods et al. in a should be taken to use the lowest CT dose that is compatible Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 2809 with the purpose. Several different tracers have been studied [80]. Preoperative localization was reliable in 96.8% of with different protocols and results. patients. Currently, no standardized image acquisition guidelines In a recent head to head comparative study including 103 exist for PET tracers for parathyroid imaging. patients with pHPT, the diagnostic performance of [18F]fluorocholine PET/CT was superior to conventional scin- Radiopharmaceuticals tigraphic methods ([99mTc]Tc-MIBI SPECT/CT, [99mTc]Tc- MIBI / Na[99mTc]TcO4 subtraction imaging, and [99mTc]Tc- 18 F-labeled choline analogues MIBI dual-phase imaging), separately or combined, with a sensitivity of 92% for [18F]fluorocholine PET/CT, compared Choline is a cellular proliferation marker. The mechanism of with 39–56% for conventional imaging, and 65% for a com- uptake of 18F-labeled or 11C-labeled choline analogues is not bination of conventional methods [81]. The impact of the fully understood. As choline is a precursor of phosphatidyl- performance of the PET/CT machine on the performance of choline, a phospholipid constituent of the cell membrane, its [18F]fluorocholine imaging in patients with negative or incon- uptake, and processing for construction and maintenance of clusive [ 99m Tc]Tc-MIBI SPECT/CT has been recently the cell membrane is a possible explanation for its accumula- assessed by Lopez-Mora et al. [82]. In a prospective series tion in hyperfunctioning parathyroid glands [76, 77]. of 33 patients with pHPT confirmed at surgery, they found Stimulation of phospholipid-dependent choline-kinase results that [18F]fluorocholine PET/CT employing an analogic scan- in increased radiolabeled choline uptake and is related to the ner could detect hyperfunctioning tissue in 22 of 33 of patients secretion of PTH in HPT [78]. with negative or inconclusive [99mTc]Tc-MIBI SPECT/CT, A commonly used choline analogue in clinical practice is while a digital scanner detected hyperfunctioning tissue in (N-[(18F)fluoromethyl]-2-hydroxy-N,N- 30 of 33 patients. The lesions detected only by the digital dimethylethanaminium ([18F]FCH or [18F]fluorocholine). system were < 10 mm in diameter on resection, highlighting Other similar radiofluorinated choline derivatives are also the potential importance of new PET/CT technologies in the available and supposedly show similar clinical behavior and detection of small parathyroid lesions. utility. Administered activity ranges from 100 to 300 MBq or Other advantages of PET/CT with 18F-labeled choline an- 1.5–3.2 MBq/kg of body mass. According to the study by Rep alogues over [99mTc]Tc-MIBI scintigraphy are the lower radi- et al., the recommended imaging time is one hour after the ation exposure [83], the higher resolution, and the shorter administration of the radiopharmaceutical, and, if possible, acquisition time. It is therefore considered an alternative preceded by imaging acquired 5 min after the injection first-line imaging method [84, 85]. (starting as dynamic acquisition and followed by static), as Potential disadvantages of PET/CT with 18F-labeled cho- some lesions may show uptake in the early phase only [79]. line analogues are higher costs, the uptake by inflammatory One acquisition 20 min after injection with delayed images in lymph nodes and thyroid nodules as a potential source of case of a negative result is also an option [40]. The field of false-positive results [86], and local reimbursement and li- view can be limited from the nose to the chest down to the censing issues. 18 base of the heart as for scintigraphy, to obtain a low radiation F-labeled choline analogues may be also used in PET/ exposure from CT. But thanks to the more rapid acquisition MRI systems. This novel method is promising in patients with with PET than with SPECT it may easily be extended to the inconclusive results of standard imaging techniques [87]. whole torso or the whole body according to the patient’s his- tory (neoplasia, skeletal disease, infection…) or incidental findings. On PET/CT machines with incremental acquisition [11C]2-hydroxy-N,N,N-trimethylethanamium ([11C]CH) and time of flight imaging, at least 2 min per bed position may be recommended. PET/CT with 18F-labeled choline ana- As mentioned above, choline is a precursor of phosphatidyl- logues yields promising results, with DRs exceeding 90%. choline, which may explain the fact that [11C]CH shows Treglia et al. in a meta-analysis of 14 choline studies (con- strong uptake in hyperfunctioning parathyroid cells [76]. taining 12 studies with 18F-labeled and 2 with 11C-labeled Noltes et al. tried to optimize the protocol for [11C]CH choline derivatives) involving 517 patients, reported pooled PET/CT imaging, taking into consideration the activity and values for the sensitivity of 95%, PPV 97%, and DR 91% on a image quality [88]. They retrospectively studied 21 patients per-patient analysis. In a per-lesion analysis, the pooled sen- with pHPT and suggested image acquisition 20 min after ad- sitivity was 92% and PPV was 92% [78]. ministration of 6.3 MBq/kg [11C]CH, with a scanning time of In addition, Hocevar et al. in a recent study demonstrated at least 5 min. Orevi et al. in a prospective pilot study includ- that patients with a single adenoma on [18F]fluorocholine ing 40 patients with pHPT indicated that [11C]CH provides PET/CT can safely and accurately undergo minimally inva- higher image quality than [99mTc]Tc-MIBI, with the same or sive parathyroidectomy without intraoperative PTH testing even superior diagnostic accuracy [89]. 2810 Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 The advantage of [11C]CH PET/CT over scintigraphy is a The major limitations of this radiopharmaceutical for more shorter acquisition time. There is fast uptake of [11C]CH in widespread use are the short physical half-life of 11 C hyperfunctioning parathyroid tissue, as well as a rapid clear- (20.3 min) which necessitates an on-site cyclotron, the de- ance of background activity. Imaging is completed within manding labeling process which requires an on-site 30 min. In addition, the radiation exposure is lower. The short radiopharmacy with competent radiochemical staff, and a physical half-life of 11C (20.3 min) results in significantly higher average positron energy which leads to more noise lower radiation exposure than using a 18F-labeled choline an- compared with 18F. Additionally, there are local reimburse- alogue, as well as other nuclear medicine techniques and 4D- ment and licensing issues. CT. On the other hand, the short physical half-life is a draw- Other PET tracers back, restricting the use of 11C to facilities with an on-site cyclotron. Additionally, a higher average positron energy of Other PET tracers are not recommended for the detection of 11 C leads to more noise on the images and poorer spatial hyperfunctioning parathyroid glands, based on currently pub- resolution compared with 18F. lished data. 18F-fluoro-D-glucose ([18F]FDG) is almost ubiq- uitously available and has the advantage of possible off-site 11 L-[methyl- C]methionine ([11C]MET) usage due to a significantly longer physical half-life of 18F (110 min) compared with 11C. However, sensitivity and [11C]MET is a PET radiopharmaceutical that was previously PPV vary considerably between the few available studies, often used as a second-line imaging tracer after negative or 0–94% and 62–100%, respectively. Therefore, this tracer does inconclusive conventional imaging. It is trapped in the hyper- not seem suitable for the detection of hyperfunctioning para- functioning parathyroid gland as it is involved in the synthesis thyroid glands compared with other standard imaging tech- of the PTH precursor [90]. The administered activity of the niques [92]. However, sometimes incidental parathyroid ade- radiopharmaceutical varies between 370 and 1100 MBq in nomas may be detected in [18F]FDG studies acquired for other different [11C]MET studies. Reported acquisition time is also reasons than HPT. 3,4-dihydroxy-6-[18F]fluoro-L-phenylala- highly variable, ranging from a start immediately after to nine (6-[18F]F-DOPA) does not appear promising, as reported 40 min after injection. In most studies, PET scanning is pre- by Lange-Nolde et al. [95]. These authors scanned 8 patients ceded or followed by a low-dose CT scan. Some authors rec- with pHPT and histologically proven parathyroid adenomas, ommend imaging at two time points, 10 min and 40 min after but none of the patients showed any detectable uptake of application of the radiopharmaceutical, preceded or followed 6-[18F]FDOPA in adenoma. O-(2-[18F]fluoroethyl)-L-tyro- by CT scanning for attenuation correction [90, 91]. The best sine ([18F]FET) also does not appear to be promising as re- parathyroid to cervical soft-tissue ratio was accomplished ported by Krakauer et al. [96]. In two patients, dual-isotope 10 min and the best parathyroid to thyroid ratio 40 min after SPECT/CT located a parathyroid adenoma, verified by histo- administration of the radiopharmaceutical [90]. pathology; only faint uptake of [18F]FET was detected in the Increased uptake at early or late imaging is considered hyperfunctioning parathyroid glands. The maximum (but low) positive. target-to-background ratio was reached 30 min after tracer Kluijfhout et al. in a meta-analysis of 14 [11C]MET studies administration. found a pooled sensitivity of 77% and a pooled PPV of 98% for the detection of hyperfunctioning parathyroid glands in the Image analysis correct quadrant [92]. There was no difference in sensitivity in patients with and without previous negative or inconclusive The reading of PET/CT or PET/MRI to localize hyperfunc- standard imaging (81% vs. 78%, respectively). However, tioning parathyroid gland(s) usually starts with visualizing Noltes et al. in a recent retrospective study found that multiple intensity projections which may show foci behind [11C]MET PET/CT is able to identify parathyroid lesions on the thyroid gland and help in detecting ectopic foci. The anal- the correct side in only 64% (18/28) of patients after prior ysis of attenuation-corrected slices in the 3 planes with and negative [99mTc]Tc-MIBI SPECT/CT and/or cUS [93]. without CT (or MRI) fusion is necessary in all cases, to precise Weber et al. prospectively studied whether [11C]MET the anatomical landmarking and the size of abnormal foci. The PET/CT is able to identify [99mTc]Tc-MIBI-negative hyper- analysis of non-attenuation-corrected images may sometimes functioning parathyroid glands in a cohort of 50 pHPT pa- be useful in the case of artifacts on CT or of incidental foci in tients [94]. Pre-surgical scanning with [11C]MET PET/CT lo- the lungs. For the neck region, the soft-tissue CT window calized hyperfunctioning parathyroid glands in 74% of pa- should be used. A reading of PET and PET/CT (MRI) fused tients with negative [ 9 9 m Tc]Tc-MIBI scintigraphy. images of organs or structures out of the neck but included in [11C]MET PET/CT detected 40 out of 57 (70%) hyperfunc- the whole field of view, should not be omitted. The soft-tissue tioning glands. CT window is adapted to the mediastinum and the breasts Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 2811 (and the liver in the absence of a specific window), but other Reporting parathyroid radionuclide imaging CT windows are recommended for lung and bone (and liver if this window is available). The scan report should include patients’ relevant identifying All foci located from the upper neck to the base of the data as well as the relevant clinical history including serum heart with an increased tracer uptake compared with the PTH and calcium levels and any further relevant details, such adjacent background should be considered. Focal accumu- as a history of MEN or history of (para)thyroid surgery. lation of radiopharmaceutical in a nodule next to the thy- The report should include a technical section, mentioning roid is suspicious for a hyperfunctioning parathyroid the protocol employed, the tracer(s) used together with admin- gland in the loco typico. A hypodense character compared istered activities and route of administration, which images with the thyroid parenchyma on CT and a SUVmax great- were acquired (planar projections, SPECT/CT, PET/CT, er than that of the thyroid parenchyma are further argu- PET/MRI, including the anatomic area), the dose-length prod- ments favoring this interpretation [35]. In the case of uct if CT has been acquired, and their respective timing and, if dual-time point acquisition, the persistence in the late im- relevant, details on image reconstruction. ages of foci visible on the early images is a further argu- Reports need to include at least the description of abnormal ment in the case of equivocal early findings, but the dis- findings (one or more hyperfunctioning parathyroid lesions) appearance of an evocative focus on early images could and localization of abnormal gland(s) expressed in terms of be due to a hyperfunctioning parathyroid gland with rapid the four thyroidal quadrants including the gland(s) depth, or clearance of the tracer. Even though the thyroid uptake of the particular ectopic location, as well as the images in which choline-based tracer is usually moderate, it is diffusely these are identified. Detection of a hyperfunctioning parathy- intense in case of thyroiditis or of Graves’ disease, mak- roid gland with [99mTc]Tc-MIBI, whose implantation in the ing the detection of foci adjacent to the thyroid gland forearm had not been recorded, was reported [97]. difficult. The main interpretation problem is a focal tracer Additionally, one should document any incidental finding, uptake inside the thyroid which corresponds in most cases such as pathological [99mTc]Tc-MIBI uptake in the pituitary to a malignant or benign thyroid nodule (in particular region (if included in the field of view) [98], or in the lungs oxyphil adenomas are [18F]FCH avid) but may also cor- [99], or 18F-labeled choline analogues foci suspicious for ma- respond to an intrathyroidal parathyroid gland [35]. In lignancy [100, 101], which should prompt further diagnostic methionine studies, thyroid nodules may also cause investigation. A frequently abnormal bone uptake of false-positive results [93]. In case of thyroid anomalies, [99mTc]Tc-MIBI has been reported by Zhao et al. in 22 it is recommended to analyze the PET/CT images with (27.8%) patients [102]. Nineteen of them showed diffusely reference to thyroid scintigraphy (with Na[123I]I if avail- increased activity in the skeleton, 2 patients had focal uptake able) to check how PET/CT foci match with the location in brown tumors, and one showed both of these patterns. and the iodine-metabolism of thyroid nodules; maximum Brown tumors, also known as osteitis fibrosa cystica, are a intensity projection and coronal slices are particularly use- specific complication of HPT, mostly in the case of sHPT or ful in this aim. Small thyroid remnants in case of partial prolonged pHPT, or parathyroid carcinoma. They are usually or total thyroidectomy may take up the PET tracer leading multiple, but also a solitary lesion may be present [103]. On to a false-positive result which may be avoided by refer- CT, brown tumors appear as lytic or multilobular cystic ring to thyroid scintigraphy. Concerning the interpretation changes. They may be detected with 18F-labeled choline ana- of ectopic foci, the main pitfall with metabolic tracers is logues whereas [99mTc]Tc-MIBI is negative [104]. In the case uptake by reactive lymph nodes. In particular [18F]FCH is of incidental bone foci, this etiology may be considered as very frequently taken up by mediastinal and/or axillary well as primary or secondary bone malignancies [105–107]. lymph nodes which are not suspicious for ectopic para- Diffuse and intense tracer uptake in the jaw may be observed thyroid glands. Uptake by one single cervical lymphade- in rare cases, being evocative of HPT-jaw tumor syndrome, a nopathy may constitute a problem for interpretation [86]. genetic disease linked with a negative prognosis [108–110]. The analysis of the CT (or MRI) component yields a more precise anatomical localisation and may also increase specificity. Cervical ultrasonography False-negative results in choline/methionine studies may occur in cases of moderate hypercalcemia and non-elevated It is recommended to perform cUS in conjunction with nuclear PTH serum levels (so-called “abnormally normal serum PTH medicine imaging. Cervical ultrasonography is often used for level). In the case of MGD, one or several hyperplastic glands parathyroid gland localization. It is also utilized for may be missed, particularly in sHPT or MEN. False-negative confirming the diagnosis of the hyperfunctioning parathyroid results may also be caused by a too restricted field of view, in gland(s) by guided FNA cytology and analysis of the FNA- particular in case of recurrence after parathyroidectomy. PTH in highly selected cases. It also provides an additional 2812 Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 evaluation of the thyroid that may change surgical manage- Medas et al. reported a lower sensitivity in patients with ment, especially in the case of coexisting (suspected) malig- concomitant thyroid disease compared with patients with nor- nant nodules [111]. mal thyroid tissue (46.7% vs. 75%) [59]. Thyroid nodules are Cervical ultrasonography is a low-cost, non-invasive (apart a common reason for false-positive results, especially if locat- from guided FNA), accurate, and highly sensitive technique in ed posteriorly [118]. This is an important issue since synchro- experienced hands [112]. nous thyroid pathology is common in pHPT patients (18% as It is performed with the patient in a supine position with a reported by Bentrem et al.) [119]. hyperextended neck, using a high-frequency (≥ 7 MHz) linear For the reasons stated above, and since it is an operator- transducer. It is recommended to perform cross-sectional and dependent technique, it is recommended to combine cUS with longitudinal images of the anterior neck region, between the parathyroid scintigraphy [73]. common carotid arteries, from the level of the carotid bifurca- For FNA-PTH, a sensitivity of 70–100%, and a specificity tion down to the superior mediastinum, particularly paying of 75–100% has been published, rendering it more reliable attention to the posterior surface of the thyroid and the region than cytology alone [120]. However, Trimboli et al. have below it. The size and location of the thyroid, thyroidal lesions, shown that despite satisfactory results reported, this procedure and any suspected parathyroid glands should be carefully doc- is not widely used because it is not well standardized from pre- umented. Owing to their small size (approximately 3 to 5 mm), to post-analytical aspects. There is no consensus with regard normal parathyroid glands are usually not identified on cUS. to the FNA-PTH reference range and upper cut-off value. Hyperfunctioning parathyroid glands are detectable due to their Some authors consider any FNA-PTH positive that is above size and echogenicity. They are usually hypoechoic, the serum PTH level [121–124], whereas others suggest an circumscribed, ovally shaped, delineated from the thyroid by FNA-PTH/serum PTH ratio of ≥ 2:1 in order to minimize the hyperechoic connective tissue. However, they may have vari- influence of sample contamination by blood [120]. ous shapes and contain fluid and, rarely, calcifications. Some However, in the case of non-diagnostic or indeterminate glands have undergone cystic degeneration, presenting as an- cytology findings, FNA-PTH might be useful. echoic lesions with dorsal echo amplification. Sometimes, a Fine-needle aspiration may harbor complications, such as peripheral artery branching into the gland can be seen. post-FNA fibrosis of the parathyroid gland and surrounding Occasionally it may be difficult to differentiate enlarged structures, making surgery more difficult and time-consuming parathyroid glands from lymph nodes [33]. [125]. It may also cause bedeviled histopathology by imitating Cheung et al. in a meta-analysis of 19 studies found that cUS malignancy. Norman et al. conducted a study that included 30 has a pooled sensitivity of 76.1% and a PPV of 93.2% in the patients who underwent FNA of a parathyroid adenoma and a preoperative localization of enlarged parathyroid glands in pHPT control group of 3000 patients who underwent surgery with- patients [113]. The diagnostic accuracy of ultrasound may be out previous FNA. On histopathology, adenomas in the con- improved when performed after radionuclide imaging [114]. trol group showed a fibrotic reaction in 4.3% of cases, while Cervical ultrasonography also has some limitations. It can- glands with previous FNA had a fibrotic reaction in 77% of not detect ectopic parathyroid glands below the neck level VI cases. The fibrotic reaction also imitated malignancy on his- and is less sensitive in the detection of small glands or MGD. topathology. Additionally, the fibrotic reaction was more Ruda et al. in a systematic review of 20,225 cases of pHPT common with repeated FNA passes. Fine-needle aspiration found that the sensitivity of cUS in patients with two adeno- was associated with a doubling of the surgery time [125]. mas was 16.2% and in MGD 34.9%, compared with 78.5% in Rarely, FNA may cause an inflammatory reaction, parathy- single-gland disease [115]. Medas et al., in a retrospective roid abscess, or hematoma [126]. Very rare complications of study of 212 patients, also reported lower cUS sensitivity in FNA include parathyromatosis [127, 128] and the potential patients with MGD compared with patients with single-gland risk of parathyroid carcinoma seeding [129, 130]. For the disease (18.7% and 66.5%, respectively) [59]. Haciyanli et al. reasons stated above, FNA cytology is recommended only reported accuracy of cUS of 40% in patients with two adeno- in highly selected cases, e.g., atypical cUS findings, or incon- mas, while the combination of cUS and [99mTc]Tc-MIBI clusive scintigraphy. yielded an accuracy of 60% [116]. False-negative results also occur with an intrathyroidal lo- cation of hyperfunctioning parathyroid glands, being Computed tomography misinterpreted as thyroid nodules. Fine-needle aspiration cy- tology accompanied by the measurement of the FNA-PTH Standard X-ray CT has limited value in the detection of en- may solve this diagnostic challenge [117]. Furthermore, en- larged parathyroid glands in pHPT [112]. larged parathyroid glands adjacent to the upper thyroid poles Four-dimensional CT (4D-CT) consists of standard CT im- may have a similar echogenicity as the thyroid gland and aging with 3 vascular phases (non-enhanced, arterial, and ve- might hence be missed [112]. nous), and the fourth dimension that allows enhancement Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 2813 evaluation over time [131, 132]. Hence, this technique also Lopez Hänninen et al. in 2000 reported a high sensitivity of provides functional data on enlarged parathyroid glands. Fast MRI for identifying hyperfunctioning parathyroid glands uptake and washout of contrast are considered typical for [141]. 1.5-T MRI detected 32 out of 39 surgically proven parathyroid adenomas [73]. abnormal parathyroid glands (82%). Sensitivity was higher This technique has similar diagnostic performance com- for adenomas compared with hyperplasia (87% and 75%, pared with [99mTc]Tc-MIBI SPECT [112], although protocols respectively). vary among institutions, which results in minor differences in Wakamatsu et al. in a study from 2003, involving 35 pa- DRs [133–135]. tients with pHPT and 4 with sHPT, reported an unsatisfactory 4D-CT has the advantage of short imaging time and is overall MRI sensitivity for the detection of hyperfunctioning promising for the detection of small and ectopic parathyroid parathyroid glands (43.4%) [142]. There were 29 patients with glands, but its drawbacks are comparably high radiation ex- the single-gland disease and 10 with MGD. The sensitivity for posure and the need for iodinated contrast medium. The dose the first group was slightly higher (48.3% vs. 37.5%, respec- of radiation delivered to the thyroid is considerably higher tively). However, they used a 0.5 T MRI, which may influ- than with standard imaging methods. Mahajan et al. reported ence sensitivity. a 57 times higher (92.0 vs. 1.6 mGy) thyroid dose compared A recent study by Argirò et al. demonstrated the correct with [99mTc]Tc-MIBI SPECT imaging [136]. As this at least localization of hyperfunctioning parathyroid glands in 45/46 in theory results in an increased risk for thyroid malignancies, patients that underwent 3 T MRI with standard clinical pulse this method should be used with caution, especially in youn- sequences, yielded an excellent preoperative diagnostic per- ger patients. Some institutions perform fewer acquisitions to formance, with a sensitivity of 97.8% and a specificity of reduce radiation exposure. However, this in turn leads to a 97.5% [143]. Furthermore, it showed a good performance in reduction in sensitivity. Kluijfhout et al. in a meta-analysis MGD (8/8 enlarged glands detected) and ectopic parathyroid of 34 studies (2563 patients) found a lower pooled sensitivity lesions (6/7 glands detected). of a single-contrast phase protocol (71%), compared with 2- Merchavy et al. in a study from 2016 reported that 4D MRI and 3-contrast phase protocols (76% and 80%, respectively) is a useful technique for the preoperative detection of parathy- [137]. They suggested that a 2-contrast phase protocol is suf- roid lesions [144]. In 10 out of 11 patients with parathyroid ficient with regard to sensitivity and radiation exposure. lesions, 4D MRI localized adenomas correctly. The reported 4D-CT is useful in the case of negative previous imaging sensitivity was 90%, and 100% after optimizing the imaging studies or in patients with distorted neck anatomy. It is a good time. The specificity was 100%. method for the preoperative detection of hyperfunctioning Nowadays, MRI is mostly used as a second-line imaging parathyroid glands after the unsuccessful initial surgery. technique. Mortenson et al. in a prospective study of 45 patients who While the use of gadolinium-based contrast agents is typi- underwent parathyroid reoperation, revealed a higher sensitiv- cally necessary, MRI does not carry any radiation exposure, ity of 4D-CT compared with [99mTc]Tc-MIBI SPECT/CT and which is a significant advantage of this technique. MRI is also neck US (88%, 54%, and 21% respectively) [138]. used as part of PET/MRI exams with 18F-labeled choline an- Combined [ 18 F]fluorocholine PET and 4D contrast- alogues and is considered particularly useful for the detection enhanced CT (4DCeCT) may be considered in pHPT patients of cystic adenomas with comparably low tracer uptake [145, with negative or inconclusive first-line imaging, as stated by 146]. Piccardo et al. [135]. They prospectively enrolled 44 pHPT The use of MRI is limited in patients with kidney failure (if patients. [18F]fluorocholine PET/4DCeCT was positive in 32 contrast medium is used) and implanted medical devices, such of 44 patients with pHPT (72.7%), and in 31 of 31 operated as cardiac pacemakers. Both kidney failure and cardiac ar- patients (100%), being superior to [18F]fluorocholine PET/CT rhythmia are associated with HPT [76]. Furthermore, it may alone (80% and 56.8%, respectively) and 4DCeCT alone also be difficult for MRI to differentiate hyperfunctioning (74% and 54.5%, respectively). parathyroid glands from lymph nodes [142]. However, the reported sensitivity of CT for a MGD is still Further larger studies are necessary to confirm the diagnos- as low as 32–53% [139]. tic performance of MRI in this setting. Magnetic resonance imaging Invasive diagnostic procedures Hyperfunctioning parathyroid glands may have variable MRI Invasive diagnostic procedures are used in case of prior un- characteristics. However, they usually show intermediate to successful parathyroid surgery and negative or equivocal non- low signal intensity on T1-weighted images and high signal invasive imaging studies. They are rarely utilized nowadays intensity on T2-weighted images [140]. due to improved standard non-invasive imaging and because 2814 Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 they carry certain risks for the patient. Invasive techniques are that not all hyperfunctioning parathyroid glands retain radio- associated with complications such as hematoma, contrast- pharmaceuticals and the thyroid in certain cases does not show induced nephropathy, and cerebrovascular infarction [73]. adequate washout. In these circumstances, dynamic or sub- Anaphylaxis due to an allergic reaction to an iodinated con- traction imaging might be helpful. trast medium is an additional complication, also observed in Another potential problem is a failure to detect ectopic non-invasive imaging (CT). Thus, invasive techniques should glands in the pericardial region, due to the normal distribution be performed by a highly experienced operator. of cardiotropic SPECT radiopharmaceuticals in neighboring myocardium. While these cases are extremely rare, they still Selective venous sampling need to be recognized. Additional problems are caused by discordant imaging re- Selective venous sampling is the most commonly utilized sults. Novel techniques, such as PET/MRI with 18F-labeled technique. Serial blood samples are obtained from the superior choline analogues, appear to be promising in patients with vena cava, bilateral brachiocephalic, internal jugular, verte- inconclusive results of standard imaging techniques [87]. bral, thymic, superior, middle, and inferior thyroid veins PET/MRI might be even more advantageous than PET/CT, [73]. An increase in PTH level from the vein drainage sites owing to less radiation exposure and better soft-tissue contrast is compared with a peripheral sample. Ibraheem et al. in a in the neck, improving the morphological correlation of PET recent meta-analysis of 12 studies found a pooled sensitivity findings. Current data exists from a few studies with up to 42 and specificity of 74% and 41%, respectively [147]. This patients [87, 145, 146, 149], the majority of patients having method had a higher pooled sensitivity compared with non- negative or equivocal standard imaging. invasive methods, mainly US and SPECT tracers, in re- Another rare but important issue is the imaging of operated patients. parathyroid carcinoma and distinguishing it from benign parathyroid lesions. Parathyroid carcinoma is typically Selective arteriography characterized by significant hypercalcemia and high PTH levels, but there are no specific biochemical features Selective arteriography can be useful in patients with altered that allow for differentiation from benign parathyroid le- venous drainage due to prior neck surgery [73]. It is performed sions. Several US features may be helpful in parathyroid by selective transarterial induction of hypocalcemia in combi- carcinoma cases, such as larger lesion size (> 3 cm), ir- nation with nonselective venous sampling. An increase in regular lesion borders with tissue invasion, heterogeneous PTH levels after stimulation is compared with baseline. A and decreased echogenicity, or tumor depth/with ratio of blush on the arteriogram is also considered a positive finding. ≥1:1 [150]. Parathyroid carcinoma, its recurrences, and Powell et al. in a study from 2009 found that arteriography is minimally invasive parathyroid carcinoma, usually accu- the best invasive procedure for localizing hyperfunctioning mulate [99mTc]Tc-MIBI [151–156], and recently it was parathyroid glands (92% PPV), before revision surgery [148]. demonstrated that parathyroid carcinoma has a higher re- tention level (mean and peak retention index) of [ 99m Tc]Tc-MIBI compared with benign lesions [157], Open issues which may be helpful in the preoperative differential di- agnosis. PET/CT with 18F-labeled choline analogues is Primary hyperparathyroidism is usually caused by a solitary able to detect minimally invasive parathyroid carcinoma, parathyroid adenoma, which is relatively easy to detect. according to recently published papers [154]. It may also However, in 15–20% of cases, it is caused by MGD, i.e., detect local and distant recurrences of parathyroid carci- multiple adenomas or hyperplastic glands, which are more noma by their high uptake [158, 159]. [18F]FDG PET/CT difficult to diagnose with SPECT/CT and PET/CT techniques, may also provide information on loco-regional and dis- cUS, 4D-CT, and MRI. Additionally, in the last decades, there tant spreading, presumably in less well-differentiated le- is a trend toward minimally invasive parathyroidectomy sions [152, 160]. One isolated case of a [99mTc]Tc-MIBI- whenever possible, which may be another reason for missed negative and [18F]FDG-negative, but [11C]MET-positive MGD. However, in suspected MGD, not identified by stan- parathyroid carcinoma local recurrence has been de- dard techniques, open neck exploration should remain as an scribed [161]. Computed tomography and MRI are useful option. Another reason for failed imaging and unsuccessful for detecting the local extent of disease, invasion of sur- surgery is an ectopic parathyroid gland. The reasons for im- rounding tissue, and distant spread. Fine-needle aspira- aging failure in this setting may be an inadequate imaging tion is not recommended in suspected parathyroid carci- technique, failure to detect a rare ectopic site, as well as the noma, because cytology is not accurate in distinguishing imprecisely reported location of the ectopic gland. An addi- malignant from benign lesions, and it may cause seeding tional problem, not only related to MGD and ectopic sites, is of cancer cells [162]. Eur J Nucl Med Mol Imaging (2021) 48:2801–2822 2815 Another issue is discussed in a recent article regarding the Liability statement lack of specific criteria for the diagnosis of minimally invasive parathyroid carcinoma [154]. It appears to be less aggressive This guideline summarizes the views of the EANM Thyroid compared with “classic” parathyroid carcinoma and authors Committee. It reflects recommendations for which the EANM suggest the importance of differentiating it from parathyroid cannot be held responsible. The recommendations should be adenoma and parathyroid carcinoma. taken into context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions. Conclusions Acknowledgements The guidelines were brought to the attention of the relevant EANM Committees and the National Societies of Nuclear The use of optimized first-line imaging for the detection and Medicine. The comments and suggestions from the EANM (Bone & precise localization of hyperfunctioning parathyroid glands is Joint, Oncology & Theranostics, Paediatrics, Physics, Radiation important as the first operation is the best moment to obtain a Protection, Radiopharmacy, and Technologist Committee) and the long-lasting cure. Combining [99mTc]Tc-MIBI SPECT/CT (Belgian, Croatian, Czech, Finnish, French, Irish, Lithuanian, Macedonian, Polish, Russian, Serbian, and Turkish) National Societies with cUS performed by an experienced sonographer is a wide- are highly appreciated and have been considered for this guideline. ly available and accepted first-line strategy. Different proto- cols exist for [99mTc]Tc-MIBI scintigraphy. Dual-phase imag- Funding Open access funding provided by University Medical Center ing with SPECT/CT is a widely used technique. Dual-tracer Rotterdam (Erasmus MC). subtraction imaging is a valuable alternative option. PET/CT Open Access This article is licensed under a Creative Commons with 18F-labeled choline analogues has shown superior re- Attribution 4.0 International License, which permits use, sharing, adap- sults; however, data from large cohorts and on cost- tation, distribution and reproduction in any medium or format, as long as effectiveness are not currently available. It may be considered you give appropriate credit to the original author(s) and the source, pro- a potential “alternative” first-line method whenever possible, vide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included as it appears to be an effective technique even in patients with in the article's Creative Commons licence, unless indicated otherwise in a negative/equivocal standard imaging findings. Other advan- credit line to the material. If material is not included in the article's tages of this technique are the high resolution, the low radia- Creative Commons licence and your intended use is not permitted by tion exposure, and the shorter acquisition time. Modern sen- statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this sitive PET/CT scanners and the use of PET/MRI for 18F-la- licence, visit http://creativecommons.org/licenses/by/4.0/. beled choline analogue imaging may result in significantly less radiation exposure compared with [ 99mTc]Tc-MIBI SPECT/CT. The drawbacks are higher costs compared with [99mTc]Tc-MIBI, as well as local reimbursement and licensing References issues. There are several second-line techniques available after negative or inconclusive first-line imaging. It is important to 1. Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin obtain concordant imaging by two techniques whenever pos- MR. 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