European Nuclear Medicine Guide
[18F]fluoromethyl-dimethyl-2-hydroxyethylammonium ([18F]fluorocholine or [18F] FCH)
[methyl-11C]trimethyl-2-hydroxyethylammonium ([methyl-11C]choline)
L-[methyl-11C]methionine
[18F]fluorocholine and [methyl-11C]choline: an increase in phospholipid-dependent choline kinase activity has been observed in parathyroid (PT) adenomas arising from hypersecretion of parathyroid hormone (PTH) [52]. Choline C5H14NO+ is a cation; there is a significant transmembrane potential of 140–180 mV (negative inside) that trends to transport cations into mitochondria. In PT adenomas, principal cells and even more oxyphilic cells are rich in mitochondrias with a large incidence of mitochondrial DNA mutations that may confer a selective advantage and contribute to the molecular pathogenesis of PT adenomas [53]. This is confirmed by the intense [18F]fluorocholine uptake by most oxyphilic (oncocytic) tumours of the thyroid gland [54].
L-[methyl-11C]methionine: radiolabelled methionine enters into the cells by passive diffusion and through several neutral amino acid transporters, mainly the LAT1 and LAT2, which are located on cell surface. Several processes contribute to induce an over-expression of LATs and increase amino acid transport, probably including increased PTH synthesis [55,56].
Detailed indications and recommendations for parathyroid PET with those three radiopharmaceuticals are available in the 2021 EANM practice guidelines for parathyroid imaging [57].
Concerning [18F]fluorocholine, in some EU members states, the marketing authorisation(s) of commercial preparation(s) include(s) “ localisation of hyperfunctioning PT glands in case of documented hyperparathyroidism (HPT)”.
The practice of parathyroid PET requires a PET centre with either a cyclotron and an appropriate radiopharmacy unit in its vicinity for [methyl-11C]choline or L-[methyl-11C]methionine (11C half-life 20 min) preparation, or available delivery of [18F]fluorocholine (18F half-life 110 min).
Compared with scintigraphy or SPECT/CT (see Chapter 8.5), parathyroid PET/CT benefits from the superior image resolution, and the rapid imaging procedure of PET, for a similar radiation exposure. If available, it may be recommended as the first line nuclear medicine procedure in HPT when surgery is scheduled [58-60].
In case of a restricted access to parathyroid PET, the priority indications for first line parathyroid PET correspond to suspicion of multiglandular hyperplasia, due to a limited sensitivity of [99mTc]Tc-sestamibi scintigraphy and/or SPECT/CT and of ultrasonography (US) [61]:
multiple endocrine neoplasia (MEN),
renal HPT,
persistent or recurrent HPT after parathyroidectomy (PTX),
normo-calcaemic HPT.
If parathyroid scintigraphy or SPECT/CT is definitely more easily available as first line functional imaging modality, parathyroid PET/CT will be indicated as a second-line modality in case of negative or discordant imaging modalities ([99mTc]Tc-sestamibi scintigraphy and neck US). The drawback of this strategy is missing the chance of detecting multiglandular HPT before PTX, in particular if one of the abnormal PTs detected on ([99mTc]Tc-sestamibi imaging prompts surgery [58,61].
Pregnancy is considered to be a contra-indication in the Marketing Authorisation of [18F]fluorocholine.
In case [18F]fluorocholine PET is considered essential in a milking mother, breastfeeding should be discontinued for 12 hours and the milk produced during this period should be discarded.
Sporadic primary HPT (pHPT): initial preoperative imaging
The preoperative imaging permits to optimise the operatory protocol of PTX, in particular by selecting those patients who can benefit from minimally invasive PTX, which has the merit to shorten the operative time, incision length, and to reduce the operatory risks.
[18F]fluorocholine. After reporting incidental PT uptake of [18F]fluorocholine in some patients referred for prostate cancer, a deliberate use in HPT has been performed in HPT since 2012. In the study by Lezaic et al. in 24 pHPT patients [62], the sensitivity of [18F]fluorocholine PET/CT was 92% vs. 49% for [99mTc]Tc-sestamibi SPECT/CT, 100% specificity for both techniques. In the study by Michaud et al. [63], in 12 patients with pHPT (n=8) or renal HPT (rHPT) (n=4) and with discordant or equivocal results on parathyroid scintigraphy and US, hyperfunctioning PT glands were localized with a sensitivity of 89% for [18F]fluorocholine PET/CT, 63% for US and 84%, for [99mTc]Tc-sestamibi scintigraphy by dual phase-dual tracer method.
In the meta-analysis by Evangelista et al. [64] including 23 studies (1,112 patients), [18F]fluorocholine PET was superior to US in detecting benign parathyroid lesions, with a sensitivity in the range of 85–100% patient-based and 50–82% lesion-based. [18F]fluorocholine PET was more sensitive than dual-phase SPECT/CT: 100% vs. 81% patient based and 100% vs. 76% lesion-based. [18F]fluorocholine was superior to SPECT/CT performed with subtraction and dual-phase protocols for the detection of adenomas and/or hyperplastic PT, with a lesion-based diagnostic accuracy of 97% vs. 88% for SPECT/CT.
The meta-analysis by Picardo et al. [65] involving 5 studies (153 patients) was focused on [18F]fluorocholine PET/CT and 4D contrast-enhanced (Ce) CT, which may also be part of the hybrid imaging PET/4D-CeCT. The pooled detection rate of [18F]fluorocholine PET/CT was 86%, vs 69% for 4D-CeCT and 86% for [18F]fluorocholine PET/4D-CeCT, while their pooled sensitivity was 89%, 77% and 93%, respectively. In conclusion, the sensitivity of [18F]fluorocholine PET/CT and [18F]fluorocholine PET/4D-CeCT was higher than that of 4D-CeCT alone, while only a slight difference using [18F]fluorocholine was observed between PET/CT and PET/4D-CeCT. Performing routinely [18F]fluorocholine PET/4D-CeCT in pHPT seems to be of little benefit and high cost in procedural constraint, radiation exposure and potential side effects of the iodine contrast agent.
The meta-analysis of Quak et al. [66] included 23 studies with [18F]fluorocholine, which mentioned patients’ outcome (1716 patients). The pooled patient-based sensitivity was 94% (95% confidence interval (CI) 90–96%) and positive predictive value 97% (CI 93–99%). Parathyroid surgery was performed in 1129 patients. The overall cure rate of PET-guided surgery was 93% (CI 87–96%).
[methyl-11C]choline: few data are available. A study found a concordance between PET/CT and surgical findings in 24 of 27 patients who underwent surgery [67].
More recently, in 30 patients, 32 parathyroid adenomas were histologically confirmed; lesion-based sensitivity of PET/CT was 85% with [methyl-11C]choline, significantly greater than 76% with [11C]methionine PET/CT, and 39% with 4D-CT [68].
L-[methyl-11C]methionine: in a metanalysis including 24 studies, sensitivity for the detection of a lesion in the correct quadrant ranged from 44% to 91%, with a pooled sensitivity of 77% (CI 71–84%). In 3 studies that included patients with negative or inconclusive conventional imaging, pooled sensitivity was 81% (CI 70–91%) [69]. Evidence has been provided that the performance of PET/CT with L-[methyl-11C]methionine to detect abnormal PTs is inferior to that with [18F]fluorocholine [70,71] or [methyl-11C]choline [68].
PT carcinoma
PT carcinoma is a rare malignant endocrine tumour. Prior to initial PTX, malignant pHPT should be considered in case of serum PTH levels 3 to 10 times above the upper limit of normal, calcemia >3 mmol/L, lesion size >3 cm possibly palpable in the neck, inhomogeneous, hypoechoic and lobulated masses on US, severe symptoms of bone (osteitis fibrosa cystica) disease and renal disease (renal stones and nephrocalcinosis). PT carcinoma is prone to recurrence and metastasis, and postoperative reviews should be carried out routinely. [18F]fluorocholine PET/CT positivity was reported in one patient in 2015 yielding a better detection than FDG PET/CT and various scintigraphic modalities [72] The role of [18F]fluorocholine PET associated with [18F]fluorodeoxyglucose (FDG) PET for staging and restaging PT carcinoma was confirmed by subsequent case reports [57,58].
However, liver metastases may be missed with PET, in relation with the accumulation of the radiopharmaceuticals in the liver. In 3 patients with recurrent PT carcinoma, [methyl-11C]choline and FDG PET/CT as well as [99mTc]Tc-sestamibi showed lesions in the neck, but failed to identify liver metastases visualised on CeCT or MRI [73].
Heritable HPT
Approximately 10% to 15% of pHPT consists of heritable forms with MEN type 1 (MEN1) being the most common, affecting 2% to 4% of patients with pHPT. HPT is often the first manifestation of the syndromic forms of heritable pHPT, MEN types 1 and 4, and HPT-jaw tumour syndrome (HPT-JT) [57,58].
HPT usually consists in multiple hyperplastic PTs: in a multicentre series, 2.4 abnormal PTs on average per patient at the initial diagnosis (n = 23) and 1.5 in previously operated cases (n = 50) [74]. In a pilot study, [18F]fluorocholine PET/CT was able to detect 72% of the abnormal PTs before initial PTX, and all of the abnormal PT in case of recurrence [75]. In the multicentre study [74], 41 MEN1 patients were operated; lesion-based sensitivity ranged across different readers from 84 to 87%, and specificity ranged from 95 to 99%. In MEN patients, [68Ga]-DOTATOC may occasionally reveal a focus in the neck evocative of abnormal PT, but its sensitivity and negative predictive value (NPV) are poor, as most of the abnormal PTs do not overexpress somatostatin receptor, and [18F]fluorocholinePET/CT is recommended [75].
Renal HPT
In the context of rHPT, the operative endpoint of surgery is not necessarily a return of serum PTH to normal levels, but a >50% drop in serum PTH level, even if it remains above upper normal value. Additionally, “success” or “cure” is defined as normal calcemia regardless of whether or not serum PTH remains elevated. A pilot study in 2014 confirmed [18F]fluorocholine as the most accurate imaging modality to localise those hyperplastic PTs [63]. Those results were confirmed in lager series [76,77] In summary, preoperatory [18F]fluorocholine PET/CT in rHPT may be helpful in localizing ectopic PT and guiding the surgical choice for PT preservation, preventing PTX-induced hypoparathyroidism. Although the mechanism of rHPT underlying PT hyperplasia is common to all PTs of a given patient, their [18F]fluorocholine uptake is generally uneven on preoperative [18F]fluorocholine PET/CT. If partial PTX is performed and the chronic kidney disease is not corrected, previously nondetectable PTs or PTs with the lowest uptake on preoperatory [18F]fluorocholine PET, particularly ectopic PTs, frequently become obviously [18F]fluorocholine-positive on follow-up PET for persistent or recurrent rHPT.
Persistent or recurrent HPT after PTX
In case of persistent or recurrent HPT after PTX, the remaining abnormal PT(s) must be accurately identified before recommending reoperation, because of the high risk of complications. In a pilot study in patients with a relapse of a previously treated HPT, [18F]fluorocholine PET/CT properly localized all sites of recurrence in both patients with sporadic HPT (n = 3) and familiar forms of HPT (n = 3) [78]
Talbot et al. [79] reported with [18F]fluorocholine PET/CT, a patient-based positivity rate of 42/54=78% and a gland-based sensitivity of 24/27=89% in case of persistent or recurrent pHPT after PTX versus 291/347=84% and 169/186=91%, respectively, in patients without previous PTX, i.e. a similar performance. In the study of Latge et al. [80], 37 patients with persistent or recurrent pHPT underwent [18F]fluorocholine PET/CT and 4DCeCT. The positivity rate and sensitivity were 88% and 95% for [18F]fluorocholine PET/CT vs 63% and 70% for 4D-CeCT; dynamic 4D-CeCT identified no additional PT missed by PET/CT, and the combination of the two techniques did not improve the detection rate or sensitivity.
[18F]fluorocholine (according to its Marketing Authorisation): 140-280 MBq for an adult of 70 kg, to be optimised according to the patient’s body mass (2-4 MBq/kg of body mass) and the performance of the PET camera.
As certain hyperfunctioning PTs are only visualised early after [18F]fluorocholine injection, it is recommended to perform
Either a PET static acquisition covering the field between nose and base of the heart, starting 5 min after injection and a second acquisition 60 minutes after injection,
or a PET static acquisition 20 min after injection and a second late acquisition 60-90 min after injection in case of non-visualisation after the acquisition at 20 min.
Depending on the patient's history or in the event of incidental findings, a static acquisition over the whole-body can also be performed.
[methyl-11C ]choline: 370 MBq, with immediate CT acquisition followed by PET acquisition [67].
L-[methyl-11C ]methionine: 370-1100 MBq. In available studies, authors performed a single acquisition 0-40 min after tracer injection (mostly 10-20 min) [56,69].
[18F] fluorocholine: the effective dose is 20 µSv/MBq. The organ with the highest absorbed dose is the kidney: 97 µGy/MBq [81]. The effective dose range per procedure is 2.0-7.4 mSv. The large range in Effective Dose, reflect differences in activity administered and scanner sensitivity
[methyl-11C ]choline: the effective dose is 4.4 µSv/MBq. The organ with the highest absorbed dose is the pancreas: 29 µGy/MBq [82]. The effective dose per procedure is around 1.6 mSv.
L-[methyl-11C ]methionine: the effective dose is 8.2 µSv/MBq. The organ with the highest absorbed dose is the bladder wall: 92 µGy/MBq [3-83]. The range in effective dose per procedure is 1.9-5.2 mSv.
The radiation exposure related to the CT scan carried out as part of a PET/CT study depends on the intended use of the CT study and may differ from patient to patient.
Caveat
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
In the usual field of view extending from the nose down to the base of the heart, [18F]fluorocholine physiologically accumulates in the salivary glands, the liver, and usually with a lower intensity in the thyroid gland and the bone marrow. The interpretation of [18F]fluorocholine PET/CT in children or adolescents referred for localisation of hyperfunctioning PTs must consider the particularities of biodistribution of [18F]fluorocholine at that age, particularly the variable physiologic uptake by thymus and eventual [18F]fluorocholine uptake by growth plates or brown adipose tissue [58]. This last pitfall can be reduced or even avoided ensuring the patient is in a warm room at the time of injection and thereafter. Likewise, as with all pitfalls, the wrong interpretation rate can be significantly reduced by analysing the matching morphostructural on CT.
Any focal uptake posterior to the thyroid lobes or in the upper mediastinum should be considered as evocative of hyperfunctioning PT. CT images should be evaluated in search for corresponding lesion(s).
The 3 most common ectopic locations of PT are the thymus, para-or retroesophageal space, and thyroid. They pose a difficult differential diagnosis with other choline-positive lesions such as thyroid adenoma or carcinoma, thymoma or reactive non-specific lymph nodes. The most frequent situation corresponds to one or several choline-positive nodule(s) inside the thyroid gland [84], most frequently due to thyroid anomalies but that may correspond to ectopic intrathyroidal PTs, particularly if no extrathyroidal evocative choline focus is visible.
Some choline-positive foci correspond to malignant lesions which should not be overlooked in the interpretation, particularly breast, lung or cervical cancers.
Bone foci may correspond to brown tumours (fibrosa cystica) which can be improved or even cured by resolution of HPT. Foci in the jaws may prompt the research of a rare heritable cause of HPT: HPT-JT.
Some independent information can be derived from the low-dose CT, such as vascular calcifications or the presence of an arteria lusoria, of great importance for the surgeon in case of a right PT [61].
More complete information on the interpretation of the PET/CT the pitfalls may be found in review articles [57,58].
L-[methyl-11C]methionine: false positive results can occur in case of benign or malignant tumours (including head and neck tumours and thyroid adenoma). False negative results may occur in case of multiple gland hyperplasia, small adenomas, and diffuse thyroid disease [69, 85].
According to its Marketing Authorisation [18F]fluorocholine should be administered to patients without fluid restriction, fasting for at least 4 hours. The utility of this short fast, intended to avoid dilution of the tracer with choline digestive intake, has not been clearly documented.
Patients should be encouraged to drink adequately and urinate as often as possible, including after the examination, to reduce radiation exposure.
In order to avoid accumulation of the tracer at the muscular level, it is recommended to avoid any significant physical activity before the examination and between the injection and the examination.