¹⁸F-choline PET/CT and PET/MRI in primary and recurrent hyperparathyroidism: a systematic review of the literature

Primary hyperparathyroidism (PHPT) is a rather common endocrinological disorder, the third most common endocrine disease after diabetes mellitus and thyroid disorders. It is characterized by one or more hyperfunctioning parathyroid glands [1], due to parathyroid adenoma (in > 80% of cases), multiple adenomas, parathyroid hyperplasia (about 15%) or parathyroid carcinoma (less than 1%) [2], [3]. People with mild PHPT are at increased risk of various comorbidities, such as nephrolithiasis, osteoporosis and fragility fractures. Surgical excision is usually a definitive treatment, though repeat surgery may be required in cases of recurrent or persistent hyperparathyroidism (fewer than 5% of patients) [4].

PHPT may also be associated with a higher risk of cardiovascular disease and mortality [5, 6]. The related mortality risk seems to be lower in patients who undergo surgery than in those treated conservatively [6]. A recent cost-effectiveness analysis on patients with non-localized PHPT showed that use of advanced imaging methods is more cost-effective than routine bilateral neck exploration [6]. Based on this evidence, it becomes essential to employ appropriate methods capable of revealing which parathyroid glands are causing PHPT. This is also important to avoid unnecessary surgery and to identify ectopic parathyroid glands.

Benign parathyroid lesions can be identified and located using morphological or functional imaging. Neck ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) have been extensively used in this setting. Dual-tracer subtraction, mainly using 99mTc-sestamibi (MIBI)/99mTc-pertechnetate scans, and/or dual-phase scintigraphy with planar acquisitions, have been widely employed in cases of hyperparathyroidism, frequently combined with US. For diagnostic purposes, single-photon emission tomography (SPET)/CT has proved the best imaging modality for identifying the site of hyperfunctioning parathyroid glands, better than either SPET alone or planar scintigraphy. That said, even SPET/CT fails to identify the gland in up 30% of cases [7].

When a combination of US and SPET/CT fails, a more effective imaging technique is needed. Radiolabeled choline PET/CT has been widely used in patients with recurrent prostate cancer [8], and it was in this context that a study published in 2013 reported incidentally detecting an 18F-fluorocholine (FCH) hotspot in a patient’s neck, which turned out to be a parathyroid adenoma [9]. In the ensuing 6 years, a number of published studies reported on the role of FCH PET/CT in identifying benign parathyroid lesions.

The aims of the present systematic review are to: (1) assess the role of FCH PET/CT and PET/MRI in patients with known PHPT; and (2) compare the diagnostic performance of FCH PET/CT or PET/MRI with other morphological and/or functional imaging modalities.

The systematic literature search generated 23 articles (see Fig. 1) concerning a total of 1112 patients investigated with FCH PET/CT for the detection of benign parathyroid lesions. Most of the studies were prospective (n = 15, 65%; 488 patients). Interestingly, 67 patients underwent FCH PET/MRI. As shown in Table 1 [12‐33], FCH PET/CT was compared in many cases with US or 99mTc-MIBI scanning, the main endpoint being to assess the accuracy of FCH PET/CT in detecting benign parathyroid lesions in cases of doubtful or negative conventional imaging. In all studies, histopathological examination was the diagnostic reference standard.

A careful analysis of the selected literature showed that a dynamic FCH PET/CT protocol was used in 4/23 studies. In particular, Michaud et al. [13] and Kluijhout et al. [14] ran a single dynamic acquisition lasting 10 min and 40 min, respectively; and Michaud et al. and Prabhu et al. [12, 15] performed a dynamic acquisition for 10-15 min followed by a static image 10 or 45 min after the injection. Static acquisitions were obtained in the other studies at a single point ranging from 10 to 60 min after the intravenous administration of FCH in 9/23 studies [4, 16, 17, 19‐23, 34]; and twice, first after 2–60 min and then after 60–120 min, in 10/23 studies. Only Rep et al. [25] reported scanning patients 3 times, at 5, 60 and 120 min after FCH injection. The FCH dosage was fixed in 16 studies, in the range of 100-230 MBq [15, 19‐28, 31‐34]; it was adjusted to the patient’s body weight in 5 (1.5–3.2 MBq/kg) and not declared in two studies [12, 16, 17, 29, 30].

FCH PET/CT was compared with US by Amadou et al. [4], Bossert et al. [30], Hocevar et al. [26], Michaud et al. [13], and Thanseer et al. [32]. FCH PET/CT proved to be superior to US in detecting benign parathyroid lesions, with a sensitivity in the range of 85.2–100% and 50–82%, respectively, on patient-based and lesion-based analysis.

Comparisons between FCH PET/CT and 99mTc-MIBI SPET/CT with a dual-phase and/or subtraction protocol were reported in numerous studies (Table 2; [4, 12‐17, 19‐34]).

Quak et al. [17], Araz et al. [20], Kluijhout et al. [16], Hocevar et al. [26], and Thanseer et al. [32] found FCH PET/CT more sensitive than dual-phase SPET/CT (100% vs. 80.7%, and 100% vs. 76.4%, respectively, for patient-based and lesion-based analyses).

Michaud et al. [12, 13], Lezaic et al. [24], Zajickova et al. [22], Rep et al. [27], Amadou et al. [4], Beheshti et al. [29], Bossert et al. [30], Grimaldi et al. [34], and Huber et al. [19] compared FCH PET/CT with 99mTc-MIBI/99mTc-tetrofosmin SPET/CT performed with both subtraction and dual-phase protocols. They found FCH PET/CT superior to SPET/CT with the subtraction and dual-phase protocols for the detection of adenoma and/or hyperplastic parathyroid, with a diagnostic accuracy of 97.4% and 87.7% for PET/CT and SPET/CT, respectively, on lesion-based analyses.

In the study by Kluijhout et al. [14], 10 patients were studied with FCH PET and MRI, and compared with the same patients examined using US and a dual-phase 99mTc-MIBI SPET/CT. While for PET/MRI the sensitivity was 90% and the positive predictive value (PPV) was 100%, MRI alone showed a sensitivity of 55.6% and a PPV of 83.3%. In Fig. 2 is reported a 65-year-old patient with persistent hyperparathyroidism after surgery who underwent FCH PET/MRI in our Department.

True positive, false positive, true negative and false positive were available in 18 studies, at patient-based analysis and in 14 studies at lesion-based analysis (Table 3). Totally, true positive findings were reported in 686 patients and 530 lesions, respectively. Conversely, the number of false negative results were 35 and 23 on patient-based and lesion-based analysis. Pooled sensitivities were 93.7% and 91.3%, on patient-based and lesion-based analysis, respectively, as illustrated in Fig. 3.

The present systematic review showed that, in a population with negative/doubtful imaging findings, FCH PET/CT is more accurate than 99mTc-MIBI scintigraphy (whatever the protocol used) and US in patients with primary or recurrent hyperparathyroidism (all 23 studies considered in the review had included patients with primary hyperparathyroidism, and two (Amadou et al. [4] and Christakis et al. [31]) also included cases of recurrent hyperparathyroidism.

It is important to bear in mind that acquisition protocols for FCH PET/CT vary considerably. This can have an important impact on how images are interpreted and could bias their reported accuracy. FCH PET/CT was nonetheless superior to conventional scintigraphic or radiological approaches in most cases, regardless of the protocol used. In the majority of the studies considered, a single static acquisition was obtained at any time between 2 and 60 min after injecting the tracer. In 6/8 studies involving single static acquisitions, this interval ranged between 30 and 60 min. Full dynamic analysis could clarify the best timing of a static acquisition more precisely. This aspect does not seem to have been addressed in the literature to date and could be an interesting topic for future research. Only the paper by Prabhu et al. [15] reported the time active curves for parathyroid adenoma, thyroid gland and lymph node, demonstrating a higher uptake in parathyroid adenoma in the first 5 min after tracer injection. Michaud et al. [13] demonstrated that abnormal foci at a parathyroid gland were visible on early images, although the significant uptake in blood vessels imposed a more careful analysis of the cross-sectional images. Rep et al. [25] reported a slightly higher accuracy and sensitivity on scans obtained after 60 min than on those obtained after 5 min (94.1 vs. 96.5% and 90.5 vs. 93.6%, respectively). They consequently suggested that, for the preoperative localization of parathyroid gland, image acquisition was optimal 1 h after administering FCH.

Eight studies reported false positive results and 17 obtained false negative findings at 18F-Choline PET/CT (see Table 3), in accordance with the patient-based analysis. False-positive and false-negative results were frequently due to misinterpretation of thyroid anomalies, or due to a high uptake in normal or hyperplastic parathyroid glands, or in case of ectopic glands or adenomas with no specific characteristics or in case of very small adenomas with a fairly low number of oxyphilic cells.

As in the case of 99mTc-MIBI SPET/CT, some authors preferred to use a dual-phase FCH PET protocol (PET/CT or PET/MRI). It should be noted, however, that the kinetic characteristics of radiolabeled choline are very different from those of 99mTc-MIBI, and so the proper timing of the former cannot be deduced directly from the latter. 99mTc-MIBI accumulates more intensely in malignant cells because of their higher mitochondrial density and transmembrane electrical potential. Non-specific mechanisms lead to the uptake in nontumor cells with a greater metabolic activity or higher density of mitochondria—a situation encountered in atypical hyperplasia or particularly active tumor-like granulation. 99mTc-MIBI uptake in parathyroid foci was found to depend not on the cell type, but rather on either the size or the functional state of a lesion (Fukumoto et al. [35]). On the other hand, tumor cells with a high proliferation rate will have a high uptake of FCH to keep up with an increased demand for the synthesis of phospholipids (Vallabhajosula et al. [36]). A possible explanation for FCH uptake in benign parathyroid adenomas seems to be the increase in phospholipid-dependent choline kinase activity arising from PTH hypersecretion (Ishizuka et al. [37]).

A number of systematic reviews and meta-analyses on FCH PET/CT have been published in the last 2 years (Table 4) (Kim et al. [38]; Treglia et al. [39]; Boccalatte et al. [40]; Broos et al. [33]). In all cases, FCH PET/CT had an optimal performance in identifying benign parathyroid lesions. To the best of our knowledge, however, our systematic review is the first to include a large number of studies (n = 23), and to compare FCH PET/CT with conventional imaging (US and 99mTc-MIBI scanning), based on per-patient and per-lesion analyses. The present review also paid attention to the timing of image acquisition. In clinical practice, it seems that FCH PET/CT could be used for localizing and identifying benign parathyroid lesions, irrespective of the severity of PHPT (Beheshti et al. [29]), and particularly in patients with equivocal or negative conventional imaging.

CT and MRI have always had a marginal role in parathyroid imaging, and been applied mainly when the results of US and 99mTc-MIBI are difficult to interpret, or when parathyroidectomy fails due to ectopic glands (Johnson et al. [41]). Recent technical advances enabling high-resolution MRI of the neck have increased the applicability of such techniques, however. Even small lesions can be reliably detected and characterized nowadays on conventional sequences or with methods like diffusion weighted imaging (DWI) (Yildiz et al. [42]). 4DCeCT combines standard multiplanar CT scanning (non-contrast, arterial and venous phases) with the fourth dimension of changes in contrast attenuation over time, providing both functional and anatomical information about the abnormal parathyroid gland. Some recent studies have reported the role of 4DCeCT in patients with persistent or recurrent parathyroid hyperfunction, showing a sensitivity until to 86% [43‐46]. Piccardo et al. [21], showed that in 31 patients, the association of 18F-Choline PET with 4DCeCT could enhance the sensitivity to 100% in patients with persistent or recurrent hyperfunctioning parathyroid.

Argiro’ et al. [47], for instance, found MRI more sensitive (97.8%) than US or 99mTc-MIBI, either alone (89.1% and 83.6%, respectively) or combined (93.4%), for the pre-surgical detection of benign parathyroid lesions, as well as for the diagnosis of multiglandular disease and ectopic parathyroid adenomas.

Yildiz et al. [48] demonstrated that DWI enables solid parathyroid lesions to be distinguished from surrounding structures, and can also detect different types of lesions with peculiar MRI characteristics on T1w and T2w sequences. They found that parathyroid adenoma and hyperplasia usually appear as small lesions with well-defined margins and contrast enhancement, while parathyroid carcinomas are larger and less homogeneous.

Finally, in a recent study, Ozturk et al. [44] correctly localized 38 parathyroid lesions using 4D MRI, reporting a sensitivity of 90.5% and a PPV of 95%.

The advantages and disadvantages of all imaging techniques that can be used in the definition of parathyroid benign lesions are listed in Table 5.

In the light of the above, an approach combining FCH PET with MRI (using PET/MRI scanners or PET/CT with MRI) represents an optimal choice, improving on the accuracy of either method. Unfortunately, the paucity of data on PET/MRI in this field prevents us from drawing any further conclusions about the diagnostic potential of this technique.

FCH PET is more accurate than conventional imaging modalities (US and 99mTc-MIBI SPET/CT, whatever the protocol used) in detecting benign parathyroid lesions. It has a potential role in both primary and recurrent hyperparathyroidism. Although it would be necessary to conduct a cost-effective analysis before adopting this imaging modality in clinical practice, it seems important to emphasize that, in selected cases, when the outcome of conventional US and scintigraphy is hard to interpret, FCH PET is an appropriate choice. PET/MRI is a very promising technique in this field, but further research is needed to fully assess its role.