Usefulness of 18F-Fluorocholine Positron Emission Tomography–Computed Tomography in Locating Lesions in HyperparathyroidismA Systematic Review
Luis Alejandro Boccalatte, MD1; Felipe Higuera, MD2; Natalia Lucía Gómez, MD1; et alAlejandro Yanzón de la Torre, MD1; Eduardo Luis Mazzaro, MD1; Ana María Galich, MD3; Carlos Collaud, MD4; Marcelo Fernando Figari, MD1
JAMA Otolaryngol Head Neck Surg. Published online May 30, 2019. doi:10.1001/jamaoto.2019.0574
Key Points
Question What is the practical use of 18F-fluorocholine positron emission tomography–computed tomography as an anatomic and functional test in hyperparathyroidism?
Findings This systematic review of 16 studies found that 18F-fluorocholine positron emission tomography–computed tomography has high sensitivity, specificity, positive predictive value, and diagnostic accuracy compared with first-line tests, where concomitant thyroid disease or ectopic glands may decrease such indices. It is a second-line test when the results of ultrasonography and sestamibi scans are negative or discordant.
Meaning 18F-fluorocholine positron emission tomography–computed tomography could be useful when there is clinical suspicion of hyperplasia, multiple lesions, persistent or recurrent hyperparathyroidism, small or ectopic adenomas, or normocalcemic hyperparathyroidism.
Abstract
Importance Identifying parathyroid glands correctly before a surgical procedure is essential to perform minimally invasive surgery. First-line tests with discordant or negative results underscore the need for more accurate imaging tests, thus decreasing the requirement for bilateral neck exploration or reintervention.
Objective To review the available evidence to determine positive predictive value, negative predictive value, sensitivity, and specificity in clinical cases in which 18F-fluorocholine positron emission tomography–computed tomography (PET/CT) could be useful as a method to locate the lesions, and the benefits and controversial aspects of the method.
Evidence Review A search was conducted using the PubMed Central and Cochrane Library databases for studies published in English from July 26, 2014, to November 30, 2018, using the search terms 18 choline, 18F choline, 18F-choline, 18 fluorocholine PET CT, hyperparathyroidism, primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, persistent hyperparathyroidism, recurrent hyperparathyroidism, ectopic hyperparathyroidism, and parathyroid adenoma. Other inclusion criteria were reporting at least 1 of the following measurements: negative or positive predictive value, sensitivity, and specificity of 18F-fluorocholine PET/CT in the diagnosis of hyperparathyroidism (HPT). Exclusion criteria were language other than English, use of a tracer other than 18F-fluorocholine, reports of a single case, and studies not related to HPT. The Oxford Centre classifications for levels of evidence were used.
Findings Sixteen studies fulfilled the inclusion criteria, comprising a total of 619 patients. Selected studies included 10 prospective cohort studies, 5 retrospective cohort studies, and 1 case series. Of the subtypes of HPT diagnosed using 18F-fluorocholine PET/CT, 579 were primary HPT, 22 were secondary HPT, 1 was tertiary HPT, and 7 were associated with multiple endocrine neoplasia type I. Pathologically, the neoplasms comprised 459 adenomas, 59 hyperplasia, and 19 double adenomas.
Conclusions and Relevance 18F-fluorcholine PET/CT may be indicated when results of first-line tests are negative or discordant and in challenging clinical situations where locating the source of HPT is difficult.
Introduction
Hyperparathyroidism (HPT) is an endocrine disorder characterized by an increase in the secretion of parathyroid hormone (PTH), with a resulting increase in calcium plasma levels, which can cause renal lithiasis, fractures, and osteoporosis, the most frequent symptoms of the disease.
The incidence of primary HPT is 66 cases among every 100 000 women and 25 among every 100 000 men per year. The incidence of persistent-recurrent HPT ranges between 2.0% and 2.5%. Representing 85% of cases, parathyroid adenoma is the most frequent cause of primary HPT, followed by hyperplasia, double adenoma, and carcinoma.1-4 In cases of HPT secondary to chronic renal disease, the surgeon has to locate the hyperfunctional glands and perform their total or subtotal resection. In tertiary HPT, the number of parathyroid glands to be resected should be based on the number of hyperfunctional foci detected by scintigraphy.
Neck ultrasonography and sestamibi scan are the first-line examinations to locate the hyperfunctional glands. However, according to the various series available, reported sensitivity rates vary for ultrasonography5-8 as well as for sestamibi.9-11 Positron emission tomography (PET) performed with computed tomography with 18F-fluorocholine (18fluorocholine PET/CT) has emerged in the past 4 years as a potential diagnostic method for HPT.
The purpose of this review is to identify known and controverted relevant aspects about 18F-fluorocholine PET/CT in HPT and present the evidence that is currently available.
Methods
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. We performed a systematic review of the studies published until November 30, 2018, that reported results for 18F-fluorocholine PET/CT and HPT, of at least 1 of the following statistics: negative predictive value (NPV), positive predictive value (PPV), sensitivity, and/or specificity. The available evidence was analyzed to assess the clinical situations where 18F-fluorocholine PET/CT could be useful as a method to locate lesions, its benefits, and controverted aspects. The selection of papers, can be seen in the PRISMA flow diagram12(eFigure in the Supplement).
This systematic review was approved by the ethics committee for research protocols of Hospital Italiano de Buenos Aires . The committee stated that informed consent was not necessary, given the type of study.
Search Methods
The studies were selected from a search of the databases of PubMed Central and the Cochrane Library for papers published in English from July 26, 2014, through November 30, 2018. One author (L.A.B.) performed the literature search, which was independently confirmed by the research area of our institution, and the small discrepancies were resolved jointly according to the selection and inclusion criteria of the systematic review. For the initial search, the following key words and Boolean operators were used: 18 choline/18F choline/18F-choline/18 fluorocholine PET CT AND (hyperparathyroidism OR primary hyperparathyroidism OR secondary hyperparathyroidism OR tertiary hyperparathyroidism OR persistent hyperparathyroidism OR recurrent hyperparathyroidism OR ectopic hyperparathyroidism OR parathyroid adenoma). We excluded studies that did not report results of at least 1 of the following: NPV, PPV, sensitivity and specificity, as well as case reports, imaging reports, use of a tracer other than 18F-fluorocholine, and studies not related to HPT.
Assessment of the Evidence
The following variables were obtained from the full-text papers: first author of the study, year of the study, number of cases, country where the study was performed, type of study, specificity positive predictive value (PPV), type of HPT, and pathologic findings. We analyzed the available evidence to assess the clinical situations where 18F-fluorocholine PET/CT could be useful as a method for locating lesions and its benefits and controverted aspects.
To assess the quality of each of the studies included, the modified evaluations of the Oxford Centre for Evidence-Based Medicine of individual studies were used. The scale comprises 5 levels; level 1 consists of systematic reviews of randomized controlled trials; level 2, of randomized controlled trials or observational studies with dramatic effect; level 3, nonrandomized, controlled cohort studies; level 4, case series; and level 5, expert opinion.
Results
Sixteen papers published from July 26, 2014, to November 30, 2018, that fulfilled the final inclusion criteria were selected, comprising 619 patients. The studies selected included 10 prospective cohorts, 5 retrospective cohorts and 1 case series. France (n = 4) and Slovenia (n = 3) were the countries with the highest number of series reported. Sensitivity was reported in all studies included. As to the subtypes of HPT diagnosed by 18F-fluorocholine PET/CT, 579 corresponded to primary HPT, 22 to secondary HPT, and 1 to tertiary HPT, and 7 were associated with multiple endocrine neoplasia type I. Pathology results were the following: 459 adenomas, 59 hyperplasia, and 19 double adenomas. Clinical situations, advantages, and controverted aspects of 18F-fluorocholine PET/CT were defined based on the available evidence. Results are depicted in the Table.13-28 Sensitivity was assessed in all of the articles and ranged between 80% and 100%. On the other hand, specificity was evaluated in 7 of the 16 studies and varied between 95% and 100%. Negative predictive value (86%-100%) and positive predictive value (87%-100%) were determined in 5 studies.
Discussion
First-Line Tests
Ultrasonography
Ultrasonography is a low-cost test that provides anatomic information and is highly operator dependent. Its sensitivity for the detection of parathyroid adenomas ranges from 70% to 100%29,30 and drops to 47% to 84% when thyroid nodules are present.31,32
Sestamibi
Sestamibi scan is a widely used functional test, with a sensitivity that ranges from 54% to 100% for identification of parathyroid adenomas, according to some reported series.33
A systematic review4 presents the sensitivity of the first-line methods according to the etiology. Ruda et al4 state that ultrasonography has a sensitivity of 78.5% for the detection of parathyroid adenomas, 34.9% for hyperplasia, and 16.2% for double adenomas, whereas for sestamibi with technetium Tc 99m, sensitivity rates are 88.9% for parathyroid adenomas, 44.5% for hyperplasia, and 29.9% for double adenomas.
Pathophysiology
The PET/CT test with 18F-fluorocholine was initially used as a tracer in prostate cancer.34 The phospholipid analogue, 18F-fluorocholine, integrates to recently synthesized membranes of proliferating cells, and its uptake by neoplastic cells is increased by choline kinases.35 In parathyroid adenomas, it has been shown that upregulation of phospholipid-dependent choline kinases is caused by an increase in PTH25,35,36 (Figure 1). Possibly, both mechanisms could be responsible for the uptake of 18F-fluorocholine in hyperfunctional parathyroid tissue.
Sensitivity and Specificity of 18F-Fluorocholine PET/CT
As depicted in the Table, the sensitivity, specificity, NPV, and PPV of PET/CT are high. Two series37,38 that assessed fluorinated tracers similar to 18F-fluorocholine in primary HPT reported sensitivities of 0% to 22%, although those studies were performed more than 10 years ago. Neumann et al11claimed that the sensitivity of Tc 99m sestamibi compared with 18F-fluorocholine PET/CT is 86% vs 43%, respectively, albeit with a lower specificity: 78% vs 90%. Other studies, among them the one by Caldarella et al,39 proposed 11C-methionine as a valid alternative tracer, similar to 18F-fluorocholine PET/CT, for the detection of parathyroid adenomas (sensitivity: 81%, detection rate: 70%); however its use is limited to few centers, since it requires a cyclotron, has a short half-life,39 and is less accurate than 18F-fluorocholine.13,18
Benefits of 18F-Fluorocholine PET/CT Compared With Other Methods
The diagnostic accuracy rate of 18F-fluorocholine PET/CT is high for the detection of parathyroid adenomas,20,21 and allows the performance of a minimally invasive surgery with less risk of postoperative hypocalcemia and damage to the recurrent laryngeal nerve, and a decrease in surgical procedure times and health care costs,15,21,23 thus resulting in a quick recovery and early hospital discharge. In addition, it has advantages over sestamibi in terms of image quality and short performance time, the latter owing to rapid kinetic properties of the tracer; such advantages increase patient adherence23,40,41 and decrease the dose of radiation administered.21,23 Rep et al23 showed that ionizing radiation levels are 7.4 mSV for sestamibi, 6.8 mSV for sestamibi scintigraphy–single-photon emission (SPECT)/CT, and 2.8 mSV for the 2 phases of 18F-fluorocholine PET/CT, emphasizing that the addition of CT to hybrid methods does not substantially increase the radiation levels received.
Other current novel methods for the diagnosis of HPT are 4D-CT and magnetic resonance–PET/CT. Four-dimensional CT is a functional and anatomic test based on the perfusion dynamics of adenomas in relation to the surrounding tissues. Brown et al42 carried out a prospective study including 99 patients comparing 4-D CT with sestamibi, emphasizing the high sensitivity of the method (75%) in cases of negative results on sestamibi, persistent or recurrent HPT, or a combination of these.43 Hinson et al44 obtained 76.5% sensitivity, 91.5% specificity, and 88.2% accuracy values and concluded that 4D-CT is a useful test for locating lesions when findings of ultrasonography and sestamibi are inconclusive, similar to 18F-fluorocholine PET/CT. Moreover, if 3 acquisition phases are obtained, the amount of radiation to which the patient is exposed is less than with SPECT (13.8 vs 18.4 mSv, P = .04).
Piccardo et al45 concluded that fusion of 4D-CT with 18F-fluorocholine PET/CT has significantly higher sensitivity (100% vs 80%) than 18F-fluorocholine PET/CT without 4D-CT. However, in spite of that advantage,45,46 it exposes the thyroid gland to more ionizing radiation, owing to its high spatial resolution,41,46-50 which is a disadvantage compared with 18F-fluorocholine PET/CT. The benefit of PET images compared with single-photon images is their ability to detect mediastinal adenomas, because high-energy gamma rays (511 keV) are less attenuated by the sternum and the thoracic cage than sestamibi gamma radiation.26Given the mentioned factors, PET is a technique that sparks great interest,18 because it provides a higher spatial resolution, increased lesion-to-noise ratio, and less attenuation, allowing detection of lesions smaller than 1 cm.
Another innovative method that has recently appeared is the fusion of magnetic resonance with 18F-fluorocholine PET/CT. The study conducted by Kluijfhout et al51 has shown a sensitivity of 90% and a PPV of 100%, which would make it a useful method in cases of primary HPT with discordant test results. Potential benefits of this method are its lower radiation exposure with respect to 18F-fluorocholine PET/CT (3.8 vs 9.5 mSv), shorter performance time than sestamibi, and the identification of lipomatous and ectopic parathyroid glands. However, the sample size of the study (10 patients) was insufficient to draw conclusions at present.
Acquisition Phases and False Results
Image acquisition times and number of phases have not been standardized yet. Several authors obtain a first image after a few minutes, followed by a late phase. However, the optimal time to acquire the image is 1 hour after administering the tracer.23 Rep et al,23 in agreement with Quack et al,20suggested keeping the early images, because some lesions can only be captured in the first few minutes. In contrast, Thanseer et al22 asserted that the first acquisition phase does not provide useful information.
Regarding false results, Mehta et al52 analyzed the histopathology results obtained from patients with primary HPT and negative or positive sestamibis who underwent surgery, concluding that the size and contents in oxyphil cells were the only differences between both groups. However, we have not found studies assessing the variables mentioned with 18F-fluorocholine PET/CT.
Of note, 18F-fluorocholine is a metabolic tracer; hence, it is not specific for parathyroid disorders. Inflammation and other malignant or benign tumors may lead to false-positive results.24,53-55 This tracer may also build up in thyroid cancer, lymph node metastases, inflammatory disorders,21,48,56 and parathyroid carcinoma.57 A history of parathyroid surgery, hyperplasia in the context of MEN I, or renal disease may negatively affect image quality on PET/CT.58-60 Hyperfunctional parathyroid glands with normal histologic features, hyperplastic glands in multiglandular disease,24 ectopic glands, nonspecific hyperplasias or adenomas, and atypical intrathyroid parathyroid adenomas may lead to false-negative results.14,16,17,25
Clinical Situations in Which 18F-Fluorocholine PET/CT May Be Useful
18F-fluorocholine PET/CT test has proven better in the diagnosis of hyperplasia or multiple or ectopic adenomas13,18,20,24 (Figure 2), even in the context of familial HPT (multiple endocrine neoplasia).24 This wide detection range is explained because nuclear medicine tests, such as PET, correlate with the individual size and volume of the affected glands.61 This differs in the case of sestamibi, which has a low diagnostic performance in patients with multiple or small lesions (16%-35%).48,61,62
In cases of persistent or recurrent HPT, locating the lesions preoperatively is important, because reintervention is associated with more complications and low cure rates63; however, series including such patients are scarce (Figure 3). 18F-fluorocholine PET/CT has shown good results in these clinical scenarios.13,18,24 In a series reported by Grimaldi et al,2418F-fluorocholine PET/CT detected all the lesions, in familial as well as sporadic disease, although the series only included 6 patients.
The high diagnostic accuracy of 18F-fluorocholine PET/CT could largely be owing to its greater ability to detect small or ectopic adenomas.13,18 Along these lines, Thanseer et al22 obtained good results in primary HPT with modest increase in PTH and negative test results, emphasizing the usefulness of this method in mild clinical cases. Bossert et al26 analyzed the potential role of PET in normocalcemic HPT, concluding that it could be a first-line test to identify abnormalities in parathyroid glands in patients with normocalcemic or hypercalcemic HPT. Sensitivity for normocalcemic HPT was 71% and 70%, in contrast with sestamibi, which detected 6% of normocalcemic HPTs.64 In summary, most series agree that negative or discordant findings on ultrasonography or sestamibi examination is the stronger indication for this method.13,15,16,18-21,24,25
Clinical Correlations
The most recent available series have assessed the correlation between standardized uptake value (SUV), metabolic status, clinical condition, and even molecular makeup, and have led to discordant conclusions. Thus, Grimaldi et al24 and Araz et al25 concluded that there is no correlation between maximum SUV and the patient’s clinical or biochemical status, whereas Kluijfhout et al18 believe there is a correlation between a high PTH value and SUV on PET. Along the same lines, Piccardo et al45 demonstrated significant correlation of calcemia with SUV, but not with PTH values.
As to molecular pathways, expression of p53 and Ki-67 could be involved in the development of parathyroid adenomas.65,66 Piccardo et al45 assessed the relation between maximum SUV and the expression of these pathways in parathyroid lesions and found a direct correlation between expression of the SUV ratio and Ki-67, and an inverse correlation between choline uptake and p53 expression. There is still much uncertainty in this area of research, and the clinical usefulness of these correlations remains unclear.
Cost
Studies assessing cost-effectiveness have been performed,67,68 analyzing first-line studies and comparing them with various strategies. First-line methods vs SPECT vs bilateral neck exploration (BNE), in the context of negative sestamibi findings, have shown that ultrasonography not only has higher expected cure rates (99.42%), but is also more effective and less costly. Ruda et al67 state that “the preoperative ultrasonography and SPECT strategies were less costly than BNE, with expected costs of US $6030 for the ultrasonography strategy, US $7131 for the SPECT strategy, and US $8384 for the BNE strategy.” However, no studies of similar quality are available for 18F-fluorocholine PET/CT.
Studies are required that comprehensively assess costs for the health care system15; nonetheless, Quack et al20 state that the benefit of 18F-fluorocholine would be avoidance of bilateral explorations of the neck and complications of persistent or recurrent HPT.26
Limitations
The main limitation of this systematic review is the small number of studies included. We have excluded unpublished research and non–English language articles, which could also bias our results. Furthermore, most of the studies analyzed are heterogeneous with respect to data source, study setting, design, country, and outcome measures. Most of the studies include a limited number of patients, which could also result in bias. On the other hand, further prospective studies regarding costs, cost-effectiveness analyses, radiation doses and risks, and SUV correlation are needed.
Conclusions
According to the available evidence, 18F-fluorocholine PET/CT provides high rates of sensitivity, specificity, PPV, and diagnostic accuracy. Most series suggest its indication when results of first-line tests are negative or discordant; however, it may also be useful in cases of hyperplasia or multiple lesions, persistent or recurrent HPT, small or ectopic adenomas, and normocalcemic HPT.
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Article Information
Accepted for Publication: March 2, 2019.
Corresponding Author: Luis Alejandro Boccalatte, MD, Department of Head and Neck Surgery, Department of General Surgery, Hospital Italiano de Buenos Aires, Work Address: Juan D. Perón 4190 (C1181ACH) Buenos Aires, Argentina (luis.boccalatte@hospitalitaliano.org.ar; luis.boccalatte@gmail.com).
Published Online: May 30, 2019. doi:10.1001/jamaoto.2019.0574
Author Contributions: Dr Boccalatte had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Boccalatte, Higuera, Mazzaro, Collaud, Figari.
Drafting of the manuscript: Boccalatte, Higuera, de la Torre, Figari.
Critical revision of the manuscript for important intellectual content: Boccalatte, Gómez, de la Torre, Mazzaro, Galich, Collaud, Figari.
Statistical analysis: Mazzaro.
Obtained funding: Collaud, Figari.
Administrative, technical, or material support: Higuera, de la Torre, Mazzaro, Collaud.
Supervision: Boccalatte, Gómez, de la Torre, Mazzaro, Galich, Collaud, Figari.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We gratefully acknowledge Fanny Mariel Rodriguez Santos, MD, of the Department of General Surgery, Hospital Italiano de Buenos Aires, for her contribution to Figure 1. Dr Rodriguez Santos was not compensated for her work on this manuscript.
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