Preoperative localization of parathyroid adenomas/hyperplasia is essential for minimally invasive surgery or unilateral neck exploration. Localization techniques include functional and anatomical methods. Among the functional methods, dual-phase parathyroid scintigraphy using 99mTc-sestamibi (MIBI) is one of the most common. Single-photon emission computed tomography using MIBI (MIBI SPECT) has been shown to be more sensitive and allows for more precise localization compared with planar scintigraphy 1,2. It has also been reported that hybrid imaging, which combines SPECT with computed tomography (SPECT/CT), contributes to surgical planning by adding anatomical information, especially in patients with ectopic adenomas or with previous neck surgery 3. A higher sensitivity of MIBI SPECT/CT compared with MIBI SPECT or planar scintigraphy has also been reported 4.
Recently, studies have explored the utility of PET using 11C-methionine (MET PET) for localization of parathyroid adenomas. In a recent meta-analysis, which included nine studies comprising 258 patients, the pooled per-patient sensitivity was 81% 5. In addition, Weber et al.6 showed high accuracy of MET PET/CT in the preoperative localization of parathyroid adenomas in a large series of cases of primary hyperparathyroidism, although Herrmann et al.7 described much lower sensitivity of MET PET in their retrospective analysis. Recently, Schalin-Jäntti et al.8 compared the performance of MET PET/CT and MIBI SPECT/CT in hyperparathyroidism along with 123I/MIBI scintigraphy and selective venous sampling. However, their patient population was limited to patients previously operated upon with persistent hyperparathyroidism before re-operation. To the best of our knowledge, there are few reports directly comparing MET PET/CT and MIBI SPECT/CT in a patient group with hyperparathyroidism that are not restricted to persistent hyperparathyroidism after operation.
The purpose of this study was to compare the performance of MET PET/CT and MIBI SPECT/CT for localizing parathyroid adenomas/hyperplasia.
Materials and methods
From July 2009 to August 2013, 23 patients (19 women and four men; age range 32–83 years) underwent both MET PET/CT and MIBI SPECT/CT for suspected primary hyperparathyroidism, fulfilling at least one of the following criteria: (a) parathyroid adenoma or hyperplasia had been confirmed surgically (n=15); or (b) they had increased serum intact parathyroid hormone (PTH) level (>65 pg/ml), increased serum calcium level (>9.9 mg/dl in 2009–2011, >10.1 mg/dl in 2012–2013), and fractional excretion of calcium greater than 0.01 (n=8). This study was approved by the ethics committee at our institute, and written informed consent was obtained from all participants.
MET PET/CT scan
PET/CT scanning was performed using a combined PET/CT scanner (Discovery ST Elite; GE Healthcare, Waukesha, Wisconsin, USA). This system integrates a PET scanner with a multidetector-row CT scanner (16 detectors). PET/CT scanning was performed at 15–34 min (mean 26 min) after intravenous injection of 441–906 MBq of MET. The scanning range was from the neck to the thorax.
MIBI scintigraphy and SPECT/CT scan
SPECT/CT was performed using a SPECT/CT scanner (Infinia Hawkeye 4; GE Healthcare). This system incorporates a dual-head gamma camera and integrated low-dose, four-slice CT. Patients were injected intravenously with ∼600 MBq of MIBI. Anterior planar images from the neck to the thorax were acquired at 15 min (early images) and 2–3 h (delayed images) after injection. SPECT/CT images were acquired from the neck to the thorax after acquisition of delayed planar images.
PET images were interpreted by consensus of at least two board-certified nuclear medicine physicians blinded to clinical information including other clinical images and serum intact PTH levels. MIBI planar images were available for interpretation of MIBI SPECT/CT. In addition, interpretations of only planar images and of SPECT+planar images of MIBI scintigraphy were also recorded. MET PET/CT and MIBI SPECT/CT images were interpreted visually. A focus of increased uptake located adjacent to the thyroid gland or in the mediastinum was considered positive for an abnormal parathyroid gland. Focal uptake detectable only in early planar imaging of MIBI scintigraphy was not considered as parathyroid uptake. Multiple foci of increased uptake in the mediastinum in MET PET/CT images were regarded not as parathyroid lesions but as lymph nodes, because inflammatory changes often cause focal uptakes of MET in mediastinal and hilar lymph nodes 9.
Standard of reference
In per-patient analysis, if MET PET/CT or MIBI SPECT/CT detected at least one positive lesion (on the correct side if the location was confirmed by surgery), the results were considered true positive. If no positive lesion was observed, the results were considered false negative.
In per-lesion analysis, only patients who underwent surgery were analyzed. If MET PET/CT or MIBI SPECT/CT could locate adenomas/hyperplastic glands on the correct side or at other specific locations (if ectopic), the results were considered true positive. If no abnormal uptake was observed in the same location, the results were considered false negative.
The sensitivities of MET PET/CT and MIBI SPECT/CT in per-patient and per-lesion analysis were calculated and compared using McNemar’s χ2-test. For patients who underwent surgery, we compared the length and volume, calculated as (length×width×height)×π/6, of adenoma/hyperplastic glands from pathological specimens between positive and negative lesions obtained using each modality by means of the unpaired t-test and the Mann–Whitney U-test. For all patients, the serum intact PTH levels were also compared between patients with and those without positive lesions in each modality using the Mann–Whitney U-test.
In each analysis, a P value less than 0.05 was considered statistically significant.
Sensitivity of MET PET/CT and MIBI SPECT/CT
Patients’ characteristics and findings are summarized in Table 1. Of 15 patients who underwent surgery, 11 single adenomas, including one mediastinal adenoma in patient 8, were confirmed in 11 patients, and 10 hyperplastic parathyroid glands were confirmed in three patients, including two patients with suspected multiple endocrine neoplasia type 1 (patients 13 and 15). In one patient, histological and clinical findings could not distinguish between adenoma and hyperplasia. This patient (patient 12) had been diagnosed with multiple endocrine neoplasia type 1 and suffered from recurrent hyperparathyroidism after total parathyroidectomy for parathyroid hyperplasia. Eight patients were clinically diagnosed with primary hyperparathyroidism but did not undergo surgery.
Table 2 summarizes the sensitivities of MET PET/CT and MIBI SPECT/CT in a per-patient analysis and in a per-lesion analysis. The sensitivities of MET PET/CT and MIBI SPECT/CT were 65 and 61%, respectively, on a per-patient basis, and no significant difference was found between the two methods (McNemar’s χ2-test). The numbers of detected lesions were the same between the three manners of interpretation of MIBI scintigraphy – namely, using only planar images, using MIBI SPECT+planar image, or using MIBI SPECT/CT+planar images. Table 3 shows the cross-tabulation of the results of MET PET/CT and MIBI SPECT/CT studies. A MET-positive, MIBI-negative case and a MET-negative, MIBI-positive case are shown in Figs 1 and 2, respectively.
The sensitivities of MET PET/CT and MIBI SPECT/CT for histologically confirmed adenomas and multiple hyperplastic glands were 91 and 73% and 30 and 30%, respectively, without a statistically significant difference (McNemar’s χ2-test).
Lesion size and intact PTH levels according to the results of MET PET/CT and MIBI SPECT/CT
The long-axis lengths and calculated volumes of uptake-positive lesions were significantly larger than those of uptake-negative lesions in MET PET/CT (unpaired t-test for length and the Mann–Whitney U-test for calculated volume). No significant difference was found in intact PTH levels between MET PET/CT-positive and MET PET/CT-negative patients (Mann–Whitney U-test) (Table 4).
The same analysis was performed on MIBI SPECT/CT results. Similar to the results of MET PET/CT, uptake-positive lesions were larger than uptake-negative lesions. No significant difference was observed in intact PTH levels between MIBI SPECT/CT uptake-positive and MIBI SPECT/CT uptake-negative patients (Table 5).
In per-patient and per-lesion analyses, the sensitivities of MET PET/CT were comparable with those of MIBI SPECT/CT for parathyroid gland pathology. To the best of our knowledge, the present study is the first to directly compare MET PET/CT with MIBI SPECT/CT in patients with primary hyperparathyroidism that was not restricted to persistent hyperparathyroidism before operation. There have been a few previous reports comparing MET PET or PET/CT with MIBI SPECT; it has been unclear whether PET or PET/CT using MET is superior to MIBI SPECT. In the study by Tang et al.10 comparing MET PET/CT with MIBI SPECT in 30 preoperative patients with primary or secondary hyperparathyroidism, MET PET/CT showed comparable sensitivity to MIBI SPECT. They reported that the sensitivities of MET PET/CT and MIBI SPECT were 92 and 95%, respectively, for adenoma, and 68 and 59%, respectively, for hyperplasia. Otto et al.11 reported the superiority of MET PET compared with MIBI SPECT for primary hyperparathyroidism related to adenoma or carcinoma, with sensitivities of MET PET and MIBI SPECT of 94 and 50%, respectively. Herrmann et al.7 reported that the sensitivity of MET PET (53%) was lower than that of MIBI SPECT (74%) for prediction of lesions on the correct side in patients with hyperparathyroidism. In this investigation, the sensitivities of MET PET/CT and MIBI SPECT/CT were comparable, and MET PET/CT had a complementary role in detection.
MIBI SPECT/CT did not detect additional lesions compared with MIBI SPECT or planar imaging in any case, although MIBI SPECT/CT allowed more detailed localization in one patient with an ectopic parathyroid gland. The comparison between MIBI SPECT/CT and SPECT is consistent with Gayed’s report demonstrating that MIBI SPECT/CT had no additional value over conventional MIBI SPECT imaging except for localization of ectopic parathyroid glands 12. In contrast, Kim et al.4 found higher sensitivity of MIBI SPECT/CT compared with MIBI SPECT, dual-phase MIBI scintigraphy, and conventional imaging. Although it is unclear whether SPECT/CT has higher sensitivity than SPECT, SPECT/CT may be recommended when an ectopic parathyroid gland is suspected. In addition, SPECT/CT has advantages for patients who have undergone previous thyroid or parathyroid surgery, who have multiglandular disease, or have nodular thyroid disease, and it improves interobserver agreement 3,13. Our results are inconsistent with previous reports showing higher sensitivities of SPECT or SPECT/CT compared with planar imaging 1,2,14,15. Although the reason for this is unclear, SPECT is theoretically considered to have an advantage over planar imaging by providing detailed information concerning a three-dimensional location 14.
Five patients showed MET-positive/MIBI-negative results and four patients showed MET-negative/MIBI-positive results, indicating these two modalities play a complementary role. MET PET/CT showed positive results in 56% (5/9) of patients who had shown negative results in MIBI SPECT/CT. Therefore, MET PET/CT would be a feasible option if MIBI-negative results are obtained in localization of adenomas/hyperplasia. Such complementary results were also observed in a previous report 10. Incorporation into PTH and its precursors is considered to be one of the mechanisms of MET uptake into adenomas/hyperplasia, whereas MIBI uptake is considered to be positively related to increased concentrations of mitochondria-rich oxyphil cells and negatively related to the expression of p-glycoprotein, or multidrug resistance-related protein 16. Such different mechanisms of tracer uptake may account for their complementary role in localizing parathyroid gland adenomas/hyperplasia.
In the present study the positive lesions in both modalities were larger than the negative ones. The correlation between lesion detectability in both modalities and lesion size or weight was observed in previous reports 17–19. Only three (38%) and one (13%) of eight lesions less than 276 μl could be detected by MET PET/CT and MIBI SPECT/CT, respectively. In contrast, both modalities depicted nine (90%) of 10 lesions equal to or larger than 276 μl.
One possible factor affecting MET and MIBI uptake is the intact PTH level. There is a previous report showing a positive correlation between MET uptake of the lesion and serum intact PTH level 11. Per-patient sensitivities of both modalities were 100% in six patients with intact PTH levels greater than 150 pg/ml in our population. However, no significant difference in intact PTH levels was observed between positive and negative cases in the two modalities, which is consistent with a previous report by Weber et al. 6.
Higher sensitivities of MET PET or PET/CT compared with our study (65% in per-patient analysis) have been reported in several previous studies. In a meta-analysis in which nine studies were included, Caldarella et al.5 reported a pooled sensitivity of 81% in patients with suspected parathyroid adenoma. Weber et al.6 recently reported a sensitivity of MET PET/CT of 90.1% for localization of parathyroid adenomas/hyperplasia in 102 preoperative patients with primary hyperparathyroidism. Conversely, Herrmann et al.7 reported lower sensitivity (54%) of MET PET in 41 patients with suspected hyperparathyroidism, validating PET findings by histological or clinical findings. In the present study, as Herrmann and colleagues reported, patients were not necessarily scheduled to undergo surgery, and such a difference in population might account for the different results in other previous reports showing higher sensitivities of MET PET or PET/CT. In three patients who showed no abnormal uptake with either modality, no parathyroid lesion was detected with other imaging modalities. These patients may have parathyroid lesions too small to be detected by diagnostic imaging. Per-patient sensitivity of MET PET/CT in patients who underwent surgery was higher (80%). However, this result may contain a bias because MET PET/CT and MIBI SPECT/CT results themselves might influence clinical management (i.e. surgical or medical therapy).
Dual-tracer parathyroid scintigraphy using a pinhole collimator has been demonstrated as facilitating more accurate localization of parathyroid lesions compared with a single-tracer, dual-phase protocol with or without pinhole collimator or SPECT 20–22. In particular, accurate localization of parathyroid lesions using this technique has been shown in cases of multiple parathyroid gland disease 23, for which the sensitivities of both MET PET/CT and MIBI SPECT/CT were insufficient in the present study. Therefore, this technique might have detected more parathyroid lesions if it had been performed. A comparison between dual-tracer scintigraphy and MET PET or PET/CT has not been fully carried out, although Schalin-Jäntti et al.8 reported comparable accuracy of these techniques in the reoperative setting of primary hyperparathyroidism.
There are several limitations in the present study. First, histological confirmation was not obtained for all lesions. Therefore, it is possible that positive findings in some patients who did not undergo surgery were false positive. However, we believe that the possibility for false-positive cases is low, because suspected enlarged parathyroid glands were detected by ultrasonography corresponding to MET or MIBI uptakes in such patients. Second, a relatively small number of patients were analyzed in this investigation. Finally, we used only delayed SPECT/CT without obtaining early SPECT/CT. There is one article demonstrating higher sensitivity of early SPECT/CT 14, and different results might have been acquired with utilization of early SPECT/CT.
The sensitivities of MET PET/CT and MIBI SPECT/CT were comparable in localizing parathyroid adenomas/hyperplasia in patients with primary hyperparathyroidism. Although the sensitivities of both modalities were not satisfactory in this investigation, these two modalities may play complementary roles. MET PET/CT would be a feasible option if negative results are obtained in conventional parathyroid scintigraphy using MIBI.
Conflicts of interest
There are no conflicts of interest.
1. Slater A, Gleeson FV. Increased sensitivity and confidence of SPECT over planar imaging in dual-phase sestamibi for parathyroid adenoma detection. Clin Nucl Med 2005; 30:1–3.
2. Lorberboym M, Minski I, Macadziob S, Nikolov G, Schachter P. Incremental diagnostic value of preoperative 99m
Tc-MIBI SPECT in patients with a parathyroid adenoma. J Nucl Med 2003; 44:904–908.
3. Krausz Y, Bettman L, Guralnik L, Yosilevsky G, Keidar Z, Bar-Shalom R, et al.. Technetium-99m-MIBI SPECT/CT in primary hyperparathyroidism
. World J Surg 2006; 30:76–83.
4. Kim YI, Jung YH, Hwang KT, Lee HY. Efficacy of 99m
Tc-sestamibi SPECT/CT for minimally invasive parathyroidectomy: comparative study with 99m
Tc-sestamibi scintigraphy, SPECT, US and CT. Ann Nucl Med 2012; 26:804–810.
5. Caldarella C, Treglia G, Isgrò MA, Giordano A. Diagnostic performance of positron emission tomography using 11
C-methionine in patients with suspected parathyroid adenoma: a meta-analysis. Endocrine 2013; 43:78–83.
6. Weber T, Maier-Funk C, Ohlhauser D, Hillenbrand A, Cammerer G, Barth TF, et al.. Accurate preoperative localization of parathyroid adenomas with C-11 methionine PET
/CT. Ann Surg 2013; 257:1124–1128.
7. Herrmann K, Takei T, Kanegae K, Shiga T, Buck AK, Altomonte J, et al.. Clinical value and limitations of [11
for detection and localization of suspected parathyroid adenomas. Mol Imaging Biol 2009; 11:356–363.
8. Schalin-Jäntti C, Ryhänen E, Heiskanen I, Seppänen M, Arola J, Schildt J, et al.. Planar scintigraphy with 123
Tc-sestamibi SPECT/CT, 11
/CT, or selective venous sampling before reoperation of primary hyperparathyroidism
? J Nucl Med 2013; 54:739–747.
9. Yasukawa T, Yoshikawa K, Aoyagi H, Yamamoto N, Tamura K, Suzuki K, et al.. Usefulness of PET
C-methionine for the detection of hilar and mediastinal lymph node metastasis in lung cancer. J Nucl Med 2000; 41:283–290.
10. Tang BN, Moreno-Reyes R, Blocklet D, Corvilain B, Cappello M, Delpierre I, et al.. Accurate pre-operative localization of pathological parathyroid glands using 11
/CT. Contrast Media Mol Imaging 2008; 3:157–163.
11. Otto D, Boerner AR, Hofmann M, Brunkhorst T, Meyer GJ, Petrich T, et al.. Pre-operative localisation of hyperfunctional parathyroid tissue with 11
. Eur J Nucl Med Mol Imaging 2004; 31:1405–1412.
12. Gayed IW, Kim EE, Broussard WF, Evans D, Lee J, Broemeling LD, et al.. The value of 99m
Tc-sestamibi SPECT/CT over conventional SPECT in the evaluation of parathyroid adenomas or hyperplasia. J Nucl Med 2005; 46:248–252.
13. Wong KK, Fig LM, Youssef E, Ferretti A, Rubello D, Gross MD. Endocrine scintigraphy with hybrid SPECT/CT. Endocr Rev 2014[Epub ahead of print].
14. Lavely WC, Goetze S, Friedman KP, Leal JP, Zhang Z, Garret-Mayer E, et al.. Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy. J Nucl Med 2007; 48:1084–1089.
15. Thomas DL, Bartel T, Menda Y, Howe J, Graham MM, Juweid ME. Single photon emission computed tomography (SPECT) should be routinely performed for the detection of parathyroid abnormalities utilizing technetium-99m sestamibi parathyroid scintigraphy. Clin Nucl Med 2009; 34:651–655.
16. Pons F, Torregrosa JV, Fuster D. Biological factors influencing parathyroid localization. Nucl Med Commun 2003; 24:121–124.
17. Oksüz MO, Dittmann H, Wicke C, Müssig K, Bares R, Pfannenberg C, Eschmann SM. Accuracy of parathyroid imaging: a comparison of planar scintigraphy, SPECT, SPECT-CT, and C-11 methionine PET
for the detection of parathyroid adenomas and glandular hyperplasia. Diagn Interv Radiol 2011; 17:297–307.
18. Sekiyama K, Akakura K, Mikami K, Mizoguchi K, Tobe T, Nakano K, et al.. Usefulness of diagnostic imaging in primary hyperparathyroidism
. Int J Urol 2003; 10:7–11.
19. Sundin A, Johansson C, Hellman P, Bergström M, Ahlström H, Jacobson GB, et al.. PET
and parathyroid L-[carbon-11]methionine accumulation in hyperparathyroidism
. J Nucl Med 1996; 37:1766–1770.
20. Caveny SA, Klingensmith WC III, Martin WE, Sage-El A, McIntyre RC Jr, Raeburn C, Wolfe P. Parathyroid imaging: the importance of dual-radiopharmaceutical simultaneous acquisition with 99m
Tc-sestamibi and 123
I. J Nucl Med Technol 2012; 40:104–110.
21. Klingensmith WC III, Koo PJ, Summerlin A, Fehrenbach BW, Karki R, Shulman BC, et al.. Parathyroid imaging: the importance of pinhole collimation with both single- and dual-tracer acquisition. J Nucl Med Technol 2013; 41:99–104.
22. Ho Shon IA, Yan W, Roach PJ, Bernard EJ, Shields M, Sywak M, et al.. Comparison of pinhole and SPECT 99m
Tc-MIBI imaging in primary hyperparathyroidism
. Nucl Med Commun 2008; 29:949–955.
23. Hindié E, Mellière D, Jeanguillaume C, Ureña P, deLabriolle-Vaylet C, Perlemuter L. Unilateral surgery for primary hyperparathyroidism
on the basis of technetium Tc 99m sestamibi and iodine 123 subtraction scanning. Arch Surg 2000; 135:1461–1468.