ORIGINAL ARTICLE

Dual-Phase 99mTc Sestamibi Scintigraphy With Neck and ThoraxSPECT/CT in Primary Hyperparathyroidism

A Single-Institution Experience

Renaud Ciappuccini, MD,* Julia Morera, MD,† Pierre Pascal, MD,* Jean-Pierre Rame, MD,‡Natacha Heutte, PhD,§¶ Nicolas Aide, MD, PhD,* Emmanuel Babin, MD, PhD,� Yves Reznik, MD, PhD,†

and Stephane Bardet, MD*

Purpose: To assess the diagnostic value of dual-phase 99mTc sestamibiscintigraphy with neck and thorax single-photon emission computed tomog-raphy/computed tomography (SPECT/CT) in patients with primary hyper-parathyroidism, and to analyze the relationships between SPECT/CT dataand serum calcium or parathyroid hormone (PTH) concentrations.Materials and Methods: 99mTc sestamibi scintigraphy was performed in 94consecutive patients. Images included early and delayed planar neck imagesand delayed neck and thorax SPECT/CT. Scintigraphy was scored positive ornegative.Results: Fifty-nine sestamibi studies (63%) were positive. SPECT/CT dem-onstrated a single focus in 56 patients, in usual parathyroid sites in 80% ofcases and in unusual sites in the remaining 20% (retrotracheal area, 7%;intrathyroidal, 9%; mediastinum, 4%), and double foci in 3. Serum calciumvalues were higher in patients with a positive scintigraphy than in those witha negative scintigraphy (2.80 vs. 2.66 mmol/L, P � 0.001) with similarfigures for serum PTH values (129 vs. 107 pg/mL, P � 0.0649). In patientswith a measurable parathyroid adenoma on integrated CT scan (n � 43), thegreatest axial diameter of the adenoma was correlated to serum calcium (r �0.405, P � 0.0071) or PTH concentrations (r � 0.589, P � 0.0001).Fifty-four patients underwent surgery, 45 with a positive, and 9 with anegative preoperative scintigraphy, resulting in a sensitivity of 92% (95% CI:80–98) and a specificity of 83% (95% CI: 36–100).Conclusions: Dual-phase 99mTc sestamibi scintigraphy with SPECT/CTenables to identify a parathyroid adenoma in about two-thirds of patientswith primary hyperparathyroidism and allows the surgeon to plan appropriatesurgery. The likelihood of scintigraphy to be positive is affected by calciumor PTH concentrations.

Key Words: sestamibi, SPECT/CT, hyperparathyroidism, surgery

(Clin Nucl Med 2012;37: 223–228)

Primary hyperparathyroidism (PHPT) is a common endocrinedisorder caused by an autonomous overproduction of parathy-

roid hormone (PTH).1 The typical biologic profile associates ele-vated serum calcium and PTH concentrations. Normal serum cal-

cium with elevated PTH levels can be observed in early phase ofPHPT.2 Finally, in some patients, high serum calcium concentra-tions can be associated with inappropriate normal PTH levels. PHPTis related to a solitary parathyroid adenoma in approximately 85% ofcases. Otherwise, multiple parathyroid adenomas (5%–12%), diffusehyperplasia (5%–15%), or parathyroid carcinoma (1%) can be ob-served. PHPT is associated with an increased risk of osteoporosis,3

of hypertension and cardiovascular morbidity,4 and with impairmentof neurocognitive function and quality of life.5 Surgery, which is theonly curative treatment, can improve some of these complications,mainly those related to bone.3,6 Preoperative localization of para-thyroid adenoma is critical, particularly when a targeted surgicalapproach (minimally invasive parathyroidectomy) is planned.7 Para-thyroid scintigraphy has proven to be the single best imagingmodality for preoperative localization of parathyroid adenomas, thatis, superior to ultrasonography (US),8 CT, and magnetic resonanceimaging.9

The 99mTc sestamibi is a tracer of choice for parathyroidimaging.10 It accumulates early in both parathyroid adenoma and thethyroid gland, and usually washes out of normal thyroid tissue morerapidly than abnormal parathyroid tissue. This is the basis of thedual-phase technique, which was first described in 1992 by Tailleferet al,11 that we have adopted in our institution. Other teams use adouble-tracer protocol, generally with 99mTc sestamibi/123I subtrac-tion scan.12 SPECT has been shown to improve the accuracy ofplanar imaging.13,14 In recent years, the availability of hybridsingle-photon emission computed tomography/computed tomogra-phy (SPECT/CT) cameras offers the opportunity to directly relatefunctional and anatomic imaging, and to precisely localize focaltracer uptake. Studies using first generation hybrid equipments havesuggested that SPECT/CT was more accurate than SPECT alone inlocating parathyroid adenomas.15,16 Little data is available, how-ever, using the most recent hybrid cameras equipped with multide-tector spiral CT.17,18

The goal of the present study was to assess the clinical valueof dual-phase 99mTc sestamibi scintigraphy with routine delayedneck and thorax SPECT/CT using this new generation of camera, inpatients affected by PHPT.

PATIENTS AND METHODS

PatientsBetween January 2006 and June 2010, 115 patients were

referred for parathyroid 99mTc sestamibi scintigraphy because ofserum calcium and/or PTH abnormalities consistent with hyperpara-thyroidism. Serum intact (1–84) PTH was measured using commer-cially available immunometric assay. Twenty-one patients withsevere kidney failure (creatinine clearance �30 mL/min), suspectedto have secondary or tertiary hyperparathyroidism, were excluded.Among the 94 remaining patients, none had evidence of multiple

Received for publication April 21, 2011; revision accepted July 10, 2011.From the *Department of Nuclear Medicine and Thyroid Unit, Centre Francois

Baclesse, Caen, France; †Department of Endocrinology, Centre Hospitalo-Universitaire, Caen, France; ‡Department of Head and Neck Surgery, at theCentre Francois Baclesse, Caen, France; §GRECAN EA-1772, Universite deCaen-Basse Normandie, Caen, France; ¶Department of Clinical Research,Centre Francois Baclesse, Caen, France; and �Department of Head and NeckSurgery, Centre Hospitalo-Universitaire, Caen, France.

Conflicts of interest and sources of funding: none declared.Reprints: Stephane Bardet, MD, Department of Nuclear Medicine and Thyroid

Unit, Centre Francois Baclesse, 3 Avenue General Harris–BP 5026, F-14076CAEN Cedex 05, France. E-mail: s.bardet@baclesse.fr.

Copyright © 2012 by Lippincott Williams & WilkinsISSN: 0363-9762/12/3703-0223

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myeloma or bone metastases, and none had vitamin D intake ordrugs that may interfere with calcium metabolism.

METHODS

Dual-Phase 99mTc Sestamibi Scintigraphy WithSPECT/CT

Patients were injected intravenously with 740 MBq (range,718–763) of 99mTc sestamibi. The image acquisitions were per-formed on a double-head gamma-camera equipped with 1.5875-cm(5/8-in) NaI crystals and a multidetector (2 rows) spiral CT (SymbiaT2; Siemens Medical Solutions, Malvern, PA).

Early and delayed neck planar images were obtained 10 and90 minutes after injection, respectively. Anterior neck images wereacquired for 10 minutes, in a 128 � 128 matrix, with a 20% windowcentered on the 140-keV photopeak using a pinhole collimator.SPECT/CT acquisition was performed immediately after the de-layed planar image. The SPECT volume session included the neckand thorax with an axial field of view of 53.3 � 38.7 cm. A 128 �128 matrix was used, and 64 40-second projections were acquiredover 360 degrees. SPECT data were reconstructed using a 3-dimen-sional iterative algorithm (ordered-subsets expectation maximiza-tion with 4 iterations and 8 subsets). Images were smoothed with a3-dimensional spatial Gaussian filter. Immediately after SPECT acqui-sition, a CT topogram was acquired followed by a spiral CT acquisitionperformed on a volume session similar to that of SPECT acquisition.CT acquisition parameters were as follows: tube current, 60 mA;collimation, 2 � 2.5 mm; pitch, 2. For CT data reconstruction, a3-mm slice thickness with 2-mm slice increment and a B70 kernelfilter were used. No contrast medium was injected during theprocedure. SPECT/CT data were analyzed on an e-soft workstation,providing transaxial, sagittal, and coronal slices of SPECT, CT, andfused SPECT/CT data. CT scan data were displayed at the neck(level, 50 Hounsfield units �HU�; width, 250 HU) or at the medias-tinum (40 and 250 HU) window settings.

The interpretation of 99mTc sestamibi scintigraphy was per-formed in consensus by 2 experienced nuclear medicine physicians(N.A., S.B.) and if necessary, in collaboration with a Head and Necksurgeon (J.P.R.). The image findings were binary scored as positiveor negative. Scintigraphy was positive when focal tracer retention inthe neck or in the mediastinum was clearly evidenced on planarand/or SPECT/CT images. Precise location of each focus wasreported. Side and upper or lower positions of each focus close to thethyroid gland were mentioned. When a corresponding nodular masswas observed on integrated CT scan, its axial diameter was mea-sured. Scintigraphy was negative when focal uptake in the neck orin the mediastinum was evidenced neither on early nor on delayedimages.

Patient Outcome After 99mTc SestamibiScintigraphy

According to the overall evaluation, including 99mTc sesta-mibi SPECT/CT data, patients underwent surgery or were followedup. Surgery consisted in minimally invasive parathyroidectomywhen 99mTc sestamibi SPECT/CT clearly identified an adenoma.Otherwise, full-neck exploration with identification of all glands wasperformed. Histopathology was performed according to the WHOcriteria for tumors of endocrine organs.19

Statistical AnalysisResults are expressed as median with range. Comparisons

were performed using nonparametric tests (�2 test, Wilcoxon test).Pearson correlation was used to analyze the relationship between theaxial diameter of the adenoma on integrated CT scan, and serumcalcium or PTH concentrations. Ninety-five percent exact confi-

dence intervals (95% CI) were calculated for sensitivity and speci-ficity. A sestamibi result was considered as a true-positive result ifthe scintigraphic data matched with surgical (for both side andlocalization) and pathologic data (parathyroid adenoma or carci-noma). A sestamibi result was scored false negative when anadenoma was found at surgery with no focal retention on scintigra-phy. A sestamibi result was considered true negative when surgicalneck exploration did not find any adenoma, in agreement with anegative scintigraphy. A sestamibi result was scored false positive ifthe surgeon did not find a parathyroid tumor where a sestamibi focuswas described. All tests were considered to be statistically signifi-cant when P value was �0.05. All tests were 2-sided. SAS 9.2statistical software was used for data analysis.

RESULTS

Patient CharacteristicsThe study group included 94 patients with a median age of 61

years (range, 18–85). There were 73 women (78%) and 21 men. Themedian total serum calcium concentration was 2.75 mmol/L (2.22 –3.46) and the serum PTH level was 121 pg/mL (24–1050 pg/mL).Among the 94 patients, we distinguished 2 groups: (1) Group 1 (n �70) including patients with typical biologic profile of PHPT becauseof high serum Ca �2.60 mmol/L and high PTH �60 pg/mL; (2)Group 2 (n � 24) including patients with less typical forms of PHPTbecause of normal Ca �2.60 and high PTH �60 (n � 18), or highCa �2.60 and normal PTH values �60 (n � 6).

99mTc Sestamibi DataOf the 94 99mTc sestamibi studies, 59 (63%) were scored

positive. A single 99mTc sestamibi focus was visible in 56 patientsand double foci were observed in 3 patients. In the former 56patients, SPECT/CT showed that focal uptake was related to anodular lesion located within the neck, close to the thyroid gland in45 patients (80%), in the retrotracheal area in 4 patients (7%) (Fig.1), within the thyroid gland in 5 patients (9%), and in an ectopicmediastinal localization in 2 patients (4%) (Fig. 2). In the latter 3patients, 1 showed 2 foci close to the thyroid gland, 1 presented anintrathyroidal uptake and a contralateral parathyroid lesion, and 1exhibited both a retrotracheal and a contralateral parathyroid focus(Fig. 3).

Serum calcium and PTH concentrations were highly corre-lated in the whole series of patients (r � 0.471, P � 0.0001) (Fig.4). Serum calcium values were higher in patients with a positive thanwith a negative 99mTc sestamibi scintigraphy (2.80 vs. 2.66 mmol/L,P � 0.001) with similar figures for serum PTH values (129 vs. 107pg/mL, P � 0.0649). Also, the proportion of positive Tc-99msestamibi studies was higher in group 1 than in group 2 (48/70, 69%vs. 11/24, 46%; P � 0.0468).

Of the 56 positive patients with a single 99mTc sestamibifocus, the corresponding parathyroid adenoma was clearly visibleand measurable on CT scan in 43 patients. In these patients, acorrelation was found between the axial diameter of the adenomaand the serum calcium concentration (r � 0.405, P � 0.0071) or thePTH level (r � 0.589, P � 0.0001) (Fig. 5).

Surgical DataOverall, 54 patients underwent surgery (46 in group 1, 8 in

group 2). Of these, 45 had a positive preoperative 99mTc sestamibiscintigraphy and 9 had a negative examination. In the 45 patientswith a positive scintigraphy, the diagnosis and the localization (sideand position) suspected on SPECT/CT were confirmed by surgicalfindings and pathologic study in 44 patients (true positives), that is,43 patients with a solitary parathyroid tumor (42 adenomas and onecarcinoma) and 1 patient with a double adenoma. Although

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SPECT/CT showed focal and moderate uptake within the thyroidgland in the remaining patient, the surgeon did not find anycorresponding adenoma (false positive). He removed the thyroidlobe and 3 of the 4 parathyroid glands; histology revealedparathyroid hyperplasia without any adenoma. Regarding the 9patients with negative preoperative scintigraphy, 4 were consid-ered as false negatives because a parathyroid adenoma wassurgically removed (all were preoperatively found by US), and 5as true negatives (2 with falsely positive neck US and 3 withnegative US). Therefore, in this surgical group, 99mTc sestamibiscintigraphy showed a sensitivity of 92% (95% CI: 80 –98) and aspecificity of 83% (95% CI: 36 –100).

DISCUSSIONIn a nonselected series of 94 consecutive patients, sestamibi

SPECT/CT clearly demonstrated the presence of a single or, more

FIGURE 2. Delayed 99mTc sestamibi SPECT/CT depicting asingle focus (A: MIP image) located in the mediastinum in a45-year-old woman with PHPT (serum calcium concentration:3 mmol/L; PTH level: 1050 pg/mL). Neck SPECT/CT acquisitionlocalized the 15 mm lesion in the aortopulmonary window (B:axial SPECT; C: CT; D: fused images) and allowed the surgeonto plan surgery and to find a 357-mg parathyroid adenoma.

FIGURE 1. Delayed 99mTc sestamibi SPECT/CT acquisition ina 77-year-old woman with PHPT (serum calciumconcentration: 2.9 mmol/L; PTH level: 229 pg/mL)showing a single focus (A: axial SPECT) related to a 10mm lesion (B: axial CT) in the retrotracheal area (C: axialfused SPECT/CT). Surgery was performed and pathologyconfirmed a parathyroid adenoma.

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rarely, a double parathyroid tumor, in 63% of patients. SPECT/CTprecisely localized sestamibi focal uptake, and most often, related itto a nodular lesion consistent with a parathyroid adenoma. Theadenoma was sited close to the thyroid gland in most patients (80%).In the remaining 20% of patients, SPECT/CT enabled to depict theadenoma in unusual sites, that is, in the retrotracheal area (7%),inside the thyroid gland (9%) or in the mediastinum (4%), and todiscover multiglandular disease in 3% of patients.

As parathyroidectomy may improve PHPT-related complica-tions in patients with mild PHPT,3,6 minimally invasive surgery isconsidered in an increasing number of patients.20 Preoperativelocalization of parathyroid adenoma remains, however, a prerequi-site for that practice. For patients with adenoma in usual sites,SPECT/CT aided the surgeon in providing not only the side, but also

the upper or lower position of the tumor. The impact of SPECT/CTwas even more critical when a single tumor was found in unusualsites or when multiglandular disease was discovered, as thesesituations represent the main causes of surgery failure.21 Further-more, although neck US has an acceptable sensitivity for identifyingadenoma sited close to or within the thyroid gland,8,22 it is anoperator-dependent imaging technique unable to visualize tumorsbehind the trachea and the tracheal esophageal groove, and in themediastinum.

To date, the relevance of the dual-phase technique using asecond generation SPECT/CT camera has been shown in a limitednumber of clinical cases.18,23 Although sestamibi scintigraphy waspositive in 63% of the whole series of patients, a proportion similarto that observed with first generation SPECT/CT,24 the sensitivityincreased up to 92% in the surgical group. Several factors such asthe content in oxyphilic rich adenoma cells25 or the expression of theP-glycoprotein (p-gp)26 may account for negative SPECT/CT stud-ies. From a technical point of view, performing delayed SPECT/CTacquisitions may yield false-negative results due to rapid washout,13

a reason why early SPECT/CT has been advocated.16,27 In negativeSPECT/CT studies, however, we did not observe significant focaluptake on early planar images in front of pathologically provenadenomas. This suggests that rapid washout might not have a majorimpact on delayed images. Could the dual-isotope subtraction tech-nique be more sensitive than the dual-phase scintigraphy? Usingsuch a 99mTc sestamibi/123I subtraction technique, and a secondgeneration SPECT/CT camera in 61 surgical patients, Neumann etal17 have reported a sensitivity of 70% for individual parathyroidglands, and of 86% on a per-patient basis, that is a proportion nothigher than that observed in our surgical group. Consistently withprevious studies,25,28 our data shows that the adenoma size as wellas the serum calcium and PTH levels most likely affects the result ofsestamibi scintigraphy. We can also hypothesize that some patients,predominantly in group 2, have biochemical abnormalities related todiseases other than PHPT such as familial benign hypocalciurichypercalcemia which can be diagnosed after an unsuccessful para-thyroidectomy29 or vitamin D deficiency.30 Sestamibi scintigraphy

FIGURE 3. MIP view (D) exhibiting 2 foci in a 82-year-old woman with PHPT (serum calcium concentration: 3.25 mmol/L;PTH level: 240 pg/mL): a right-sided retrotracheal localization (A: axial SPECT; B: CT; C: fused images) and a left-sided focusclose to the thyroid gland in the lower parathyroid position (E–G). Owing to rapid impairment of cognitive function andgeneral status, surgery was not performed.

FIGURE 4. Correlation between serum calcium and PTHconcentrations (r � 0.471, P � 0.0001). Blue dots representpatients with a negative 99mTc sestamibi scintigraphy andred dots patients with a positive one.

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also yields false-positive results due to retention in thyroid nod-ules.31 However, SPECT/CT allows depicting true-positive intrathy-roidal adenomas for which planar imaging alone could be mislead-ing for surgical planning.

In conclusion, dual-phase 99mTc sestamibi scintigraphy withSPECT/CT enables to identify a parathyroid adenoma in routinepractice in about two-thirds of patients with biologic abnormalitiesconsistent with PHPT. Our data suggests that serum calcium andPTH levels, as well as the adenoma size affect the likelihood ofscintigraphy to be positive. Dual-phase 99mTc sestamibi scintigraphywith SPECT/CT has a major impact on parathyroid surgery both forpatients having parathyroid tumors in usual sites, and for those withadenoma in unusual sites or multiglandular disease.

ACKNOWLEDGMENTSThe authors thank Helen Lapasset for assistance in reviewing

the manuscript.

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FIGURE 5. Correlation between the axial diameter ofparathyroid adenoma and the serum calcium concentration(r � 0.405, P � 0.0071) (A) or the PTH level (r � 0.589,P � 0.0001) (B) in 43 patients presenting a single 99mTcsestamibi focus with a measurable mass on integrated CTscan.

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