Clinical Hemorheology and Microcirculation 58 (2014) 515–520 DOI 10.3233/CH-131800 IOS Press
515
The role of contrast-enhanced ultrasonography (CEUS) in comparison with 99m Technetium-sestamibi scintigraphy for localization diagnostic of primary hyperparathyroidism Ayman Aghaa,1,∗ , Matthias Hornunga,1 , Hans J. Schlitta , Christian Stroszczynskib and Ernst-Michael Jungb a b
Department of Surgery, University Hospital Regensburg, Regensburg, Germany Department of Radiology, University Hospital Regensburg, Regensburg, Germany
Received: 2 October 2013 Accepted: 16 October 2013 Abstract. INTRODUCTION: Correct preoperative detection of parathyroid gland adenoma (PA) in the case of primary hyperparathyroidism (pHPT) is the requirement for unilateral cervical exploration associated with lower morbidity. We present our experience with contrast-enhanced ultrasonography (CEUS) as diagnostic tool for the preoperative localization of PA in pHPT in comparison to the 99m Technetium-sestamibi scintigraphy. METHODS: Between 8/2009–5/2013 143 patients with pHPT received surgical interventions in the Department of Surgery at the University Hospital of Regensburg. In all patients contrast-enhanced ultrasonography (CEUS) was performed as diagnostic tool for the localization of pathological parathyroid glands. By one experienced examiner CEUS was performed after bolus injection of 1–2.4 ml contrast agent with storage of digital cine loops from the arterial phase (15–45 s) to the late phase (3 Min). Criteria for a parathyroid adenoma were marginal hypervascularisation in the arterial phase and wash out in the late phase. 74 patients received 99m Technetium-sestamibi scintigraphy. The sensitivity of both diagnostic tools was analyzed in comparison to the intraoperative and histological findings. RESULTS: CEUS revealed a sensitivity of 95.9% for the detection of pathological parathyroid glands and even of 97.1% for patients without scintigrapy in comparison to 60.8% for 99m Technetium-sestamibi scintigraphy. Sensitivity of CEUS in patients with negative scintigraphy was 96.3%. In multivariate regression analysis detection of small PA compared to scintigraphy was better by trend but did not reach significance (p = 0.019). Follow-up with a minimum of 8 weeks showed normal serum levels of calcium and parathyroid hormone in all patients except one. CONCLUSIONS: CEUS represents a new diagnostic method for the localization of parathyroid gland adenomas independent on findings in scintigraphy. In the present of appropriate expertise in CEUS no further diagnostic procedures are required. Keywords: Contrast-enhanced hyperparathyroidism
ultrasonography,
99m
Technetium-sestamibi
1
scintigraphy,
diagnostic
of
primary
Both authors contributed equally. Corresponding author: Ayman Agha, M.D., Department of Surgery, University Hospital Regensburg, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. E-mail: [email protected]. ∗
1386-0291/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
516
A. Agha et al. / The role of CEUS in comparison with 99m Technetium-sestamibi scintigraphy
1. Introduction Correct localization of parathyroid gland adenomas enables minimal invasive procedure with the unilateral exploration and therefore, decreases the operative morbidity. Nowadays, 99m Technetium-sestamibi scintigraphy represents one of the most important method for localization in patients with pHPT, since it was established for detection of parathyroid gland adenomas in 1989 [8]. In literature sensitivity of this procedure for solitary adenomas is reported between 54 and 96% [7, 13–15]. These results are partially dependent on the examiner and are negative influenced by double adenomas, thyroid nodules, cervical lymphadenopathy and thyroiditis [9, 18]. Negative findings in scintigraphy further diagnostic procedures for the exact localization of parathyroid gland adenomas are required. Based on our experience with contrast-enhanced ultrasonography (CEUS) for the detection of microcirculation and microvascularisation of PA in patients with pHPT [21] retrospective data of 30 patients comparing CEUS to other diagnostic modalities (conventional ultrasonography, 99m Technetium-sestamibi scintigraphy and magnetic resonance imaging) could be published [1, 11]. Furthermore, a subsequent prospective study revealed significant advantages of CEUS in patients with different risk factors like concomitant goiter, double adenomas and patients with previous neck surgery [2]. In the present large series we compared preoperative localization of parathyroid gland adenomas in patients with pHPT via CEUS and 99m Technetium-sestamibi scintigraphy.
2. Material and methods From 08/2009–5/2013 143 patients with pHPT treated at the University Hospital of Regensburg were included in this study. Exclusion criteria were persistent or recurrent pHPT and secondary hyperparathyroidism as well as reported allergy to contrast agent. Since our first publication about pHPT and CEUS [1] conventional ultrasonography and CEUS are the only procedures for localization in the case of diagnosed pHPT. Negative findings in CEUS or supposed ectopic localization lead to further methods like scintigraphy or MRI. But some patients already received external scintigraphy to localize parathyroid gland adenoma. Therefore, scintigraphies of 74 patients could be compared to CEUS. But CEUS examiner did not know the result of the additional scintigraphies. As described the dynamic CEUS was carried out with bolus injection of up to 2.4 ml sulphur hexafluoride microbubble (SonoVue®/BRACCO, Italy), a contrast agent of the second generation [10], followed by 10 ml saline solution (NaCl) via a central venous catheter [1]. The CEUS examination of the thyroid and the parathyroid glands’ region were performed from one experienced examiner including a documentation of dynamic imaging sequences up to 2 minutes using a multi-frequency linear probe (6–9 MHz/LOGIQ E9/GE). Fundamental B mode was used for measurements of the right and left part of the thyroid gland and for the characterization of the parenchymal structure. Pathologically findings for the parathyroid glands were most often lower echogenic lesions side by side of the thyroid gland with particulary marginal hypervascularisation in Colour Coded Doppler Sonograhy (CCDS). Typical findings for CEUS in cases of parathyroid adenomas were the early arterial hypervascularisation from the margin to the center and wash out in the late phase. Approval of the Institutional Review Board has been obtained and written informed consent was given by all patients. Follow-up of the calcium serum level was performed immediately after the operation and after 8 weeks.
A. Agha et al. / The role of CEUS in comparison with 99m Technetium-sestamibi scintigraphy
517
For statistic evaluation we used SPSS (version 16.0 SPSS for windows, LEAD technologies). For the evaluation of the distribution patterns, the Wilcoxon signed rank test, the Kappa-Test and the MannWhitney test was employed. Differences with p < 0.05 were regarded as statistically significant. 3. Results In total, 113 women and 30 men with symptomatic pHPT and a median age of 60 years were included (Table 1). 74 patients received a 99m Technetium-sestamibi scintigraphy, which were compared to CEUS. Regarding the preoperative investigations of parathyroid hormone, calcium, phosphorus and alkaline phosphatase both groups (scintigraphy: n = 74 and CEUS: n = 143) had similar results (Table 1). Sensitivity of CEUS was independent on adenoma size with 97.2% higher in comparison with 99m Technetium-sestamibi scintigraphy (60.8%). Univariate analysis revealed that small parathyroid adenomas were significant higher localized with CEUS than with scintigraphy (p = 0.018). Sensitivity of CEUS was in patients with negative scintigraphy 96.3% and in patients without scintigraphy 97.2% (Table 2). Table 1 Patients characteristics and preoperative laboratory indexes Variable
Scintigraphy n (%)
Enhanced-ultrasonography (CEUS), n (%)
Age (years), mean (range) Sex (female/male), n (%) Preoperative parathyroid hormone (pg/ml) Preoperative serum calcium (mmol/l) Phosphorus (mmol/l) Alkaline phosphatase u/l Primary operation, n (%) Previous thyroid/parathyroid surgery, n (%) Symptomatic disease, n (%)
63 (21–92) 59 (79.7)/15 (20.3) 155 (66–1760) 2.8 (2.6–3.6) 0.77 (0.3–1.4) 118 (55–156) 64 (86.5) 10 (13.5) 74 (100)
60 (20–92) 113 (79)/29 (21) 146 (65–1160) 2.77 (2.64–4.8) 0.78 (0.3–1.5) 113 (47–156) 125 (87.4) 18 (12.6) 143 (100)
Table 2 Sensitivity of CEUS (n = 143) and 99m Technetium-sestamibi scintigraphy (n = 74) in detection of pHPT Technique Patients with scintigraphy (n = 74) Sensitivity Adenoma size (cm), range Patients with negative scintigraphy (n = 27) Sensitivity Adenoma size (cm), range Patients without scintigraphy (n = 69) Sensitivity Adenoma size (cm), range
Scintigraphy n (%)
Enhanced ultrasonography (CEUS), n (%)
p value
45 (60.8) 1.6 (0.6–4.0)
139 (97.2) 1.3 (0.7–3.6)
0.019 0.018
– 1.3 (0.6–3.4)
137 (96.3) 1.1 (0.6–2.8)
n.s
– 1.9 (0.5–3.2)
139 (97.2) 1.6 (0.9–2.1)
n.s
518
A. Agha et al. / The role of CEUS in comparison with 99m Technetium-sestamibi scintigraphy Table 3 Multivariate logistic regression analysis of different variables
Diagnostic procedure
Age (years)
Gender (f/m)
Pre-op calcium (mmol/l)
Pre-op PTH (pg/ml)
Pre-op phosphorus (pg/ml)
Gland size (cm)
CEUS p value Scintigraphy p value
0.109 0.064
0.998 0.999
0.594 0.618
0.953 0.895
0.744 0.899
0.266 0.019
Multivariate regression analysis revealed no significant differences concerning gender, preoperative calcium, preoperative parathyroid hormone and alkaline phosphatase for detection of hyperfunctional parathyroid gland adenoma between conventional scintigraphy and CEUS, however only the gland size could be found as significant factor for the higher sensitivity of CEUS compared to scintigraphy (Table 3). Concerning the surgical procedure 28% from the scintigraphy-group and 41% from the CEUS-group could be operated by minimal invasive approach p = 0.343. The operation time was in both groups similar without significant difference (scintigraphy vs. CEUS-group: 65 min (27–142) vs. 70 min (23–114)), p = 0.59. The postoperative surgical complications and histological findings were comparable in both groups. Conversion from minimal invasive technique to conventional surgery was necessary in one case of CEUS-group due to intraoperative diagnosis of a papillary thyroid carcinoma. 4. Discussion Our group already established Contrast-enhanced ultrasonography (CEUS) as diagnostic tool for localization of pathological parathyroid glands [1, 2, 11]. CEUS enables quantification of microvascularisation [12] up to capillaries and gives important preoperative information about parathyroid gland adenomas. Using middle frequent probes (6–9 Hz) CEUS shows intratumoral vascularisation of adenomas up to a deth of 4 cm with significant enhancement of hypervascularisation of the adenoma rim over a median of at least 40 sec (30–55 sec). Exact localization of parathyroid gland adenomas are the most important requirement for the unilateral exploration in minimal invasive technique. 99m Technetium-sestamibi scintigraphy has been established as obligatory method for preoperative localization in the case of pHPT [8]. Results of this study reveal that scintigraphy is limit by size of the parathyroid adenoma, level of calcium and PTH as well as the oxophile parts of the adenoma and in particular by concomitant goiter [2, 4–6, 10, 12, 17, 20]. A further diagnostic method is required in the case of negative findings in scintigraphy. Since the first description of CEUS in pHPT [1] 99m Technetium-sestamibi scintigraphy is not longer performed as primary diagnostic tool in our hospital. Sensitivity of CEUS for the localization of parathyroid gland adenomas in our cohort is about 97% and therefore higher than any other diagnostic procedure. In particular CEUS has special advantages in the presence of concomitant goiter, cervical lymphadenopathy, but also in the detection of multiple gland disease even after previous neck surgery [2]. Using a multifrequency probe (6–9 Hz) microvascularisation of the thyroid with a median of at least 3 min (2–5 min) after bolus injection can be detected and can be differentiated to parathyroid gland adenomas. This allows a sufficient time window to examine both parathyroidal regions regarding parathyroid adenomas.
A. Agha et al. / The role of CEUS in comparison with 99m Technetium-sestamibi scintigraphy
519
Considering the 74 patients, who received an scintigraphy, sensitivity of CEUS was 97.2% versus 60.8% for 99m Technetium-sestamibi scintigraphy. In the univariate analysis significance was reached regarding adenoma size (0.6–4 cm) and a clear trend could be detected in small adenomas (p = 0.019). In patients with a negative scintigraphy (n = 27) the sensitivity of CEUS was 96.3%. Even in the cohort of 69 patients without scintigraphy the sensitivity of CEUS was 97.2% without significance regarding the adenoma size. Using multivariate analysis there was no significant difference between both procedures (scintigraphy and CEUS) in gender, preoperative calcium, PTH and phosphate level but the gland size could be found as significant factor for the higher sensitivity of CEUS compared to conventional ultrasonography (Table 3). A further advantage of CEUS is the detection of parathyroid cystic lesions. Complicated cystic adenomas can be localized by the identification of adenomas with a size of only 6 mm in particular in cases of negative findings in scintigraphy due to the characteristic arterial hypervascularisation at the rim of the tumor. These results justify not to perform scintigraphy in the case of positive localization in CEUS. Ectopic parathyroid gland adenomas are a challenge in preoperative diagnosis. Such localizations like in the mediastinum are not visible for CEUS. Therefore, additional methods like MRI, methionin-PET are still required [3, 16, 19]. In spite of its high sensitivity in preoperative detection of parathyroid gland adenomas CEUS does not represent the standard procedure area-wide due to the required expertise of the examiner. At the moment the use of this new method with relatively low time costs in the case of sHPT is subject of our studies. 5. Conclusion Our study shows that CEUS represents a very useful and reliable method with a high sensitivity in the preoperative diagnosis of pHPT. No further method is required for the localization of parathyroid gland adenomas when CEUS reveals positive finding performed by a well trained examiner. Further diagnostic procedures are only needed in the presence of ectopic localization. References [1] A. Agha, M. Hornung, J. Rennert, W. Uller, H. Lighvani, H.J. Schlitt, E.M. Jung, Contrast-enhanced ultrasonography for localization of pathologic glands in patients with primary hyperparathyroidism, Surgery 151 (2012), 580–586. [2] A. Agha, M. Hornung, C. Stroszczynski, H.J. Schlitt and E.M. Jung, Highly efficient localization of pathological glands in primary hyperparathyroidism using contrast-enhanced ultrasonography (CEUS) in comparison with conventional ultrasonography, J Clin Endocrinol Metab 98 (2013), 2019–2025. [3] A.D. Beggs and S.F. Hain, Localization of parathyroid adenomas using 11C-methionine positron emission tomography, Nucl Med Commun 26 (2005), 133–136. [4] E. Berber, R.T. Parikh, N. Ballem, C.N. Garner, M. Milas and A.E. Siperstein, Factors contributing to negative parathyroid localization: An analysis of 1000 patients, Surgery 144 (2008), 74–79. [5] A.O. Bergenfelz, G. Wallin, S. Jansson, H. Eriksson, H. Mårtensson, P. Christiansen, E. Reihnér, Impact of modern techniques on short-term outcome after surgery for primary hyperparathyroidism: A multicenter study comprising 2,708 patients, Langenbecks Arch Surg 394 (2009), 851–860. [6] D. Calva-Cerqueira, B.J. Smith, M.L. Hostetler, G. Lal, Y. Menda, T.M. O’Dorisio, J.R. Howe, Minimally invasive parathyroidectomy and preoperative MIBI scans: Correlation of gland weight and preoperative PTH, J Am Coll Surg 205(4 Suppl) (2007), 38–S44. [7] D. Chien and H. Jacene, Imaging of parathyroid glands, Otolaryngol Clin North Am 43 (2010), 399–415, x.
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[8] A.J. Coakley, A.G. Kettle, C.P. Wells, M.J. O’Doherty and R.E. Collins, 99Tcm sestamibi–a new agent for parathyroid imaging, Nucl Med Commun 10 (1989), 791–794. [9] Y. Erbil, U. Barbaros, B.T. Yanik, A. Salmaslio˘glu, M. Tunaci, I. Adalet, A. Bozbora, S. Ozarma˘gan, Impact of gland morphology and concomitant thyroid nodules on preoperative localization of parathyroid adenomas, Laryngoscope 116 (2006), 580–585. [10] C. Greis, Quantitative evaluation of microvascular blood flow by contrast-enhanced ultrasound (CEUS), Clin Hemorheol Microcirc 49 (2011), 137–149. [11] M. Hornung, E.M. Jung, C. Stroszczynski, H.J. Schlitt and A. Agha, Contrast-enhanced ultrasonography (CEUS) using early dynamic in microcirculation for localization of pathological parathyroid glands: First-line or complimentary diagnostic modality? Clin Hemorheol Microcirc 49 (2011), 83–90. [12] E.M. Jung, D.A. Clevert, A.G. Schreyer, S. Schmitt, J. Rennert, R. Kubale, S. Feuerbach and F. Jung, Evaluation of quantitative contrast harmonic imaging to assess malignancy of liver tumors: A prospective controlled two-center study, World J Gastroenterol 13 (2007), 6356–6364. [13] W.C. Lavely, S. Goetze, K.P. Friedman, J.P. Leal, Z. Zhang, E. Garret-Mayer, A.P. Dackiw, R.P. Tufano, M.A. Zeiger, H.A. Ziessman, Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy, J Nucl Med 48 (2007), 1084–1089. [14] D. Moka, E. Voth, M. Dietlein, A. Larena-Avellaneda and H. Schicha, Preoperative localization of parathyroid adenomas using 99mTc-MIBI scintigraphy, Am J Med 108 (2000), 733–736. [15] S. Nasiri, A. Soroush, A.P. Hashemi, A. Hedayat, K. Donboli and F. Mehrkhani, Parathyroid adenoma Localization, Med J Islam Repub Iran 26 (2012), 103–109. [16] D. Otto, A.R. Boerner, M. Hofmann, T. Brunkhorst, G.J. Meyer, T. Petrich, G.F. Scheumann, W.H. Knapp, Pre-operative localisation of hyperfunctional parathyroid tissue with 11C-methionine PET, Eur J Nucl Med Mol Imaging 31 (2004), 1405–1412. [17] G. Pata, C. Casella, S. Besuzio, F. Mittempergher and B. Salerni, Clinical appraisal of 99m technetium-sestamibi SPECT/CT compared to conventional SPECT in patients with primary hyperparathyroidism and concomitant nodular goiter, Thyroid 20 (2010), 1121–1127. [18] J.M. Ruda, C.S. Hollenbeak and B.C. Stack, A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003, Otolaryngol Head Neck Surg 132 (2005), 359–372. [19] C. Schalin-Jäntti, E. Ryhänen, I. Heiskanen, M. Seppänen, J. Arola, J. Schildt, M. Väisänen, L. Nelimarkka, I. Lisinen, V. Aalto, P. Nuutila, M.J. Välimäki, Planar scintigraphy with 123I/99mTc-sestamibi, 99mTc-sestamibi SPECT/CT, 11Cmethionine PET/CT, or selective venous sampling before reoperation of primary hyperparathyroidism? J Nucl Med 54 (2013), 739–747. [20] S.P. Stawicki, M. El Chaar, D.R. Baillie, N.P. Jaik and F.P. Estrada, Correlations between biochemical testing, pathology findings and preoperative sestamibi scans: A retrospective study of the minimally invasive radioguided parathyroidectomy (MIRP) approach, Nucl Med Rev Cent East Eur 10 (2007), 82–86. [21] W. Uller, E.M. Jung, M. Hornung, C. Ross, W. Jung, H.J. Schlitt, C. Stroszczynski, A. Agha, Evaluation of the microvascularization of pathologic parathyroid glands in patients with primary hyperparathyroidism using conventional ultrasound and contrast-enhanced ultrasound, Clin Hemorheol Microcirc 48 (2011), 95–103.
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515
The role of contrast-enhanced ultrasonography (CEUS) in comparison with 99m Technetium-sestamibi scintigraphy for localization diagnostic of primary hyperparathyroidism Ayman Aghaa,1,∗ , Matthias Hornunga,1 , Hans J. Schlitta , Christian Stroszczynskib and Ernst-Michael Jungb a b
Department of Surgery, University Hospital Regensburg, Regensburg, Germany Department of Radiology, University Hospital Regensburg, Regensburg, Germany
Received: 2 October 2013 Accepted: 16 October 2013 Abstract. INTRODUCTION: Correct preoperative detection of parathyroid gland adenoma (PA) in the case of primary hyperparathyroidism (pHPT) is the requirement for unilateral cervical exploration associated with lower morbidity. We present our experience with contrast-enhanced ultrasonography (CEUS) as diagnostic tool for the preoperative localization of PA in pHPT in comparison to the 99m Technetium-sestamibi scintigraphy. METHODS: Between 8/2009–5/2013 143 patients with pHPT received surgical interventions in the Department of Surgery at the University Hospital of Regensburg. In all patients contrast-enhanced ultrasonography (CEUS) was performed as diagnostic tool for the localization of pathological parathyroid glands. By one experienced examiner CEUS was performed after bolus injection of 1–2.4 ml contrast agent with storage of digital cine loops from the arterial phase (15–45 s) to the late phase (3 Min). Criteria for a parathyroid adenoma were marginal hypervascularisation in the arterial phase and wash out in the late phase. 74 patients received 99m Technetium-sestamibi scintigraphy. The sensitivity of both diagnostic tools was analyzed in comparison to the intraoperative and histological findings. RESULTS: CEUS revealed a sensitivity of 95.9% for the detection of pathological parathyroid glands and even of 97.1% for patients without scintigrapy in comparison to 60.8% for 99m Technetium-sestamibi scintigraphy. Sensitivity of CEUS in patients with negative scintigraphy was 96.3%. In multivariate regression analysis detection of small PA compared to scintigraphy was better by trend but did not reach significance (p = 0.019). Follow-up with a minimum of 8 weeks showed normal serum levels of calcium and parathyroid hormone in all patients except one. CONCLUSIONS: CEUS represents a new diagnostic method for the localization of parathyroid gland adenomas independent on findings in scintigraphy. In the present of appropriate expertise in CEUS no further diagnostic procedures are required. Keywords: Contrast-enhanced hyperparathyroidism
ultrasonography,
99m
Technetium-sestamibi
1
scintigraphy,
diagnostic
of
primary
Both authors contributed equally. Corresponding author: Ayman Agha, M.D., Department of Surgery, University Hospital Regensburg, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. E-mail: [email protected]. ∗
1386-0291/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
516
A. Agha et al. / The role of CEUS in comparison with 99m Technetium-sestamibi scintigraphy
1. Introduction Correct localization of parathyroid gland adenomas enables minimal invasive procedure with the unilateral exploration and therefore, decreases the operative morbidity. Nowadays, 99m Technetium-sestamibi scintigraphy represents one of the most important method for localization in patients with pHPT, since it was established for detection of parathyroid gland adenomas in 1989 [8]. In literature sensitivity of this procedure for solitary adenomas is reported between 54 and 96% [7, 13–15]. These results are partially dependent on the examiner and are negative influenced by double adenomas, thyroid nodules, cervical lymphadenopathy and thyroiditis [9, 18]. Negative findings in scintigraphy further diagnostic procedures for the exact localization of parathyroid gland adenomas are required. Based on our experience with contrast-enhanced ultrasonography (CEUS) for the detection of microcirculation and microvascularisation of PA in patients with pHPT [21] retrospective data of 30 patients comparing CEUS to other diagnostic modalities (conventional ultrasonography, 99m Technetium-sestamibi scintigraphy and magnetic resonance imaging) could be published [1, 11]. Furthermore, a subsequent prospective study revealed significant advantages of CEUS in patients with different risk factors like concomitant goiter, double adenomas and patients with previous neck surgery [2]. In the present large series we compared preoperative localization of parathyroid gland adenomas in patients with pHPT via CEUS and 99m Technetium-sestamibi scintigraphy.
2. Material and methods From 08/2009–5/2013 143 patients with pHPT treated at the University Hospital of Regensburg were included in this study. Exclusion criteria were persistent or recurrent pHPT and secondary hyperparathyroidism as well as reported allergy to contrast agent. Since our first publication about pHPT and CEUS [1] conventional ultrasonography and CEUS are the only procedures for localization in the case of diagnosed pHPT. Negative findings in CEUS or supposed ectopic localization lead to further methods like scintigraphy or MRI. But some patients already received external scintigraphy to localize parathyroid gland adenoma. Therefore, scintigraphies of 74 patients could be compared to CEUS. But CEUS examiner did not know the result of the additional scintigraphies. As described the dynamic CEUS was carried out with bolus injection of up to 2.4 ml sulphur hexafluoride microbubble (SonoVue®/BRACCO, Italy), a contrast agent of the second generation [10], followed by 10 ml saline solution (NaCl) via a central venous catheter [1]. The CEUS examination of the thyroid and the parathyroid glands’ region were performed from one experienced examiner including a documentation of dynamic imaging sequences up to 2 minutes using a multi-frequency linear probe (6–9 MHz/LOGIQ E9/GE). Fundamental B mode was used for measurements of the right and left part of the thyroid gland and for the characterization of the parenchymal structure. Pathologically findings for the parathyroid glands were most often lower echogenic lesions side by side of the thyroid gland with particulary marginal hypervascularisation in Colour Coded Doppler Sonograhy (CCDS). Typical findings for CEUS in cases of parathyroid adenomas were the early arterial hypervascularisation from the margin to the center and wash out in the late phase. Approval of the Institutional Review Board has been obtained and written informed consent was given by all patients. Follow-up of the calcium serum level was performed immediately after the operation and after 8 weeks.
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517
For statistic evaluation we used SPSS (version 16.0 SPSS for windows, LEAD technologies). For the evaluation of the distribution patterns, the Wilcoxon signed rank test, the Kappa-Test and the MannWhitney test was employed. Differences with p < 0.05 were regarded as statistically significant. 3. Results In total, 113 women and 30 men with symptomatic pHPT and a median age of 60 years were included (Table 1). 74 patients received a 99m Technetium-sestamibi scintigraphy, which were compared to CEUS. Regarding the preoperative investigations of parathyroid hormone, calcium, phosphorus and alkaline phosphatase both groups (scintigraphy: n = 74 and CEUS: n = 143) had similar results (Table 1). Sensitivity of CEUS was independent on adenoma size with 97.2% higher in comparison with 99m Technetium-sestamibi scintigraphy (60.8%). Univariate analysis revealed that small parathyroid adenomas were significant higher localized with CEUS than with scintigraphy (p = 0.018). Sensitivity of CEUS was in patients with negative scintigraphy 96.3% and in patients without scintigraphy 97.2% (Table 2). Table 1 Patients characteristics and preoperative laboratory indexes Variable
Scintigraphy n (%)
Enhanced-ultrasonography (CEUS), n (%)
Age (years), mean (range) Sex (female/male), n (%) Preoperative parathyroid hormone (pg/ml) Preoperative serum calcium (mmol/l) Phosphorus (mmol/l) Alkaline phosphatase u/l Primary operation, n (%) Previous thyroid/parathyroid surgery, n (%) Symptomatic disease, n (%)
63 (21–92) 59 (79.7)/15 (20.3) 155 (66–1760) 2.8 (2.6–3.6) 0.77 (0.3–1.4) 118 (55–156) 64 (86.5) 10 (13.5) 74 (100)
60 (20–92) 113 (79)/29 (21) 146 (65–1160) 2.77 (2.64–4.8) 0.78 (0.3–1.5) 113 (47–156) 125 (87.4) 18 (12.6) 143 (100)
Table 2 Sensitivity of CEUS (n = 143) and 99m Technetium-sestamibi scintigraphy (n = 74) in detection of pHPT Technique Patients with scintigraphy (n = 74) Sensitivity Adenoma size (cm), range Patients with negative scintigraphy (n = 27) Sensitivity Adenoma size (cm), range Patients without scintigraphy (n = 69) Sensitivity Adenoma size (cm), range
Scintigraphy n (%)
Enhanced ultrasonography (CEUS), n (%)
p value
45 (60.8) 1.6 (0.6–4.0)
139 (97.2) 1.3 (0.7–3.6)
0.019 0.018
– 1.3 (0.6–3.4)
137 (96.3) 1.1 (0.6–2.8)
n.s
– 1.9 (0.5–3.2)
139 (97.2) 1.6 (0.9–2.1)
n.s
518
A. Agha et al. / The role of CEUS in comparison with 99m Technetium-sestamibi scintigraphy Table 3 Multivariate logistic regression analysis of different variables
Diagnostic procedure
Age (years)
Gender (f/m)
Pre-op calcium (mmol/l)
Pre-op PTH (pg/ml)
Pre-op phosphorus (pg/ml)
Gland size (cm)
CEUS p value Scintigraphy p value
0.109 0.064
0.998 0.999
0.594 0.618
0.953 0.895
0.744 0.899
0.266 0.019
Multivariate regression analysis revealed no significant differences concerning gender, preoperative calcium, preoperative parathyroid hormone and alkaline phosphatase for detection of hyperfunctional parathyroid gland adenoma between conventional scintigraphy and CEUS, however only the gland size could be found as significant factor for the higher sensitivity of CEUS compared to scintigraphy (Table 3). Concerning the surgical procedure 28% from the scintigraphy-group and 41% from the CEUS-group could be operated by minimal invasive approach p = 0.343. The operation time was in both groups similar without significant difference (scintigraphy vs. CEUS-group: 65 min (27–142) vs. 70 min (23–114)), p = 0.59. The postoperative surgical complications and histological findings were comparable in both groups. Conversion from minimal invasive technique to conventional surgery was necessary in one case of CEUS-group due to intraoperative diagnosis of a papillary thyroid carcinoma. 4. Discussion Our group already established Contrast-enhanced ultrasonography (CEUS) as diagnostic tool for localization of pathological parathyroid glands [1, 2, 11]. CEUS enables quantification of microvascularisation [12] up to capillaries and gives important preoperative information about parathyroid gland adenomas. Using middle frequent probes (6–9 Hz) CEUS shows intratumoral vascularisation of adenomas up to a deth of 4 cm with significant enhancement of hypervascularisation of the adenoma rim over a median of at least 40 sec (30–55 sec). Exact localization of parathyroid gland adenomas are the most important requirement for the unilateral exploration in minimal invasive technique. 99m Technetium-sestamibi scintigraphy has been established as obligatory method for preoperative localization in the case of pHPT [8]. Results of this study reveal that scintigraphy is limit by size of the parathyroid adenoma, level of calcium and PTH as well as the oxophile parts of the adenoma and in particular by concomitant goiter [2, 4–6, 10, 12, 17, 20]. A further diagnostic method is required in the case of negative findings in scintigraphy. Since the first description of CEUS in pHPT [1] 99m Technetium-sestamibi scintigraphy is not longer performed as primary diagnostic tool in our hospital. Sensitivity of CEUS for the localization of parathyroid gland adenomas in our cohort is about 97% and therefore higher than any other diagnostic procedure. In particular CEUS has special advantages in the presence of concomitant goiter, cervical lymphadenopathy, but also in the detection of multiple gland disease even after previous neck surgery [2]. Using a multifrequency probe (6–9 Hz) microvascularisation of the thyroid with a median of at least 3 min (2–5 min) after bolus injection can be detected and can be differentiated to parathyroid gland adenomas. This allows a sufficient time window to examine both parathyroidal regions regarding parathyroid adenomas.
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Considering the 74 patients, who received an scintigraphy, sensitivity of CEUS was 97.2% versus 60.8% for 99m Technetium-sestamibi scintigraphy. In the univariate analysis significance was reached regarding adenoma size (0.6–4 cm) and a clear trend could be detected in small adenomas (p = 0.019). In patients with a negative scintigraphy (n = 27) the sensitivity of CEUS was 96.3%. Even in the cohort of 69 patients without scintigraphy the sensitivity of CEUS was 97.2% without significance regarding the adenoma size. Using multivariate analysis there was no significant difference between both procedures (scintigraphy and CEUS) in gender, preoperative calcium, PTH and phosphate level but the gland size could be found as significant factor for the higher sensitivity of CEUS compared to conventional ultrasonography (Table 3). A further advantage of CEUS is the detection of parathyroid cystic lesions. Complicated cystic adenomas can be localized by the identification of adenomas with a size of only 6 mm in particular in cases of negative findings in scintigraphy due to the characteristic arterial hypervascularisation at the rim of the tumor. These results justify not to perform scintigraphy in the case of positive localization in CEUS. Ectopic parathyroid gland adenomas are a challenge in preoperative diagnosis. Such localizations like in the mediastinum are not visible for CEUS. Therefore, additional methods like MRI, methionin-PET are still required [3, 16, 19]. In spite of its high sensitivity in preoperative detection of parathyroid gland adenomas CEUS does not represent the standard procedure area-wide due to the required expertise of the examiner. At the moment the use of this new method with relatively low time costs in the case of sHPT is subject of our studies. 5. Conclusion Our study shows that CEUS represents a very useful and reliable method with a high sensitivity in the preoperative diagnosis of pHPT. No further method is required for the localization of parathyroid gland adenomas when CEUS reveals positive finding performed by a well trained examiner. Further diagnostic procedures are only needed in the presence of ectopic localization. References [1] A. Agha, M. Hornung, J. Rennert, W. Uller, H. Lighvani, H.J. Schlitt, E.M. Jung, Contrast-enhanced ultrasonography for localization of pathologic glands in patients with primary hyperparathyroidism, Surgery 151 (2012), 580–586. [2] A. Agha, M. Hornung, C. Stroszczynski, H.J. Schlitt and E.M. Jung, Highly efficient localization of pathological glands in primary hyperparathyroidism using contrast-enhanced ultrasonography (CEUS) in comparison with conventional ultrasonography, J Clin Endocrinol Metab 98 (2013), 2019–2025. [3] A.D. Beggs and S.F. Hain, Localization of parathyroid adenomas using 11C-methionine positron emission tomography, Nucl Med Commun 26 (2005), 133–136. [4] E. Berber, R.T. Parikh, N. Ballem, C.N. Garner, M. Milas and A.E. Siperstein, Factors contributing to negative parathyroid localization: An analysis of 1000 patients, Surgery 144 (2008), 74–79. [5] A.O. Bergenfelz, G. Wallin, S. Jansson, H. Eriksson, H. Mårtensson, P. Christiansen, E. Reihnér, Impact of modern techniques on short-term outcome after surgery for primary hyperparathyroidism: A multicenter study comprising 2,708 patients, Langenbecks Arch Surg 394 (2009), 851–860. [6] D. Calva-Cerqueira, B.J. Smith, M.L. Hostetler, G. Lal, Y. Menda, T.M. O’Dorisio, J.R. Howe, Minimally invasive parathyroidectomy and preoperative MIBI scans: Correlation of gland weight and preoperative PTH, J Am Coll Surg 205(4 Suppl) (2007), 38–S44. [7] D. Chien and H. Jacene, Imaging of parathyroid glands, Otolaryngol Clin North Am 43 (2010), 399–415, x.
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