European Journal of Endocrinology (2000) 143 755±760 ISSN 0804-4643

CLINICAL STUDY Advantages of combined technetium-99m-sestamibi scintigraphy and high-resolution ultrasonography in parathyroid localization: comparative study in 91 patients with primary hyperparathyroidism F Lumachi1 , P Zucchetta3, M C Marzola3, P Boccagni2, F Angelini4, F Bui3, D F D'Amico2 and G Favia1 1Endocrine Surgery Unit, 2Department of Surgical and Gastroenterological Sciences and 3Nuclear Medicine, Department of Diagnostic Medical Sciences, University of Padua, School of Medicine, via Giustiniani 2, 35128 Padova, Italy and 4Radiology Service, Padua City Hospital, 35128 Padova, Italy (Correspondence should be addressed to F Lumachi, Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, via Giustiniani 2, 35128 Padova, Italy; Email: [email protected])

Abstract Objective: To evaluate the usefulness of the combination of 99mTc-sestamibi/99mTc-pertechnetate subtraction scintigraphy (SS) and high-resolution neck ultrasonography (US) in patients with primary hyperparathyroidism (pHPT) undergoing parathyroidectomy. Design and Methods: Ninety-one patients with proved pHPT were studied, excluding patients with persistent or recurrent disease. There were 65 (71.4%) women and 26 (28.6%) men, with a median age of 59 years (range 18±78 years). All patients underwent both SS and US prior to surgery, and the results were compared with operative and histological findings. The intraoperative quick-parathyroid hormone assay was available for 52 (57.1%) patients. When multiglandular disease was found, both SS and US were considered truly positive only when at least two enlarged parathyroid (PT) glands had been localized. Results: Eighty-three (91.2%) solitary PT adenomas and three (3.3%) carcinomas were found. Moreover, two (2.2%) patients had a double adenoma and three (3.3%) patients had diffuse PT hyperplasia. The overall sensitivity of combined SS US was 94.5% (86.8% and 80.4% for SS and US respectively). There was a significant P , 0:05; Student's‡ t-test) difference in size between the PT glands correctly identified and undetected by SS, whereas the site of the removed PT tumors significantly P , 0:05; Fisher exact test) influenced only the US sensitivity. Conclusions: When the preoperative localization of the PT glands is chosen, the combination of SS and US represents a reliable noninvasive localization technique and should be considered for use in each patient with pHPT undergoing surgery.

European Journal of Endocrinology 143 755±760

Introduction The aim of this study was to evaluate sensitivity and usefulness of high-resolution neck ultrasonography The incidence of primary hyperparathyroidism (pHPT) (US) and 99mTc-sestamibi/99mTc-pertechnetate subtrac- is increasing and was estimated to be 42/100 000 per tion scintigraphy (SS) as preoperative noninvasive year, while in women over 60 years of age the average localization procedures in patients with pHPT under- annual incidence rate approaches 190 cases/100 000 going PTx. per year (1, 2). Parathyroidectomy (PTx) should be considered in most symptomatic patients with con- firmed pHPT, and bilateral neck exploration represents Subjects and methods the standard initial surgical procedure since, in recent Ninety-one consecutive patients (26 (28.6%) men and series, the overall reported cure rates may reach 95± 65 (71.4%) women, median age 59 years, range 18± 98% (3, 4). Localization studies were often performed 78 years) with proved pHPT underwent both US and SS to simplify and shorten surgical exploration, but prior to successful PTx. Patients undergoing reexplora- nevertheless a significant reduction in morbidity and tion for recurrent or persistent pHPT were excluded. All duration of surgery was not reported in all studies and, patients were cured of hypercalcemia. for some surgeons, preoperative imaging of the para- US was performed using 7.5- or 10-MHz real-time thyroid (PT) glands was unnecessary (5±8). transducers and images were obtained from the angle q 2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org

Downloaded from Bioscientifica.com at 09/28/2021 03:00:05AM via free access 756 F Lumachi and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2000) 143 of the mandible to the sternal notch. The sonographic Table 1 Results obtained using SS and US (TP true positive, FN false negative, FP false positive). ˆ appearance of an enlarged PT gland on grey-scale ˆ ˆ imaging was a hypoechoic nodule posterior or lateral to Technique TP (%) FN (%) FP (%) Sensitivity PPV the thyroid lobe, but separate from it and nonadherent to surrounding tissues. SS 79 12 0 86.8% 100% SS was carried out using a single detector gamma (86.8%) (13.2%) camera with a parallel-hole high-resolution collimator US 70 17 4 80.4% 94.6% interfaced to a computer. Patients were injected with (76.9%) (18.7%) (4.4%) 370 MBq 99mTc-methoxyisobutylisonitrile (sestamibi) and 3 planar images (neck and mediastinum, anterior view, matrix 256 256; 300 s per view) were obtained three (3.3%) PT carcinomas; moreover, three (3.3%) 2±15 min later. Three more images were acquired after patients had diffuse PT hyperplasia. The mean size 150 MBq 99mTc-pertechnetate administration. Image (maximal diameter) of the removed PT glands was subtraction was obtained according to standard tech- 19:32 ^ 9:41 mm median 17; range 8±40 mm niques and positive scan imaging was defined as a and they were in a typical siteˆ in 74 (81.3%)ˆ patients.† relative increased sestamibi uptake area persisting after Only in patients with solitary adenomas n 83 were images subtraction, as previously described (9). the PT glands in an ectopic position n 17 ˆ; mainly† in In any case, a successful bilateral neck exploration the upper mediastinum n 6 andˆ behind† the was performed and the excised PT glands were esophagus n 4 or the tracheaˆ † n 4 : In all measured by the pathologist. Operative and histological patients n 52ˆ ; †the intraoperative quick-PTH ˆ † assay findings were compared with the results of each significantly ˆ (mean† PTH values 150:80 ^ 27:83 localizing procedure. Intraoperative quick-parathyroid compared with 19:70 ^ 6:65 ng=ˆl; P 0:00 fell hormone (PTH) assay was available for 52 (57.1%) after removal of the abnormal PT gland(s).ˆ † patients and the serum PTH levels were assayed prior to Table 1 shows the sensitivity and PPV of SS and US. PT gland excision and 10±15 min after PTx. False positive results using US occurred in two patients The results were considered true-positive (TP) when with an ectopic PT adenoma and in two patients with the abnormal PT gland(s) found at operation had been multinodular goiter. SS was negative in 7/70 (10.0%) correctly detected by the imaging techniques, false- patients with TP US, and US was negative in 11/79 positive (FP) when US or SS did not show any diseased (13.9%) patients with TP SS. gland, and false-negative (FN) if no enlarged PT glands In the group of patients with solitary tumors n were localized. In patients with multiglandular disease 86 ; the sensitivity of SS and US was 88.4% and 82.1% ˆ both SS and US were considered TP only when at least respectively.† US correctly localized the PT adenomas in two hyperfunctioning PT glands had been correctly 7 out of the 10 patients with negative SS, thus the identified. Sensitivity was defined as TP= TP FN and overall sensitivity of combined SS and US was 96.5%. the positive predictive value (PPV) was defined‡ † as In the patients with multiglandular disease n 5 ; 16 TP= TP FP : All reported data are expressed as enlarged typically located PT glands (4 adenomas ˆ † and ‡ † means ^ standard deviation (S.D.) and comparisons 12 hyperplastic PT glands) were found and subtotal between different groups were performed using two- PTx was performed in patients n 3 with diffuse tailed Student's t-test and the Fisher exact test, when hyperplasia. Both SS and US correctly ˆ localized† the PT appropriate. The analysis of variance was also used, carcinomas n 3 ; the double adenomas n 2 ; two and in all cases, differences were considered significant abnormal PT glandsˆ † in one patient with PT hyperplasiaˆ † at P , 0:05: and one enlarged gland in the others. There was a significant P , 0:05 difference in the mean size of solitary PT adenomas †n 83 correctly Results identified and undetected by SS (Table ˆ 2).† The site In the overall population, the analysis of variance (typical or ectopic) of the removed abnormal PT glands showed a significant F 125:82; r 0:5359; did not affect P NS the results obtained by SS, but P 0:00 correlation between ˆ mean serumˆ calcium influenced P , 0ˆ:05 †US sensitivity (Table 3). 2ˆ:89 ^ 0†:36 mmol=l and intact-PTH 185:5 ^ † 155 :3ng=l levels. No† difference P not significant (NS)) in age† between male (M) and femaleˆ (F) patients Discussion M 52:0 ^ 16:4; F 58:2 ^ 12:6 years) was found, In the 1980s, sensitivity for PT localization in patients whereas ˆ the mean serumˆ calcium M 3:03 ^ 0:47; with pHPT without previous surgery ranged between F 2:83 ^ 0:28 mmol=l and PTH ˆM 235:8 ^ 35 and 74% (PT scintigraphy) and between 34 and 210ˆ :3; F 169:4 ^ 119†:5ng=l values wereˆ signifi- 82% (US) (10). The 1990 National Institutes of Health cantly P ,ˆ 0:05 lower in women.† (NIH) Consensus Development Conference concluded Histopathological † findings included 83 (91.2%) that preoperative imaging was rarely indicated, had not solitary adenomas, two (2.2%) double adenomas and proven to be cost-effective and did not shorten surgical www.eje.org

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Table 2 Differences between patients with solitary PT adenomas n 83 correctly detected (TP) and undetected (FN) by SS and US mean ^ standard deviation; P values using Student's t-test). ˆ †

Scintigraphy Ultrasonography Parameters TP P FN TP P FN

No. of patients 73 (88.0%) 10 (12.0%) 64 (81.0%) 15 (19.0%) Age (years) 56.5 ^ 14.4 0.337 51.8 ^ 15.0 54.6 ^ 14.0 0.156 60.6 ^ 17.6 Ca (mmol/l) 2.89 ^ 0.36 0.266 2.76 ^ 0.17 2.89 ^ 0.34 0.218 2.77 ^ 29.90 PTH (ng/l) 181.9 ^ 133.9 0.144 118.3 ^ 60.3 169.9 ^ 18.68 0.117 198.7 ^ 143.3 Size (mm) 20.0 ^ 9.6 0.034 13.4 ^ 2.9 18.8 ^ 7.9 0.276 21.8 ^ 15.1 time (11). However, since 1996 sensitivity of non- Since the usefulness of localization procedures invasive techniques has improved, especially in patients correlates with the number of preoperatively detected with solitary PT adenoma, reaching 77±100% (SS) and hyperfunctioning PT glands, sensitivity in patients with 77±91% (US) with an average of 87% and 77% pHPT due to multiglandular disease may be lower, respectively (Tables 4 and 5). A few studies have although it has also been suggested that SS can help reported results of US and MIBI techniques (15, 21, 33) distinguish hyperplasia from adenomatous disease but none reported sensitivity of combined US SS in (17). However, in 85±90% of the patients pHPT is patients with pHPT. In our series, patients undergoing‡ attributed to a single PT adenoma, even if a great re-exploration were excluded, and the overall sensitiv- variation exists in the reported incidence of multi- ity of combined SS and US was 94.5%, whereas in those glandular disease (42). PT carcinoma is a rare tumor with single or double parathyroid tumors n 88 it that in our experience was easy to detect preoperatively was 96.6%. Moreover, SS sensitivity did significantly ˆ † because of its relatively large size, usually ranging P , 0:05 correlate with the size of the PT adenoma, between 1.5 and 4.5 cm (43). as previously† observed (12, 13) but not with the site of Unilateral neck exploration and minimally invasive, the abnormal PT glands, and thus SS and US should be radioguided or endoscopic surgery would be feasible if considered complementary. the site of the abnormal PT glands were known Data from recent studies showed that more than preoperatively. In this setting, the importance of 95% of PT adenomas may be correctly detected by noninvasive localizing procedures becomes evident 99mTc-sestamibi scintigraphy (16, 20, 22). Different (44±47). In any case, a careful bilateral neck explora- techniques were used in performing PT scintigraphy, tion should be performed in the following situations: (i) both with 99mTc-sestamibi alone (12, 29, 30) and no enlarged PT glands visualized, (ii) equivocal results 99mTc-sestamibi in conjunction with 123Ior99mTc- of localizing procedures, (iii) SS and US not in pertechnetate for thyroid image subtraction (9, 26, agreement, or (iv) detection of two or more enlarged 27), with similar results. Dual phase imaging with PT glands (33, 47). single-photon emission computer tomography (SPECT) After excision of each abnormal PT gland, an seems to be a promising procedure for the detection of intraoperative PTH assay represents the principal hyperfunctioning PT tissue, both increasing the sensi- determinant of correction of the hyperparathyroid tivity of 99mTc-sestamibi scintigraphy and appearing state and should be available for all patients with particularly useful in localizing mediastinal glands (38, pHPT undergoing surgery (42, 48, 49). In most studies, 39). In recent reports US sensitivity ranges between routine use of 99mTc-sestamibi scintigraphy, neck 76% and 91% and may improve using color and power ultrasonography and quick-PTH measurement was Doppler sonography (36, 40). Increased sensitivity considered safe and cost-effective, significantly reduc- using PTH assay in the needle aspirates of suspicious ing operative time, facilitating successful limited neck PT adenomas was also reported (41). exploration and improving the success rate of PTx,

Table 3 Results obtained in patients with PT tumors localized in typical (n = 66) and ectopic (n = 17) sites using SS and US. Four patients (2 with ectopic parathyroid adenomas and 2 with tumors in typical site) had false positive results using US Site site of the PT adenomas; P values using Fisher's exact test). ˆ

Scintigraphy Ultrasonography Site TP P FN TP P FN

Typical 59 (89.4%) 7 (10.6%) 58 (90.6%) 6 (9.4%) 0.420 0.001 Ectopic 14 (82.4%) 3 (17.6%) 6 (40.0%) 9 (60.0%)

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Table 4 Sensitivity of parathyroid (PT) scintigraphy in patients with primary hyperparathyroidism due to a solitary PT adenoma or multiglandular disease, in series of 25 cases or more reported since 1996.

Solitary PT adenomas Multiglandular disease Reference Year Technique No. of patients TP Sensitivity (%) No. of PT glands TP Sensitivity (%)

McHenry et al. (14) 1996 (1) 95 77 81.0 Chapuis et al. (15) 1996 (2) 70 56 80.0 Sfakianakis et al. (16) 1996 (3) 53 51 96.2 Johnston et al. (17) 1996 (4) 38 34 89.5 19 15 78.9 Perez-Monte et al. (18) 1996 (3) 37 34 91.9 Malhotra et al. (19) 1996 (4) 26 26 100 69 36 52.2 Caixas et al. (20) 1997 (2) 70 70 100 23 14 60.9 Staudenherz et al. (21) 1997 (3) 53 41 77.4 Chen et al. (22) 1997 (4) 40 39 97.5 33 29 87.9 Gallowitsch et al. (23) 1997 (5) 36 34 94.4 Bergenfelz et al. (24) 1997 (4) 36 31 86.1 Blocklet et al. (25) 1997 (2) 32 27 84.4 Shen et al. (8) 1997 n.r. 28 20 71.4 31 11 35.5 Pattou et al. (26) 1998 (6) 75 65 86.7 56 23 41.1 Hindie et al. (27) 1998 (4) 59 56 94.9 15 12 80.0 Apostolopoulos et al. (28) 1998 (7) 45 39 86.7 Blanco et al. (29) 1998 (2) 26 24 92.3 48 30 62.5 Bhatnager et al. (12) 1998 (2) 25 21 84.0 Klieger & O'Mara (30) 1998 (2) 25 21 84.0 Song et al. (31) 1999 (2) 44 40 90.9 Takami et al. (32) 1999 (3) 52 47 90.4 Purcell et al. (33) 1999 (2) 58 33 56.9 Present series 2000 (4) 83 73 88.0 16 8 50.0

Overall 1106 959 86.7 310 178 57.4

(1) 99mTc-sestamibi/123I subtraction scan and single-photon emission tomography (SPECT); (2) 99mTc-sestamibi alone; (3) dual-phase 99mTc-sestamibi scan, with or without SPECT; (4) 99mTc-sestamibi/99mTc-pertechnetate subtraction scan, with or without SPECT; (5) 99mTc-tetrofosmin and SPECT; (6) 99mTc- sestamibi/123I subtraction scan; (7) 99mTc-tetrofosmin/99mTc-pertechnetate subtraction scan; TP true positive result; No. of PT glands number of parathyroid glands excised; n:r: not referred. ˆ ˆ ˆ

Table 5 Sensitivity of parathyroid ultrasonography in patients with primary hyperparathyroidism, in series of 25 cases or more reported since 1996.

Reference Year No. of patients TP Sensitivity (%)

Arkles et al. (34) 1996 100 76 76.0 Chapuis et al. (15) 1996 447 340 76.0 Staudenherz et al. (21) 1997 52 30 57.7 Vogel et al. (35) 1998 77 69 89.6 Lane et al. (36) 1998 44 40 90.9 Ammori et al. (37) 1998 65 52 80.0 Ryan et al. (13) 1999 93 61 66.0 Lumachi et al. (9) 1999 148 120 81.1

Overall 1026 788 76.8 especially in patients with ectopic PT glands (9, 16, 34, In conclusion, when a preoperative localization of 50±52). Some authors estimated that US and PT the PT glands is chosen, the combination of SS and US scintigraphy charges accounted for only 2% and 5% represents a reliable noninvasive technique and should respectively of the total charges for PTx, and that the be considered for use in each patient undergoing added cost of protracted or failed exploration neutra- surgery for pHPT. lized the costs of SS and US which are equivalent to 60 min operative time or less (13, 48, 53). In spite of that some surgeons, on account of low sensitivity obtained with preoperative localization procedures in Acknowledgements their experience, consider imaging of the PT glands This paper was presented in part at The Endocrine unnecessary and recommend a careful bilateral neck Society 80th Annual Meeting, New Orleans, LA, USA, exploration in all patients with pHPT (6, 8, 54). June 24±27 1998. www.eje.org

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