Sestamibi Scintigraphy, Topography, and Histopathology of Parathyroid Glands in Secondary Hyperparathyroidism

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1 Sestamibi Scintigraphy, Topography, and Histopathology of Parathyroid Glands in Secondary Hyperparathyroidism Carlo Lomonte, MD, Nicola Buonvino, MD, Michele Selvaggiolo, MD, Mario Dassira, MD, Giovanni Grasso, MD, Luigi Vernaglione, MD, and Carlo Basile, MD Background: Several imaging techniques presently are available to assess the location of hyperplastic parathyroid glands. The purpose of the present study is to assess the place of dual-phase technetium Tc 99m-sestamibi (MIBI) scintigraphy in the preoperative localization of hyperplastic parathyroid glands in patients with severe secondary hyperparathyroidism (SHPT). Methods: We studied 35 consecutive adult white hemodialysis patients undergoing a first parathyroidectomy after performing MIBI scintigraphy. Hyperplasia of the parathyroid glands was classified as diffuse (DH) or nodular (NH). Statistical analysis was conducted by comparing patients with MIBI-negative (no focal area of increased uptake) with MIBI-positive (>1 focal area of increased uptake) results and stratifying parathyroid glands according to location (superior and inferior). Results: MIBI scintigraphy showed focal areas of increased uptake in at least 1 gland in 25 patients (71.4%). Total number of focal areas of increased uptake was 42 of 121 glands removed (sensitivity, 34.7%; specificity, 100%). One hundred one glands showed NH and 20 glands showed DH. The 25 patients with MIBI-positive results had 85 pathological glands removed, and the 10 patients with MIBI-negative results had 36 pathological glands removed: in the former, most glands showed NH (77 of 85 glands; 90.6%), and in the latter, 24 of 36 glands showed NH (66.7%; P at chi-square test). The sensitivity of MIBI scintigraphy for distinguishing specific subtypes of hyperplasia was 37.6% (38 of 101 glands) for NH and 20.0% (4 of 20 glands) for DH (P ). The following values were significantly greater in inferior compared with superior glands: (1) estimated weight ( versus g; P 0.04), (2) percentage of MIBI positivity (34 of 42 inferior glands [80.9%] versus 8 of 42 superior glands [19.1%]; P ), and (3) percentage of localization permitted by MIBI scintigraphy (34 of 63 inferior glands [54.0%] versus 8 of 58 superior glands [13.8%]; P ). Thus, NH, although equally distributed between inferior (53 of 63 glands) and superior (48 of 58 glands) glands, showed a percentage of MIBI positivity significantly greater in inferior (34 of 53 glands [64.1%]) compared with superior glands (8 of 48 glands [16.7%]; P ). Conclusion: MIBI scintigraphy did not show high sensitivity in identifying hyperplastic glands, although it was able to identify those with NH better than those with DH. Thus, MIBI scintigraphy has limited value preoperatively for patients with SHPT. Estimated weight, percentage of MIBI positivity, and percentage of localization permitted by MIBI scintigraphy were significantly greater in inferior glands. Am J Kidney Dis 48: by the National Kidney Foundation, Inc. INDEX WORDS: Hemodialysis (HD); hyperparathyroidism; sestamibi (MIBI) scintigraphy; parathyroidectomy. ALARGE NUMBER OF UREMIC patients develop secondary hyperparathyroidism (SHPT). In a minority of patients, parathyroid overfunction persists, progressively escapes medical control, and eventually becomes extremely severe, requiring surgical correction. Reasons for the failure of response of parathyroid glands From the Divisions of Nephrology and Surgery and Nuclear Medicine Unit, Miulli General Hospital, Acquaviva delle Fonti; and Division of Nephrology, Hospital of Manduria, Italy. Received April 6, 2006; accepted in revised form June 22, Originally published online as doi: /j.ajkd on August 15, Support: None. Potential conflicts of interest: None. Address reprint requests to Carlo Basile, MD, Via C. Battisti 192, Taranto, Italy. basile.miulli@ libero.it 2006 by the National Kidney Foundation, Inc /06/ $32.00/0 doi: /j.ajkd to the wide therapeutic armamentarium currently available must be looked for in several domains, such as intrinsic factors linked to the large volume of the glands themselves, with nodular hyperplasia (NH), decreased density of vitamin D and calcium-sensing receptors, and persistent hyperphosphatemia. 1 In patients with severe SHPT requiring parathyroidectomy, such parathyroid imaging as ultrasound, computed tomography, magnetic resonance imaging, and parathyroid scintigraphy usually is not required preoperatively, although it may be helpful in patients for whom reexploration is required or those with recurrent SHPT. 2 However, no study compared results with and without preoperative imaging. In particular, the place of dual-phase technetium Tc 99m-sestamibi (MIBI) scintigraphy in uremic patients with SHPT remains a matter of debate. 2-4 It recently was shown that MIBI scintigraphy can be used as a marker of proliferative parathyroid gland activity, 5 as well 638 American Journal of Kidney Diseases, Vol 48, No 4 (October), 2006: pp

2 MIBI SCINTIGRAPHY IN SECONDARY HYPERPARATHYROIDISM 639 as a useful tool to distinguish NH from diffuse type (DH) parathyroid hyperplasia. 6 The purpose of the present study is to assess the value of MIBI scintigraphy by analyzing some parathyroid gland characteristics, such as weight, topographic characteristics, and histopathologic characteristics, in 35 consecutive adult white hemodialysis patients undergoing a first parathyroidectomy because of refractory SHPT. METHODS Study Population We studied 35 consecutive adult white hemodialysis patients referred to our division from 6 dialysis units of our region to undergo a first parathyroidectomy. Of note, no patient was affected by diabetic nephropathy. Indications for surgical correction of SHPT in these patients were the presence of 1 or more of the following clinical and/or laboratory factors: pruritus not responsive to any treatment (16 patients), Achilles tendon rupture (2 patients), persistent hyperphosphatemia (11 patients), refractoriness to vitamin D therapy (either intravenous or oral; 20 patients; however, all patients had stopped such treatment for at least 1 month before MIBI scintigraphy), persistent serum immunoreactive parathyroid hormone (ipth) levels greater than 800 pg/ml ( 800 ng/l; 35 patients), severe radiological signs of osteitis fibrosa (22 patients), and parathyroid gland size greater than 1 cm (by means of ultrasound imaging; 20 patients). The only inclusion criterion was that MIBI scintigraphy had to be performed in the Nuclear Medicine unit of our hospital using the following protocol. MIBI Parathyroid Scintigraphy MIBI scintigraphy was performed using intravenous administration of 99m Tc-hexakis-2-methoxy-isobutylisonitrile (MIBI), 700 MBq/70 kg body weight, after which dual-phase radionuclide scintigraphy was performed. Images of the anterior neck were obtained by using a highresolution parallel-hole collimator, and images of the chest were obtained by using a large-field-of-view collimator at 15 minutes and 3 hours after injection of MIBI. Images were considered positive when 1 or more clearly defined focal areas of abnormal uptake in the thyroid areas, with respect to the surrounding tissues, were visible on early images and persisted on late images (washout). Scintigraphic imaging was considered negative when these criteria were not fulfilled. 7 Surgical Procedures No intraoperative adjuncts to improve localization of parathyroid glands, such as radioguided surgery 8 or intraoperative ipth testing, 9 were adopted. Subtotal parathyroidectomy (7/8) was performed in 12 patients, and total parathyroidectomy with no forearm implantation was performed in 10 patients; 3 glands were detected and removed in 7 patients, and only 2 glands could be found and removed in 6 patients; thus, total number of pathological glands removed was 121 of the potential 140. All patients undergoing total parathyroidectomy also underwent cervical thymectomy. Histological Studies of Parathyroid Glands The anatomic site of each gland removed was recorded; each removed gland was measured with a sterile ruler and its dimensions were recorded. Weight (grams) was estimated as already reported. 5 Histological studies of parathyroid glands with light microscopy were performed by the same pathologist on 7 serial sections of the glands in a blinded fashion. Histopathologic studies showed that parathyroid hyperplasia in patients with SHPT can change from DH to early nodularity and then to NH, shifting from a polyclonal to a monoclonal proliferation. DH is defined as increased numbers of parenchymal cells with normal lobular structures, and NH is defined as at least 1 well-circumscribed encapsulated nodule with virtually fat cell free accumulation of parenchymal cells. 10 Furthermore, semiquantitative analysis of glands was performed according to cell type. 5,11 The focus in the present study is exclusively on oxyphil cells. Biochemical Analysis Serum levels of albumin, ipth, calcium, and phosphate were determined at the time of parathyroidectomy. Serum calcium and phosphate were measured 4 hours postparathyroidectomy and 3 times a day during the 5 consecutive postparathyroidectomy days; the 3 daily measurements of serum calcium and phosphate levels were averaged for each patient. Serum ipth levels were measured on postparathyroidectomy day 3. Serum albumin, calcium, and phosphate levels were measured by using routine automated methods. Serum ipth levels were measured by using chemiluminescence immunoassay (Nichols, San Juan Capistrano, CA; normal range, 10 to 65 pg/ml [10 to 65 ng/l]). Measured serum calcium levels were adjusted by albumin levels as follows when they were less than 4.0 g/dl: Calcium measured calcium levels [(4.0 albumin levels) 0.8] mg/dl. 12 Only 1 patient with serum albumin levels less than 4.0 g/dl ( 40 g/l) needed such a correction. Statistical Analyses Statistical analysis was conducted by comparing patients with MIBI-negative (no focal area of increased uptake) with MIBI-positive ( 1 focal areas of increased uptake) results and stratifying parathyroid glands according to location (superior and inferior). Distribution of data was studied by means of the Kolmogorov-Smirnov test. Non normally distributed data underwent log transformation. Comparisons of continuous variables between groups were made by means of Student t-test for unpaired data, whereas chi-square test was used for distributions between groups of categorical variables. All statistical inferences were performed using the SPSS software package, version 10 (SPSS Inc, Chicago, IL). Data are expressed as mean SD or percentage of total, and P less than 0.05 is assumed as statistically significant. RESULTS Table 1 lists demographic, clinical, and biochemical characteristics of the entire cohort of

3 640 Table 1. Patient Demographic, Clinical, and Biochemical Characteristics No. of patients 35 Sex (men/women) 13/22 Age (y) Dialysis duration (mo) Serum calcium (mg/dl) Serum phosphorus (mg/dl) Serum ipth (pg/ml) 1, Underlying nephropathy (%) Glomerular 40.0 Tubulointerstitial 54.3 Vascular 5.7 NOTE. Data expressed as mean SD and percentage. To convert serum calcium in mg/dl to mmol/l, multiply by ; serum phosphate in mg/dl to mmol/l, multiply by ; serum ipth in pg/ml to ng/l, multiply by 1. LOMONTE ET AL 35 patients. MIBI scintigraphy showed focal areas of increased uptake in at least 1 gland in 25 patients (71.4%). Total number of focal areas of increased uptake was 42, none of which was ectopic (Table 2); and total number of pathological glands removed was 121; thus, the sensitivity of MIBI scintigraphy for localizing hyperplastic glands by comparing scan with pathological findings was only 34.7% (42 of 121 glands). Specificity was 100%, ie, all imaging-predicted glands subsequently were found by the surgeon. One hundred one glands showed NH and 20 glands showed DH. The 25 patients with MIBI-positive ( 1 focal areas of increased uptake) results had 85 pathological glands removed: this means that 49.4% of these glands (42 of 85 glands) could be localized by MIBI scintigraphy; most showed NH (77 of 85 glands; 90.6%). The 10 patients with MIBI-negative (no focal area of increased uptake) results had 36 pathological glands removed: 24 glands showed NH (66.7%). The latter prevalence was significantly different from that of the same form of hyperplasia in patients with MIBI-positive results (P at chisquare test; Table 2). There was a significant difference in sex comparing patients with MIBIpositive with MIBI-negative results, with women more represented than men in MIBI-positive patients (P ; Table 2). No significant differences were found in age, dialysis duration, estimated weight of glands removed, oxyphil cell number, or preparathyroidectomy and postparathyroidectomy serum calcium, phosphate, and logipth levels comparing patients with MIBIpositive with MIBI-negative results (Table 2). Table 2. Comparison of Histological and Biochemical Data Between Patients With MIBI-Positive and MIBI-Negative Results MIBI Positive MIBI Negative P No. of patients No. of focal areas of increased uptake 42 0 No. of glands removed Nodular hyperplasia 77/85 (90.6%) 24/36 (66.7%) Diffuse hyperplasia 8/85 (9.4%) 12/36 (33.3%) Log oxyphil cells NS Sex (men/women) 7/18 6/ Age (y) NS Dialysis duration (mo) NS Weight of glands removed (g) NS Preparathyroidectomy serum calcium (mg/dl) NS Postparathyroidectomy serum calcium (mg/dl) NS Preparathyroidectomy serum phosphorus (mg/dl) NS Postparathyroidectomy serum phosphorus (mg/dl) NS Preparathyroidectomy serum log ipth (pg/ml) NS Postparathyroidectomy serum log ipth (pg/ml) NS NOTE. Data expressed as mean SD and percentage. Serum ipth and oxyphil cells were non normally distributed and were log transformed. Postparathyroidectomy serum calcium, phosphate, and ipth levels measured on postparathyroidectomy day 3. Student t-test for unpaired data and chi-square test were used for statistical analysis. To convert serum calcium in mg/dl to mmol/l, multiply by ; serum phosphate in mg/dl to mmol/l, multiply by ; serum ipth in pg/ml to ng/l, multiply by 1. Abbreviation: NS, not significant.

4 MIBI SCINTIGRAPHY IN SECONDARY HYPERPARATHYROIDISM 641 Serum ipth levels measured on postparathyroidectomy day 3 were greater than 100 pg/ml ( 100 ng/l) in 8 of 25 patients with MIBIpositive results and 2 of 10 patients with MIBInegative results (not shown in tables or figures). The sensitivity of MIBI scintigraphy for distinguishing specific subtypes of hyperplasia was 37.6% (38 of 101 glands) for NH and 20.0% (4 of 20 glands) for DH (P ). The following values were significantly greater in inferior compared with superior glands: (1) estimated weight ( versus g; P 0.04), (2) percentage of MIBI positivity (34 of 42 inferior glands [80.9%] versus 8 of 42 superior glands [19.1%]; P ), and (3) percentage of localization permitted by MIBI scintigraphy (34 of 63 inferior glands [54.0%] versus 8 of 58 superior glands [13.8%]; P ). Thus, NH, although equally distributed between inferior (53 of 63 glands) and superior glands (48 of 58 glands), showed a percentage of MIBI positivity significantly greater in inferior glands (34 of 53 glands [64.1%]) compared with superior glands (8 of 48 glands [16.7%]; P ; Table 3). DISCUSSION The present report confirms data already published: (1) for the capability of MIBI scintigraphy being positively associated with specific subtypes of hyperplasia, Nishida et al 6 recently Table 3. Comparison of Histological Characteristics, MIBI Positivity, and Weight of Superior and Inferior Parathyroid Glands Inferior Superior P No. of glands removed NS No. of glands with NH NS No. of focal areas of increased uptake 34/42 8/ No. of glands localized by MIBI 34/63 8/ No. of glands with NH and MIBI positivity 34/53 8/ Weight of glands removed (g) NOTE. Data expressed as mean SD. Student t-test for unpaired data and chi-square test were used for statistical analysis. Abbreviation: NS, not significant. showed that it could be used clinically to distinguish NH from DH of parathyroid glands (sensitivity, 76.2% for NH versus 28.6% for DH). Our data show the same trend, but with a much lower rate of sensitivity for detecting specific subtypes of hyperplasia (37.6% for NH versus 20.0% for DH); and (2) for the sensitivity of MIBI scintigraphy for localizing hyperplastic glands in patients with SHPT, we compared scans with pathological findings, which is considered the gold standard. The spectrum of sensitivity reported to date in the literature is wide, with the following ranking: 83.0% (18 patients, Takebayashi et al 13 ), 82.6% (18 patients, Chesser et al 14 ), 73.7% (9 patients, Piga et al 15 ), 69.4% (14 patients, Nishida et al 6 ), 66.7% (27 patients, Torregrosa et al 16 ), 54.0% (22 patients, Torregrosa et al 17 ), 50.0% (21 patients, Olaizola et al 4 ), 50.0% (18 patients, Custódio et al 5 ), 49.3% (174 patients, Guillem et al 18 ), 39.0% (30 patients, Gotthardt et al 19 ), and 34.7% (35 patients), the present report. Taken together, these data confirm that MIBI scintigraphy is of limited help in the exploration of uremic patients with severe SHPT before a first surgical parathyroidectomy. 3,4,16-19 Thus, the following questions might be raised: (1) is preoperative examination by means of double-phase[99m Tc]-MIBI parathyroid scintigraphy useful in the management of patients with SHPT, as reported by some investigators, 20 or, conversely, is the classic French aphorism the best way of detecting parathyroid glands is that of localizing a good surgeon of parathyroid glands still true?; and (2) are there more imaging techniques useful in the exploration of uremic patients with severe SHPT before or during a first surgical parathyroidectomy? 21,22 For question 1, our answer, in agreement with the National Kidney Foundation Kidney Dialysis Outcomes Quality Initiative guidelines for parathyroidectomy, is that MIBI scintigraphy has limited value preoperatively for patients with SHPT, and it is more effective in the diagnosis of primary hyperparathyroidism and locating a gland that was missed on initial exploration in the setting of recurrent SHPT. 2 However, despite the low sensitivity of MIBI scintigraphy in localizing hyperplastic glands, some investigators agree with other important roles of MIBI scintigraphy: (1) it is able to detect ectopic glands, thus avoiding reoperation, a very important issue in these patients affected by a

5 642 high morbidity 17,21,22 ; (2) MIBI-negative parathyroid glands may suggest that the histological subtype of DH is more probable than NH: thus, some investigators suggested they should be preserved as remnant tissue after subtotal parathyroidectomy or chosen as graft tissue after total parathyroidectomy with autografting 16 ; and (3) MIBI positivity may suggest that the histological subtype of NH is more probable than DH: thus, some investigators suggested it may be used to determine when patients have reached a point of no return in their response to medical treatment, including calcitriol pulse therapy. 5,16 For question 2, a recent report suggested that radioguided parathyroidectomy in patients with SHPT was very successful: all patients were injected with 10 mci of 99m Tc-MIBI an average of 1 to 2 hours before surgery. In the operating room, an 11-mm collimated gamma probe was used to scan for counts: the investigators found that all hyperplastic glands had high 99m Tc-MIBI uptake. 8 Furthermore, a recent trend in parathyroid scintigraphy is the use of subtraction iodine 123/99 mtc-mibi, which also may increase the sensitivity of double-phase[99m Tc]-MIBI parathyroid scintigraphy, 21,22 although some caveats about the implementation of this technique in patients with SHPT are mandatory, such as the high radiation exposure and high costs. Therefore, the conclusion may be drawn that the lack of MIBI positivity by means of MIBI scintigraphy probably represents the inability to detect such uptake by using conventional imaging techniques. Furthermore, the present report is able to provide new insights into understanding the reasons for inferior results for MIBI scintigraphy imaging for multiglandular parathyroid hyperplasia. We tried to explore the relationship between topographic characteristics of parathyroid glands and MIBI scintigraphy in patients with SHPT, and to the best of our knowledge, only 2 reports to date dealt with this problem. 17,18 The very recent report by Guillem et al 18 showed the following results in the largest case series reported in the literature (174 patients with SHPT with both preoperative parathyroid echography and/or scintigraphy): (1) mean weights and diameters of parathyroid glands were significantly greater in those with positive than negative examination results; and (2) upper glands were detected LOMONTE ET AL by the 2 imaging techniques less frequently than inferior glands. 18 We show in the present report that the estimated weight of inferior glands was significantly greater than that of superior glands. Furthermore, most MIBI-positive results were in the lower glands (34 of 42 glands) and the capability of MIBI scintigraphy for detecting pathological glands in each quadrant of the thyroid gland was strikingly greater for inferior (34 of 63 glands; 54.0%) than superior glands (8 of 58 glands; 13.8%). In other words, the surgeon removed essentially the same number of pathological glands (63 glands in the lower quadrants, 58 glands in the upper quadrants). However, more than half the former could be detected by MIBI versus only 13.8% of the latter. It is well known that MIBI positivity appears to be related to uptake by mitochondria-rich oxyphil cells of the parathyroid glands, 3 degree of cellular activity, 5 and cell-cycle phases. 17 Furthermore, MIBI positivity is associated prevalently with NH (our data and 6 ). In addition, it was shown that parathyroid tissue that expresses either P-glycoprotein or the multidrug-resistance protein is less likely to accumulate MIBI. 23,24 However, 1 more factor must be included among those explaining MIBI uptake, ie, topographic characteristics of parathyroid glands, with inferior glands capturing more MIBI than superior glands. What can be the explanation for this phenomenon? We are able to propose 2 explanations, which remain speculative. The first derives from the different embryology: the inferior glands, or parathyroid III, arise from the third pharyngeal pouch, and the superior glands, sometimes referred to as parathyroid IV, arise from the fourth pharyngeal pouch. 3 The second explanation derives from the different vascular anatomy: inferior parathyroid glands receive their vascular supply from the inferior thyroid arteries, whereas superior glands receive their vascular supply prevalently from the superior thyroid arteries The inferior thyroid artery, which is larger, arises from the first part of the subclavian artery, whereas the superior thyroid artery arises from the first part of the external carotid artery. Nonselective angiography in whites was able to recognize inferior vessels better than superior vessels. 27 In an analogous way, MIBI uptake by the lower glands might be greater because of a sort of first-pass effect.

6 MIBI SCINTIGRAPHY IN SECONDARY HYPERPARATHYROIDISM 643 Last, we could not confirm the correlation between either MIBI positivity and serum ipth levels in patients with SHPT 15,28 or estimated gland weight and high MIBI scores (according to the classification of Custódio et al 5 ). The explanation is very simple: in our hands, although it is true that the 25 patients with MIBI-positive results had a very high prevalence of NH (77 of 85 glands removed; 90.6%), it must be realized that the 10 patients with MIBI-negative results also had a large prevalence of NH (24 of 36 glands removed; 66.7%). Thus, the overlapping distribution of NH in both groups was able to nullify any difference in serum ipth levels and estimated weights between patients with MIBI-positive and MIBI-negative results. In conclusion, MIBI scintigraphy did not show high sensitivity in identifying hyperplastic glands, although it was able to identify patients with NH better than those with DH. 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7 Hindiè H, Ureña P, Jeanguillaume C, et al: Preoperative imaging of parathyroid glands with technetium-99mlabelled sestamibi and iodine-123 subtraction scanning in secondary hyperparathyroidism. Lancet 353: , Yamaguchi S, Yachiku S, Hashimoto H, et al: Relation between 99m-methoxyisobutylisonitrile accumulation and multidrug resistance protein in the parathyroid glands. World J Surg 26:29-34, Sun SS, Shiau YC, Lin CC, Kao A, Lee CC: Correlation between P-glycoprotein (P-gp) expression in parathyroid and Tc-99m MIBI parathyroid image findings. Nucl Med Biol 28: , 2001 LOMONTE ET AL 25. Nobori M, Saiki S, Tanaka N, Harihara Y, Shindo S, Fujimoto Y: Blood supply of the parathyroid gland from the superior thyroid artery. Surgery 115: , Johansson K, Ander S, Lennquist S, Smeds S: Human parathyroid blood supply determined by laser-doppler flowmetry. World J Surg 18: , Toni R, Della Casa C, Mosca S, Malaguti A, Castorina S, Roti E: Anthropological variations in the anatomy of human thyroid arteries. Thyroid 13: , Hung GU, Wang SJ, Lin WY: Tc-99m MIBI parathyroid scintigraphy and intact parathyroid hormone levels in hyperparathyroidism. Clin Nucl Med 28: , 2003